IAP SPECIALTY SERIES ON Rational Antimicrobial Practice in Pediatrics

IAP SPECIALTY SERIES ON Rational Antimicrobial Practice in Pediatrics Second Edition

Founder Editor Dr Nitin K Shah

Editors Dr Tanu Singhal Consultant Pediatrician and Infectious Disease Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute Mumbai, Maharashtra, India Dr Nitin K Shah Professor and Consultant Department of Pediatrics PD Hinduja Hospital and Medical Research Center Mumbai, Maharashtra, India

Co-ordinating Editor Dr Sailesh Gupta Honorary Secretary General Indian Academy of Pediatrics Kailash Darshan, Kennedy Bridge Mumbai, Maharashtra, India Foreword Dr CP Bansal IAP President 2013 Dr Rohit Agrawal IAP President 2012 IAP National Publication House, Gwalior

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Rational Antimicrobial Practice in Pediatrics

Second Edition : 2013 ISBN: 978-93-5090-363-6

Printed at Ajanta Offset Contributors

Apurba Ghosh Keya Mariam Kunnekel Director Consultant Pediatrician Institute of Child Health Noida, Uttar Pradesh, India Kolkata, West Bengal, India KS Laxmi Archana Kher Senior Resident Consultant Pediatrician Department of Pediatrics Ex-Professor of Pediatrics Advance Pediatric Center Seth GS Medical College and KEM Hospital Postgraduate Institute of Medical Education Mumbai, Maharashtra, India and Research Ashok Kapse Chandigarh, India Consultant Pediatrician Kumud P Mehta Surat, Gujarat, India Consultant Pediatric Nephrologist Baldev S Prajapati Bai Jerbai Wadia Hospital for Children Professor Mumbai, Maharashtra, India GCS Medical College Hospital and Lalitha Iyer Research Center Consultant Pediatrician Ahmedabad, Gujarat, India White Plains Hospital Camilla Rodrigues New York, USA Consultant Microbiologist PD Hinduja National Hospital and Mallar Mukherjee Medical Research Center Senior Registrar Mumbai, Maharashtra, India Institute of Child Health Kolkata, West Bengal, India Deepak Karpe Consultant Pediatrician Md Umar Tak Department of Pediatrics Department of Pediatrics KEM Hospital Lady Hardinge Medical College and Pune, Maharashtra, India Assoc Kalawati Saran Childrens’ Hospital Deepchand Khandelwal New Delhi, India Research Officer Department of Pediatrics Meenu Singh All India Institute of Medical Sciences Professor of Pediatrics New Delhi, India Advanced Pediatric Center Postgraduate Institute of Indu Khosla Medical Education and Research Consultant Pediatrician Chandigarh, India Mumbai, Maharashtra, India Jaideep A Gogtay Monjori Mitra Medical Director Associate Professor Cipla Limited Institute of Child Health Mumbai, Maharashtra, India Kolkata, West Bengal, India vi Rational Antimicrobial Practice in Pediatrics

MR Lokeshwar Pradnya Gadgil Consultant Pediatrician and Pediatric Consultant Neurologist Hematologist Oncologist Kokilaben Dhirubhai Ambani Hospital Lilavati Hospital Mumbai, Maharashtra, India Mumbai, Maharashtra, India Pratima Shah Neha Gupta Consultant Pediatrician Assitant Consultant in Internal Medicine and Ankur Institute of Child Health Infectious Diseases Ahmedabad, Gujarat, India PD Hinduja National Hospital and Medical Research Center Prawin Kumar Mumbai, Maharashtra, India Pediatric Pulmonology Division Department of Pediatrics Nigam Prakash Narain All India Institute of Medical Sciences Associate Professor Pediatrics New Delhi, India Patna Medical College Patna, Bihar, India Preeti Shanbag Professor and Head Niranjan Shendurnikar Department of Pediatrics Consultant Pediatrician ESI-PGIMSR and MGM Hospital Ankur Hospital, Vadodara, Gujarat, India Mumbai, Maharashtra, India Nishant Verma Rajal B Prajapati Senior Resident Associate Professor All India Institute of Medical Sciences Sheth VS General Hospital New Delhi, India AMC MET Medical College Ahmedabad, Gujarat, India Nitin K Shah Professor and Consultant Raju C Shah Department of Pediatrics Consultant Pediatrician PD Hinduja Hospital and Ankur Institute of Child Health Medical Research Center Ahmedabad, Gujarat, India Mumbai, Maharashtra, India Rakesh Lodha Nupur Ganguly Associate Professor Associate Professor Department of Pediatrics Institute of Child Health All India Institute of Medical Sciences Kolkata, West Bengal, India New Delhi, India Pallavi Bhargava Rasik Shah Consultant Infectious Diseases Consultant Pediatric Surgeon and Allegiance Health Care Laparoscopist Jackson, Michigan, USA PD Hinduja Hospital and Medical Research Institute Pankaj Vohra Mumbai, Maharashtra, India Diplomate of the American Board of Pediatric Gastroenterology Ritabrata Kundu Hepatology and Nutrition Professor of Pediatrics Max Healthcare Institute of Child Health Kolkata, West Bengal, India Poonam Mehta Pediatric Pulmonology Division S Balasubramanian Department of Pediatrics Senior Consultant All India Institute of Medical Sciences Kanchi Kamakoti CHILDS Trust Hospital New Delhi, India Chennai, Tamil Nadu, India Contributors vii

Saheli Misra Suhas Prabhu Assistant Professor Consultant Pediatrician Institute of Child Health PD Hinduja National Hospital and Kolkata, West Bengal, India Medical Research Center Mumbai, Maharashtra, India Sangeeta Amladi Head Sumanth Amperayani Medical Services, Kaya Skin Clinic Senior Registrar Kanchi Kamakoti CHILDS Trust Hospital Mumbai, Maharashtra, India Chennai, Tamil Nadu, India Shilpa Kalane Sunit Singhi Neonatologist Professor Department of Pediatrics Department of Pediatrics KEM Hospital Advance Pediatric Center Pune, Maharashtra, India Postgraduate Institute of Medical Education and Research, Chandigarh, India Shinjini Bhatnagar Professor and Head Tanmay Amladi Pediatric Biology Center Consultant Pediatrician, UAE Translational Health Science and Tanu Singhal Technology Institute Consultant Pediatrician and Gurgaon, Haryana, India Infectious Disease Kokilaben Dhirubhai Ambani Hospital Shreya Singh and Medical Research Institute Department of Microbiology Mumbai, Maharashtra, India All India Institute of Medical Sciences New Delhi, India Uma Ali Consultant Pediatric Nephrologist Simantini Jog Bai Jerbai Wadia Hospital for Children Consultant Microbiologist Mumbai, Maharashtra, India Royal Cornwall Hospital NHS Trust UK Umesh Vaidya Consultant Neonatologist SK Kabra KEM Hospital Pediatric Pulmonology Division Pune, Maharashtra, India Department of Pediatrics All India Institute of Medical Sciences Vandana Gopal Consultant Pediatrician and New Delhi, India Pediatric Intensivist Soonu Udani Vadodara Critical Child Care Center Consultant in Pediatrics and Vadodara, Gujarat, India Pediatric Critical Care PD Hinduja National Hospital and Medical Varinder Singh Research Center Professor of Pediatrics Lady Hardinge Medical College and Mumbai, Maharashtra, India Assoc Kalawati Saran Childrens’ Hospital Soumya Tiwari New Delhi, India Department of Pediatrics Vijay N Yewale Lady Hardinge Medical College and Consultant Pediatrician Assoc Kalawati Saran Children’s Hospital Yewale Hospital and Vashi Criticare New Delhi, India Navi Mumbai, Maharashtra, India viii Rational Antimicrobial Practice in Pediatrics

Vijay V VP Udani Consultant Pediatric Rheumatologist Consultant Pediatric Neurologist Navi Mumbai, Maharashtra, India PD Hinduja National Hospital and Medical Research Center Vishal Mukhija Mumbai, Maharashtra, India Consultant Pediatrician YK Amdekar Mumbai, Maharashtra, India Consultant Pediatrician Vivek Kak Jaslok Hospital and Research Center Consultant Infectious Diseases Mumbai, Maharashtra, India Alleguiance Health Care Jackson, Michigan, USA Foreword

Dear Reader, The book that you hold is the fulfilment of the dreams of the doyens of Indian Academy of Pediatrics. For many years, the need for good Indian books in every specialty of pediatrics was felt. The Indian Academy of Pediatrics has no dearth of great teachers and writers in the various subspecialties to author these books. Their dedicated and diligent labor has created the beautiful and eminently readable book that you hold. An Indian book by Indian authors will appropriately suit the needs of the readers in India and in countries with similar geographical and sociocultural milieus. Although the first editions of the IAP subspecialty series were published in 2006, we proudly present to you a second, completely revised and updated edition. The IAP specialty series books serve the purpose of providing evidence based, authentic and uniform information to IAP members, other pediatricians, and students of pediatrics in the country. Guidelines and established protocols on disease management will be very helpful for pediatricians in their everyday practice. Creating a book is such as the birth of a baby. Right from conception to delivery, there is a long and complex process. It is very labor intensive, time-consuming work that involves considerable financial expense too. To streamline the entire process from writing to editing to publishing to distribution and sales of books, it was envisioned to have an additional wing of IAP, and which is established as “IAP National Publication House (IAP NPH)” at Gwalior. Knowledge has no limits and seekers of knowledge can access the subject from anywhere in the world. We understand that books published by IAP NPH will be read and referred not only in India but also in many parts of the world. Objective of IAP NPH, therefore, is to provide standardized content and world class quality. With this objective, printed books are to be made available throughout the globe and distribution will also be done through online editions. Publishing 7 books at a time is a mammoth task and for this we collaborated with the second largest medical publisher in the world, i.e. M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India. What you are reading, the world is also reading. Our writers are getting worldwide exposure and readers are getting world class books at reasonable cost. It needs to be mentioned here that all authors and editors have dedicated the royalty from sale of books to IAP and have thereby done a selfless service for our mother organization. By buying this book, you are also contributing to IAP in a significant manner. Finally, we express our pride and happiness in being associated with this project and in reaching this valuable book to you. We wish you a happy and contented reading. Dr CP Bansal IAP President 2013 Dr Rohit Agrawal IAP President 2012

Preface

Antimicrobial therapy is an integral part of pediatric practice. If practised inappropriately, it can lead to treatment failure as well as antimicrobial resistance. Though several textbooks on similar issues are available, a need was felt to bring out a compendium that discusses these issues in light of Indian epidemiology. The first edition released in 2006 was very well received. Antimicrobial therapy is a dynamic subject; there is evolution in antimicrobial resistance as well as new drugs are approved and marketed. Several such sentinel events have occurred in the past 6 years. Remarkable is the increase in community-acquired - resistant Staphylococcus aureus (MRSA) infections and the evolution and spread of -resistant gram-negative bacteria. To address these and other changes in antimicrobial treatment options and guidelines, it was considered necessary to bring out a revised edition. It gives us great pleasure in presenting the second edition of this book. We hope that this text is useful to practising pediatricians and postgraduates not only in India but also South Asia. If this book helps even a little bit in stemming the rise of the antimicrobial resistance monster, the efforts of the contributors and editors will be suitable rewarded.

Tanu Singhal Nitin K Shah

Contents

SECTION 1: BASICS OF MICROBIOLOGY AND PHARMACOLOGY 1. Antimicrobial Resistance ...... 1 Simantini Jog, Camilla Rodrigues 2. Antimicrobial Sensitivity Testing ...... 13 Simantini Jog, Camilla Rodrigues 3. Pharmacokinetics and Pharmacodynamics of Antimicrobial Drugs ...... 23 Jaideep A Gogtay 4. , and Beta Lactam-Beta Lactamase Inhibitor Combinations...... 27 Raju C Shah, Pratima Shah, Pradnya Gadgil 5. ...... 40 Baldev S Prajapati, Rajal B Prajapati 6. ...... 51 Nishant Verma, Rakesh Lodha 7. ...... 62 Preeti Shanbag 8. , Azalides and ...... 75 Niranjan Shendurnikar, Vandana Gopal 9. Quinolones ...... 89 Indu Khosla, Vishal Mukhija, Vijay V 10. Glycopeptides, Oxazolidinones and ...... 98 Pallavi Bhargava, Vivek Kak, Tanu Singhal 11. Miscellaneous Antibacterial Drugs ...... 113 Baldev S Prajapati, Rajal B Prajapati xiv Rational Antimicrobial Practice in Pediatrics 12. and ...... 129 Nishant Verma, Deepchand Khandelwal, Rakesh Lodha 13. Antifungals...... 149 Tanu Singhal, Pradnya Gadgil 14. Antivirals ...... 170 Vijay N Yewale

SECTION 2: ANTIMICROBIAL THERAPY OF INFECTIONS 15. General Principles of Antimicrobial Therapy ...... 183 YK Amdekar 16. Antimicrobial Therapy in Acute Gastroenteritis ...... 189 Shinjini Bhatnagar, Keya Mariam Kunnekel, Pankaj Vohra 17. Antimicrobial Therapy in Upper Respiratory Tract Infections ..... 202 Saheli Misra, Ritabrata Kundu, Nupur Ganguli 18. Antimicrobial Therapy in Community Acquired Pneumonia ...... 212 Poonam Mehta, Prawin Kumar, SK Kabra 19. Antimicrobial Therapy and Drainage of Empyema Thoracis...... 225 Rasik Shah, Pradnya Gadgil 20. Chemotherapy of Childhood Tuberculosis ...... 228 Varinder Singh, Md Umar Tak, Soumya Tiwari 21. Antimicrobial Therapy in Enteric Fever...... 250 Tanu Singhal, Nitin K Shah 22. Antimicrobial Therapy in Urinary Tract Infections ...... 261 Kumud P Mehta, Uma Ali 23. Antimicrobial Therapy in Skin and Soft Tissue Infections ...... 271 Tanmay Amladi, Sangeeta Amladi 24. Antimicrobial Therapy in Skeletal Infections ...... 278 Apurba Ghosh, Monjori Mitra, Mallar Mukherjee 25. Antimicrobial Therapy in CNS Infections ...... 289 Lalitha Iyer, VP Udani Contents xv 26. Antimicrobial Therapy in Neonatal Sepsis ...... 303 Umesh Vaidya, Deepak Karpe, Shilpa Kalane 27. Antimicrobial Therapy in Septic Shock ...... 314 Sunit Singhi, KS Laxmi 28. Antimicrobial Therapy in Nosocomial Infections ...... 321 Soonu Udani, Neha Gupta 29. Antimicrobial Therapy in Febrile Neutropenia ...... 331 Nitin K Shah, MR Lokeshwar 30. Antimicrobial Prophylaxis ...... 344 Meenu Singh, Shreya Singh 31. Antimalarial Therapy ...... 364 Tanu Singhal, Ashok Kapse 32. Antimicrobial Therapy in Visceral Leishmaniasis (Kala-azar) ...... 392 Nigam Prakash Narain 33. Antiretroviral Therapy ...... 399 Archana Kher 34. Anthelmintic Therapy ...... 415 S Balasubramanian, Sumanth Amperayani

SECTION 3: CASE SCENARIOS IN ANTIMICROBIAL THERAPY 35. Antimicrobial Therapy: Illustrative Cases ...... 423 Tanu Singhal

SECTION 4: READY RECKONER FOR DOSAGE OF ANTIMICROBIAL DRUGS 36. Antimicrobial Formulary ...... 433 Suhas Prabhu

Index ...... 469 Section 1: Basics of Microbiology andAntimicrobial Pharmacology Resistance 1 11 Antimicrobial Resistance Simantini Jog, Camilla Rodrigues

 INTRODUCTION Infections kill at least 13 million people every year, mostly in the developing world. Whilst use of antimicrobials has greatly diminished mortality in infectious diseases, bacteria have quickly evolved and developed resistance to many of these drugs. Resistance confers a survival advantage and just as bacteria have adapted to every ecological niche on earth, so too they have learnt to adjust to the world of . Resistant bacteria have no qualms about begging, borrowing, stealing chunks of genetic material from other bacteria in order to survive. The upsurge in drug resistance is due to a number of factors, the most prominent being the inappropriate and excessive use of antimicrobial agents. We did not bargain for this undercurrent of genetic exchange in our exploitation of antimicrobials. Antimicrobial resistance (AMR) is a global emergency. Resistant organisms are difficult to treat, pose challenges for infection control practices in hospitals, adversely impact hospital in-patient stays and mortality and are a huge burden in terms of health-care costs.

Terminology Natural Resistance That which is beyond the usual spectrum of an antimicrobial. Example: Aerobic gram-negative bacilli are naturally resistant to .

Acquired Resistance Microbial resistance in a previously sensitive organism Example: -resistant H. influenzae—due to  lactamase production. 2 Rational Antimicrobial Practice in Pediatrics

Intermediate or Relative Resistance Gradual increase in minimum inhibitory concentration (MIC) of organisms over time, but organisms still susceptible to at achievable serum and tissue concentrations. Example: S. pneumoniae and —the definition of susceptibility of S. pneumoniae to penicillin has changed to reflect the site of infection and route of therapy.

High Level or Absolute Resistance Sudden increase in MIC of a single isolate during or after therapy. High-grade resistance cannot be overcome by increasing antibiotic concentrations even with higher than the usual clinical doses. Example: Often seen with P. aeruginosa to aminoglycosides or quinolones.

Pseudo-resistance Resistance by in vitro susceptibility testing but are effective in vivo. Example: E. coli and K. pneumoniae resistance to /ampicillin.

Cross-resistance Cross-resistance among a group of antibiotics requires the use of another class of antibiotics to eliminate the resistant organism. With some organisms, cross-resistance within an antibiotic class does not mean that other members are resistant. Strains of resistant P. aeruginosa are sensitive to . resistant methicillin-sensitive S. aureus (MSSA) is susceptible to and uniformly susceptible to . Similarly, many strains of S. pneumoniae are resistant to tetracycline, but few, if any, are resistant to doxycycline. With other organisms, class cross-resistance is complete. Gram-negative bacilli producing extended-spectrum  lactamases are resistant to all third generation cephalosporins.

Mechanisms of Antimicrobial Resistance Bacteria become resistant by essentially four mechanisms:

Inactivating Enzymes These include inactivating enzymes, lactamases, acetyl transferase, etc. Aminoglycosides such as gentamicin, amikacin, and are broad-spectrum antimicrobials used to treat infections caused primarily by aerobic gram-negative bacilli. These agents also are used in combination with a  lactam antibiotic to treat gram-positives. The most common mechanism of resistance to aminoglycosides is through producing aminoglycoside-modifying enzymes (AME) that inactivate the drug. Beta lactamases are enzymes that split the amide bond of beta lactam ring and are encoded by chromosomal or transferable genes (plasmids/transposons). Several classes of the enzymes have been described. Beta lactamases are produced by gram-positive organisms (Staphylococci, Enterococci), gram-negative organisms as well as anaerobes (Fusobacteria, Clostridia, B. fragilis). Today extended spectrum beta lactamases (ESBL) Antimicrobial Resistance 3 in E. coli and K. pneumoniae, derepressed mutants including Amp C in organisms with inducible beta lactamase and metallo beta lactamases (MBL) in P. aeruginosa and other coliforms like K. pneumoniae are being found with increasing frequency in hospitals.

Alteration of the Target Site Structural modifications result in a lower affinity of the target site for the antibiotic so that the antibiotic binding to the target is decreased or totally eliminated. For penicillin resistance in Streptococcus pneumoniae the mechanism involves alterations in one or more of the penicillin binding proteins (PBP). The genes that code for the altered PBP are termed “mosaics” as they consist of segments of native pneumococcal DNA mixed with segments of foreign DNA presumably from other penicillin resistant organisms such as viridans Streptococci that have been mopped up by the Pneumococcus and incorporated into the chromosome. Methicillin resistant S. aureus (MRSA), which codes for an altered penicillin binding protein, renders all  lactam antibiotics ineffective. Fluoroquinolones act on the bacterial enzymes topoisomerase IV and DNA gyrase. These enzymes are required for efficient cell division. Four subunits of topoisomerase IV exist, two C (Par C) and two E (Par E) subunits encoded by par C and par E genes while DNA gyrase is composed of two A (Gyr A) and two B (Gyr B) subunits encoded by gyr A and gyr B genes. DNA gyrase is the primary site of action in the gram-negative bacilli whereas topoisomerase IV is the principle target of quinolones in gram-positive bacteria. Resistance to fluoroquinolones occurs by target modification in a step-wise fashion, resulting from mutations in the quinolone-resistance-determining region (QRDR) of par C (low level) and/or gyr A (high level).

Alteration of Bacterial Cell Membrane Outer membrane permeability There are structural differences between the cell walls of gram-positive and gram-negative organisms. Gram-positive bacteria have a single cell membrane with a generous external layer of . For  lactam and glycopeptide antibiotics, which do not have to traverse the plasma membrane to exert their activity, transport across the membranes of gram-positive bacteria is no issue at all. Gram-negative bacteria possess an inner plasma membrane and an outer cell membrane between which is an attenuated peptidoglycan layer. The outer cell membrane includes lipopolysaccharides with tightly bound hydrocarbon molecules, which impede hydrophobic substances like and . Porin proteins The passage of hydrophilic antibiotics is facilitated by porins. Porin proteins are arranged to form water filled diffusion channels through which antibiotics traverse. Negatively charged molecules move more slowly across the membrane than do more positively charged molecules or zwitterions. Beta lactams with bulky side chains such as cross the membrane poorly. , a zwitterionic hydrophilic compound with a very compact structure, however, performs the best. In , imipenem gains 4 Rational Antimicrobial Practice in Pediatrics entry not through the main porin protein but through a specific transport protein designated D2. Resistance to imipenem is by decreased permeability through this porin channel.

Antibiotic Efflux In case of certain bacteria, an important mechanism of resistance is active removal of antibiotics from the bacterial cell so that intracellular concentrations of antibiotics never reach a sufficiently high level to exert antimicrobial activity. This efflux mechanism is energy dependent. This is a prime defense for bacteria against and macrolides. Also is responsible for Pseudomonas being resistance to .

Molecular Genetics of Antibiotic Resistance Genetic variability that helps in evolution of microbes is the result of mutations. Point mutations result in a change in a nucleotide base pair, which is referred to as micro- evolutionary change. For example, point mutations at critical locations on old  lactamase genes are responsible for the newly recognized extended spectrum  lactamases (ESBL). A macroevolutionary change is a whole scale rearrangement of large DNA segments at a single event. This includes inversion, duplication, insertion, deletion or transposition of large sequences of DNA from one location of a bacterial chromosome or plasmid to another. Plasmids are extrachromosomal circular double stranded DNA pieces that act independently of the chromosome. Chromosomal DNA is relatively stable whereas plasmid DNA is easily mobilized from one strain to another. They are adapted to serve as agents of genetic evolution and resistance genes dissemination. The linking of resistance genes for multiple antibiotics on a plasmid allows bulk transfer of resistance characterizing many newly resistant organisms. Transposons translocate from one area of a chromosome to another or between chromosome and plasmid or bacteriophage DNA. They are not capable of autonomous replication and hence exist on a replicon like chromosome, plasmid or bacteriophage. For example, transposon is responsible for tetracycline resistance in N. gonorrhoeae, Mycoplasma hominis and Ureaplasma urealyticum. Some transposons or plasmids have genetic elements termed integrons that enable them to capture exogenous genes. A number of genes may, therefore, be inserted into a given integron, resulting in resistance to multiple antimicrobial drugs or possibly allowing the accumulation of both regulatory and structural genes in the same transposon. Insertion elements as integrons specialize in picking up “gene resistant cassettes” for rapid and efficient transfer of resistance. Foreign DNA is acquired and carried by plasmids, bacteriophges, naked DNA sequences or transposable genetic elements. The resistance genes can then spread to other bacteria by processes like transformation (parts of DNA acquired by bacteria from external environment), transduction (bacteriophages which are bacteria specific viruses that help transfer DNA between bacteria) or conjugation (transfer via direct cell to cell contact). Antimicrobial Resistance 5

Bacterial resistance is somewhat different in the hospital and the community. Though interchangeable, each of these 2 environments represents different bacterial flora, different reservoirs, and different selective pressures.

Resistance in Gram-Positive Organisms Streptococcus Pneumoniae Pneumococcal resistance to  lactams has been increasing over the last decade. In 1999, the Invasive Bacterial Infection Surveillance (IBIS) group reported penicillin resistance in 1.3%, chloramphenicol resistance in 56% and resistance to cotrimoxazole in 17% of isolates respectively. At our center in Mumbai in the year 2003, we detected penicillin resistance in 12% of invasive and noninvasive isolates of S. pneumoniae, compared to 0% in 1992. Today, however, most nonmeningeal pneumococcal infections can be treated by standard doses of /ampicillin as the new CLSI breakpoints for penicillin have different breakpoints for meningeal and nonmeningeal sites. This change was prompted by the fact was no difference noted in the clinical outcome of nonmeningeal infections in patients who were drug resistant by the earlier breakpoints. Mechanism Pneumococcal resistance to  lactam antibiotics is a function of altered PBP (1a, 1b, 2a, 2b, 2c), transpeptidases involved in synthesis. Pneumococcal serotypes most commonly associated with drug resistance are those most often responsible for infection and carriage in children, 6, 14, 19 and 23. Risk factors for acquisition of drug resistant S. pneumoniae (DRSP) include: 1. Previous antimicrobial therapy 2. Day care center attendance 3. Prior hospitalization Identification in the laboratory The use of disk (1 g) is required to screen for beta lactam resistance. If oxacillin is resistant, for meningitis, Pen MIC > 0.12 mg/mL regarded as R, however, for pneumonia, Pen MIC > 8 mg/mL regarded as R. Management Penicillin susceptible Pneumococci are susceptible to all commonly used cephalosporins. Penicillin intermediate strains are resistant to all first and many second-generation cephalosporins but are susceptible to some third-generation cephalosporins including and as well as high doses of amoxicillin (80–100 mg/kg/day). One half of highly penicillin resistant Pneumococci are also resistant to cefotaxime and ceftriaxone, a higher proportion are resistant to and nearly all are resistant to . They are, however, susceptible to other drugs such as and .

Resistance in Enterococcus Species Enterococci are naturally tolerant to penicillins and resistant to cephalosporins, clindamycin and achievable serum levels of aminoglycoside. resistance is due to poor 6 Rational Antimicrobial Practice in Pediatrics affinity of the antibiotic for enterococcal PBP. Natural low level aminoglycoside resistance is the result of inability of aminoglycosides to penetrate the cell wall; but in the presence of cell wall active drugs such as ampicillin or vancomycin, aminoglycosides are able to penetrate and work. High-level gentamicin resistance in enterococci has rapidly spread worldwide. This also is strongly associated with nosocomial acquisition. Such strains do not demonstrate synergistic killing when aminoglycosides are combined with penicillin or vancomycin. Most of such resistance is carried on transposons and is plasmid mediated. Detection of high-level gentamicin resistance requires testing with a disk with high concentration of gentamicin or (e.g. > 500 g/mL). Chromosomal high level penicillin resistance is a species-specific characteristic of E. faecium. Such strains are likely to be nosocomially acquired. High-level penicillin resistant E. faecium are also resistant to imipenem and lactam- lactamase inhibitors and are often glycopeptide resistant. Since ampicillin or penicillin resistance among enterococci due to  lactamase production are not reliably detected using routine disk diffusion or dilution methods, a direct nitrocefin based beta lactamase test is recommended for the isolates of enterococci from blood and CSF. A positive beta lactamase test indicates resistance to penicillins, , as well as .

Vancomycin-Resistant Enterococci (VRE) Glycopeptides are large complex molecules that do not enter the bacterial cell. Vancomycin resistance mechanisms involve a complex series of reactions that ultimately result in the building of the cell wall by bypassing the D-alanine-D-alanine containing pentapeptide intermediate structure, thus eliminating the glycopeptide target. Risk factors for VRE colonization/infection • Exposure to antibiotics such as broad-spectrum cephalosporins, fluoroquinolones, vancomycin • Longer length of hospital and ICU stay • Intra-hospital transfers • Liver transplant requiring surgical re-exploration. Vancomycin-resistant enterococci are characterized phenotypically as van A, van B, and van C strains based on levels of resistance to vancomycin, cross-resistance to and inducible or constitutive nature of resistance. Strains exhibiting the Van A phenotype show an acquired inducible high level resistance to vancomycin and teicoplanin. Van B phenotype is associated with moderate to high level resistance to vancomycin but the isolates remain sensitive to teicoplanin. The Van C phenotype can be inducible or constitutive chromosomally mediated but rarely seen in Enterococci causing human infection. A fourth vancomycin resistant genotype Van D, described in a strain of E. faecium exhibits moderate levels of resistance to vancomycin and teicoplanin. A fifth Van E genotype has also been described in E. faecalis. Strict adherence to infection control measures to limit the spread of such isolates in the hospital setting is of critical importance. Antimicrobial Resistance 7

Management Most strains of VRE. faecalis retain susceptibility to ampicillin and penicillin, which can be used for therapy. VRE. faecium isolates are usually highly resistant to ampicillin and may have high-level aminoglycoside resistance. Linezolid has excellent in vitro activity against E. faecium and E. faecalis and is effective in treating infections caused by VRE. Resistance to oxazolidinone antibiotics like linezolid is rare but can occur in Enterococci and Staphylococci. It is usually mutational and can be selected during treatment, especially long courses of the antibiotic. Plasmid mediated resistance occurs by the cfr gene which modifies the ribosomal RNA blocking the binding of linezolid. E. faecium isolates resistant to linezolid have been recently encountered in UK, the index case being a patient who fell ill on arrival to a hospital in UK from India. The concerned isolates were cfr gene positive. Quinupristin – dalfopristin demonstrates bacteriostatic activity against most VRE faecium but has no activity against E. faecalis. Daptomycin is a relatively newer drug that can be used to treat VRE.

Resistance in Staphylococcus Aureus Methicillin-Resistant Staphylococcus Aureus (MRSA) Methicillin resistance in Staphylococci is mostly mediated by the mec A gene encoding for a single additional PBP, PBP 2a with low affinity for all  lactams. This gene is widely distributed in both coagulase positive and coagulase negative staphylococci and is carried on a transposon. Expression of this gene can be constitutive or inducible. MRSA isolates containing mec A are resistant to all  lactam antibiotics. Most nosocomial and health care associated isolates frequently carry other multiple resistance determinants. However, most community acquired MRSA strains are susceptible to multiple classes of antibiotics other than lactams, including trimethoprim-sulphamethoxazole, clindamycin, aminoglycosides, tetracyclines. Risk factors for nosocomial bacteremia caused by MRSA include: • Presence of severe systemic disease • Presence of indwelling central venous catheters or other devices • Increased length of stay in the hospital • Prior antimicrobial exposure. The spread of MRSA from nosocomial to health care associated settings and the emergence of community acquired MRSA (CA-MRSA) are concerning developments. The occurrence of true CA-MRSA infections in otherwise healthy individuals without risk factors is increasing in incidence, particularly in pediatric populations. The methicillin resistance mechanism in CA-MRSA is predominantly associated with the SSC mec type IV variant of the mec gene. The Panton-Valentine leukocidin is a potent virulence factor of CA-MRSA. 8 Rational Antimicrobial Practice in Pediatrics

Management Methicillin-resistant Staphylococcus aureus resistance rates across India vary but seem to increase over time. Community acquired (CA) MRSA in India may not conform strictly to the conventional case definition of CA-MRSA infection with no history of surgery, hospitalization, presence of a percutaneous device or indwelling catheter, dialysis within the previous year, previous MRSA infection or colonization, hospitalization > 48 hr before culture. The epidemiology includes SCC mec IV, V with far fewer antibiotic resistance genes and positive for PVL (Panton Valentine leukocidin) genes. In India, CA-MRSA is likely to expand its resistance profile as it is fit, rapidly evolving and probably may displace hospital acquired MRSA. We are seeing increasingly more resistance to ciprofloxacin in CA-MRSA and increasing prevalence in the health care setting without apparent risk factors. For CA-MRSA infections, clindamycin is often effective (should be restricted to erythromycin susceptible isolates). Other options include trimethoprim-sulphamethoxazole, fluoroquinolones (never used on its own), tetracycline and linezolid. Vancomycin, an option, must be given intravenously which complicates outpatient therapy. The treatment of choice for nosocomial and healthcare associated MRSA infections is intravenous vancomycin or teicoplanin. Interestingly, vancomycin is a less active anti-staphylococcal agent than a beta lactam against methicillin susceptible strains. Gentamicin is synergistic with vancomycin in vitro and can be used for bacteremia and endovascular infections. Rifampicin plus vancomycin combination may be particularly useful in the CSF and with infections of foreign bodies. Rifampicin resistance emerges quickly when the drug is used alone. Linezolid which has good in vitro activity against both MSSA and MRSA is effective in the treatment of skin and soft tissue infection and nosocomial pneumonia caused by MRSA.

Vancomycin-Resistant Staphylococcus Aureus (VRSA) Since 1996, reports of infections caused by MRSA with intermediate susceptibility to vancomycin (MIC 8–16 µg/mL) termed as vancomycin intermediate S. aureus (VISA/GISA or glycopeptide intermediate S. aureus) began to emerge. Independent risk factors for infections caused by VISA include prior infection caused by MRSA and antecedent vancomycin use within 3 months of VISA infection. In Mumbai, we are seeing creeping MICs to vancomycin with a mean of 1,33 g/mL. In S. aureus, vancomycin resistance is known to be conferred by the van A resistance cluster which also mediates glycopeptide resistance in some enterococcal species. The breakpoints for glycopeptides have now been modified as serious infections with VISA/ GISA are not treatable with increased doses of glycopeptides. In fact, with infections caused by S. aureus isolates with MIC to vancomycin of 2 µg/mL, clinical response may be impaired when glycopeptides are used for treatment. S. aureus isolates with MIC to glycopeptides >2 µg/mL are now reported resistant (GRSA or glycopeptide resistant S. aureus). Antimicrobial Resistance 9

Resistance in Gram-Negative Organisms Haemophilus Influenzae This is a common community pathogen implicated in the acute exacerbation of chronic bronchitis in adults and meningitis/bacteremia/pneumonia in young children. Beta lactam resistance among clinical isolates of H. influenzae arises by  lactamase production and, to a lesser extent, by PBP modifications and outer membrane permeability. Among these diverse mechanism, TEM-1 beta lactamases is by far the most prevalent, accounting for > 90% of ampicillin resistance encountered in this organism, especially among the capsular type, serotype b. H. influenzae also produces another enzyme, ROB-1, with a similar substrate profile as TEM-1. Resistance to ampicillin, chloramphenicol and cotrimoxazole was reported in 46%, 60% and 55% of isolates in 2002 (IBIS study). Management H. influenzae that produces  lactamase is best treated with a  lactam- lactamase inhibitor combination or in more serious infections with an intravenous third generation cephalosporin such as ceftriaxone.

Salmonella Typhi and Salmonella Paratyphi A Enteric fever is the most important etiology of fever of unknown origin in the community in developing countries. For decades, chloramphenicol, cotrimoxazole and amoxicillin were the mainstay drugs in the treatment of typhoid. Plasmid-mediated resistance to these three drugs necessitated the search for other options. Fluoroquinolones introduced at that time seemed to be an ideal option when introduced. There has been a gradual increase in the MIC of ciprofloxacin from 0.0004 in 1990 to 1 µg/mL in 2002. Since these levels and the disk diffusion diameters are still within the susceptible range as per CLSI standards, laboratories continue to report the strains as sensitive to ciprofloxacin. The new CLSI guidelines 2012 have addressed this issue and lowered the MIC of ciprofloxacin to <0,25 g/mL and increased to zone diameter to >31 for susceptibility. Clinical failure is common today with the use of quinolones to treat enteric fever. Nalidixic acid resistance in vitro correlates with high ciprofloxacin MIC and reliably predicts poor clinical outcome with quinolone usage in the usual doses and thus can be used to guide the choice of therapy. At our center in Mumbai, nalidixic acid resistance has increased from 0% in 1990 to 90% in 2003. Also seen with increasing quinolone resistance is return in susceptibility to older drugs such as cotrimoxazole, chloramphenicol and amoxicillin. The % susceptibility across 15 centers in India to ampicillin, chloramphenicol and cotrimoxazole was found to be 89,95 and 94.5 respectively in 2010. Treatment depends on the susceptibility to nalidixic acid. In the case of NARST (Nalidixic acid resistant Salmonella typhi), it is prudent to give a third generation cephalosporin such as ceftriaxone in a sick patient. Other options for out-patient therapy include the use of , and if susceptible cotrimoxazole or amoxicillin. 10 Rational Antimicrobial Practice in Pediatrics

Resistance in other Gram-Negative Bacilli

Extended Spectrum  Lactamase (ESBL) ESBLs are enzymes produced by gram-negative bacilli that have the ability to inactivate  lactams containing an oxyimino group (i.e. third-generation cephalosporins and ). They are known as “extended spectrum” because they are able to hydrolyze a broader spectrum of  lactams than the simple parent  lactamases from which they are derived. ESBLs are plasmid-mediated enzymes, most commonly found in Klebsiella pneumoniae but also in Escherichia coli, Proteus mirabilis, Salmonella and other gram- negative bacilli. Treatment of infections by ESBL producers is a growing challenge. These organisms display in vitro susceptibility to third-generation cephalosporins but treatment failures occur in vivo. Such organisms are also more resistant to other classes of antibiotics like aminoglycosides and quinolones. It is important for the clinical laboratory to employ methods to detect the presence of an ESBL. Carbapenems (imipenem and meropenem) are effective in the treatment of these isolates. Cefepime and beta lactam-beta lactamase inhibitor antibiotics possess good in vitro activity against some ESBL expressing organisms but should not be used for treating serious infections. Many strains producing ESBLs demonstrate an inoculum effect in that the MIC of the expanded spectrum cephalosporins rises as the inoculums of the organism increases. In India ESBLs rates are high and in E. coli and Klebsiella spps vary from from 58–87%.

Amp C  Lactamase Amp C lactamases can be chromosomal or plasmid mediated, the presence of which is a species specific characteristic of some organisms such as Enterobacter, Serratia, Citrobacter, Proteus vulgaris, Morganella, Acinetobacter, Pseudomonas, etc. Exposure to particular  lactams like cephalosporins, , monobactams and extended spectrum penicillins causes induction of Amp C production to high levels in these bacteria, thus the organism can become resistant on treatment. Mutations can lead to hyperinduction or constitutive hyperproduction of Amp C. Beta lactam-beta lactamase inhibitor combinations are ineffective against Amp C producing isolates. Cefepime, a fourth generation cephalosporin that is a much weaker inducer of Amp C production and carbapenems are usually the only available treatment options. Laboratory detection of Amp C producing isolates poses a unique challenge. Up to 30% Amp C genes have been detected in E. coli and Klebsiella pneumoniae with a majority of strains co-producing ESBLs.

Carbapenemases Carbapenem resistance is mediated through 2 types of carbapenem hydrolyzing enzymes, namely serine carbapenemases and metallo  lactamases (MBLs). The MBL like all  lactamases can be divided into those that are normally chromosomally mediated (Stenotrophomonas maltophilia) and those that are encoded by transferable genes. Carbapenem resistance in Pseudomonas aeruginosa (also in Enterobacter spp and other Antimicrobial Resistance 11 chromosomal Amp C producing organisms as Serratia, Citrobacter) can also occur by mutational loss of porin channels or by the efflux mechanism. Today the 5 commonest carbapenemases in Enterobacteriaceae are KPC, IMP-1, VIM, NDM and OXA-48. Risk factors for acquisition of imipenem resistant P. aeruginosa: • ICU stay • Prolonged hospital stay • Exposure to imipenem, piperacillin and aminoglycosides. In case of multidrug resistant P. aeruginosa infection, intravenous colistin/ B is a therapeutic option although renal toxicity is often a limiting factor. Due to high prevalence of antibiotic resistance and the potential for emergence of resistance, deep seated Pseudomonas infections may be treated with two active agents demonstrating additive or synergistic activity, such as a  lactam in combination with either an aminoglycoside or fluoroquinolone during the initial stages of therapy. After the burden of infection is decreased, de-escalation to a single antibiotic is appropriate. New Delhi Metallo  lactamases (NDM-1) is an enzyme capable of destroying carbapenems, most often seen in K. pneumoniae and E. coli. This type of resistance has been circulating in India since 2007 and has now been reported in Australia, USA, Holland, France, Canada, Sweden and UK. The characteristic risk factor is health-care contact in the Indian subcontinent. It is a plasmid encoded enzyme that can be transferred between bacteria. The emergence of this enzyme has become a major public health concern globally.

Strategies to Combat AMR Antimicrobial resistance is the result of inappropriate and irrational use of antimicrobials in not only human medicine but also in animal husbandry. Sound surveillance systems are key in identifying the problem in the first place. The antimicrobial armamentarium to combat resistant bacteria is dwindling. The following will be crucial in the control of AMR: • Physician education and awareness to prevent misuse of antibiotics • Strict antimicrobial policies in hospitals based on local antimicrobial resistance patterns • Rigorous adherence to infection control guidelines • Reducing the use of antibiotics with high potential for resistance and rotating them with low potential resistance drugs • Good antibiotic stewardship with antibiotic policies that work • Eliminating inappropriate therapy for “look alike” non-infectious clinical syndromes that mimic sepsis and for colonizing flora • De-escalation of broad-spectrum antibiotic therapy once sensitivities are available • Optimizing adequate antibiotic dosing for different groups of drugs keeping pharmacokinetic and pharmacodynamic principles in mind. Despite ongoing efforts to curtail antibiotic use and implement aggressive infection control efforts, emergence of new resistant pathogens continues to bring more challenges to the clinician and the clinical microbiology laboratory. 12 Rational Antimicrobial Practice in Pediatrics

 RECOMMENDED READING 1. Antibiogram of S. enterica serovar typhi and S. enterica serovar paratyphi A: a multicenter study from India. Indian Network for Surveillance of Antimicrobial Resistance Group • INSAR. WHO South-East Asia Journal of Public Health 2012;1(2):182-8. 2. Antimicrobial Drug Resistance. Emerging Infectious Diseases. 2005;11:6. 3. Biswas S, Watwani J, Vadwai V, Shetty A, Kelkar R, Rodrigues C. Comparative in vitro activities of daptomycin, vancomycin, teicoplanin, and linezolid against resistant gram-positive bacterial isolates from two large centers in western India. International J Antimicrob Agents 2012. 10.1016/ j.ijantimicag.2012.07.013. 4. Castanheira M, Deshpande LM, Mathai D, Bell JM, Jones RN, Mendes RE. Early Dissemination of NDM-1 and OXA-181 producing Enterobacteriaceae in Indian Hospitals-—Report from the SENTRY antimicrobial surveillance program (2006-2007). Antimicrobial Agents and Chemotherapy. 2011;55:1274-8. 5. Chandel DS, Johnson JA, Chaudhry RR, Sharma NN, Shinkre NN, Parida S, et al. Extended-spectrum beta-lactamase-producing gram-negative bacteria causing neonatal sepsis in India in rural and urban settings. J Med Microbiol. 2011;60(Pt4):500-7. 6. D’Souza N, Rodrigues C, Mehta A. Molecular characterization of Methicillin Resistant Staphylococcus aureus with emergence of epidemic clones of Sequence Type (ST) 22 and ST 772 in Mumbai, India. Journal of Clinical Microbiology 2010;48(5):1806-11. 7. Deshpande P, Rodrigues C, Shetty A, Kapadia F, Hegde A, Soman R; New Delhi Metallo beta lactamase—NDM -1 in Enterobacteriaceae ;Treatment options with carbapenems compromised. JAPI 2010:58;147-9. 8. Flaws ML, Traver R, Verma P. Update on Antimicrobial Resistance. Available at www.m/o-online.com. Accessed on 05/04/2005. 9. http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/AntimicrobialResistance/downloaded 30 September 2012. 10. Invasive Bacterial Infections Surveillance (IBIS) Group of the International Clinical Epidemiology Network. Are Haemophilus influenzae infections a significant problem in India? A Prospective Study and Review. Clin Infect Dis. 2002;34:949-57. 11. Jean SS, Hsueh PR. High burden of antibimicrobial resistance in Asia. Int J Antimicrob Agents. 2011;37:291-5. doi:10.1016/j.ijantimicag. 2011.01.009.39. 12. Kaye KS, Engemann JJ, Fraimow HS, Abrutyn E. Pathogens resistant to antimicrobial agents: epidemiology, molecular mechanisms and clinical management. Inf Dis Clin North America. 2004;18:467-511. 13. Koneman EW, Allen SD, Janda WM, Schreckenberger PC, Cwinn W Jr. Colour Atlas and Textbook of Diagnostic Microbiology (5th edition), Lippincott, Philadelphia, New York, 1997. p785-856. 14. Opal SM, Medeiros AA. Molecular mechanisms of Antibiotic Resistance in Bacteria. In: Mandell GL, Bennett JE, Dolin R (Eds). Principles and Practice of Infectious Diseases (6th edition). Elsevier Churchill Livingstone, Philadelphia, Pennysylvania, 2005:p253-70. 15. Pitout JD, Sanders CC, Sanders WE Jr. Antimicrobial resistance with focus on -lactam resistance in Gram-negative bacilli. The American Journal of Medicine. 1997;103:51-9. 16. Rodrigues C, Shenai S, Mehta A. Enteric fever in Mumbai, India: the good news and the bad news. Clin Infect Dis 2003;36:535. 17. Shanthi M, Sekar U, Arunagiri K, Sekar B. Detection of Amp C genes encoding for beta-lactamases in Escherichia coli and Klebsiella pneumoniae. Indian Journal of Medical Microbiology. 2012;30(3):2905. 18. Song JH, Lee NY, Ichiyama S, Yoshida R, Hirakata Y, Fu W, et al. Spread of drug-resistant Streptococcus pneumoniae in Asian countries: Asian Network for Suveillance of Resistant Pathogens (ANSORP) Study. Clin Infect Dis 1999;28:1206-11. Antimicrobial Sensitivity Testing 13 22 Antimicrobial Sensitivity Testing Simantini Jog, Camilla Rodrigues

 INTRODUCTION One of the principal functions of a clinical microbiology laboratory is to carry out antimicrobial sensitivity testing (AST), which helps guide the clinician in management of various infectious diseases. With the worldwide development and spread of antimicrobial resistance, treatment options are increasingly limited to newer expensive antimicrobial agents. Hence the laboratory must give high priority to well standardized in vitro antimicrobial susceptibility tests, which generate reliable data. The main objectives of susceptibility testing are: • To perform susceptibility testing for pathogens for which well standardized methods are available • To guide the clinician in the selection of the most appropriate antimicrobial agent for that particular clinical situation. The report should also provide the clinician with alternative agents to which the organism is susceptible • To perform quantitative measurement of the sensitivity of pathogens with direct therapeutic relevance, e.g. penicillin minimum inhibitory concentrations (MIC) for S. pneumoniae

Interpretation of Results of Susceptibility Testing Susceptible There is a high probability that the patient will respond to treatment with the appropriate dosage of that antimicrobial agent.

Resistant Treatment with the antimicrobial agent is likely to fail. 14 Rational Antimicrobial Practice in Pediatrics

Intermediate With the agents that can be safely administered at higher doses, this category implies that higher doses may be required to ensure efficacy or that the agent may prove efficacious if it is normally concentrated in an infected body fluid, e.g. urine. For body compartments where drug penetration is restricted even in the presence of inflammation, e.g. CSF, it suggests that extreme caution should be taken in the use of the agent. Thus, this category represents a “buffer” zone that prevents strains with borderline susceptibility from being incorrectly categorized as resistant or as sensitive.

Evaluation of Susceptibility Tests The following convention is used to evaluate susceptibility tests: • Very major error—Characterization of a resistant isolate as susceptible. • Major error—Characterization of a susceptible isolate as resistant. • Minor error—Characterization of a susceptible or resistant isolate as intermediate or characterization of an intermediate isolate as susceptible or resistant.

Antimicrobial Susceptibility Testing Methods • Agar dilution • Broth dilution (Macrobroth dilution and Microbroth dilution) • Disk diffusion • Antibiotic gradient methods • Automated instrument methods.

The laboratories worldwide adhere to standardized protocols in order to achieve reproducible results. Clinical and laboratory standards institute—CLSI (formerly National Committee for Clinical Laboratory Standards—NCCLS) is one such organization in USA that publishes standards for susceptibility testing on a continuing basis. BSAC—the British Society of Antimicrobial Chemotherapy and EUCAST—European Committee on Antimicrobial Susceptibility Testing are some of the other examples of such organizations in UK and Europe respectively. It is also important that revised procedures and current recommendations be promptly followed by all clinical laboratories.

Selection of Antimicrobial Agents for AST The choice of antimicrobial agents for AST depends on the organism isolated, the site of infection, the clinical practice setting in which the laboratory functions, the patterns of antibiotic usage and bacterial resistance in the community. Those agents that are prescribed by the physicians on a daily basis should be tested. CLSI publishes tables listing the antimicrobials appropriate for testing various groups of aerobic and fastidious bacteria. These guidelines indicate drugs that are most appropriate for testing each organism group and for treatment based on the specimen source, e.g. CSF, blood, urine or feces. It also includes a few agents that may be tested as surrogates for other agents due to the greater ability of a particular agent to detect resistance to closely related drugs, e.g. the use of oxacillin to predict overall beta lactam resistance in staphylococci. Antimicrobial Sensitivity Testing 15

Dilution Methods Agar Dilution Susceptibility Test Method A standardized suspension of bacteria is inoculated onto a series of agar plates, each containing a different concentration of antibiotic. Organisms sensitive to the concentration of the antibiotic contained in the given agar plate do not produce a circle of growth at the inoculum site, whereas, if resistant appear as circular colonies. For example, a series of agar plates containing 1, 4, 8, 16 and 32 µg/mL of antibiotic are used to determine the susceptibility of the organism being tested. If the organism grows on the first three plates but not in the plate with 16 µg/ml of the antibiotic, the MIC value is16 µg/mL.

Advantages • Well-standardized reliable technique • Can be used as a reference for evaluating the accuracy of the other testing systems • Simultaneous testing of a large number of isolates with a few drugs is efficient • Microbial contamination can be readily detected by agar methods as compared to broth methods.

Disadvantage • Preparation of plates is labor intensive and time consuming.

Macrodilution Broth Susceptibility Test Method Serial dilutions of the antimicrobial agent are made in the broth after which a standard suspension of bacteria is added. A tube free of antibiotic serves as a growth control. The tubes are then incubated at 35°C for 16-20 hr. Cloudiness indicates bacterial growth that has not been inhibited by the concentration of the antibiotic contained in the medium. The MIC is determined as the lowest concentration of the antibiotic in µg/mL that prevents in vitro growth of bacteria. In this method, the broth volume for each antimicrobial concentration is > 1.0 mL (usually 2 mL).

Advantages • Reference method • Well-standardized and reliable technique • Useful for research purposes.

Disadvantage • Time consuming and laborious. 16 Rational Antimicrobial Practice in Pediatrics

Microdilution Broth Susceptibility Test Method The principle is the same as macrodilution broth method except that the test is done in a series of microtube wells that are molded into a plastic plate. Each plate may contain 80, 96 or more wells depending on the number and concentration of antibiotics to be included in the susceptibility test panel. The volume of the antimicrobial dilution is most often 0.1 µL. The antibiotic containing trays are stacked and stored at –20°C in appropriate cover to avoid contamination and evaporation. Various viewing devices are available to facilitate the examination of the wells for growth. The simplest and most reliable is a parabolic magnifying mirror and tray stand allowing clear visual inspection of the undersides of the trays. Growth is determined by comparison with the growth control well and is generally indicated by turbidity throughout the well or by buttons in the well buttons.

Advantages • Reliable standardized reference method • Convenient simultaneous testing of several antimicrobial agents against individual isolates • The precision of dilution in large volumes is combined with the ease of testing in microtiter plates • Local production of plates allows the use of a tailored panel of antibiotics.

Disadvantage • Versatility of antimicrobial selection available with commercial broth microdilution trays is more limited compared with the selection available by preparing the panels in-house.

Breakpoint Susceptibility Tests These are methods by which antimicrobial agents are tested only at the specific concentrations necessary for differentiating between categories of susceptible, intermediate and resistant rather than in the range of doubling dilutions used to determine the MIC. When two drug concentrations adjacent to the breakpoints defining the intermediate and resistant categories are selected, growth at both the concentrations indicates resistance, growth at the lower concentration only signifies an intermediate result and no growth at either concentration is interpreted as susceptible.

Advantage • Greater number and variety of antimicrobial agents can be incorporated into a broth microdilution panel setup for breakpoint testing rather than full range dilution testing

Disadvantages • Routine quality control at such panels is more complex • The exact MIC of the isolate is not available Antimicrobial Sensitivity Testing 17

Indications for Use of Dilution Methods and Determination of MIC Minimum invasive concentration determination is not required for routine clinical practice. Specific indications for determining MIC include: • Testing isolates from patients with endocarditis or osteomyelitis • For research purposes, in order to evaluate the relative degrees of susceptibility of bacteria to various antimicrobial agents • Some species for which standard disk diffusion test is not well calibrated, e.g. Stenotrophomonas maltophilia, Burkholderia cepacia • Some species for which no disk test standards exist—Corynebacterium spp, Bacillus spp • Some species for which MIC is needed to guide selection of therapy and appropriate dosing—penicillin and cephalosporin resistant S. pneumoniae.

Quality Control (QC) in Dilution Methods This is essential: • To evaluate precision and accuracy of the test • To monitor reagent performance • To evaluate competency of the individual conducting the test. Certain reference strains as indicated below are used for QC purposes. • E. coli ATCC 25922 • P. aeruginosa TTCC 27853 • Enterococcus faecalis ATCC 29212 • S. aureus ATCC 29213 CLSI recommendations for storage and subculture should be followed. The acceptable quality control MIC ranges for the various reference strains are given in the CLSI document. Representative panels for each new batch prepared in-house or each new shipment obtained commercially should be subjected to quality control. In addition to this, QC should be performed daily. Two consecutive “out of control” MIC’s or more than 2 nonconsecutive “out of control values” in 20 consecutive tests indicate problems in the procedure that must be identified and solved. If accuracy can be documented, daily testing may be replaced by weekly testing.

Disk Diffusion Susceptibility Tests Principle and Method Commercially prepared filter paper disks impregnated with a specified single concentration of an antimicrobial agent are applied to the surface of an agar medium inoculated with the test organism. When the disk comes into contact with the moist agar surface, water is absorbed into the filter paper and the antibiotic starts diffusing into the surrounding medium. As the distance from the disk increases, the concentration of the antimicrobial agent decreases logarithmically, creating a gradient in the agar medium surrounding 18 Rational Antimicrobial Practice in Pediatrics each disk. Simultaneous growth of bacteria occurs on the agar surface when a critical cell mass of bacteria is reached and the inhibitory activity of the antibiotic is overcome. The points at which the critical cell mass is reached appear as a sharply marginated circle of bacterial growth with the middle of the disk forming the center of the circle. The concentration of the antibiotic at this interface of growing and inhibited bacteria is known as the critical concentration and approximates the MIC of the dilution tests. Criteria for the maximum number of disks for plate size should be followed to avoid overlapping of the zones. After incubation for 16–18 hr, the zone diameters of complete inhibition including the disk diameter are measured to the nearest whole millimeter with calipers or a ruler. The measuring device is held at the back of the inverted petridish which is illuminated with reflected light located a few inches above a black, nonreflecting background. When isolates of Staphylococci or Enterococci are tested, any growth within the zone of inhibition around the oxacillin disk or vancomycin disk is indicative of resistance. For other bacteria, presence of colonies within a clear zone of inhibition may indicate testing of a mixed culture or the selection of high frequency mutants indicative of resistance to that agent, e.g. Enterobacter spp with penicillins and cephalosporins. With Proteus spp, the thin film of swarming visible in an otherwise obvious zone of inhibition is disregarded and the zone diameter is measured from the point of 80% inhibition of growth. This is due to initial growth of the bacteria during the significant lag period before the antimicrobial agent begins to impact on the bacterial growth. The zone diameters are measured around each disk and are interpreted on the basis of CLSI guidelines and the organisms reported as susceptible, intermediate or resistant to the antimicrobial agent tested.

Advantages • Technically simple to perform • Reproducible • Relatively inexpensive reagents • No special equipment required • Susceptibility results provided are easily understood by the clinicians • Flexible as regards to the antimicrobial agents selected for testing.

Disadvantages • Standardized for only a limited number of organisms • Inadequate for the detection of vancomycin intermediate S. aureus, oxacillin heteroresistant staphylococci, low level (Van-B type) vancomycin resistant Enterococci • Provides a qualitative and not a quantitative result.

Quality Control (QC) in Disk Diffusion Tests Reference strains—same as for dilution susceptibility tests. Generally, the results of 1 in every 20 tests in a series of tests may be out of the accepted limits as set in Antimicrobial Sensitivity Testing 19

CLSI. If a second result falls outside the stated limits, corrective action has to be taken. Apart from testing each new batch of Mueller-Hinton agar with the reference strains, a QC must be done before a new lot of antimicrobial disks is introduced. Also, appropriate reference strains should be tested each day the disk diffusion test is performed. No more than 3 of 30 zone inhibition diameters may be outside the accepted limits published by the CLSI. When this criterion is fulfilled, each reference strain needs to be tested weekly.

Gradient Diffusion Method E test (AB Biodisk, Solna, Sweden) This is a method for quantitative antimicrobial susceptibility testing. A preformed antimicrobial gradient diffuses from a plastic coated strip into an agar medium inoculated with the test organism. The MIC is directly read from a scale on the plastic strip at a point where the ellipse of the organism growth intercepts the strip.

Advantages • Very simple • Flexible like the disk diffusion test • Can be used to test fastidious, anaerobic bacteria.

Disadvantage • Expensive at a cost of Rs. 100-150/- per drug.

Automated Instrument Methods Many laboratories have automated MIC systems which utilize a tray or other types of panels containing varying concentrations of several antimicrobial agents. Following inoculation, the panels are incubated in the instrument and MIC endpoints are read automatically. Sophisticated software enables MIC to be interpreted and reports are printed automatically. Examples of automated systems 1. Vitek system (BioMerieux Vitek, Inc., Hazelwood, MO) 2. MicroScan system (Dade MicroScan, Inc., West Sacramento, CA)

Choice of Method for Antimicrobial Susceptibility Testing The advantage of microdilution or agar gradient diffusion methods is the generation of a quantitative result in the form of minimum inhibitory concentration (MIC) rather than a category result. These methods can also be used to test anaerobic or fastidious organisms that cannot be tested by disk diffusion method. The Kirby-Bauer disk diffusion method is, however, the most common method used worldwide. The two major advantages of this method are its low cost and flexibility in drug selection. There is also a direct relationship between the size of the zone of inhibition and the MIC. Both dilution and disk diffusion 20 Rational Antimicrobial Practice in Pediatrics methods have similar inter- and intra-laboratory reproducibility. Hence, the disk diffusion method is sufficient for the vast majority of common rapidly growing bacteria. There are only a limited number of specific clinical indications for determining MIC to assist in patient management and these have been discussed earlier. The automated systems generate results much faster than the manual methods; however, a major challenge posed by such systems is the inflexibility of the standard panels of antimicrobial agents that can be tested. In any case, accuracy should not be sacrificed in an effort to generate a rapid susceptibility testing result. The choice of method for antimicrobial sensitivity testing also depends largely on the local needs and resources.

Caveats of AST Several other factors influence the outcome of antimicrobial therapy which cannot be addressed by in vitro tests. These include:

Factors Related to the Antimicrobial Agents • Pharmacokinetic factors: The penetration of antibiotics at the site of infection is one issue that cannot be addressed by the in vitro tests. High levels of antibiotics are achieved at sites of excretion from the body, e.g. urine and bile, whereas low levels relative to serum are found in prostatic fluid, bone, CSF. For example, aminoglycosides are ineffective in the treatment of Legionella infections despite excellent in vitro activity due to their poor penetration into macrophages which is the site of bacterial growth. • Pharmacodynamic factors: Interactions between the antimicrobial agent and the pathogen.

Factors Related to the Patient These include immune function, site of infection and the presence of prosthetic devices.

Why Antibiotics do not Work? While guiding the choice of an antimicrobial agent, the in vitro susceptibility test results have to be considered along with the above mentioned factors as well as with clinical evidence of efficacy of the agents. There are various reasons why antibiotics may not work despite correct susceptibility and they include: 1. Incorrect spectrum: Problems with spectrum occur when coverage by an antibiotic class is assumed and there is a subsequent lack of clinical response. Inadequate antibiotic coverage results from not covering pathogen(s) in a given situation, e.g. intra-abdominal infection. Treatment of serious intra-abdominal infection should include coverage directed against both aerobic gram-negative bacilli and Bacteroides fragilis. 2. In vivo versus in vitro susceptibility: Susceptibility tests are based on rapidly growing aerobic organisms determined to be sensitive by established breakpoints in achievable serum concentrations using clinically achievable doses. There are common pitfalls to be avoided in over reliance on in vitro susceptibility data. Trimethoprim sulfamethoxazole (TMP/SMX) is usually reported as active against Klebsiella pneumoniae Antimicrobial Sensitivity Testing 21

in vitro. Clinically, TMP/SMX is not effective in vivo to treat Klebsiella infections. Aminoglycosides alone have little antistreptococcal activity, but when combined with penicillin, aminoglycosides are active against Streptococci, including group D Streptococci. 3. Inadequate blood/tissue levels: In general, there is a step-down in concentration between the blood and tissue levels with beta-lactam antibiotics. With cephalosporins, in most well vascularized organs (excluding special locations, e.g. the urinary tract, central nervous system, prostate), tissue levels are about one quarter of simultaneous serum levels. Adequate tissue concentrations in most areas of the body are regularly achieved using the full doses of antibiotics. 4. Antibiotic tissue penetration problems: Most antibiotics penetrate well-defined abscesses poorly, if at all. Surgical drainage remains the cornerstone of the therapeutic approach in the patient with abscesses. Infections involving foreign implant material usually have a glycocalyx around the foreign body which form a biofilm and these cannot be eliminated by antimicrobial therapy. Such infections almost always required removal of the prosthetic device. Infections involving certain anatomic sites in the body are protected from the effects of most antibiotics given in the usually recommended doses, e.g. the cerebrospinal fluid, prostate. In subacute or chronic prostatitis, however, in which inflammation dependent penetration is not vital drugs with high lipid solubility such as doxycycline, TMP-SMX, quinolones are preferable. 5. Colonization versus infection: The mere recovery of an organism does not implicate its etiological role in the underlying infectious disease process. Certain organisms are almost always associated with colonization and only rarely cause invasive disease, e.g. Citrobacter spp. Organisms as Enterobacter spp cause disease in a narrow range of clinical circumstances, e.g. IV line infections, catheter associated bacteriuria, etc. The recovery of Pseudomonas aeruginosa from an endotracheal specimen in an intubated patient in an intensive care unit likewise may represent colonization. Treating colonization not only wastes vital resources but is almost always unsuccessful. 6. Drug fever: Fever may result from the patient’s reaction with a given medication, and often it may be the sole manifestation to a given drug.

Interpretative Reading If organisms are identified up to species level and a sufficient range of antimicrobials are tested then the underlying resistance mechanisms can be inferred from the available data.

 RECOMMENDED READING 1. Cormican M, Whyte T, Hanahoe B. Antimicrobial Susceptibility Testing in Ireland: An introduction to the methods of the National Committee for Clinical Laboratory Standards (NCCLS) http : //www.amls.ie/ ast 110402.htm. 2. Jorgensen JH, Turnidge JD. Susceptibility Test Methods: Dilution and Disc Diffusion Methods. In Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolker RH (Eds). Manual of Clinical Microbiology (9th edition). ASM Press, Washington DC, 2003: p1102-7. 22 Rational Antimicrobial Practice in Pediatrics

CONCLUSIONS 1. Various determining factors need to be kept in mind when performing AST on bacterial isolates. For example, in case normal flora is isolated, sensitivity should not be done as it only leads to further discrepancies between in vitro testing and clinical outcome. Also, when organisms have a predictable susceptibility, e.g. S. pyogenes, additional susceptibility testing need not be done. 2. When interpreting susceptibility tests, larger zones do not indicate that the antimicrobial is more susceptible. Susceptibility tests have to be interpreted as per the CLSI criteria as susceptible, intermediate and resistant. 3. Appropriate control strains must be used and interpretative standards must be followed. 4. For certain isolates, zone diameters have not been provided by the CLSI and it is a must to do the AST by MIC methods in such cases. For example, nonfermenters other than P. aeruginosa and Acinetobacter spp. 5. In vitro results are deceptive for MRSA and beta lactams and these isolates should not be reported as susceptible to beta lactams. Enterococcus spp may yield susceptible results in vitro for aminoglycosides but these agents should never be used alone for treating these infections.

3. Jorgensen JH. Laboratory issues in the detection and reporting of Antibacterial resistance. Inf Dis Clin North America 1997;11:785-802. 4. Koneman EW, Allen SD, Janda WM, Schreckenberger PC, Cwinn W Jr. Colour Atlas and Textbook of Diagnostic Microbiology (5th edition). Lippincott, Philadelphia, New York, 1997: p785-856. 5. Livermore DM, Winstanley TG, Shannon KP. Interpretative reading: recognizing the unusual and inferring resistance mechanisms from resistance phenotypes. http://bsac.org.uk/wp-content/uploads/ 2012/02/Chapter_11.pdf Downloaded 30 September 2012. 6. Louie M, Cokerill FR III. Susceptibility Testing: Phenotypic and Genotypic Tests for Bacteria and Mycobacteria. Inf Dis Clin North America 2001;15:1205-26. 7. Turnidge JD, Ferraro MJ, Jorgensen JH. Susceptibility Test Methods: General considerations. In Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolker RH (Eds). Manual of Clinical Microbiology (9th edition). ASM Press, Washington DC, 2003: p 1102-7. Pharmacokinetics and Pharmacodynamics of Antimicrobial Drugs 23 33 Pharmacokinetics and Pharmacodynamics of Antimicrobial Drugs Jaideep A Gogtay

 INTRODUCTION Over the last 10-15 years there has been a growing interest in the pharmacodynamics and pharmacokinetics parameters of antimicrobial agents and their correlation with the clinical and bacteriological efficacy of the drugs and linked to this is the occurrence of bacterial resistance.

What is Meant by Pharmcodynamics and Pharmacokinetics? Pharmcodynamics (PD) describes the effect of the drug on the body and the microorganisms while pharmacokinetics (PK) describes the plasma time-concentration course of the drug. It is well-known that for a drug to achieve its effect (PD), it has to achieve a certain concentration at the site of the infection via the plasma (PK) (Figure 1). Looking at PK-PD together links drug exposure to the antimicrobial and clinical effects after administration of the drug to a patient.

Figure 1: The relationship between pharmacokinetics and pharmacodynamics of drugs 24 Rational Antimicrobial Practice in Pediatrics

Figure 2: Plasma time concentration curve of a drug and various PK-PD parameters

Figure 2 shows a typical course of a drug after oral administration. The drug achieves its maximum concentration (Cmax) at a particular time point (Tmax) and is metabolized and finally eliminated from the body depending on its half life. The ‘area under the curve” (AUC) represents the total body exposure to the drug. When this is plotted on the same graph as the minimal inhibitory concentration (MIC) of the drug against a particular organism, we begin to understand the concept of PK-PD of antibacterial agents.

Types of Killing by Antibacterial Agents (Table 1) Antibacterial agents have broadly two types of killings based on their PK-PD. 1. ‘Concentration dependent killing’ is determined by how much greater is Cmax above the MIC and the ratio Cmax/MIC is calculated. The minimum ratio should be 10 and the greater the ratio, greater is the kill power of the antimicrobial agent. An excellent example of this is the aminoglycoside class of drugs which produce similar or better results when the total dose is given as a once daily injection versus twice or thrice daily. 2. On the other hand beta lactam antibiotics demonstrate ‘time dependent killing’ which means that the efficacy is dependent on how long in the dosing interval the concentration of the drug remains above the MIC levels. The efficacy is optimum if the beta lactam remains above the MIC of the organism for at least 40–50% of the dosing interval. Studies have shown that the bacteriological efficacy is greater than 80% in such cases. Hence often more frequent administration of beta lactam may be needed for bacterial killing. In children with otitis media bacteriological cure rates of 80–85% were observed when the serum concentrations exceeded the MIC for 40–50% of the doing interval and increased to nearly 100% when it was 60-70% of the dosing interval. Table 2 shows the probability of achieving the PK-PD target of piperacillin- tazobactam (P-T) against E. coli and Klebsiella which were extended spectrum beta Pharmacokinetics and Pharmacodynamics of Antimicrobial Drugs 25

TABLE 1 Shows the type of killing for different antibacterial agents Pattern of activity Antibiotics Goal of therapy PK-PD parameter

Concentration Aminoglyosides Maximize Cmax/MIC dependent killing Fluoroquinolones concentrations (should be > 10) and prolonged Daptomycin and 24 h persistent effects Ketolides AUC/MIC (Should be > 125) Time dependant Carbapanems Maximize duration T/MIC (at least 40–50% killing Cephalosporins of exposure of the dosing interval) Erythromycin Linezolid Penicillin Time dependent Azithromycin Maximize amount 24 h AUC/MIC killing and moderate Clindamycin of exposure to prolonged persistent Oxazolidinones effects Tetracyclines Vancomycin

TABLE 2 The probability of attaining PK-PD target measures when using piperacillin-tazobactam Regimen Probability of PK-PD target measures 30% 40% 50% 60% 70% E. coli 3.375 g every 4 hours 0.96 0.92 0.9 0.86 0.77 3.375 g every 6 hours 0.91 0.86 0.73 0.50 0.28 K. pneumoniae 3.375 g every 4 hours 0.77 0.72 0.65 0.57 0.48 3.375 g every 6 hours 0.69 0.57 0.43 0.29 0.16

lactamase producing phenotypes. For example, giving P-T at a dose of 3.375 g every 6 hours had a 73% probability of achieving concentrations greater then MIC against E. coli for 50% of the dosing interval. This increased to 90% if the same dose was given every 4 hours. Studies have also suggested that giving meropenem as an over 4 hours as compared to a bolus doses reduces the risk of failure and a retrospective Japanese study showed a significant difference in mortality. For beta lactam, antibiotics increasing the dose so as to increasing Cmax more than 4 times MIC does not usually result in achieving greater killing. 3. A third type of killing is for drugs such as azithromycin which depends primarily on the total exposure of the organism of the drug and the 24 h AUC/MIC is the main determinant which should be more than 100. 26 Rational Antimicrobial Practice in Pediatrics

CONCLUSIONS There are several proof of concept studies that have suggested that the application of PK-PD principles to the use of antibiotics results in improved efficacy and decreases the risk of resistance since the exposure to the antimicrobial is not suboptimal. However one parameter that is important in this relationship of PK and PD is the MIC of the offending pathogen. As newer antimicrobial agents are developed, investigating the PK-PD has become an integral part of the drug development process.

 RECOMMENDED READING 1. Barker CI, Standing JF, Turner MA, McElnay JC, Sharland M. Antibiotic dosing in children in Europe: can we grade the evidence from pharmacokinetic/pharmacodynamic studies—and when is enough data enough? Curr Opin Infect Dis. 2012;25:235-42. 2. Cooper TW, Pass SE, Brouse SD, Hall Ii RG. Can Pharmacokinetic and Pharmacodynamic Principles Be Applied to the Treatment of Multidrug-Resistant Acinetobacter? Ann Pharmacother. 2011;45:229- 40. 3. Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics in otitis Media. Pediatr Inf Dis J. 1995;15:255-9. 4. Ebert SC. Application of pharmacokinetics and pharmacodynamics to antibiotic selection. P and T. 2004;29:244-53. 5. Frimodlt Moller N. How predictive is PK/PD for antibacterial agents. Int J Antimicrob Agents. 2002;19:333-39. 6. Itabashi S. Clinical efficacy of prolonged (4 hours) drip infusion of meropenem against severe pneumonia. Jpn J Antibiot. 2007;60:161-70. 7. MacGowan A. Revisiting Beta-lactams—PK/PD improves dosing of old antibiotics. Curr Opin Pharmacol. 2011;11:470-6. 8. Martinez MN, Papich MG, Drusano GL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother. 2012;56:2795-805. 9. Ryback MJ. Pharmacodynamics: Relation to antimicrobial resistance. Am J Infection Control. 2006;34:S38-45. Penicillins, Monobactams and Beta Lactam-Beta Lactamase Inhibitor 27 44 Penicillins, Monobactams and Beta Lactam-Beta Lactamase Inhibitor Combinations Raju C Shah, Pratima Shah, Pradnya Gadgil

Beta lactam antibiotics are antibiotics possessing a beta lactam ring and include penicillins, cephalosporins, monobactams and carbapenems.

 PENICILLINS Introduction Penicillin was the first antibiotic to be used clinically in 1941. It was originally obtained from the fungus Penicillium notatum but the present source is Penicillium crysogenum. The penicillin nucleus consists of a fused thiazolidine and beta lactam ring to which side chains are attached through an amide linkage. Different side chains can be attached resulting in different semisynthetic penicillins with unique antibacterial activities and different pharmacokinetics. At the carboxyl end of thiazolidine ring, salts may be formed with Na+ and K+, which impart stability.

Mechanism of Action All beta lactam antibiotics interfere with the synthesis of bacterial cell wall. Bacterial cell wall is made of UDP-N-acetyl muramic acid (NAM) and UDP-N-acetyl glucosamine. These peptidoglycan residues are linked together forming long strands. The final step is cleavage of the terminal D-alanine of the peptide chain by transpeptidase, which then facilitates cross-linking of the peptide chains thus providing stability and rigidity to the cell wall. This transpeptidase is inhibited by beta lactam antibiotics hence producing cell wall deficient (CWD) forms, which are prone to lysis. 28 Rational Antimicrobial Practice in Pediatrics

The cell wall of gram-positive bacteria is almost entirely made of peptidoglycan in comparison to gram-negative bacteria, which explains why penicillin is more effective against gram positive bacteria. Blood, pus, tissue fluid do not interfere with the antibacterial action of beta lactam antibiotics.

Penicillin-G (Benzyl Penicillin) There are four types of natural penicillins designated F, G, X and K. Out of these, penicillin-G (PnG) has a benzyl side chain, and has the most desirable properties and is used clinically.

Antibacterial Spectrum PnG is narrow spectrum antibiotic; activity is limited primarily to gram-positive bacteria and few others. Streptococci (except enterococci) are highly sensitive. Most strains of S. aureus are resistant. Gonococci and to some extent meningococci have developed partial or high degree of resistance. Most of the gram-positive bacilli are highly sensitive. Most of the gram-negative bacilli, M. tuberculosis, rickettsiae and Chlamydia are resistant.

Bacterial Resistance Two types: • Natural: This is due to deeper location of PBP’s under lipoprotein barrier where PnG is unable to penetrate. • Acquired: It is mainly by production of penicillinase enzyme, which opens the beta lactam ring and inactivates PnG. It is acquired through a plasmid by conjugation or transduction. 2nd mechanism is that bacteria develop low affinity PBP’s, which do not bind to penicillin tightly. 3rd mechanism is either loss or alteration in porin channels in cell wall, which transport the antibiotics.

Pharmacokinetics PnG is acid labile. The oral absorption is poor and infants who have low acidity absorb only one third of the dose. It reaches most body fluids but penetration in serous cavities and CSF is poor. It is poorly metabolized and rapidly excreted by kidney, 10% by GFR and rest by tubular secretion. Neonates have imperfect tubular secretion so t1/2 is longer which reaches adult levels by 3 months of age.

Adverse Effects 1. Local irritancy and direct toxicity: Pain at IM injection site, nausea on oral intake and thrombophlebitis of injected vein are dose related expression of irritancy. Large accidental IV injection can cause CNS signs/symptoms. 2. Hypersensitivity: An incidence of 1–10% is reported. Frequent manifestations are rashes, itching, urticaria and fever, anaphylaxis rare (1 to 4/10,000). Allergy is more after parenteral rather than oral route. Allergy is higher with procaine penicillin and the course of allergy is unpredictable. There is partial cross-sensitivity between different Penicillins, Monobactams and Beta Lactam-Beta Lactamase Inhibitor 29

types of penicillins. An intradermal test using benzylpenicilloyl polylysine is done to rule out immediate type of hypersensitivity. 3. Superinfections: Rare due to narrow spectrum. 4. Jarisch-Herxheimer reaction: It occurs in syphilitic patients. It last for 12–72 hours does not recur and does not need interruption of therapy.

Preparations and Dose Sodium penicillin G (Crystalline PnG) injection. Usual dose 100,000–250,000 units/kg/ day q 4–6 hourly IV or IM (maximum dose 400,000 units/kg/day, 24 million units). Potassium penicillin G for oral use Repository PnG injection: Given deep IM, releases PnG slowly 1. Procaine PnG injection: Levels are sustained for 1–2 days. Usual dose is 50,000 units/kg/day q 24 hourly IM. 2. Benzathine penicillin G: Levels are sustained for weeks. Dose is 600,000–12,00,000 units IM every 3-4 weeks.

Therapeutic Uses • PnG retains its place as the drug of choice for syphilis, anthrax, diphtheria, rat bite fever, erysipeloid, tetanus, trench mouth, actinomycosis and gas gangrene. • PnG remains the drug of choice for treatment of infections caused by sensitive strains of S. pneumoniae particularly pneumonia. In high doses it works well against intermediate resistant Streptococcus pneumoniae as well. • It is universally effective against Group A beta hemolytic streptococcal infections such as streptococcal pharyngitis, scarlet fever and invasive infections. Three weekly benzathine penicillin is the agent of choice for rheumatic fever prophylaxis. It is also useful for treatment of viridans streptococcal infections such as endocarditis if the isolate is penicillin sensitive. • Most anaerobes are sensitive to PnG with exception of B. fragilis. It is useful drug for periodontal infections, lung and brain abscess. • PnG was till recently the drug of choice for meningococcal infections but it does not eliminates the carrier state and there are reports of increasing resistance in meningococci. • PnG is no longer the therapy of choice, unless it is known that gonococcal isolates of particular geographical area are susceptible. • It is effective against Lyme’s disease but tetracyclines are the drugs of choice.

Semisynthetic Penicillins The aims of producing semisynthetic penicillins have been to overcome the shortcomings of PnG, which are: 1. Poor oral efficacy 2. Susceptibility to penicillinase 3. Narrow spectrum of activity 30 Rational Antimicrobial Practice in Pediatrics

Classification 1. Acid resistant alternatives to PnG: (penicillin V) 2. Penicillinase resistant penicillins: Methicillin, oxacillin, , nafcillin 3. Extended spectrum penicillins: a. Amino/penicillins: Ampicillin, amoxycillin, b. Carboxypenicillins: , c. Ureidopenicillins: , piperacillin d. 4. Combinations of penicillins with beta lactamase inhibitors such as , sulbactam and tazobactam.

Phenoxymethylpenicillin (Penicillin V) It is acid stable and hence oral bioavailability is better. The antibacterial spectrum of Penicillin V is identical to PnG, but it is about 1/5th the potency of PnG against Neisseria, other gram-negative bacteria and anaerobes. It is commonly prescribed for treatment of streptococcal pharyngitis and for prophylaxis in patients with asplenia and hyposplenia. Usual dose is 25–50 mg/kg/day q 6–8 hourly (maximum dose 3 gm/day). Penicillinase Resistant Penicillins Methicillin It is highly penicillinase resistant but not acid resistant. The main therapeutic indication is infection caused by penicillinase producing staphylococci. Hematuria, albuminuria and reversible interstitial nephritis are unique adverse effects and it has largely been replaced by cloxacillin.

Cloxacillin Highly penicillinase and acid resistant. Oral bioavailability is however variable. It is more active than methicillin against penicillinase producing staphylococci. It is the most commonly used drug for treating staphylococcal infections in India. Usual dose is 50–100 mg/ kg/day q 6 hourly IV or oral. For serious infections dose can be increased to 200 mg/ kg/day given 4 hourly (maximum dose 12 gm/day).

Nafcillin It is penicillinase resistant and only partially acid resistant. Hepatitis and neutropenia are occasional side effects.

Therapeutic Indication of Penicillinase Resistant Penicillins These agents, in general, are less effective against organisms susceptible to PnG and are not useful against gram-negative organisms. Their use should be restricted to the treatment of infections that are known or suspected to be caused by methicillin sensitive staphylococcal (MSSA) infections. Owing to their narrow spectrum of action they are the drugs of first choice for MSSA. Penicillins, Monobactams and Beta Lactam-Beta Lactamase Inhibitor 31

Aminopenicillins Ampicillin It is active against all organisms sensitive to PnG; additionally many gram-negative bacilli, e.g. H. influenzae, E. coli, Proteus, Salmonella and Shigella are inhibited. It is not penicillinase resistant. There is increasing prevalence of resistance to ampicillin in Shigella, H. influenzae, Moraxella catarrhalis and S. pneumoniae. Oral absorption is adequate. Diarrhea is frequent and it alters intestinal flora owing to its broad spectrum. It produces high incidence of rashes (10%) especially in patients with infectious mononucleosis. Proben acid retards normal excretion of ampicillin. Usual childhood dose is 100–200 mg/kg/day q 6 hourly IV/IM or oral. For meningitis the dose is 200–400 mg/kg/day q 4-6 hourly IV. A fixed dose combination of ampicillin and cloxacillin is available and used frequently. This combination is not synergistic since cloxacillin is not active against gram negative organisms and ampicillin is not active against staphylococci. Thus, for any given infection one of the component is useless and adds to cost and adverse effects.

Bacampicillin It is a prodrug of ampicillin. Tissue penetration is better and incidence of diarrhea is claimed to be lower.

Amoxicillin It is close congener of ampicillin similar to it in all respects except that oral absorption is better, incidence of diarrhea is less and it is less active against Shigella. Usual childhood dose is 25–50 mg/kg/day q 8 hourly oral. For suspected penicillin resistant Pneumococcus a higher dose of 80–90 mg/kg/day is recommended.

Therapeutic Indications for Aminopenicillins • Pediatric respiratory infections: They are first line drugs for management of otitis media, bacterial sinusitis, streptococcal pharyngitis and community acquired pneumonia. However, since they are not penicillinase resistant they do not cover beta lactamase producing organisms such as H. influenzae and M. catarrhalis. With increasing prevalence of resistance in S. pneumoniae, ampicillin/amoxicillin in standard doses may be ineffective. Hence, using a beta lactamase inhibitor or increase in dose may be required for severe/unresponsive infections. • Pediatric urinary tract infections: Rising incidence of beta lactamase production in E. coli and Klebsiella has reduced the utility of these drugs for this indication. • Enteric fever: With return of sensitivity in S. typhi/paratyphi, ampicillin in doses of 100 mg/kg may be considered for out-patient therapy. However, tolerability to high doses is a problem. • Treatment and prophylaxis of infective endocarditis. • Drug of choice for Listeria and group B streptococcal disease 32 Rational Antimicrobial Practice in Pediatrics

• The use of aminopenicillins in therapy of serious community acquired infections such as meningitis, neonatal sepsis, upper UTI, severe pneumonia, intrabdominal sepsis has been largely replaced by third generation cephalosporins.

Carboxypenicillins and Ureidopenicillins Carbenicillin It is neither penicillinase resistant nor acid resistant. It is, however, very active against Pseudomonas aeruginosa and indole positive proteus. High doses are associated with bleeding due to platelet dysfunction. Dose is 400–600 mg/kg/day q 4-6 hourly IV or IM.

Ticarcillin It is more potent than carbenicillin against Pseudomonas. Like carbenicillin is susceptible to penicillinase, has a high sodium load and also interferes with platelet aggregation. Usual dose is 200–400 mg/kg/day q 4–6 hourly IV. In cystic fibrosis higher doses of 400–600 mg/kg/day have been used.

Piperacillin It’s antipseudomonal activity is 8 times more than carbenicillin. Usual dose is 200–300 mg/kg/day q 4-6 hourly IV (maximum dose is 24 gm/day).

Therapeutic Indications of Antipseudomonal Penicillins These agents are indicated for treatment of patients with serious infections caused by gram-negative bacteria such as Pseudomonas, indole positive Proteus, Enterobacter. They are relatively less effective against E. coli and Klebsiella as compared to third generation cephalosporins. These mainly include nosocomial infections, infections in burns patients and the immunocompromised. However, with the increasing prevalence of extended spectrum beta lactamases and Amp C beta lactamases they have lost most of their utility unless combined with beta lactamase inhibitors.

 BETA LACTAM ANTIBIOTICS/BETA LACTAMASE INHIBITOR COMBINATIONS The efficacy of beta lactam antibiotics has been seriously hampered with the emergence of bacteria producing beta lactamase. Hence the combination of beta lactam antibiotics with beta lactamase inhibitor drugs has proved to be an easy and efficient way of tackling bacterial resistance and improving clinical efficacy. Beta lactamase inhibitors act by binding and inactivating the beta lactamase, hence protecting the beta lactam antibiotic from hydrolysis. They also potentiate the activity of the beta lactam antibiotic by binding directly to the penicillin binding proteins. Some like sulbactam also have moderate intrinsic antibacterial activity. Three beta lactamase inhibitors are currently available—clavulanic acid, sulbactam and tazobactam. Their combinations are discussed here. Penicillins, Monobactams and Beta Lactam-Beta Lactamase Inhibitor 33

Amoxicillin/Clavulanic Acid Amoxicillin/clavulanate is a broad spectrum antibacterial combination that has been used widely for over 2 decades for treatment of respiratory tract infections.

Antibacterial Spectrum Gram-positive spectrum includes streptococci spp, beta lactamase producing strains of S. aureus and Enterococcus species. Gram-negative spectrum includes the first generation beta lactamase producing strains of Escherichia coli, Klebsiella spp, Proteus spp, H. influenzae, Moraxella catrrhalis, Bacteroides fragilis and Neisseria gonorrhoeae.

Pharmacokinetics The combination ratio varies from 1:2 to 1:6 (amoxicillin: clavulanic acid). Amoxicillin and clavulanic acid are both well absorbed from the gastrointestinal tract, reaching peak serum levels 60–90 and 40–120 minutes respectively after separate oral administration. Combining the two drugs does not affect their pharmacokinetics. Amoxicillin demonstrates linear pharmacokinetics. Its penetration into respiratory tract secretions is greater than those of ampicillin at peak serum concentrations of each. Also the levels of clavulanic acid in the respiratory tract secretions are comparable to those of amoxicillin despite the obvious dose difference. The elimination half lives of amoxicillin and clavulanic acid are also similar. Amoxicillin is excreted in the urine mostly unmetabolized whereas clavulanic acid is excreted via the feces, urine and lungs.

Indications • Respiratory tract infections including otitis media, sinusitis, recurrent streptococcal pharyngitis and uncomplicated community acquired pneumonia, exacerbations of chronic bronchitis • Skin and soft tissue infections • Oral, dental infections, infections following animal bites.

Dosage • Oral—20–40 mg/kg/day of the amoxicillin component in 2–3 divided doses (maximum 3 g daily) • Intravenous—50–100 mg/kg of the amoxicillin component daily in divided doses 6–8 hourly.

Adverse Effects Gastrointestinal side effects include nausea, vomiting, diarrhoea; rarely pseudomembranous colitis. Clavulanic acid increases the risk of diarrhea and preparations with lesser amount of clavulanic acid are now available. Other side effects include rashes; hypersensitivity reactions; cholestatic jaundice; changes in liver function tests. 34 Rational Antimicrobial Practice in Pediatrics

Piperacillin-Tazobactam Piperacillin is a potent, broad-spectrum . Tazobactam is a triazolymethyl penicillanic acid sulphone -lactamase inhibitor.

Antibacterial Spectrum Gram-negative spectrum includes beta lactamase and extended spectrum beta lactamase producing Pseudomonas aeruginosa, Enterobacteriaceae spp., Escherichia coli, Klebsiella pneumoniae, Proteus spp, Salmonella spp, Shigella spp, Haemophilus influenzae, Neisseria gonorrhoeae. Gram-positive spectrum includes beta lactamase producing S. aureus, Staphylococcus epidermidis, Streptococcus spp and Enterococcus faecalis. It has excellent gram-positive and gram-negative anaerobic coverage. It is not effective against Amp C and metallo beta lactamase producing strains of gram-negative bacilli.

Pharmacokinetics and Pharmacodynamics It is conventionally used in a ratio of 8:1. The pharmacokinetics of piperacillin combined with tazobactam are similar to those of piperacillin alone. In contrast, tazobactam administered with piperacillin achieves higher plasma concentrations and has a longer half-life than tazobactam administered alone. Within 30 minues of infusion, piperacillin/ tazobactam achieves 16-85% of plasma concentrations in skin, muscle, lung, gallbladder, and intestinal mucosa. Plasma and tissue levels remain above the MIC90s of major pathogens for 2 hours postadministration.

Dosage Usual dose is 150–400 mg/kg/day of piperacillin given 6-8 hourly as intravenous injection over 3–5 minutes or by intravenous infusion over 30 minutes. Maximum dose is 4.5 g every 6 hours. There is some evidence that continuous infusions of piperacillin tazobactam are superior to intermittent infusions and may be indicated in therapy of infections due to multidrug resistant pathogens when other therapeutic options are not available.

Adverse Effects Allergic reactions including rash and eosinophilia. Each gram provides 1.9 mEq of sodium and can produce sodium overload. In large doses can cause serum sickness like reactions. Painful when given intramuscularly. Can produce elevation of liver enzymes. It can cause false-positive tests for aspergillosis by galactomannan estimation.

Ticarcillin-Clavulanate Ticarcillin-clavulanic acid was one of the first beta lactam antibiotic—beta lactamase inhibitor combination made available for parenteral use. Penicillins, Monobactams and Beta Lactam-Beta Lactamase Inhibitor 35

Antibacterial Spectrum Gram-positive spectrum includes S. aureus (methicillin sensitive), S. epidermidis and Streptococcus spp. Gram-negative spectrum includes beta lacatamase producing H. influenzae, Moraxella catarrhalis, B. fragilis, Neisseria gonorrhoeae and extended spectrum beta lactamase producing Escherichia coli, Klebsiella spp, Proteus spp. It has moderate anti-Pseudomonas activity. It has unique activity against Stenotrophomonas maltophilia.

Pharmacodynamics/Pharmacokinetics Concomitant administration of both substances has little effect on the kinetics of either agent alone. It is used in a ratio of 15-30:1. The mean serum half-lives are 1 hour for both drugs. The dose of ticarcillin needs adjustment if creatinine clearance is less than 60 mL/min as it is mainly excreted by the kidneys. But increasing the dosing interval in patients with end-stage renal disease may lead to periods of insufficient clavulanic acid to protect ticarcillin from beta lactamase degradation. Both drugs achieve adequate levels in body fluids such as blister fluid, bone, bile and joint fluid.

Dosage Intravenous 80 mg/kg of ticarcillin every 6–8 hours (every 12 hours in neonates).

Adverse Effects Rash, allergic reactions, eosinophilia. Painful if given intramuscularly. Each gram provides 5–6 mEq of sodium and can produce sodium overload. Interferes with platelet aggregation and can cause elevation of live enzymes and hemorrhagic cystitis (more frequent in children).

Cefoperazone-Sulbactam -sulbactam is traditionally available in ratios of 2:1 or 1:1. Not FDA approved for use in the United States. As with other beta lactamase inhibitors, sulbactam irreversibly inhibits beta lactamases via acyl-enzyme complex formation. This allows cefoperazone to exhibit time dependent bacterial killing by binding to PBP-1 and -3 receptors. Sulbactam also possesses intrinsic antibacterial activity, exerted through PBP-2 targets. This property proves to be of great value in infections caused by Acinetobacter species. Sulbactam and cefoperazone are mainly excreted via urine. Sulbactam also distributes well in body fluids and tissues though data about CNS penetration is insufficient as yet. The main side effects of cefoperazone sulbactam include hypersensitivity, interference with platelet aggregation, hypoprothrombinemia and elevation of liver enzymes.

Cefepime Tazobactam Cefepime tazobactam is a relatively new beta lactam-beta lactamase inhibitor combination. It is available in a ratio of 8:1 (1 g of cefepime with 125 mg of tazobactam). The drug 36 Rational Antimicrobial Practice in Pediatrics is not FDA approved. It is purported to be a superior beta lactam-beta lactamase combination since cefepime is more stable than other third generation cephalosporins against Amp C. In vitro studies from India show superior sensitivity of various gram-negative bacteria to cefepime tazobactam as compared to other BL-BLI’s like piperacillin tazobactam and cefoperazone sulbactam. Clinical efficacy is yet to be established.

Therapeutic Uses of Piperacillin Tazobactam, Ticarcillin Clavulanate, Cefoperazone Sulbactam and Cefepime Tazobactam Their main use is in empirical treatment of suspected polymicrobial infection, especially those with beta lactamase producing organisms, pending susceptibility results. These include nosocomial infections (catheter related blood stream infections, ventilator associated pneumonia, catheter related urinary tract infections, surgical site infections), nosocomially acquired neonatal sepsis, infections in immunocompromised especially febrile neutropenia and serious polymicrobial community acquired infections such as intra-abdominal and pelvic infections. Addition of metronidazole to the treatment regimen is not required. They should not be used to treat CNS infections as the penetration of the beta lactamase inhibitor in the CNS is suboptimal. It should be remembered that beta lactam and beta lactamase inhibitor combinations are not the drugs of choice for treating serious infections due to ESBL producing organisms. This is because of the inoculum effect whereby the MIC of the organism increases with increasing bacterial load and, coexistence of other mechanisms of resistance such as Amp C in gram-negative bacteria which make these combinations ineffective and less published experience. Serious infections due to ESBL producing organisms should be treated with carbapenems and these combinations reserved for nonserious infections where organism burden is less. There are no studies comparing the three combinations with each other. However, there are subtle differences between the three drugs which may help deciding choice of drug. Tazobactam is the most potent beta lactamase inhibitor for the CTX M type of beta lactamases prevalent in India. Ticar-clav has inferior Pseudomonas activity then the other two and, therefore, an inferior drug for treating nosocomial infections and infections in immunocompromised. Cefo-sulbactam causes hypoprothrombinemia and may increase ESBL prevalence in the hospital setting where it is used. The clinical superiority of cefepime tazobactam over others is yet to be established

Ampicillin-Sulbactam Another combination of sulbactam which has been in use for a while is with ampicillin.

Antibacterial Spectrum Effective against gram-positive bacteria with the exception of MRSA. Gram-negative spectrum includes extended spectrum beta lactamase producing enterobacteriaceae mainly E. coli and Klebsiella. No anti-Pseudomonas activity. Particularly effective against multi- drug resistant Acinetobacter infections. Penicillins, Monobactams and Beta Lactam-Beta Lactamase Inhibitor 37

Pharmacokinetics Ampicillin-sulbactam is used in a ratio of 1.5-2: 1. Protein binding is 28% for ampicillin and 38% for sulbactam. These drugs are eliminated primarily by the kidney, and their elimination may be decreased in neonates as a consequence of underdeveloped renal function. For the same reason dose modification is required in renal failure. Pharmacokinetic studies have demonstrated high drug concentrations at a variety of infection sites, including cerebrospinal fluid, peritoneal fluid and bone.

Dosage 100–200 mg/kg/day of ampicillin in 6 hourly doses; total dose of sulbactam should not exceed 4 g/day.

Indications May be used for empirically treating serious community acquired polymicrobial infections such as intra-abdominal, soft tissue and pelvic infections. This drug is not appropriate as empirical therapy for nosocomial and infections in immunocompromised where Pseudomonas is a possibility. It can be used once culture and sensitivity results are available especially when the culprit is Acinetobacter.

Indigenous BL-BLI Combinations In India many indigenous combinations are available now. These include combinations of clavulanate with , , cefixime and cefpodoxime; combination of sulbactum with ceftriaxone, cefepime and carbapenems; combination of tazobactam with cefotaxime and ceftriaxone. The problems associated with these products are manifold 1. They have been launched without adequate research into pharmacokinetic compatibility of the partner drugs and clinical efficacy. 2. They are being promoted for management of community acquired infections such as meningitis, enteric fever and respiratory tract infections. Most of the causative organisms for these infections do not produce resistance by production of beta lactamases (Meningococcus, Salmonella, Pneumococcus) or even if they produce beta lactamase, the beta lactam component is effective by itself (beta lactamase producing HIB is susceptible to all third generation cephalosporins). Hence addition of the BLI does not give any added advantage. Paradoxically it may cause accidental under dosing of the effective beta lactam component if the dose is calculated for the entire combination (e.g. 1 g of ceftriaxone-tazobactam has only 500 mg of ceftriaxone). Additionally, the BLI component increases side effects, cost of therapy and potentiates the development of extended spectrum beta lactamases (ESBL) mediated resistance. 3. The potential role of the parenteral BL-BLI combinations is for treatment of nosocomial infections by ESBL producing organisms. Here again the limitation is the poor activity against nosocomial pathogens such as Pseudomonas and Acinetobacter of ceftriaxone/ cefotaxime based combinations unlike the good activity of piperacillin/cefoperazone based combinations. 38 Rational Antimicrobial Practice in Pediatrics

4. Cefixime/cefpodoxime are misused widely; the addition of clavulanic acid to these drugs makes the outlook even more bleak. The only potential role of these drugs is in the out-patient management of urinary tract infections due to ESBL producing organisms, an emerging problem. More efficacy data is needed to support this indication.

 MONOBACTAMS Aztreonam Monobactams are beta lactams whose structure differs from that of other beta lactams because they contain a monocyclic nucleus. Monobactams were first isolated from Chromobacterium violaceum and modified thereafter to yield aztreonam, the only currently available .

Antibacterial Spectrum Its synthetic structure determines specific areas of activity, including enhanced activity against Pseudomonas species, exceptional activity against gram-negative bacteria, stability to first generation beta lactamases and lack of activity against gram-positive bacteria. It is not stable against extended spectrum beta lactamase producing enterobacteriaceae. It is, however, stable against the metallo-beta lactamase enzymes.

Mechanism of Action Aztreonam has a high affinity for the protein-binding protein 3 (PBP-3) of aerobic gram- negative bacteria. Most of these organisms are inhibited and killed at low concentrations of the drug. Aztreonam binds poorly to PBP sites of the aerobic gram-positive and anaerobic bacteria and consequently has relatively poor inhibitory effects against these bacteria.

Pharmacokinetics Aztreonam is widely distributed in the body tissues and fluids, and the average elimination half-life is 1.7 hours. Intramuscular dosing results in peak serum levels in approximately one hour, while intravenous dosing results in peak levels within five minutes. Concentrations above the MIC90 for most gram-negative bacteria are also present within bone, prostate and cerebrospinal fluid. Between 60 and 70 percent of the drug is excreted unchanged in the urine. Serum clearance of aztreonam is directly proportional to creatinine clearance. Dosage adjustment must, therefore, be made in the presence of reduced clearance.

Dosage 30–50 mg/kg every 6–8 hours; maximum 8 g daily.

Adverse Effects Gastrointestinal disturbances—nausea, vomiting, diarrhea, abdominal cramps; mouth ulcers, altered taste, gastrointestinal bleeding, and very rarely antibiotic-associated colitis. Penicillins, Monobactams and Beta Lactam-Beta Lactamase Inhibitor 39

Occasionally thrombocytopenia, neutropenia and hepatitis injection-site reactions, skin rash and eosinophilia may be seen.

Therapeutic Uses The main use of aztreonam is as a substitute to penicillins/cephalosporins in management of serious gram-negative infections when there is history of serious allergy/hypersensitivity to these agents. These indications include community acquired infections of the urinary tract, sepsis, intra-abdominal and gynecologic infections, nosocomial infections, febrile neutropenia, enteric fever, gonorrhea. Though the restricted antimicrobial spectrum of aztreonam is an advantage, however, concurrent initial therapy with other antimicrobial agents is recommended in patients who are seriously ill and at risk for gram-positive or anaerobic infections. The utility of aztreonam in treating nosocomial and even some community acquired infections (like UTI) is now limited due to the increasing prevalence of ESBL which destroy aztreonam. Rarely aztreonam may be used for metallo-beta lactamase producing carbapenem resistant isolates which are sensitive to aztreonam.

 RECOMMENDED READING 1. Antimicrobial agents: Penicillin, Cephalosporins and other -lactam antibiotics. In: Goodman and Gilman’s-The Pharmacological basis of Therapeutics. Hardman, Limbird (Eds). 10th edition, McGraw Hill Publishing. 2001.pp1189-1218. 2. Bush LM, Johnson CC. Ureidopenicillins and beta-lactam/beta-lactamase inhibitor combinations. Infect Dis Clin North Am. 2000;14:409-33. 3. Lee N, Yuen KY, Kumana CR. Clinical role of beta-lactam/beta-lactamase inhibitor combinations. Drugs. 2003;63:1511-24. 4. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005;18:657-86. 5. Rittenbury MS. How and why aztreonam works. Surg Gynecol Obstet. 1990;171S:19-23. 40 Rational Antimicrobial Practice in Pediatrics 55 Cephalosporins Baldev S Prajapati, Rajal B Prajapati

 INTRODUCTION Giuseppe Brotuz observed the good health of recreational bathers on heavily polluted beaches of Gulf of Cagliari on the Southern Coast of Sardinia. He studied the microbial flora of seawater near a sewage out fall and isolated a strain of Cephalosporium acremonium. This strain secreted material with activity against a number of gram-positive and gram- negative bacteria. A series of experiments by him and Professor Howard Florey of Str William Dunn School of Pathology, Oxford lead to production of the antibiotic in 1951.1 It was active only against certain gram-positive bacteria. Hence, it was called cephalosporin P. Meanwhile, another molecule was found and it was named as cephalosporin N as it was active against gram-negative bacteria. Its name was changed to penicillin N when it was found to have a structure similar to penicillin. The efforts were going on to isolate penicillin N from impurities, another substance was detected and it was named cephalosporin C. The nucleus of cephalosporin C was isolated in 1960 and it opened the doors for future research.2

Relevant Chemical Aspects All cephalosporins consist of four membered beta lactam ring bound to a six membered dihydrothiazine ring. It is called cephalosporin or cephem nucleus. It includes a carbon double bond between positions 3 and 4. Variations on the 7-acylamino side chain and substitutions on the cephem ring have yielded a variety of cephalosporin compounds with different activity profiles. For example, the presence of an Cephalosporin (Cepham) nucleus aminomethoxy group at this position as found in cefuroxime, cefotaxime and ceftriaxone confers increased beta lactamase stability with some loss of activity against gram-positive organisms.2-4 The presence of propylcarboxy Cephalosporins 41 group as in a case of at this location produces superior antipseudomonal activity.5 Substitutions at position 3 of the dihydrothiazine ring play a major role in pharmacokinetics.

Classification The explosive growth of cephalosporins makes a system of classification most desirable. Cephalosporins may be classified by their chemical structure, clinical pharmacology, resistance to beta lactamase or antimicrobial spectrum, but the well accepted system of classification by ‘Generations’ is very useful. Classification by generations is based on general features of antimicrobial activity; it also follows the sequence of their discovery.2-4,6

Mechanism of Action2-4 Like penicillins, cephalosporins act by binding to penicillin binding protein’s (PBP’s) and inhibiting bacterial cell wall synthesis. The highly stressed amide group of the beta lactam ring is conformationally similar to D–alanyl–D–alanine bond of the peptidoglycan pentapeptide. Consequently, the bacterial enzymes mistake cephalosporins for their normal substrates and react with them to yield stable covalent esters, which lack catalytic activity. This in turn interferes with normal synthesis of the peptidoglycan cover.

Mechanism of Resistance2-4 Bacterial resistance to cephalosporins is achieved by distinct mechanisms. • Inability of the drug to reach the site of action, e.g. decreased permeability through the outer membrane of gram-negative organisms. • Alterations in PBP’s. Alterations take place in antibiotic binding proteins and as a result the interaction does not take place, e.g. cephalosporin resistant pneumococci. • Beta lactamase enzymes. This is the most common mechanism. These enzymes hydrolyze the beta lactam ring. Cephalosporins are variably susceptible to beta lactamases; a good example is the relative resistance of second and third generation agents to hydrolysis by beta lactamases produced by gram-negative organisms compared to first generation agents. However, the exception is the extended spectrum beta lactamases (ESBL’s) that hydrolyze the oxyiminoside chain of cefotaxime, ceftriaxone, ceftazidime. This plasmid mediated trait is most often associated with Klebsiella pneumoniae and E. coli but can be transferred to other enteric bacilli. The Amp C group of beta lactamases classically produced by Enterobacter, Citrobacter, Serratia and Pseudomonas hydrolyze all cephalosporins with the exception of cefepime and are not inhibited by the beta lactamase inhibitors either.

Spectrum of Activity2-8 Cephalosporins can be considered as true broad-spectrum antibiotics given their wide spectrum of activity. The first generation cephalosporins have good activity against gram- positive bacteria and relatively modest activity against gram-negative organisms. The second-generation cephalosporins retain gram-positive activity and have increased activity 42 Rational Antimicrobial Practice in Pediatrics against certain gram-negative pathogens. The third generation agents are somewhat less active against gram-positive cocci, but much more active against enteric gram- negative organisms. The fourth generation cephalosporins have greater beta lactamase stability and an extended spectrum of activity against both gram-positive as well as gram-negative organisms including pseudomonas. None of the currently available cephalosporins have good activity Enterococcus, Mycoplasma, Campylobacter, Listeria and C. difficile.

Clinical Pharamacokinetics Cephalosporins formulated for oral administration have excellent bioavailability (more than 80%) with the possible exception of cefpodoxime proxetil.4 The third generation cephalosporins have exquisite antimicrobial activity and achieve sufficient concentrations for use in central nervous system (CNS) infections. These agents include cefotaxime, ceftriaxone and . Cephalosporins also cross the placenta. They are found in high concentrations in synovial and pericardial fluids. Penetration into the aqueous humor of the eye is relatively good after systemic administration of third generation cephalosporins.3-5 Cephalosporins are primarily excreted by kidney, so dosage should be altered in patients with renal insufficiency. Third generation cephalosporins specifically cefoperazone and ceftriaxone have significant biliary excretion. They are useful in the treatment of hepatobiliary infections.2-4 Biliary sludge formation by precipitated drug, especially with ceftriaxone is quite common.4 They may increase alteration of gut flora. Cefotaxime, cephalothin and cephapirin share the property of hepatic biotransformation to potentially active desacetylated compounds. These metabolites have less antimicrobial activity than their parent compounds. Only desacetyl cefotaxime contribute significantly to the microbial action of its parent compound, cefotaxime. None of the other cephalosporins appear to undergo appreciable metabolism in this way.3,4

Adverse Reactions2-4,7-9 The cephalosporins are remarkably free from major adverse reactions. Still any cephalosporins can cause anaphylactic reaction, especially in patients with a previous history of immediate hypersensitivity reaction to cephalosporin or penicillin.4 Other hypersensitivity reactions include acute interstitial nephritis, autoimmune thrombocytopenia, pulmonary eosinophilia, serum sickness like reaction, rash and drug fever. Antibiotic associated diarrhea and pseudomembranous colitis also can occur. Reversible biliary pseudolithiasis seen in children receiving large doses of ceftriaxone is due to precipitation of calcium salts of the drug and can cause transient pain but is not an indication for cholecystectomy.10-12 Ceftriaxone has been associated with rapidly fatal immune mediated hemolytic anemia in patients with underlying sickle cell and myelocytic leukemia in those who had received multiple previous courses of ceftriaxone therapy.7,9 The local side effects of cephalosporins are known in form of pain following intramuscular injection and thrombophlebitis following intravenous infusion.2 For many of the Cephalosporins 43 cephalosporins, intramuscular administration using lidocaine as a solvent is recommended by the manufacturer. Thrombophlebitis following intravenous infusion of cephalosporins can be minimized by increasing the dilution of the drug, slowing infusion rate and introducing a filter into the infusion system.4

Drug Interactions2-5 Cephalosporins containing the tetra azo lethiomethyl side chain (cefoparazone, moxalactum, ) have warfarin like activity, antiplatelet effects and disulfiram like reactions. Cephalosporins increase the risk of nephrotoxicity of other agents such as aminoglycosides, vancomycin etc. Absorption of cefpodoxime is reduced by H2 antagonist like famotidine other agents increasing gastric pH.

 SPECIFIC AGENTS First Generation Cephalosporins They are active against most gram-positive cocci including penicillinase producing and nonpenicillinase producing S. aureus, S. epidermidis, streptococci and pneumococci. These agents have limited activity against some gram-negative bacteria including E. coli, Klebsiella pneumoniae and Proteus mirabilis but not H. influenzae.5

Oral First Generation Cephalosporins2-4,5-8 The first generation cephalosporins for oral use include cephalexin, cefadroxil and cephradine. Cephalexin and cefadroxil are available in India. These agents have a similar antibacterial spectrum (detailed earlier). Cephalexin is well absorbed but due to its short half-life it requires QID dosing. Cefadroxil has a longer half-life that allows for BID administration. These agents are used in the treatment of skin and soft tissue infections and streptococcal pharyngitis. As they have some activity against E. coli, Klebsiella pneumoniae and Proteus mirabilis, these agents can be used to treat urinary tract infections caused by susceptible strains of these organisms.

Parental First Generation Cephalosporins5 The parental first generation cephalosporins (mainly ) are the drugs of choice for perioperative prophylaxis before orthopedic, vascular, cardiac and neurosurgical procedures. Additionally due to good antistaphylococcal activity cefazolin is also an alternative to cloxacillin for treatment of serious soft tissue, bone and joint infections caused by methicillin sensitive S. aureus.

Second Generation Cephalosporins The second generation cephalosporins have spectrum of activity of the first generation cephalosporins with added activity against gram-negative organisms such as H. influenzae, N. meningitidis and M. catarrhalis.5,8 44 Rational Antimicrobial Practice in Pediatrics

Cefuroxime Axetil It is available in a pediatric suspension with BID dosing schedule. This compound is an ester prodrug to facilitate its absorption, but this characteristic causes an unpleasant metallic after taste.8 Food enhances the absorption of drug in stomach. Indications include pharyngitis, otitis media, sinusitis, lower respiratory tract infections, soft tissue and urinary tract infections. This compound is useful for switch on therapy after the patient responds to initial parenteral cefuroxime therapy. Its safety and effectiveness for use in infants younger than 3 months is not established.5 It is an expensive drug.

Cefprozil has a similar spectrum to that of , but more palatable. Its safety and effectiveness has not been established in children below 6 months of age.5

Cefaclor It has a spectrum of activity similar to other second generation cephalosporins, except for its somewhat limited activity against H. influenzae, S. aureus and penicillin nonsusceptible pneumococci. has been associated with an unusual serum sickness like reaction that appears to be due to an inherited defect in the handling of metabolic products of the drug. This adverse effect, the requirement of TID dosing and the limited spectrum of activity make cefaclor a poor choice for treatment of most pediatric infections.5,7,8

Cefuroxime Among the parenteral second-generation cephalosporins, cefuroxime remains a frequent first choice for the treatment of community-acquired pneumonia in children, due to its efficacy against beta lactamase producing H. influenzae, M. catarrhalis, pneumococci and methicillin sensitive S. aureus. Cefuroxime has demonstrable CNS penetration, but its use for treatment of bacterial meningitis is associated with delayed sterilization of cerebrospinal fluid (CSF) and therefore it is not recommended for empiric treatment of bacterial meningitis in children.5,7,8

Third Generation Cephalosporins2-5,7,8 (Table 1) Third generation cephalosporins have greatly enhanced the armamentarium against serious and life-threatening neonatal and childhood infections. Third generation cephalosporins were introduced in 1980. The most widely used parenteral third generation cephalosporins are cefotaxime, ceftriaxone and ceftazidime. They are less active than first generation against gram-positive cocci. However, due to pharmacodynamic reasons ceftriaxone and cefotaxime are the only cephalosporins suitable against penicillin resistant pneumococci. They exhibit increased antibacterial activity against many gram-negative organisms like enteric bacilli, H. influenzae, N. meningitidis, N. gonorrhoeae and M. catarrhalis. Among the third generation cephalosporins, ceftazidime and cefoperazone are active against Pseudomonas aeruginosa. However, the usefulness of these agents in nosocomial infections Cephalosporins 45 has become seriously limited in current day practice due to widespread prevalence of extended-spectrum beta lactamases (ESBLs) and Amp C enzymes.

Oral Third General Cephalosporins These drugs are being increasingly prescribed for out-patient therapy of pediatric infections. However, with the risk of promoting drug resistance especially ESBLs, they must be used with great discretion and only when lesser and narrow spectrum antimicrobials will not work. Cefixime Cefixime was the first oral third generation cephalosporin to become available. Perhaps, it is the reason for its rampant use in the practice. It has poor activity against Streptococcus pneumoniae, S. aureus and Pseudomonas. It is useful in the treatment of urinary tract infections, dysentery and enteric fever. Cefixime does not work in respiratory tract infections. Broadly speaking, cefixime may be used in the infections developing below the diaphragm and not above the diaphragm. Its half-life is long and therefore can be administered in dose of 8–10 mg/kg/day once a day. For enteric fever, however, the recommended dose is 20 mg/kg/day in two divided doses for 14 days. Cefpodoxime Proxetil It is the only active ester producing third generation cephalosporin cefpodoxime. It causes an unpleasant metallic after taste.8 Unlike cefixime, it has good activity against pneumococci, streptococci and methicillin susceptible S. aureus. It is highly active against Enterobacteriaceae. It has also been found useful in enteric fever. It is used mainly for respiratory, urinary and skin and soft tissue infections.5 It is a once a day oral cephalosporin with good activity against gram-negative organisms, but not against S. aureus. Its use is limited by poor clinical efficacy against pneumococci.8 It has a broad-spectrum of antimicrobial activity against several organisms including S. pneumoniae and S. aureus. Its clinical utility is in acute otitis media, streptococcal pharyngitis, skin and soft tissue infections and uncomplicated urinary tract infections.7,8 Cefprozil It is another oral third generation cephalosporin which has antimicrobial activity almost same as cefdinir. It has been found effective in otitis media, respiratory tract infections and skin and soft tissue infections.

Parenteral Third Generation Cephalosporins Cefotaxime Cefotaxime was the first of third generation parenteral cephalosporins to become available.2 The drug has good activity against many gram-positive and gram-negative aerobic bacteria. Indications for cefotaxime include community acquired pneumonia, meningitis, mastoiditis, 46 Rational Antimicrobial Practice in Pediatrics pyelonephritis, gonorrhea and enteric fever.2-5 Its activity against S. aureus is poor and it should not be used for serious infections when this pathogen is likely. Cefotaxime is preferred to other cephalosporins in neonates because it has been used more extensively and does not compete with bilirubin for protein binding. Dose of cefotaxime for common infections is 100–150 mg/kg/day, 12 hourly or 8 hourly, but in bacterial meningitis and enteric fever, it should be used in dose of 200 mg/kg/day, 6 hourly. Ceftriaxone The distinguishing features of this cephalosporin are its longer duration of action and effectiveness in a wide range of serious infections including bacterial meningitis. It has excellent CSF penetration. Cerebrospinal fluid sterilization is more rapid with ceftriaxone compared to other cephalosporins.10 Ceftriaxone is the empirical treatment of choice in bacterial meningitis in children above the age of 2 months. Other indications are multidrug resistant typhoid fever, community acquired pneumonia, complicated urinary tract infection, abdominal sepsis and septicemia. It enjoys unique position of distinction in the treatment of multidrug resistant enteric fever.11-14 Initially, its response was obtained in 2 to 3 days in a case of enteric fever, but now it may take a longer time, 5 to 7 days. This should not be interpreted as failure of drug and one should not change the drug hurriedly. Ceftriaxone resistant enteric fever though rare has been reported in the literature. The dose of ceftriaxone is 50–100 mg/kg/day in single or two divided doses by IV or IM route. In a case of bacterial meningitis and enteric fever, ceftriaxone should be used in 100 mg/kg/day in two divided doses by IV route only. For bacterial meningitis single dose and IM route is not recommended. Ceftriaxone for IV route should not be administered as the bolus dose. The calculated amount of reconstituted ceftriaxone should be taken in 50 or 100 cc normal saline and it should be infused over 30 to 45 minutes. It may cause biliary sludging and reversible pseudolithiasis. This side effect is more common in children. The patients of enteric fever on ceftriaxone therapy on ultrasonography (USG) study of abdomen may be interpreted having gallstone due to biliary sludging and pseudolithiasis.15 They should be followed up with repeat USG study at appropriate time before labeling them having gallstone. Its affinity to bind albumin can cause displacement of bilirubin. Due to this reason, its use is restricted in neonates as it may cause or aggravate hyperbilirubinemia.5 Drug fever and skin rashes are also known. Anaphylaxis is very rare but it has been reported. Transient rise in liver enzymes is also seen in the practice. Hemolytic anemia, thrombocytopenia and leukopenia may occur due to ceftriaxone. Concomitant use of aminoglycosides and frusemide may increase the chances of nephrotoxicity, secondary candidiasis is also seen. Ceftazidime The most prominent feature of this molecule is its high activity against Pseudomonas and, therefore, it should be kept reserved for this organism. Ceftazidime has been found more active in vitro against Pseudomonas than cefoperazone or piperacillin.5,7,8 However, ceftazidime is significantly less active than either cefotaxime or ceftriaxone against penicillin nonsusceptible pneumococci limiting its use in treatment of pneumonia. Ceftazidime has Cephalosporins 47 been specifically used in febrile neutropenia, burns, cystic fibrosis, etc.5,7,8 Its use should be restricted to situations where pseudomonas is the likely organism. Cefoperazone Like ceftazidime, it differs from other third generation cephalosporins in having stronger activity on pseudomonas. It is also good for S. typhi and B. fragilis. Its indications are febrile neutropenia, biliary infections, septicemia, complicated urinary tract infections, etc. It has been found effective also in multidrug resistant enteric fever.5,13 It can cause bleeding due to hypoprothrombinemia which can be reversed by administration of vitamin K.2,9 It has poor CSF penetration and should not be used for meningitis. A combination of cefoperazone with sulbactam is available for treatment of extended-spectrum beta lactamase (ESBL) infections. Ceftizoxime It has antibacterial action similar to cefotaxime with superior gram-positive activity and antipseudomonal activity. It has been found useful in bacterial meningitis.5

Combinations of Third Generation Cephalosporins with Probiotics16 The combinations of lactobacillus with cefixime and cefpodoxime are available in Indian market and are used rampantly in the practice without any scientific basis. The routine addition of a probiotic to an antibiotic is irrational. Role of routine supplementation of an antibiotic with a probiotic to prevent antibiotic associated diarrhea is uncertain. The dose of probiotic for prevention of antibiotic associated diarrhea is quite high which is lacking with the combinations. The pharmacokinetic compatibility of both the molecules has not been demonstrated. None of these products have been approved for use in any developed country.

Fourth Generation Cephalosporins (Table 1) These include cefepime and . Both are dipolar ionic compounds that diffuse more rapidly in gram-negative bacteria and are poor inducers and substrates for beta lactamases.5,7,8

Cefepime Cefepime has gram-positive coverage similar to cefotaxime and ceftriaxone and excellent gram-negative activity. Its antipseudomonal activity is comparable to ceftazidime. Most importantly it is more stable as compared to the third generation cephalosporins against ESBL producing E. coli and Klebsiella and Amp C producing Pseudomonas, Enterobacter Citrobacter and Serratia. However, it exhibits an inoculum effect, i.e. the MIC to cefepime rises with rising bacterial load. Cefepime is indicated in severe respiratory tract infections, skin and soft tissue infections, bacterial meningitis, complicated urinary tract infections,5,7,8,17,18 intra-abdominal infections, sepsis, neonatal septicemia, osteomyelitis, septic arthritis, etc. It may also be used for empirical therapy for resistant gram-negative infections such as nosocomial infections, 48 Rational Antimicrobial Practice in Pediatrics

TABLE 1 Dosage of third and fourth generation cephalosporins Molecule Dose mg/kg/day Route of administration Interval Cefixime 8 Oral Single dose For typhoid: 20 Oral 12 hourly Cefpodoxime proxetil 10 Oral 12 hourly Cefdinir 14 Oral 12 hourly Ceftibuten 9 Oral Single dose Cefprozil 15–20 Oral 12 hourly Cefotaxime 100–150 IV/IM 8 hourly Bacterial IV/IM 6 hourly Meningitis: 200 Ceftriaxone 50–100 IV/IM Single dose or Bacterial meningitis 12 hourly and typhoid:100 12 hourly Ceftizoxime 50–200 IV/IM 6–8 hourly Cefoperazone 50–100 IV/IM 8–12 hourly Ceftazidime Newborn: 100 IV/IM 6–8 hourly Children: 150–200 Cefepime 100 IV/IM 12 hourly Cefpirome 50–100 IV/IM 12 hourly infections in immunocompromised patients, febrile neutropenia and cystic fibrosis.19 However, because of the inoculum effect it should not be used for serious infections due to suspected ESBL and Amp C producing strains. In this scenario only carbapenems should be used. Cefepime has no any added advantage over cefotaxime or ceftriaxone in bacterial meningitis. The dose of cefepime is 50 mg/kg 12 hourly and 50 mg/kg 8 hourly in severe infections. It has been approved in patients older than 2 months. Bactericidal activity is synergistic when combined with aminoglycosides. It may cause phlebitis, headache, blurred vision, rash, urticaria, fever and GI tract disturbances. Transient elevation of hepatic enzymes is known.

Cefpirome Cefpirome is another fourth generation cephalosporin. It is potentially useful agent for therapy of childhood bacterial meningitis because of enhanced activity against pneumococci and good penetration into the CSF.20 In view of the almost similar efficacy of third generation cephalosporins and fourth generation cephalosporins for most severe community acquired infections and limitations of the fourth generation cephalosporins for severe nosocomial infections (due to inoculum effect) the fourth generation cephalosporins have not really broken any new ground in treatment of bacterial infections.

Emerging Cephalosporins21 The development of bacterial resistance to cephalosporins has fuelled growing need for new drugs to treat the emerging resistant organisms. There are several organisms Cephalosporins 49 that have been recognized as presenting serious threats as methicillin resistant staphylococci, ESBL producing E. coli and Klebsiella species, Acinetobacter species, Pseudomonas aeruginosa, vancomycin resistant Enterococcus faecium. The fifth generation cephalosporins combine the activity of third and fourth generation cephalosporins with the first documented in vitro activity of any beta lactam agent against community acquired methicillin resistant Staphylococcus aureus. These agents have been designed to bind to and inactivate PBP2a, which confers resistance to MRSA to all other currently available beta lactam agents. Ceftaroline and are two new agents.22,23 Ceftobiprole menogaril is the first member of a new series of advanced cephalosporins with activity against MRSA. The drug received an approvable letter from United States Food and Drug Administration (FDA) in March 2008 and from Health Canada in June 2008 for the treatment of complicated skin and skin structure infections including diabetic foot infections. Ceftaroline is a broad-spectrum cephalosporin currently under clinical investigation for the treatment of complicated skin and skin structure infections including those caused by MRSA and community acquired pneumonia.22,23

 REFERENCES 1. Abraham EP. Cephalosporins 1945-86. Drugs 1987;34:1-14. 2. Hathi GS. Cephalosporins Today in Recent Advances in Pediatrics. Gupte S (Ed). Jaypee Brothers Medical Publishers (P) Ltd. New Delhi, 1994;4:357-82. 3. Tripathi KD. Essentials of Medical Pharmacology, 5th edition. Jaypee Brothers Medical Publishers (P) Ltd. New Delhi, 2003;662-7. 4. Mandell GL, Sande MA. The Cephalosporins. In: The Pharmacological and basis of therapeutics: Goodman and Gilman (Eds), et al. 8th edition. Pergamon Press, New York, 1991:1085-92. 5. John S, Jason S. Antimicrobial Agents. In: Principles and Practice of Pediatric Infectious Diseases, Long SS, Pickering LK, Prober CG (Eds). 3rd edition, Elsevier, Churchill Livingstone, 2008;1420-60. 6. Goldberg DM. The Cephalosporins. Med Clin North Am. 1987;71:1113-33. 7. Bowlware KL, Stull T. Antimicrobial agents in pediatrics. Infect Dis Clin N Am. 2004;18:513-31. 8. Update on cephalosporins in pediatrics. In clinical updates in pediatric infectious disease. Published by National Foundation for Infectious Diseases, 2001;4(1). 9. Norrby SR. Side effects of cephalosporins. Drugs. 1987:34(Suppl.2):105-20. 10. LeBel MH, Joyt MJ, McCracken GH Jr. Comparative efficacy of ceftriaxone and cefuroxime for treatment of bacterial meningitis. J Pediatr 1994;114:1049-54. 11. Gupta AK, Wadwa A, Anand NK. Ceftriaxone. Indian Pediatr. 1990;27:381-3. 12. Heim-Duthoy KL, Caperton EM, Pollock R, et al. Apparent biliary pseudolithiasis during ceftriaxone therapy Antimicrobs Agents Chemother. 1990;34:1146-9. 13. Gulati S. Maruwala RK, Singhi S, et al. Third generation cephalosporins in multidrug resistant typhoid fever. Indian Pediatr. 1992;29:513-16. 14. Mishra S, Niranjan S, Kumar H, et al. Cefriaxone: Use in multidrug resistant typhoid fever. Indian Pediatr. 1993;30:67-70. 15. Schaad UB, Wedgewood—Kruco J, et al. Reversible ceftriaxone associated biliary pseudolithiasis in children. Lancet. 1988;2:1411-13. 16. Singhal T. Irrational fixed dose antibiotic combinations. In: Shivananda, Yewale V, Prajapati B, Kundu R (Eds) : Rational Antimicrobial Therapy—Desktop reference Manual Mumbai : IAP Infectious Disease Chapter Publication. 2009;57. 17. Saez LX, O’ryan M. Cefpime in the empiric treatment of meningitis in children. Pediatr Infec Dis. 2001;20:356-61. 50 Rational Antimicrobial Practice in Pediatrics

18. Kurchavov VA, Beloborodeva NV, Biriukov AV, Vostrikova Tlu, Rogatina EL, Krutskikh EN. The comparative activity of cefepime and other current antibiotics against microorganisms isolated from patients in pediatric intensive therapy units. Antibiot. Khimifer. 1999;44:23-30. 19. Chunag YY, Hung IJ, Yang CP, et al. Cefepime versus ceftazidime as empiric monotherapy for fever and neutropenia in children with cancer. Pediatr Infect Dis J. 2000;21:203-9. 20. Wakiguchi H, Fujieda M, Maecta A, Shimazaki Y, Ohishi N, Takechi T, et al. Clinical efficacy of cefpirome against various infectious diseases in children. Jpn J Antibiot. 1991;44:241-5. 21. Malcolm GP. Anti-infectives Emerging Cephalosporins. Drugs. 2007;12(4):511-24. 22. Zhanel GG, Sniezek G, et al: Ceftaroline : A novel broad-spectrum cephalosporin with activity against methizillin resistant Staphylococcus aureus. Drugs. 2009;6:809-31. 23. Vidaillac C, Ryback MJ. Ceftobiprole. First cephalosporin with activity against methicillin-resistant staphylococcus aureus. Pharmacotherapy. 2009;29:511-25. Carbapenems 51 66 Carbapenems Nishant Verma, Rakesh Lodha

 INTRODUCTION Serious bacterial infections in children cause significant morbidity and mortality and need effective antimicrobial agents to combat them. With widespread use of third generation cephalosporins, there has been the emergence of strains of bacteria that produce Extended Spectrum Beta Lactamases (ESBLs) which are capable of hydrolyzing third generation cephalosporins, penicillins and aztreonam. They are most often associated with Klebsiella pneumoniae and Escherichia coli, but can be produced by other gram-negative bacilli as well. Data from AIIMS, New Delhi, shows an increasing prevalence (66.8-71.5 %) of infections due to ESBL positive bacteria.1,2 In addition to the ESBLs, certain gram negative bacteria (GNB) such as Pseudomonas, Serratia, Citrobacter and Enterobacter produce chromosomally mediated Amp C -lactamases. These hydrolyse cephalosporins and penicillins and are not inhibited by beta lactamase inhibitors. In addition, plasmid mediated Amp C -lactamases, first reported in 1988, which differ from the chromosomal Amp C in being noninducible have further complicated management of gram-negative infections. Carbapenems are the most potent class of -lactams, with stability against ESBL and Amp C chromosomal -lactamases. They have a relatively broad spectrum of activity against gram negative and gram positive organisms, including anaerobes. The commonly used members of this class of antibiotics include; imipenem and meropenem. , , , and have been the later additions to this class.

Chemistry Carbapenems are derivatives of theinamycin, a compound produced by the soil organism, cattleya, which was first discovered in 1976. Like other beta lactams, carbapenems contain a four-member lactam ring fused to a five-member thiazolidinic secondary ring through the nitrogen and adjacent tetrahedral carbon atom. The basic structure differs from that of penicillins only by the substitution of sulphur for a carbon 52 Rational Antimicrobial Practice in Pediatrics at position 1 and an unsaturated bond between C2 and C3 in the five-member ring. It is the side chains attached to this basic two-ring structure that differentiate the carbapenems from each other.

Mechanism of Action Carbapenems, like other -lactams, exhibit their bactericidal activity by binding to critical Penicillin binding proteins (PBP). This inhibits growth and also results in damage to the cell wall, thus causing cell lysis and death. This interaction occurs near the cell surface in gram-positive bacteria. However, in gram-negative bacteria, carbapenems first gain entry into the periplasmic space between the cell wall and surrounding membrane by passing through channels in the membrane that normally function to provide access for essential nutrients (Porin channels). The ability to pass through these channels, along with a high affinity for critical PBPs and resistance to a broad range of -lactamases, is thought to account for the broader spectrum of activity of carbapenems versus most other antibiotics.3 Different members of the carbapenem class exhibit a varying affinity for different PBPs, like, imipenem binds preferentially to PBP2, followed by PBP1a and 1b, and has weak affinity for PBP3, while meropenem preferentially binds to PBPs 2, 3 and 4.3

Drug Resistance To combat infections by multidrug resistant bacteria, carbapenems are amongst the last resort especially in intensive care units (ICU’s) and high risk wards. Resistance to them, is however increasing rapidly. In a study from AIIMS, which looked into the prevalence of carbapenem resistance among ESBL positive GNB isolates, it was found that 22.16% isolates were resistant to meropenem and 17.32% to imipenem. Maximum resistance was seen in pseudomonas species.4 Resistance may be mediated by the following mechanisms: a. Production of carbapenemases. These are either chromosomally encoded or plasmid- mediated metallo/serine enzymes that hydrolyze the beta lactam ring of virtually all -lactams, including carbapenems. In 2009, an increasing number of carbapenem resistant Enterobacteriaceae strains were identified in UK hospital patients, many of whom were recently hospitalized in India and Pakistan. A new type of MBL was isolated from these patients and was designated as NDM-1 (New Delhi Metallo-1).5 Data from the SMART (Study for Monitoring Antimicrobial Trends) 2009 study, which evaluated 235 ertapenem nonsusceptible isolates of Enterobacteriaceae, found that 66 (28%) isolates had a carbapenamase gene. Of these NDM-1 was identified in 33 isolates and all the NDM-1 carrying isolates were from patients in India.6 This rapid spread of NDM-1 is causing major concern in the clinical microbiology community. The increasing prevalence of Klebsiella pneumoniae carbapenemase (KPC), a serine carbapenemase worldwide is also an increasing cause for concern. b. Alteration of critical PBPs. c. Down regulation of porin channels. d. Active efflux of the drug from the cell by a multidrug efflux pump. Carbapenems 53

The resistance to carbapenems in Pseudomonas spp primarily results from mechanism (c) and (d). Though a single mutation that reduces porin channels (OprD mutants) can confer resistance to imipenem, resistance to meropenem requires two independent mutations, a mutation to reduce porin channels (OprD mutation), as well as a mutation to upregulate cellular efflux mechanisms (nalB mutation at the mexR locus).7 Consequently, the rate of selection of resistance to meropenem in vitro is lower than that for imipenem.

Pharmacokinetics All the currently available carbapenems (except Tebipenem, an oral drug approved only in Japan) are formulated as parenteral agents as they are not absorbed from the intestinal tract.8 Intravenous infusion of imipenem-cilastatin results in penetration of the drug into almost all tissues (lung, bone, skin, fascia, endometrium, myometrium) and body fluids (aqueous and vitreous humor, pleural and peritoneal fluid, bile). Meropenem has good tissue penetration and penetration studies in CSF show that at doses of 40 mg/kg, its CSF concentration is much higher than the reported MIC90 for most bacterial pathogens associated with meningitis. However, as with other -lactams, its penetration into CSF is effective only in the presence of inflamed meninges. The plasma half life of both the drugs is approximately 1 hour and peak plasma levels attained after intravenous dose decline to less than 1 g/mL after 4 to 6 hours. The usual dosing interval is 6 hours for imipenem and 8 hours for meropenem in patients with normal renal function. Ertapenem is extensively bound to plasma proteins; as a result, it has a longer half- life and is suitable for once daily administration. Imipenem undergoes hydrolysis by the enzyme Dehydropeptidase-1 (DHP-1) in the brush border of proximal renal tubular cells and hence it is always administered with an inhibitor of DHP-1, cilastatin, in a ratio of 1:1 to achieve an appropriate in vivo half- life and prevent potential nephrotoxicity. In the presence of cilastatin, 60–70% of imipenem is excreted unchanged in urine. Meropenem, ertapenem and doripenem demonstrate increased stability to DHP-1 and are administered without a DHP-1 inhibitor. Approximately 70% of meropenem is excreted renally as the parent compound. Ertapenem is eliminated mainly through glomerular filtration and secretory process. As kidneys are the primary route of elimination of carbapenems, different levels of renal impairment require dosage and/or dosage interval changes (Table 1).9 The pharmacokinetics of carbapenems show age-associated changes. Their elimination half-life is the longest in preterm neonates and it decreases with advancing age. The volume of distribution of meropenem is greater in infants than in children in view of their reduced renal functional capacity and increased extracellular fluid volume. Similar studies with imipenem-cilastatin in preterm neonates show linear elimination pharmacokinetics with peak plasma concentrations showing a linear increase with increase in doses. Imipenem and meropenem are available as dry powder in vials, which should be stored below 25°C before reconstitution. After reconstitution, they may be kept at room temperature for up to 2 hours and under refrigeration (4°C) for up to 24 hours. The 54 Rational Antimicrobial Practice in Pediatrics

TABLE 1 Dose modification of imipenem and meropenem in renal insufficiency36 Creatinine clearance Imipenem-Cilastatin Meropenem 2 (ml/min/1.73 m ) % individual Dose % individual Dose dose interval dose interval >50 50–100 % q6–8 h 100% q 8 h (mild insufficiency) 10–50 25–50 % q8 h 50–100 % q 12 h (moderate insufficiency) <10 25% q12 h 50% q 24 h (severe insufficiency) detailed pharmacokinetic data and dosing for these compounds in children is shown in Table 2. Doses less than or equal to 500 mg should be given by intravenous infusion over 15 to 30 minutes and those more than 500 mg over 40–60 minutes. Studies show that administering the carbapenem over 3–4 hours as infusion may help in treatment of infections with organisms with relatively higher MIC.

TABLE 2 Comparison of the characteristics of each carbapenem (modified from3) Characteristic Imipenem-Cilastatin Meropenem Ertapenem FDA status Approved 1985 Approved 1996 Approved 2001 Age Dose <1 week: 25 mg/kg > 3 mo: 20 mg/kg 3 mo to 12 yr: and q12 h q8 h 15 mg/kg q12 h Dosing interval 1–4 weeks: Meningitis: Adults: 1 gm q 24 h 25 mg/kg q8 h 40 mg/kg q 8 h 4 wk to 3 mo: Respiratory infection 25 mg/kg q6 h in cystic fibrosis: 3 mo to12 yr: 40 mg/kg q 8 h 15–25 mg/kg q6 h Adults and children Max daily dose: 2 g >50 kg: 0.5-1 g Adults: 0.5–1 g q 6–8 h q 6–8 h Half-life ~ 1 h ~ 1 h ~ 4 h Protein binding 20% 2% 85–95 % Stability in aqueous ~ 4 h ~ 6 h ~ 6 h solutionat room temperature Renal excretion 70% 70% 80% Spectrum Better action on Better action on No action on Gram + cocci compared GNB compared to P. aeruginosa, to meropenem imipenem Acinetobacter Carbapenems 55

Pharmacodynamics The activity of carbapenems is dependent on the time for which the drug levels remain above the Minimal Inhibitory Concentration (MIC) for the organism (T>MIC). AT > MIC of ~20% is required for bacteriostatic effects while T>MIC of ~40% achieves bactericidal effects.10 Unlike other -lactams, carbapenems also exhibit a Post-Antibiotic Effect (PAE) against both gram-positive and gram-negative bacteria. So their effect may last even longer than that predicted by their half life and on evaluating the PAE of imipenem against E. coli at varying drug concentrations and times of exposure, the area under the concentration-time curve (AUC) is a better predictor of the PAE than concentration or time alone. Carbapenems provide a significant advantage in treating ESBL +ve strains since they do not exhibit the “Innoculum Effect”. Cefepime can theoretically be used for the treatment of ESBL +ve strains and can demonstrate effective levels above the MIC values (1 mg/L) for a colony count of 105 CFU/ml. However at higher bacterial loads, like 107 CFU/mL, the MIC for Cefepime increases dramatically (64 mg/L).11 This reduced efficacy in relation to the size of the innoculum has been called the “Innoculum Effect”. In addition to this effect, use of cefepime has also been associated with selection of ESBL +ve strains and outbreaks of infection and with higher mortality as compared to carbapenems. Hence cefepime may not be effective for treatment of severe bacterial infections with ESBL +ve strains. In contrast, the MIC data of Meropenem does not show the Innoculum Effect. Its MIC for a bacterial load of 107 CFU/mL is not very high as compared to that for 105 CFU/mL.12 Clinical studies show that the plasma trough concentrations (8.5 ± 1 mg/L) on an 8 hour dosing schedule remain persistently above the MIC values for most infecting organisms.13

Spectrum of Activity The carbapenems possess broad spectrum in vitro activity against gram-positive and gram-negative aerobic and anaerobic bacteria. However, none of the carbapenems demonstrate clinically useful activity against E. faecium, MRSA, Burkholderia cepacia, Stenotrophomonas maltophila, Chlamydia and Mycoplasma. Based on their affinity for various PBPs, there can be differences in the activity of individual carbapenems14 and can be broadly grouped into three. There are subtle differences between drugs within a group also. Group 1 includes ertapenem which has lesser action on bacteria like Pseudomonas and Acinetobacter but suitable for community acquired infections caused by ESBL producing bacteria.3 Group 2, has imipenem, meropenem, biapenem and doripenem with better action on Pseudomonas, Acinetobacter and enterococci and hence better suited for nosocomial infections. Within the group, imipenem has better activity against gram-positive cocci while meropenem is better against GNB.3 In vitro, meropenem is more potent than imipenem-cilastatin against Enterobacteriaceae, P. aeruginosa and Acinetobacter.15 Group 3 has investigational carbapenems with activity on MRSA as well. 56 Rational Antimicrobial Practice in Pediatrics

Clinical Use Carbapenems have broad-spectrum antibacterial activity and are therefore useful agents for treatment of nosocomial infections, infections in immunocompromised, polymicrobial infections and for presumptive therapy in serious bacterial infections before identification of the infecting organism. They should be used judiciously to avoid the development of resistance. Of the available carbapenems, imipenem-cilastatin, meropenem and ertapenem are approved by the FDA for use in children, the latter two only for those above 3 months. Doripenem is currently approved only for those above 18 years of age. Imipenem was the first carbapenem approved for clinical use in 1985. It is still widely used, despite its disadvantages compared with newer carbapenems. In children, imipenem has shown good efficacy in the treatment of cellulitis, osteomyelitis, septic arthritis, lymphadenitis, renal infections, pneumonia and wound infections.16 Initial empirical therapy with imipenem in children with cancer having febrile neutropenia has been found to be effective and well tolerated in comparison to the combination of ceftazidime and vancomycin.17 In neonates, it has shown good activity against sepsis caused by K. pneumoniae. Its use in children with skin, soft tissue, bone and joint infections and intra-abdominal infections has also shown good results. Imipenem-cilastatin is not approved by the FDA for the treatment of bacterial meningitis in children in view of its propensity to cause seizures. The overall incidence of seizures is 2%, with a slightly higher incidence noted in children with cancer (3.6%).18 A study of imipenem-cilastatin use in children with suspected bacterial meningitis was in fact terminated when 33% of children with meningitis developed seizures after imipenem administration.19 The pathogenesis of its neurotoxicity is by virtue of its interaction with GABAA receptor and this interaction depends upon the side chain of the second carbon atom in the carbapenem nucleus. The more basic the side chain is, the better is the 20 binding to the GABAA receptor, and this results in higher convulsant activity. Imipenem and panipenem have basic C-2 side chains whereas meropenem’s side chain is not. Hence imipenem should not be used in treatment of CNS infections in children. Meropenem was initially approved for use in adults and children in 1996 and since then a number of clinical studies in children have defined its role in serious bacterial infections. Meropenem has been used as empirical monotherapy for the treatment of febrile neutropenia in children with various malignancies. A number of studies have assessed its efficacy in comparison to the commonly used third generation cephalosporins in this patient subgroup. These studies found that meropenem has efficacy similar to ceftazidime or combination of piperacillin and amikacin in febrile neutropenia patients.21,22 In India, where prevalence of ESBL producing strains is very high, carbapenems will be more efficacious than the cephalosporins. Meropenem has also been used for the treatment of infections of the lower respiratory tract, the urinary tract, the skin, septicemia, meningitis and intra-abdominal infections (though clinically-relevant resistance has been reported in some strains of enterococci) in children.23 In studies evaluating meropenem for childhood meningitis,24,25 efficacy and the rates of seizure activity during therapy were comparable between patients who received meropenem and those who received comparator agents Carbapenems 57

(either cefotaxime or ceftriaxone). Hence, meropenem is approved by the FDA for the treatment of meningitis in children greater than 3 months of age. Even though meropenem is approved by FDA for use in children above 3 months only, there is a significant off-label use in newborn and infant patients younger than three months of age. In neonates with sepsis due to multidrug resistant gram-negative organisms, meropenem showed excellent results (100% cure rates for sepsis and 87.5% for nosocomial pneumonia) with almost no side effects in this age group.26 Ertapenem was approved for use in 2001. It is considered to belong to its own separate class within the carbapenem group because its pharmacologic properties and spectrum of activity are different enough from those of imipenem and meropenem. Ertapenem has a high protein-binding percentage and a long half-life, permitting once-daily administration. Dosing appears to be less susceptible to the effects of renal dysfunction. Ertapenem has only limited activity against GNB’s such as P. aeruginosa, B. cepacia and Acinetobacter spp, hence its use should be limited to treating serious community- acquired infections; it should not be routinely used empirically to treat nosocomial infections.27 The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program was a longitudinal antimicrobial resistance surveillance study initiated in 1997; by its final year (2008), the program had expanded to greater than 100 participant medical centers worldwide, located in Europe, North America, South America, and Asia, to monitor for changes in the in vitro activity of meropenem and other broad-spectrum anti microbial agents.28 The MYSTIC data has documented the continued high potency and wide spectrum of activity of meropenem worldwide against Enterobacteriaceae isolates, including those with ESBL and Amp C-producing resistance mechanisms.28 MYSTIC data from pediatric ICU show that more than 90% isolates are susceptible to carbapenems, the rate of increase in resistance is slow and that a greater number of P. aeruginosa are susceptible to meropenem as compared to imipenem-cilastatin.29 Recently, there has been a significant increase in the spread of carbapenemases among various Enterobacteriaceae species. The most important of these are the serine carbapenamases of the KPC (Klebsiella pneumonia carbapenamase) family and the recently reported metallo--lactamase NDM-1.6 Therefore, owing to the huge cost of therapy, the risk of resistance and limited availability of more superior drugs covering gram negative organisms, carbapenems should be used with great discretion. They should be used only for therapy of multi drug resistant nosocomial infections and infections in the immunocompromised. Use of carbapenems other than ertapenem for community acquired infections should be avoided as other effective agents are available. If started empirically, de-escalation should be done once culture reports are available.

Cost of Therapy Each gram of meropenem/imipenem costs between Rs. 2000–3000. The cost of therapy for a 10 kg child at a dose of 100 mg/kg/d for 10 days will be approximately Rs. 20000–30000. 58 Rational Antimicrobial Practice in Pediatrics

Side Effects Carbapenems are contraindicated in patients with known hypersensitivity to any component. In those with history of serious penicillin/beta lactam hypersensitivity reactions, carbapenems should be used with great caution. Before initiating therapy, an enquiry should be made regarding history of previous anaphylactic reactions and history of allergy to multiple allergens. Imipenem-cilastatin is generally well tolerated and serious side effects requiring cessation of therapy are rare. Side effects include local reactions in the form of erythema, induration and thrombophlebitis; nausea, vomiting, diarrhea, oligura/anuria and renal failure. In addition, a harmless discoloration of urine has been seen in children. Laboratory abnormalities include transient thrombocytosis, liver enzyme elevations, eosinophilia and neutropenia. Imipenem-cilastatin has pro-convulsive tendency and its use is not recommended in suspected CNS infections in children (as discussed above). Norrby et al reviewed the safety profile of meropenem in a large patient population.30 The review evaluated 758 pediatric patient episodes of treatment with meropenem, including 246 with meningitis. The study compared meropenem to cephalosporin-based therapies. Meropenem was administered in doses of 10, 20 and 40 mg/kg. There were no major differences between the meropenem and comparator groups with respect to age, clinical condition, or severity of infection. Drug-related adverse events occurred in 16% of meropenem-treated and 11% of cephalosporin-treated patients. The most common drug- related clinical adverse events reported in the meropenem group were diarrhea, rash, nausea/vomiting and injection site inflammation. Diarrhea (4.1%) and rash (2.2%) were the only adverse events related to therapy with meropenem occurring in more than 1% of pediatric patients. Even when taking into account non-drug-related adverse events, no specific event was reported in more than 5% of meropenem treatment exposures, reflecting a low frequency for individual adverse events. The most common laboratory adverse effects were thrombocytosis and increase in liver function tests; these events occurred in a low proportion of patients and were not considered to be clinically significant.30

Drug Interactions There are reports of occurrence of seizures on concurrent administration of Imipenem- cilastatin with ganciclovir and their concomitant use is not recommended unless the benefit outweighs the risk. Concomitant administration of imipenem with cyclosporin is also known to cause central nervous system effects in the form of confusion, agitation and tremor. Concomitant administration with probenecid results in minimal increase in plasma levels and half-life of imipenem but the levels of cilastatin are almost doubled. The urinary recovery of imipenem is reduced to 60% of the administered dose and hence its concomitant administration is not recommended.

Newer Carbapenems Besides imipenem, meropenem and ertapenem, several new carbapenem compounds are on the horizon. Doripenem is an investigational carbapenem that has completed Carbapenems 59

Phase III studies, and is now being marketed worldwide for the treatment of complicated intra-abdominal infections, complicated urinary tract infections and nosocomial pneumonia.3 It has better activity against gram-positive organisms than meropenem and better activity against gram-negative organisms than imipenem. Studies have shown lower MIC’s in Pseudomonas aeruginosa against doripenem as compared to other carbapenems. However, superior clinical efficacy has not been demonstrated. In addition there are a number of other newer carbapenems like, Biapenem, Lenapenem, Panipenem/Betamipron, Tebipenem. Biapenem and lenapenem have typical carbapenem pharmacokinetics and broad-spectrum activity and have been claimed to have better activity against resistant strains of Pseudomonas aeruginosa. Panipenem is always co-administered with betamipron, which acts as a nephroprotectant by inhibiting the accumulation of panipenem in the renal cortex.31 Biapenem and Panipenem have been marketed in Japan.32 Tebipenem, a novel oral carbapenem, is undergoing phase II clinical trials in Japan, and there is only a limited published data on its role in therapy at present.33 , a member of the unique class of -lactams is not a carbapenem. It has different chemical and microbiological properties compared with carbapenems. It demonstrates broad-spectrum in vitro antimicrobial activity against many gram-positive and gram-negative aerobes and anaerobes, and is resistant to hydrolysis by nearly all -lactamases. The evidence supports faropenem as a promising new oral -lactam with proven efficacy and safety for the treatment of a variety of community-aquired infections.34 Faropenem has recently been introduced in India. Trinems (previously tribactams) have a carbapenem-related structure but with a cyclohexane ring attached across carbons 1 and 2. Sanfetrinem, which is the first member of the family to be developed, can be administered orally as a hexatil ester.35

CONCLUSIONS Carbapenems are efficacious and safe for treatment of a wide variety of serious bacterial infections in children including nosocomial and polymicrobial infections. They can be used as a monotherapy or in combination with other antimicrobials for the treatment of gram- negative ESBL producing strains. However, as with any other antibiotic, they have potential for misuse as well. There is a need to emphasize on the rational use of antimicrobials and strictly adhere to the concept of “reserve drugs” to minimize the misuse of available antimicrobials. Overuse should be avoided to prevent the development of resistant strains, some of which are already emerging. In addition, regular antimicrobial susceptibility surveillance is essential. Several newer agents are under development but need to undergo extensive clinical trials in children before their efficacy and safety can be reliably established.

 REFERENCES 1. Mathur P, Kapil A, Das BK, Dhawan B. Prevalence of extended spectrum beta lactamase producing gram negative bacteria in a tertiary care hospital. Indian J Med Res. 2002;115:153-7. 2. Mohanty S, Kapil A, Dhawan B, Das BK. Bacteriological and antimicrobial susceptibility profile of soft tissue infections from Northern India. Indian J Med Sci. 2004;58:10-5. 60 Rational Antimicrobial Practice in Pediatrics

3. Nicolau DP. Carbapenems: a potent class of antibiotics. Expert Opin Pharmacother. 2008;9(1):23-37. 4. Gupta E, Mohanty S, Sood S, Dhawan B, Das BK, Kapil A. Emerging resistance to carbapenems in a tertiary care hospital in north India. Indian J Med Res. 2006;124:95-8. 5. Multi-resistant hospital bacteria linked to India and Pakistan, health Protection report. 2009;3(26):3. www.hpa.org 6. Lascols C, Hackel M, Marshall SH, Hujer AM, Bouchillon S, Badal R, Hoban D, Bonomo RA. Increasing prevalence and dissemination of NDM-1 metallo-beta-lactamase in India: data from the SMART study (2009). J Antimicrob Chemother. 2011;66:1992-7. 7. Livermore DM. Of Pseudomonas, porins, pumps and carbapenems. J Antimicrob Chemother. 2001;47:247-50. 8. Hawkey PM, Livermore DM. Carbapenem antibiotics for serious infections. BMJ. 2012;344:e3236. 9. Zhanel GG, Wiebe R, Dilay L, Thomson K, Rubinstein E, Hoban DJ, Noreddin AM, Karlowsky JA. Comparative Review of the Carbapenems. Drugs. 2007;67(7):1027-52. 10. Nix DE, Majumdar AK, DiNubile MJ. Pharmacokinetics and pharmacodynamics of ertapenem: an overview for clinicians. J Antimicrob Chemother. 2004;53(2): ii23-8. 11. Thauvin-Eliopoulos C, Tripodi MF, Moellering RC Jr, Eliopoulos GM. Efficacies of piperacillin-tazobactam and cefepime in rats with experimental intra-abdominal abscesses due to an extended-spectrum beta-lactamase-producing strain of Klebsiella pneumoniae. Antimicrob Agents Chemother. 1997;41:1053-7. 12. Thomson K, Moland ES. Cefepime, piperacillin-tazobactam, and the inoculum effect in tests with extended-spectrum beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2001;45:3548. 13. Thalhammer F, Schenk P, Burgmann H, El Menyawi I, Hollenstein UM, Alexander R. Rosenkranz AR, et al. Single-Dose Pharmacokinetics of Meropenem during Continuous Venovenous Hemofiltration. Antimicrob Agents Chemother. 1998;42:2417-20. 14. Joseph, J, Rodvold KA. The role of carbapenems in the treatment of severe nosocomial respiratory tract infections. Expert Opin Pharmacother 2008;9(4):561-75. 15. Jones RN, Sader HS, Fritsche TR. Comparative activity of doripenem and three other carbapenems tested against gram-negative bacilli with various beta-lactamase resistance mechanisms. Diagn Microbiol Infect Dis. 2005;52(1):71-4. 16. Alpert G, Dagan R, Connor E, Campos JM, Bloh M, Powell KR, et al. Imipenem/cilastatin for the treatment of infections in hospitalized children. Am J Dis Child 1985;139:1153-6. 17. Riikonen P. Imipenem compared with Ceftazidime plus Vancomycin as initial therapy for fever in neutropenic children with cancer. Pediatr Infect Dis J. 1991;10:918-23. 18. Karadeniz C, Oguz A, Canter B, et al. Incidence of Seizures in pediatric cancer patients treated with Imipenem-Cilastatin. Pediatr Hematol Oncol. 2000;17:585-90. 19. Wong VK, Wright HT Jr, Ross LA et al. Imipenem-Cilastatin in treatment of bacterial meningitis in children. Pediatr Infect Dis J. 1991;10:122-5. 20. Norrby SR. Neurotoxicity of Carbapenem antibiotics: consequences for their use in bacterial meningitis. J Antimicrob Chemother. 2000;45:5-7. 21. Fleischhack G, Hartmann C, Simon A, et al. Meropenem versus Ceftazidime as empirical monotherapy in febrile neutropenia of pediatric patients with cancer. J Antimicrob Chemother. 2001;47:841-53. 22. Duzova A, Kutluk T, Kanra G, Buyukpamukcu M, Akyuz C, Secmeer G, Ceyhan M. Monotherapy with meropenem versus combination therapy with piperacillin plus amikacin as empiric therapy for neutropenic fever in children with lymphoma and solid tumors. Turk J Pediatr. 2001;43:105-9. 23. Hsu HL, Lu CY, Tseng HY, Lee PI, Lai HP, Lin WC, et al. Empirical monotherapy with meropenem in serious bacterial infections in children. J Microbiol Immunol Infect. 2001;34:275-80. 24. Klugman KP, Dagan R and the Meropenem Meningitis Study Group. Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Antimicrob Agents Chemother. 1995;39:1140-6. 25. Odio CM, Puig JR, Feris JM, Khan WN, Rodriguez WJ, McCracken GH Jr, et al. Prospective, randomized, investigator-blinded study of the efficacy and safety of meropenem vs. cefotaxime therapy in bacterial meningitis in children. Meropenem Meningitis Study Group. Pediatr Infect Dis J. 1999;18:581- 90. Carbapenems 61

26. Koksal N, Hacimustafaoglu M, Bagci S, Celebi S. Meropenem in neonatal severe infections due to multiresistant gram-negative bacteria. Indian J Pediatr. 2001;68:15-9. 27. Keating GM, Perry CM. Ertapenem: a review of its use in the treatment of bacterial infections. Drugs. 2005;65:2151-78. 28. Rhomberg PR, Jones RN. Summary trends for the Meropenem Yearly Susceptibility Test Information Collection Program: a 10-year experience in the United States (1999-2008). Diagnostic Microbiology and Infectious Disease. 2009;65:414-26. 29. Patzer JA, Dzierzanowska D, Turner PJ. Trends in antimicrobial susceptibility of gram-negative isolates from a paediatric intensive care unit in Warsaw: results from the MYSTIC programme (1997-2007). J Antimicrob Chemother; 2008. 30. Norrby SR, Gildon KM. Safety profile of meropenem: a review of nearly 5,000 patients treated with meropenem. Scand J Infect Dis.1999;31:3-10. 31. Kurihara A, Naganuma H, Hisaoka M, Tokiwa H, Kawahara Y. Prediction of Human Pharmacokinetics of Panipenem-Betamipron, a New Carbapenem, from Animal Data. Antimicrob Agents Chemother. 1992;36:1810-6. 32. Goa KL, Noble S. Panipenem/betamipron. Drugs. 2003; 63(9):913-25. 33. Kobayashi R, Konomi M, Hasegawa K, et al. In vitro activity of tebipenem, a new oral carbapenem antibiotic, against penicillin-nonsusceptible Streptococcus pneumoniae. Antimicrob Agents Chemother. 2005;49(3):889-94. 34. Schurek KN, Wiebe R, Karlowsky JA, et al. Faropenem: review of a new oral penem. Exp Rev Antiinf Ther. 2007;5(2):185-98. 35. Babini GS, Yuan M, Livermore DM. Interactions of -lactamases with sanfetrinem (GV 104326) compared to those with imipenem and with oral beta-lactams. Antimicrob Agents Chemother. 1998;42:1168-75. 36. Nechyba C, Gunn VL. Drugs in Renal Failure. In, Nechyba C, Gunn VL (Eds). The Harriet Lane Handbook: A manual for Pediatric House Officers. 16th edition, Philadelphia: Mosby; 2002. pp 943. 62 Rational Antimicrobial Practice in Pediatrics 77 Aminoglycosides Preeti Shanbag

 INTRODUCTION The aminoglycosides are a class of bactericidal antibiotics, characterized by the presence of a six-carbon aminocyclitol ring covalently bonded to amino-sugar groups.1 The first aminoglycoside, streptomycin, was isolated from Streptomyces griseus in 1943. , isolated from Streptomyces fradiae, had better activity than streptomycin against aerobic gram-negative bacilli, but because of its formidable toxicity, could not be used systemically. Gentamicin, isolated from in 1963, was a breakthrough in the treatment of gram-negative bacillary infections, including those caused by Pseudomonas aeruginosa. Other aminoglycosides were subsequently developed, including amikacin, netilmicin and tobramycin, which are all currently available for systemic use.1

Mechanism of Action2-4 Traditionally, the antibacterial properties of aminoglycosides were believed to result from inhibition of bacterial protein synthesis through irreversible binding to the 30S bacterial ribosome. This explanation, however, does not account for the potent bactericidal properties of these agents, since other antibiotics that inhibit the synthesis of proteins (such as tetracyclines) are not bactericidal. Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake. This rapid action at the outer membrane probably accounts for most of the bactericidal activity.2 Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobes. Bacterial killing is concentration-dependent: the higher the concentration, the greater is the rate at which bacteria are killed. A postantibiotic effect, i.e. residual bactericidal activity persisting after the serum concentration has fallen below the minimum inhibitory concentration (MIC) also is characteristic of aminoglycoside antibiotics; the duration of this effect also is concentration dependent. These properties probably account for the efficacy of once-daily dosing of aminoglycosides. Aminoglycosides 63

Spectrum of Activity2-4 Aminoglycosides are rapidly bactericidal, against a broad range of aerobic gram-negative bacilli (including P. aeruginosa), but lack activity against anaerobes. Although there is activity against some gram-positive aerobic cocci, it is unreliable. Aminoglycosides are also effective against M. tuberculosis complex and many atypical mycobacteria. The aminoglycosides are generally used against gram-positive cocci, such as enterococci and staphylococci, only in combination with cell-wall active antibiotics such as -lactam drugs or vancomycin to achieve synergistic bactericidal activity. This phenomenon has been demonstrated with multiple organisms and in multiple animal models.2 This activity has been best demonstrated to be important clinically in infective endocarditis caused by enterococci and in S. epidermidis endocarditis on a prosthetic valve. It has been suggested that synergism may also be important in serious P. aeruginosa infections, and in infections caused by gram-negative bacilli in neutropenic patients.

Drug Resistance Bacteria may be resistant to aminoglycosides because of failure of the antibiotic to penetrate intracellularly, low affinity of the drug for the bacterial ribosome, or inactivation of the drug by microbial enzymes. Clinically, most resistance to aminoglycosides is caused by bacterial inactivation by intracellular enzymes. Because of structural differences, amikacin is not inactivated by the common enzymes that inactivate gentamicin and tobramycin. Therefore, a large proportion of the gram-negative aerobes that are resistant to gentamicin and tobramycin are sensitive to amikacin. In addition, with increased use of amikacin, a lower incidence of resistance has been observed compared with increased use of gentamicin and tobramycin.3 P. aeruginosa may show adaptive resistance to aminoglycosides. This occurs when formerly susceptible populations become less susceptible to the antibiotic as a result of decreased intracellular concentrations of the antibiotic. This decrease may result in colonization, slow clinical response or failure of the antibiotic despite sensitivity on in vitro testing.5 Aminoglycosides are often combined with a beta lactam drug in the treatment of Staphylococcus aureus infection. This combination enhances bactericidal activity, whereas aminoglycoside monotherapy may allow resistant staphylococci to persist during therapy and cause a clinical relapse once the antibiotic is discontinued.1 Infective endocarditis that is due to enterococci with high levels of resistance to aminoglycosides is becoming increasingly common. All enterococci have low-level resistance to aminoglycosides because of their anaerobic metabolism. In the treatment of bacterial endocarditis, a beta lactam drug is also used synergistically to facilitate aminoglycoside penetration into the cell. When high-level resistance occurs, it is typically due to the production of inactivating enzymes by the bacteria. Because of the increasing frequency of this resistance, all enterococci should be tested for high level aminoglycoside resistance.6 64 Rational Antimicrobial Practice in Pediatrics

As with all antibiotics, resistance to aminoglycosides is becoming increasingly prevalent. Repeated use of aminoglycosides, especially when only one type is employed, leads to an increased incidence of resistance.6 Nevertheless, resistance to aminoglycosides requires long periods of exposure or very large inocula of organisms and occurs less frequently than with other agents, such as third-generation cephalosporins.1

Pharmacokinetics3,4 Absorption Aminoglycosides are highly polar cations and therefore poorly absorbed from the gastrointestinal tract. Less than 1% of a dose is absorbed after either oral or rectal administration. Long-term oral or rectal administration of aminoglycosides may result in accumulation to toxic concentrations in patients with renal impairment. Instillation of these drugs into body cavities with serosal surfaces may also result in rapid absorption and unexpected toxicity, i.e. neuromuscular blockade. Similarly intoxication may occur when aminoglycosides are applied topically for long periods to large wounds, burns or cutaneous ulcers especially in the face of renal insufficiency. All the aminoglycosides are absorbed rapidly from intramuscular sites of injection. Peak concentrations in plasma occur after 30–90 minutes and are similar to those observed 30 minutes after completion of an intravenous infusion of an equal dose over a 30-minute period. In critically ill patients, especially those in shock, absorption of drug may be reduced from intramuscular sites because of poor perfusion.

Distribution Aminoglycosides are primarily distributed within the extracellular fluid. Thus, the presence of disease states or iatrogenic situations that alter fluid balance may necessitate dosage modifications. When used parenterally, adequate drug concentrations are typically found in bone, synovial fluid and peritoneal fluid. Penetration of biologic membranes is poor because of the drug’s polar structure, and intracellular concentrations are usually low, with the exception of the proximal renal tubule. Endotracheal administration results in higher bronchial levels compared with systemic administration, but differences in clinical outcome have not been consistent. Following parenteral administration of an aminoglycosides, subtherapeutic concentrations are usually found in the cerebrospinal fluid, vitreous fluid, prostate and brain.3

Elimination Aminoglycosides are rapidly excreted by glomerular filtration, resulting in a plasma half- life varying from two hours in a patient with “normal” renal function to 30 to 60 hours in patients who are functionally anephric.4 The half-life of aminoglycosides in the renal cortex is approximately 100 hours, so repetitive dosing may result in renal accumulation and toxicity. Determination of the concentration of drug in plasma is an essential guide to the proper administration of aminoglycosides. In patients with life-threatening systemic infections, aminoglycoside concentrations should be determined several times per week Aminoglycosides 65

(more frequently if renal function is changing) and should be determined within 24 to 48 hours of a change in dosage. Aminoglycosides can be removed from the body by either hemodialysis or peritoneal dialysis. Approximately 50% of the administered dose is removed in 12 hours by hemodialysis, which has been used for the treatment of overdosage. As a general rule, a dose equal to half the loading dose administered after each hemodialysis should maintain the plasma concentration in the desired range; however, a number of variables make this a rough approximation at best. Continuous arteriovenous hemofiltration (CAVH) and continuous venovenous hemofiltration (CVVH) will result in aminoglycoside clearances approximately equivalent to 15 and 15 to 30 mL/min of creatinine clearance, respectively, depending on the flow rate. The amount of aminoglycoside removed can be replaced by administering approximately 15% to 30% of the maximum daily dose each day. Frequent monitoring of plasma drug concentrations is again crucial.3 Peritoneal dialysis is less effective than hemodialysis in removing aminoglycosides. Clearance rates are approximately 5 to 10 mL/min for the various drugs but are highly variable. If a patient who requires dialysis has bacterial peritonitis, a therapeutic concentration of the aminoglycoside probably will not be achieved in the peritoneal fluid because the ratio of the concentration in plasma to that in peritoneal fluid may be 10:1. Thus, it is recommended that antibiotic be added to the dialysate to achieve concentrations equal to those desired in plasma. For intermittent dosing via peritoneal dialysate, 2 mg/kg of amikacin is added to the bag once a day. The corresponding dose for gentamicin, netilmicin, or tobramycin is 0.6 mg/kg. For continuous dosing, the dose for amikacin is 12 mg/L (25 mg/L loading dose in the first bag), and the dose for gentamicin, netilmicin, or tobramycin is 4 mg/L in each bag (8 mg/L loading dose). This should be preceded by administration of a loading dose, either parenterally or in dialysis fluid.3 Aminoglycosides can be inactivated by various penicillins in vitro and in patients with end-stage renal failure, thus making dosage recommendations even more difficult. Amikacin appears to be the least affected by this interaction.

Clinical Uses These potent antimicrobials are used as prophylaxis and treatment in a variety of clinical situations (Table 1).4 Aminoglycosides are not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are susceptible to these antibiotics and are not susceptible to antibiotics having less potential for toxicity. Gentamicin is the aminoglycoside used most often because of its low cost and reliable activity against gram-negative aerobes. However, local resistance patterns should influence the choice of therapy. In general, gentamicin, tobramycin and amikacin are used in similar circumstances, often interchangeably.3 Tobramycin may be the aminoglycoside of choice for use against P. aeruginosa because it has shown greater in vitro activity. Nevertheless, the clinical significance of this activity has been questioned.1 Amikacin is particularly effective when used against bacteria that are resistant to other 66 Rational Antimicrobial Practice in Pediatrics

TABLE 1 Common clinical uses of aminoglycosides • Serious, life-threatening gram-negative infection • Complicated skin, bone or soft tissue infection • Complicated urinary tract infection • Septicemia • Peritonitis and other severe intra-abdominal infections • Severe pelvic inflammatory disease • Endocarditis • Mycobacterial infection • Neonatal sepsis • Ocular infections (topical) • Otitis externa (topical)

aminoglycosides, since its chemical structure makes it less susceptible to inactivating enzymes.3 Depending on local patterns of resistance, amikacin may be the preferred agent for serious nosocomial infections caused by gram-negative bacilli. Tobramycin is specifically formulated for administration by inhalation. When inhaled, tobramycin is concentrated in the airways and is indicated for the management of cystic fibrosis patients with P. aeruginosa. Streptomycin is used in the intensive phase of tuberculosis therapy as an alternative to ethambutol. It is also used when there is toxicity, hepatic dysfunction or intolerance to the usual antitubercular drugs. Streptomycin is also used in treatment of plague, tularemia and brucellosis. It is also used in endocardial infections due to Streptococcus viridans, and Enterococcus faecalis concomitantly with penicillin. Kanamycin may be considered as initial therapy in the treatment of infection due to E. coli, Proteus species (both indole-positive and indole-negative), Enterobacter aerogenes, Klebsiella pneumoniae, Serratia marcescens, Acinetobacter species.4 The decision to continue therapy with the drug should be based on results of the susceptibility tests and the response of the infection to therapy. Kanamycin is also used along with other drugs in the management of multidrug-resistant tuberculosis. Netilmicin sulfate injection is indicated for the short-term treatment of patients of all ages, including neonates, infants, and children with serious or life-threatening bacterial infections caused by susceptible strains.4 Neomycin was previously administered orally as an adjunct in the treatment of hepatic encephalopathy but the preparation is no longer available. It is now available for topical use only. Aminoglycosides 67

Drug Dosage, Frequency and Duration of Use3,7-15 Once Daily Dosing of Aminoglycosides Current practice is to give the total daily dose as a single injection, although historically it was administered as two or three equally divided doses. The pharmacodynamic characteristics of aminoglycosides that allow the use of once- daily dosing are (i) concentration-dependent killing; (ii) postantibiotic effect (PAE) and postantibiotic leukocyte enhancement (PALE); and (iii) adaptive resistance.

Concentration-Dependent Killing8 Bacterial killing by aminoglycosides is concentration-dependent. In vitro studies have shown increases in the rate of bacterial killing as aminoglycoside concentrations increase. A strong relationship between peak aminoglycoside concentrations and response to therapy has been described in a cohort of patients with serious gram-negative bacillary infections treated with thrice-daily dosing of gentamicin or tobramycin. This suggests that concentration- dependent killing is clinically important. It might be expected that bolus dosing of aminoglycoside antibiotics, with resultant higher peak levels, would result in improved clinical efficacy.

Postantibiotic Effect8 The use of once-daily dosing regimens in aminoglycoside therapy results in intervals during which drug concentrations are below the MIC. This might foster concern that target pathogens would proliferate once concentrations of drug fall below the MIC; however, aminoglycoside antibiotics have a potent postantibiotic effect (PAE); that is, suppression of bacterial growth persists despite concentrations of antibiotic below the MIC. An aminoglycoside PAE has been demonstrated with both staphylococci and with gram- negative bacilli. The measured duration of PAE tends to be longer in vivo than in vitro, even in neutropenic animals, suggesting that this difference is not only due to the presence of host neutrophils. The PAE in vivo following aminoglycoside administration is prolonged and lasts from 1 to 13 hours in animal models of gram-negative bacterial infection. The PAE is extended by higher doses of aminoglycosides and concurrent administration of a cell-wall active antibiotic-enhanced phagocytosis of aminoglycoside-exposed bacteria by host leukocytes has also been observed in vitro. This has been referred to as post- antibiotic leukocyte enhancement (PALE).

Adaptive Resistance 5,9 The term adaptive resistance refers to the reduction in rate of bacterial killing by an antibiotic following pre-exposure to that drug. Adaptive resistance to aminoglycoside agents has been observed principally in P. aeruginosa but also in other gram-negative bacilli. Adaptive resistance to aminoglycosides appears to be transient and reversible. The mechanism of adaptive resistance may be a decrease in drug uptake by aminoglycoside- exposed organisms caused by down-regulation of enzymes that control accelerated energy- 68 Rational Antimicrobial Practice in Pediatrics dependent uptake of aminoglycoside antibiotics. Adaptive resistance peaks between 6 and 16 hours after drug administration, although it may last longer following higher doses of drug. Once-daily dosing may circumvent the possibility of adaptive resistance through the provision of a drug-free interval. The transient nature of adaptive resistance means that organisms exposed to once-daily doses of aminoglycosides can revert to the sensitive phenotype during the interval when antibiotic concentrations are low.

Clinical Efficacy of Once-Daily Dosing10-15 The possibility of increased efficacy with once-daily aminoglycoside dosing has been evaluated in a multitude of randomized clinical trials. The interpretation of these studies has been complicated by the fact that individual trials have had insufficient power to determine whether observed differences in efficacy between once-daily and multiple- daily dosage regimens are due to chance alone. Meta-analysis has been used in an attempt to synthesize the data contained in these multiple studies.10-12 The performance of these meta-analyses has been complicated by heterogeneity in the patient populations, disease states, and drug regimens studied, and the different definitions of drug efficacy used. Most meta-analyses have shown an improvement in the clinical efficacy of once-daily aminoglycoside dosing; for example, the meta-analyses by Ali and Goetz10 and Bailey et al11 found once-daily dosing to be associated with a 4% to 5% decrease in risk of clinical failure. The heterogeneity of the studies evaluated has led some authors to perform subgroup analyses, with exclusion of some study types. Investigators have found that estimates of efficacy do not change when analyses are restricted to intravenous (as opposed to intramuscular) dosing,10 infections with microbiologically documented cure,11 or infections in neutropenic individuals.11,12 Despite methodologic flaws in the available literature, current evidence would suggest that when single and multiple daily dosing regimens are compared there is no difference in efficacy, and there is a trend toward reduced toxicity with the single regimens. Several studies have evaluated the use of once-daily dosing of aminoglycosides in pediatric populations.13,14 These studies have included children younger than 6 months and children with neutropenia and sepsis. Pharmacokinetic analyses have suggested that children have a higher volume of distribution than adults and that higher antibiotic dose per unit of body mass may be warranted in children. Once-daily dosing appears to be safe and effective in children.

Clinical Use of Once-Daily Aminoglycoside Regimens: Dosing of Once-Daily Aminoglycosides It has been suggested that once-daily doses should be based upon maximum daily doses of aminoglycoside antibiotics (5 mg/kg/day for gentamicin and tobramycin, 6.5 mg/kg/day for netilmicin, and 15 mg/kg/day for amikacin).10 Aminoglycosides 69

Monitoring of Levels with Once-Daily Aminoglycosides8 Traditional multiple-daily dosing of aminoglycoside antibiotics requires the determination of both peak and trough serum levels; measurement of peak concentrations is not necessary with once-daily full dosage aminoglycoside administration, as serum concentrations will be predictably high. Some authors have suggested that monitoring trough concentrations only, with dose adjustments for troughs greater than 2 mg/L, should prove adequate in individuals on decreased dose once-daily dosing regimens. This monitoring scheme, however, does not allow clinicians to appreciate under dosage of drug and will delay adjustment of the dosing regimen. Another proposed approach to monitoring of once-daily dosage, which overcomes these limitations, is monitoring with a drug level taken 8 hours after infusion. Netilmicin levels between 1.5 and 6 mg/L 8 hours after infusion appear to be safe and effective, and this approach permits adjustment of drug dosage before the next dose is given.

Individuals with Altered Volume of Distribution Individuals with a variety of pathologic states, including ascites, septic shock, severe burns, and pancreatitis as well as pregnant and postpartum women have increased volumes of distribution for aminoglycoside antibiotics.16 It is unclear whether existing data on once-daily dosage can be safely extrapolated to these populations, and it may be prudent to avoid the use of once-daily dosage in these groups until further data are available.

Use in Selected Disease States Infections in Individuals with Neutropenia Postantibiotic leukocyte enhancement of bacterial killing is expected to be impaired in individuals with neutropenia, and some animal experiments have demonstrated once- daily dosing of aminoglycoside antibiotics to be less effective in neutropenic animals than in non-neutropenic animals. Because of this, concern has been raised that once- daily aminoglycoside dosage is inappropriate in neutropenic individuals. Randomized trials comparing once-daily to multiple-daily dosing of netilmicin, tobramycin, and amikacin in combination with beta lactam antibiotics have been performed.17 These studies have included individuals with neutropenia and fever without a documented focus as well as individuals with a septic focus or bacteremia. All studies included individuals with granulocyte count less than 100 cells/mm3, and in one trial, prolonged (> 7 days) neutropenia was present in more than half the study subjects. No significant difference was seen between once-daily and multiple-daily dosing of aminoglycosides, either within individual trials or when these trials were subjected to a meta-analysis. Presently available data suggest that once-daily and multiple-daily dosing of aminoglycosides in combination with beta lactam antibiotics are equally effective for individuals with neutropenia and fever. 70 Rational Antimicrobial Practice in Pediatrics

Gram-positive Coccal Endocarditis Aminoglycosides are commonly used to provide antibacterial synergy against infecting organisms in bacterial endocarditis caused by gram-positive organisms (including viridans streptococci, enterococci, and staphylococci). Traditionally, the synergistic doses of aminoglycosides used in the treatment of endocarditis have been lower than those used for serious gram-negative infections (target serum peak levels 3-4 mg/L). The use of once-daily dosing of aminoglycosides in enterococcal endocarditis has been assessed in vitro and in animal models. Multiple-daily dosing regimens to be superior to once-daily regimens in the treatment of experimental enterococcal endocarditis.11 Once-daily gentamicin dosing for streptococcal endocarditis has been assessed in a randomized clinical trial, comparing 4 weeks of ceftriaxone (2 g/d) to 2 weeks of ceftriaxone combined with gentamicin.17 This study showed cure rates of 96% in both treatment groups. The use of once-daily dosing of aminoglycoside therapy in the treatment of staphylococcal endocarditis has not been assessed. At present, the use of once-daily dosing of aminoglycosides for the treatment of gram- positive coccal endocarditis remains controversial, and further data are needed before such regimens can be recommended. Cost11 A comparison of the costs of single daily dosing and traditional multiple dosing should include not only the cost of the antibiotic but also the costs of labor, laboratory monitoring and drug toxicity. A pharmaco-economic comparison of single daily dosing versus traditional dosing of gentamicin found a 54 percent reduction in drug supply and labor costs with single daily dosing. The same study showed a 62 percent reduction in monitoring costs with single daily dosing. Since single daily dosing is often at least equally effective (and may be less toxic and more cost effective), it may be the preferred method of administration in most clinical situations.

Individual Aminoglycosides Streptomycin Tuberculosis: 20–40 mg/kg/day once daily, not to exceed 1 g/day, or 20–40 mg/kg/ day dose twice weekly under direct observation, not to exceed 1.5 g/dose, usually discontinued after 2–3 months. Other infections including enterococcal endocarditis (in combination with penicillin for 4 weeks) and streptococcal endocarditis (1 week): 20–40 mg/kg/day divided every 12 hours. However, streptomycin is rarely used for this indication and has been replaced by gentamicin whose toxicity is primarily renal and reversible whereas the toxicity of streptomycin is vestibular and irreversible. Plague: 30 mg/kg/day divided every 8-12 hours till patient is afebrile for at least 3 days. Tularemia: Streptomycin (or gentamicin is the drug of choice for the treatment of tularemia. The recommended dose is 15–25 mg/kg/day for 7–10 days. Aminoglycosides 71

Gentamicin Gentamicin is the aminoglycoside of first choice because of its low cost and reliable activity against all but the most resistant gram-negative aerobes. Gentamicin preparations are available for parenteral, ophthalmic and topical administration. In the multiple-daily dosing regime, gentamicin sulphate is given in a loading dose of 2 mg/kg followed by 3–5 mg/kg in 3 divided doses intramuscular or intravenous. The once-daily dose of gentamicin sulphate is 5 mg/kg given over 30–60 minutes for patients with normal renal function (maximum daily dose 240 mg). In newborns the dose is 3 mg/kg once daily for preterm infants < 35 weeks gestation and 4 mg/kg once daily for newborns > 35 weeks gestation.

Amikacin Amikacin has the broadest-spectrum of antimicrobial activity of the group. Because of its resistance to many of the aminoglycoside-inactivating enzymes, it has a special role in hospitals where gentamicin- and tobramycin-resistant organisms are prevalent. Amikacin is active against a vast majority of gram-negative bacilli including most strains of Proteus, P. aeruginosa and Serratia. It is also active against nearly all strains of Klebsiella, E. coli and Enterobacter that are resistant to gentamicin and tobramycin. Unusual pathogens like Acinetobacter, Providencia and Flavobacter and strains of Pseudomonas other than P. aeruginosa show resistance to amikacin. Amikacin is less active than gentamicin against enterococci and must not be used. It is not active against the majority of gram- positive anaerobic bacteria. It is active against M. tuberculosis, including streptomycin- resistant strains and atypical mycobacteria. Dosage for treatment of non-tuberculous mycobacterial infection is 15 mg/kg/day as a single dose (max daily dose 1000 mg). Adjustment must be made in renal insufficiency (Table 2).

Netilmycin Netilmycin is useful for the treatment of serious infections due to susceptible Enterobacteriaceae and other aerobic gram-negative bacilli. It is effective against certain gentamicin-resistant pathogens with the exception of enterococci. Dosage Neonates (less than 6 weeks): 4.0–6.5 mg/kg/day given as 2.0–3.25 mg/kg every 12 hours. Infants and children (6 weeks through 12 years): 5.5–8.0 mg/kg/day given either as 1.8–2.7 mg/kg every 8 hours, or as 2.7–4.0 mg/kg every 12 hours.

Kanamycin Available in India as an intramuscular preparation. 15–30 mg/kg/day divided every 8–12 hours, not to exceed 1 gm per day. For MDR tuberculosis can be given as single dose 15 mg/kg/day. 72 Rational Antimicrobial Practice in Pediatrics

TABLE 2 Suggested single daily dosage requirement of aminoglycosides: Adjustment for renal insufficiency Estimated Dosage interval in hours Dosage in mg/kg creatinine clearance Gentamicin/ Amikacin/ Netilmycin Gentamicin/ Amikacin/ Netilmycin (mL/min) Tobramycin Kanamycin/ Tobramycin Kanamycin/ Streptomycin Streptomycin >80 24 24 24 5 15 6.5 70 24 24 24 4 12 5 60 24 - - 4 - - 50 24 24 24 3.5 7.5 4 40 24 - - 2.5 - - 30 24 24 24 2.5 4 2 20 48 48 48 4 7.5 3 10 48 48 48 3 4 2.5 Hemo- 48 48 48 2 3 2 dialysis*

* Dose post-dialysis

Duration of Treatment It is desirable to limit the duration of treatment with aminoglycosides to short-term whenever feasible. The usual duration of treatment of all patients is 7–14 days. In complicated infections, a longer course of therapy may be necessary. Although prolonged courses of aminoglycosides have been well tolerated, it is particularly important that patients treated for longer than the usual period be carefully monitored for changes in renal, auditory, and vestibular functions. Dosage should be adjusted if clinically indicated.

Monitoring16,18 Monitoring parameters are urinanalysis, urine output, blood urea nitrogen, serum creatinine and peak and trough drug levels. One should be alert to ototoxicity and audiograms should be done if necessary. Not all pediatric patients who receive aminoglycosides require therapeutic drug monitoring. Indications for measuring aminoglycoside concentrations are: • Treatment course > 5 days • Patients with decreased or changing renal function • Infants < 3 months of age • Signs of ototoxicity or nephrotoxicity • Patients on hemodialysis or chronic ambulatory peritoneal dialysis • Clinical need for higher doses or longer intervals (cystic fibrosis, major burns, endocarditis, febrile granulocytopenia) • Concomitant use of other nephrotoxic agents. Aminoglycosides 73

Drug Interactions and Adverse Effects17,20 Because the body does not metabolize aminoglycosides, aminoglycoside activity TABLE 3 Risk factors predisposing to aminoglycoside is unchanged by induction or inhibition nephrotoxicity of metabolic enzymes, such as those in Potentially alterable factors the cytochrome P450 system. Certain • Use of diuretics* medications may increase the risk of • Effective circulating volume depletion renal toxicity with aminoglycoside use • Use of other nephrotoxic medications (Table 3). • Concomitant use of amphotericin The toxicities of aminoglycosides • Use of ACE (angiotensin converting enzyme) inhibitors† include nephrotoxicity, ototoxicity • Use of nonsteroidal anti-inflammatory agents† (vestibular and auditory) and, rarely, • Radiographic contrast exposure neuromuscular blockade and hypersen- • Use of cisplatin sitivity reactions. Nephrotoxicity receives Unalterable factors the most attention, perhaps because of • Age • Pre-existing renal disease easier documentation of reduced renal function, but is usually reversible. * May cause effective circulating volume depletion † May cause prerenal acute renal failure in the Nephrotoxicity results from renal cortical setting of volume depletion accumulation resulting in tubular cell degeneration and sloughing.10 Examination of urine sediment may reveal dark-brown, fine or granulated casts consistent with acute tubular necrosis but not specific for aminoglycoside renal toxicity. Although serum creatinine levels are frequently monitored during aminoglycoside use, an elevation of serum creatinine is more likely to reflect glomerular damage rather than tubular damage. In most clinical trials of aminoglycosides, however, nephrotoxicity has been defined by an elevation of serum creatinine. Periodic monitoring of serum creatinine concentrations may alert the clinician to renal toxicity. Ototoxicity is usually irreversible. Originally, ototoxicity was believed to result from transiently high peak serum concentrations, resulting in a high concentration of drug in the inner ear. Recent studies in animal models have indicated that aminoglycoside accumulation in the ear is dose-dependent but saturable. Once a threshold concentration of the antibiotic has been reached, increasing the drug concentration results in no further uptake.3 In order to minimize toxicity 1. Aminoglycosides should be used only when their unique antibiotic potency is needed, such as treatment of infection in critically ill patients, and in nosocomial infections or infections with organisms resistant to less toxic therapies. 2. The clinician should change to a potentially less toxic antibiotic as soon as the infecting organism and its antibiotic sensitivities have been determined. 3. Potential risk factors that predispose to nephrotoxicity should be identified and, when possible, corrected (Table 3). 74 Rational Antimicrobial Practice in Pediatrics

CONCLUSIONS Aminoglycosides are important agents of the anti microbial armamentarium most often as adjuncts to other drugs. Toxicity concerns warrant that they should be used with discretion, when other options are not available for the shortest possible duration with careful monitoring and as once daily therapy.

 REFERENCES 1. Gilbert DN. Aminoglycosides. In: Mandell GL, Bennett JE, Dolin R (Eds). Douglas and Bennett’s Principles and Practice of Infectious Diseases. New York: Churchill Livingston. 1995:279-301. 2. Montie T, Patamasucon P. Aminoglycosides: the complex problem of antibiotic mechanisms and clinical applications. Eur J Clin Microbiol Infect Dis. 1995;14:85-7. 3. Chambers HF, Sande MA. The Aminoglycosides. In: Hardman JG, Limbird LE (Eds). Goodman and Gilman’s The Pharmacological Basis Of Therapeutics. New York: McGraw-Hill. 1996:1103-21. 4. Lortholary O, Tod M, Cohen Y, Petitjean O. Aminoglycosides. Med Clin North Am. 1995;79:761-87. 5. Karlowsky JA, Zelenitsky SA, Zhanel GG. Aminoglycoside adaptive resistance Pharmacotherapy. 1997;17:549-55. 6. Swatrz MN. Use of antimicrobial agents and drug resistance. N Engl J Med. 1997;337:491-2. 7. Livornese LL, Slavin D, Gilbert B, Robbins P, Santoro J. Use of antibacterial agents in renal failure. Infect Dis Clin North Am. 2004;18:551-79. 8 Craig WA, Gundmundson S. Postantibiotic effect. In: Lorian V (Ed). Antibiotics in Laboratory Medicine. Baltimore: Williams and Wilkins 1991:403-31. 9 Barclay ML, Begg MJ, Chambers ST. Adaptive resistance following single doses of gentamicin in a dynamic in vitro model. Antimicrob Agents Chemother. 1992;36:1951-7. 10 Ali MZ, Goetz M. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis. 1997;24:796-809. 11 Bailey T, Little J, Littenberg B, et al. A meta-analysis of extended interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis. 1997;24:786-95. 12 Barza M, Ioannidis J, Cappelleri J, et al. Single or multiple daily doses of aminoglycosides: A meta- analysis. BMJ. 1996;312:338-44. 13 Elhanan K, Siplovich L, Raz R. Gentamicin once-daily versus thrice-daily in children. J Antimicrob Chemother. 1995;35:327-32. 14 Marik P, Havlik I, Monteagudo F, et al. The pharmacokinetics of amikacin in critically ill adult and paediatric patients: Comparison of once-daily and twice-daily dosing regimens. J Antimicrob Chemother. 1991;27 (Suppl C): 81-9. 15 Hatala R, Dinh TT, Cook DJ. Single daily dosing of aminoglycosides in immunocompromised adults: A systematic review. Clin Infect Dis. 1997; 24:810-5. 16 Hock R, Anderson RJ. Prevention of drug-induced nephrotoxicity in the intensive care unit. J Crit Care. 1995;10:33-43. 17 Sexton DJ, Tenenbaum MJ, Wilson WR, et al. Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin- susceptible streptococci. Endocarditis Treatment Consortium Group. Clin Infect Dis. 1998;27:1470-4. 18 Choudhury D, Ahmed Z. Drug-induced nephrotoxicity. Med Clin North Am. 1997;81:705-17. 19 Dager W. Aminoglycoside pharmacokinetics: Volume of distribution in specific adult patient subgroups. Ann Pharmacother. 1994;28:944-51. 20 Marangos MN, Nicolau DP, Quintiliani R, et al. Influence of gentamicin dosing interval on the efficacy of penicillin-containing regimens in experimental Enterococcus faecalis endocarditis. J Antimicrob Chemother. 1997;39:519-22. Macrolides, Azalides and Ketolides 75 88 Macrolides, Azalides and Ketolides Niranjan Shendurnikar, Vandana Gopal

 INTRODUCTION The prototype , erythromycin, was isolated in 1952 from the metabolic products of a strain of Streptomyces erythreus obtained from Philippine soil.1 It has been in use since for the treatment of upper respiratory tract and skin and soft tissue infections caused by susceptible organisms, especially in the penicillin-allergic patient. Additionally, erythromycin is effective for the treatment of infections caused by some atypical pathogens, including Legionella, Mycoplasma, and Chlamydia.2 Several drawbacks have, however, limited the use of this naturally occurring macrolide, including erratic bioavailability, frequent gastrointestinal intolerance and a short serum half-life.2,3 Subsequent structural modifications of this parent compound resulted in the development of erythromycin salts with enhanced bioavailability. Advanced macrolide antimicrobials have been synthesized by altering the erythromycin base resulting in compounds with extended spectrum of activity, favorable pharmacodynamics, once-a-day administration, and good tolerability. In 1991 and 1992, the US Food and Drug Administration (FDA) approved two of these agents, and azithromycin, for clinical use. Since their introduction, these advanced macrolides have been used extensively for the treatment of respiratory tract infections, sexually transmitted diseases, and infections caused by Helicobacter and Mycobacterium avium complex.2,3 Other second-generation macrolides include , and . A variety of compounds, which, like erythromycin exist in nature, have been isolated, including , , , and .1 Miocamycin, and and are other macrolides.4 Ketolides, a new class of macrolides, share many of the characteristics of the advanced macrolides. Additionally, their in vitro spectrum of activity includes strains of gram-positive organisms (Streptococcus pneumoniae, Streptococcus pyogenes), which are macrolide- resistant.2 The first member, , specifically developed for the treatment of 76 Rational Antimicrobial Practice in Pediatrics respiratory tract infections, had been approved for clinical use in Europe, and was recently approved by the US FDA for the treatment of mild-to-moderate community-acquired pneumonia (including multidrug-resistant isolates of S. pneumoniae) and acute bacterial sinusitis.2,5

Chemical Structure Erythromycin is a macrolide antibiotic whose structure consists of a macrocyclic 14-membered lactone ring attached to two sugar moieties (L-cladinose and desosamine). In the acidic environment of the stomach, it is rapidly degraded to a hemiketal form and then to the spiroketal form. The hemiketal intermediate may be responsible for the gastrointestinal adverse effects associated with erythromycin.2 The various erythromycin salts include stearate, estolate and ethylsuccinate. Clarithromycin (6-O-methylerythromycin), a semisynthetic macrolide, is a more acid-stable antimicrobial and prevents the degradation of the erythromycin base to the hemiketal intermediate. This results in improved oral bioavailability and reduced gastrointestinal intolerance. Clarithromycin demonstrates equal or better in vitro activity against gram-positive organisms compared with erythromycin.2 Azithromycin, a dibasic 15-membered ring macrolide derivative, is more appropriately referred to as an “azalide”. The structural change makes the compound more stable in acid, significantly increases the serum half-life and tissue penetration, and results in increased activity against gram-negative organisms and decreased activity against some gram-positive organisms when compared with erythromycin. Azithromycin is two- fold to four-fold less active than erythromycin against susceptible gram-positive organisms but the MIC’s are still within achievable therapeutic levels.2 Ketolides, a new group of 14-membered macrolides, are synthesized by the substitution of the characteristic keto group for the L-cladinose moiety at position C3, which promotes greater acid stability and prevents induction of macrolide-lincosamide- B (mLSB) resistance (see later). The prototype, telithromycin, additionally, has an 11, 12 carbamate extension, which enhances binding to the bacterial ribosome and in vitro activity. Telithromycin is two-fold to eight-fold more active against erythromycin-susceptible strains of S. aureus compared with clarithromycin and azithromycin.2, 5

Mechanism of Action and Resistance The macrolides suppress RNA-dependent protein synthesis, inhibit bacterial growth, and generally are considered to be bacteriostatic.6 The macrolide and antimicrobials exert their antibacterial effects by reversibly binding to the 50S subunit of the bacterial ribosome. This interaction inhibits RNA-dependent protein synthesis by preventing transpeptidation and translocation reactions. Both the macrolides and ketolides bind to domain V of the 50S subunit on the 23S ribosomal RNA (rRNA). The ketolides bind with a 10- to 100-fold higher affinity to the ribosome than erythromycin. Additionally, the ketolides, unlike the macrolides, have a greater affinity to bind to domain II of the 50S subunit on the 23S rRNA, enabling it to maintain antimicrobial activity against bacterial strains that are macrolide-resistant because of alterations in the domain V binding site.2,5 Macrolides, Azalides and Ketolides 77

Macrolides and lincomycins resemble each other in binding site, antibacterial activity, and mode of action. Therefore, concurrent use of these antibiotics is not indicated because of competitive inhibition.7 Macrolide resistance principally arises from either an alteration of the drug-binding site on the ribosome by methylation, or by active drug efflux. Altered binding confers high-level resistance to all macrolide, azalide, lincosamide (clindamycin), and streptogramin type B compounds, a phenotype that is known as “mLSB resistance”. Resistance by methylation of an adenine residue in domain V of the 23S rRNA is mediated by the erythromycin ribosome methylase (erm) genes and is the most common mechanism. Methylation prevents binding of the macrolides and ketolides to domain V and results in high-level macrolide resistance (MICs 64 mg/L). Ketolides presumably maintain their antimicrobial activity by virtue of their ability to bind to an alternative site, domain II of the 23S rRNA. Methylase may either be induced or constitutively expressed, and resistance to erythromycin implies cross-resistance to clarithromycin and azithromycin. Telithromycin maintains activity against macrolide-resistant strains of S. aureus that have an inducible 2,6 mLSB gene but not against strains where resistance is constitutively expressed. Both clarithromycin and azithromycin can induce methylase production resulting in resistance. The 3-ketone substitution of telithromycin, however, does not induce methylase production. Limited data are available regarding ketolide-specific mechanisms of resistance.2 Drug efflux, the second important mechanism of macrolide resistance, is mediated by the macrolide efflux (mef) genes and is specific for 14- and 15-membered macrolides. Macrolide resistance is usually low-level (MICs 1–32 mg/L) and in vitro susceptibility to ketolides, , and is maintained.2 Telithromycin is a poor substrate for the efflux pumps that are effective against erythromycin and other macrolides.5 Similar to penicillin resistance, macrolide resistance in vitro may not result in treatment failures for levels of resistance that can be exceeded by tissue levels of certain macrolides chiefly azithromycin.8 Macrolide resistance in S. pneumoniae is most commonly caused by either ribosomal methylation (ermA, ermB) resulting in inducible cross-resistance to lincomycins and streptogramins (mLSB phenotype) or to efflux pumps (mefA, mefE) resulting in variable- level resistance to macrolides alone (M phenotype).9 The increase in macrolide resistance from 10.6% to 20.4% among invasive isolates in the United States from 1995 to 1999 was almost entirely caused by an increase in M phenotype strains.10 The clinical implications of M-type resistance for use of newer macrolides and azalides remains controversial, but these isolates can be treated with clindamycin. Similarly for treatment of community- acquired MRSA infections, clindamycin is often effective, but should be restricted to erythromycin-susceptible isolates (i.e. to those strains with macrolide resistance mediated by efflux and not by methylating enzymes).9 A third mechanism of macrolide resistance, drug inactivation, is believed to be of minor clinical importance.6 Unlike resistance to -lactam drugs, where a gradual, often slight increase in the MIC is seen (because multiple-step changes in the cell-wall -lactam receptors are needed to reach high resistance), resistance of S. pneumoniae to macrolides can be raised with a one-step mutation and is always associated with clinically significant increases in MIC.11 78 Rational Antimicrobial Practice in Pediatrics

Pharmacokinetics and Pharmacodynamics Erythromycin base and its various oral salts (estolate, stearate, ethylsuccinate) are absorbed well from the fasting GI tract. Food reduces absorption of all but the estolate form.6 As erythromycin is degraded in an acidic environment, oral bioavailability is variable and depends on the preparation studied.2 Enteric-coating of erythromycin base overcomes acid lability but can delay therapeutic blood levels (unpredictably) and does not decrease the incidence of common erythromycin GI adverse effects.6 Enteric-coated erythromycin can be taken with food.1 Erythromycin stearate is converted to base in vivo and produces serum levels that are identical to that of uncoated base. The ethylsuccinate salt is used frequently when an oral suspension is needed, because only the estolate and ethylsuccinate salts are available in this dosage formulation. Intravenous administration is associated with phlebitis. Erythromycin is excreted primarily in bile (bile concentrations exceed 10 times those in plasma); only 2% to 5% is excreted in urine. Erythromycin diffuses readily into most tissues except brain and cerebrospinal fluid, crosses the placenta, and is present in breast milk.6 The structural alterations of the erythromycin base used to synthesize the advanced macrolides and ketolides result in improved pharmacokinetic properties. Table 1 shows a comparison of these properties.2 Clarithromycin and azithromycin are more acid-stable and have greater oral bioavailability (55% and 37%, respectively). The oral bioavailability of the suspension formulation of clarithromycin is similar to the equivalent tablet doses. The extended-release formulations of clarithromycin should be administered with food, whereas the immediate-release tablets can be taken with or without food.2 Clarithromycin is biotransformed rapidly to its active, 14-hydroxy metabolite, which peaks 3 hours after administration.6 The bioavailability of the tablet or suspension formulations of azithromycin is not affected by meals.2 The absorption of azithromycin is decreased with food and

TABLE 1 Comparative pharmacokinetics of the ketolide telithromycin and macrolide antibiotics2 Parameter Erythromycin Azithromycin Clarithromycin Telithromycin Bioavailability (%) 25 37 55 57

Cmax (mg/L) 0.3–0.9 0.4 2.1–2.4 1.9–2

tmax (h) 3–4 2 2 1 t½ (h) 2–3 40–68 3–5 7.16–13 AUC (mg · h/L) 8 3.4 19 7.9–8.25

* Mean values after a single 500 mg oral dose (azithromycin or clarithromycin) or 800 mg dose (telithromycin) AUC Area under plasma concentration time curve Cmax Peak serum concentration tmax Time to peak serum concentration t1/2 Serum half-life Macrolides, Azalides and Ketolides 79 therefore, it should be taken 1 to 2 hours before a meal.1 Aluminum- and magnesium- containing antacids reduce the peak serum concentrations of azithromycin but not the total absorption.2 Both clarithromycin and azithromycin may also be given parenterally.3 Oral absorption of telithromycin is excellent (90%); however, 33% of the dose undergoes first-pass metabolism resulting in an absolute oral bioavailability of 57%. The bioavailability, rate, and extent of absorption of telithromycin are unaffected by food.2 The macrolides and ketolides are lipophilic and are extensively distributed in body fluids and tissues.2 Azithromycin is taken up, rapidly and extensively, from the circulation into intracellular compartments, followed by a much slower release.6 Tissue concentrations do not peak until 48 hours after administration of azithromycin and persist for several days afterward.2 The elimination of azithromycin is polyexponential. The initial serum half-life is 11 to 14 hours, followed by a more prolonged half-life of approximately 68 hours as drug is slowly removed from the tissue.1 Clarithromycin concentrates well in tissues (better than erythromycin) but azithromycin’s steady-state tissue or fluid concentrations are substantially higher than serum levels.6 Mean tissue concentrations of clarithromycin are 2- to 20-fold greater than serum concentrations and those of azithromycin 10- to 100-fold greater than serum concentrations. Both drugs are also concentrated in alveolar macrophages and polymorphonuclear cells.2 Azithromycin remains in pulmonary macrophages, tonsillar tissue, and genital or pelvic tissue for extended periods of time with a mean tissue half-life of 2 to 4 days. This feature allows single-dose therapy for STDs and 3- to 5-day regimens for skin, soft tissue, and some respiratory infections.6 The terminal half-life of azithromycin and telithromycin are long enough to allow once- daily dosing. Twice-daily dosing of the immediate-release formulation of clarithromycin is necessary based on the terminal half-life of 4 to 5 hours.2 Like -lactams, vancomycin and clindamycin, macrolides demonstrate time-dependent killing (i.e. longer time with the drug concentration above the MIC of the target organism increases bacterial killing).3 They also have significant post antibiotic effects.12 The goal of the macrolide dosing regimen is therefore to optimize the amount of drug exposure, with the ratio of AUC (area under the serum-concentration-time curve) to MIC being the major parameter correlating with efficacy. For S pneumoniae, the therapeutic goal is to achieve an AUC to MIC ratio of 25–35.12 Clarithromycin is metabolized in the liver by the cytochrome P-450 3A4 (CYP3A4) enzymes to the active 14-hydroxy form and other products. 30 to 40 percent of an oral dose of clarithromycin is excreted in the urine either unchanged or as the active 14-hydroxy metabolite. The remainder is excreted into the bile. In patients with moderate- to-severe renal impairment (i.e. creatinine clearance less than 30 mL/min), the dose should be reduced. In patients with moderate-to-severe hepatic impairment and normal renal function, there is less metabolism of clarithromycin to the 14-hydroxy form resulting in decreased peak plasma concentrations of the metabolite and increased renal excretion of unchanged clarithromycin. Dosing modifications do not seem to be necessary for these patients.2 Azithromycin elimination is primarily in the feces as the unchanged drug and urinary excretion is minimal. Unlike clarithromycin, azithromycin does not interact 80 Rational Antimicrobial Practice in Pediatrics with the cytochrome P-450 system. In patients with mild or moderate hepatic impairment, dosing modifications do not seem to be necessary.2 Telithromycin is eliminated by multiple pathways including unchanged drug in feces (7%) and urine (13%) and the remainder by hepatic metabolism by the CYP3A4 and 1A isoenzymes. Approximately 17% of a single 800 mg (adult) dose is excreted in the urine and the rest in the feces. Dosing modifications are not necessary when administering telithromycin to patients with hepatic impairment because pharmacokinetics is not significantly changed due to a compensatory increase in renal excretion.2

Spectrum of Activity The macrolides have activity against susceptible strains of Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus pyogenes.3 They are generally inactive against MRSA except CA MRSA. Staphylococci and streptococci that are resistant to erythromycin are also resistant to azithromycin and clarithromycin. Telithromycin is more active in vitro against S. pneumoniae compared with clarithromycin and azithromycin and maintains activity against strains that are macrolide-resistant.2 The structural modifications in the newer macrolides broaden the spectrum of activity. Clarithromycin has superior gram-positive activity and azithromycin has superior gram- negative activity when compared to erythromycin. Both newer macrolides have significantly improved effectiveness against Haemophilus influenzae and Moraxella catarrhalis, although clarithromycin’s activity is significant only when combined with its synergistic 14-hydroxy metabolite.6 Clarithromycin itself has activity similar to erythromycin against H. influenzae. When combined with its active metabolite 14-hydroxyclarithromycin, however, synergistic or additive activity occurs and the MIC decreases two-fold to four-fold. Azithromycin and telithromycin are even more active against H. influenzae with a MIC four-fold to eight-fold lower than erythromycin.2 The advanced macrolides and ketolides also demonstrate enhanced activity against other respiratory pathogens. Clarithromycin seems more active than azithromycin and erythromycin against Legionella pneumophila and Chlamydia pneumoniae, whereas azithromycin demonstrates better in vitro activity against Moraxella catarrhalis and Mycoplasma pneumoniae.2 Telithromycin has excellent in vitro activity against Mycoplasma, Chlamydia, and Legionella and is more active compared with the macrolides.2 Telithromycin is also more effective against unusual anaerobes.1 Azithromycin and clarithromycin have similar or increased in vitro activity against genital pathogens compared with erythromycin. Neisseria gonorrhoeae, Haemophilus ducreyi, and Ureaplasma urealyticum are susceptible to both antibiotics with azithromycin demonstrating better activity as evidenced by a lower MIC. Clarithromycin is approximately 10-fold more active than erythromycin against Chlamydia trachomatis, whereas azithromycin activity is similar to that of erythromycin.2 Azithromycin has the best gram-negative activity of the group.3 Azithromycin has activity against enteric pathogens including Escherichia coli, Salmonella spp, Yersinia enterocolitica, and Shigella spp. Clarithromycin and telithromycin have no in vitro activity against these Macrolides, Azalides and Ketolides 81 gram-negative organisms. Azithromycin is more active against Campylobacter jejuni than erythromycin or clarithromycin, whereas clarithromycin has greater activity against Helicobacter pylori.2 Azithromycin also has activity against organisms contracted via animal bites, such as Pasteurella multocida, and human mouth bites, such as Eikenella corrodens.1 Clarithromycin is the most active macrolide against nontuberculous mycobacteria, notably, Mycobacterium avium-intracellulare (MAC), at concentrations that are achievable in lung tissue. Treponema pallidum is susceptible to both newer macrolides.6 Azithromycin has activity equivalent to erythromycin against Toxoplasma gondii.1 It must be remembered that in vitro MIC measurements do not take into account properties of an antimicrobial like tissue penetration, intracellular half-life or postantibiotic effect and thus may not predict its relative efficacy at the site of infection.2 Azithromycin also shows some activity against plasmodia. However, currently, there is no evidence for the superiority or equivalence of azithromycin monotherapy or combination therapy for the treatment of P. falciparum or P. vivax compared with other antimalarials or with the current first-line antimalarial combinations.14 Although it is known that macrolides posses immunomodulatory properties, it is difficult to independently assess the immunomodulatory and antimicrobial effects. Administration of macrolides has been shown to be beneficial in patients with chronic pulmonary inflammatory diseases, including diffuse pan bronchiolitis, cystic fibrosis and asthma. Whether macrolides also exert favorable immunomodulatory effects during acute pulmonary infection is less clear. Moreover, even the exact mechanism of the beneficial effect of macrolides is a matter of debate. In vitro and effects of macrolides show that these drugs can moderate the inflammatory response independent of antibacterial activity.13

Clinical Indications Upper Respiratory Tract Infections Like erythromycin, clarithromycin, azithromycin and telithromycin are effective against the most frequently isolated bacterial causes of acute pharyngitis, otitis media, and sinusitis. The advantage with these newer oral agents is a shorter course of therapy administered conveniently once or twice a day.2 Azithromycin is approved for the treatment of otitis media and pharyngitis. Currently, clarithromycin is approved for the treatment of pharyngitis caused by S. pyogenes. In clinical trials, clarithromycin, azithromycin and telithromycin have been shown to be equally effective as commonly used agents for the treatment of acute sinusitis.2 An area of concern is the increasing macrolide resistance that is being reported with some of the common pathogens, particularly Streptococcus pneumoniae, group A streptococci, and H. influenzae. A longitudinal study conducted in a pediatric population detected the emergence of erythromycin resistance in 50% of pharyngeal isolates of group A streptococci.15 Azithromycin has been demonstrated to perform no better than placebo in the treatment of acute otitis media caused by penicillin-nonsusceptible bacteria. Owing to increasing resistance, the routine use of macrolides in upper respiratory tract infections should be avoided and limited only to patients with significant penicillin allergy.3 82 Rational Antimicrobial Practice in Pediatrics

Lower Respiratory Tract Infections Azithromycin and clarithromycin can be used as initial empiric therapy for community- acquired pneumonia because of the potential presence of atypical bacterial pathogens.6 As infection with an atypical pathogen is unlikely in children two months to five years of age, the recommended treatment in these patients is amoxicillin. A second generation cephalosporin or macrolide is recommended in those who are allergic to penicillin. Macrolides are recommended for the ambulatory treatment of community-acquired pneumonia in children older than five years, because of the increased likelihood of infection with M. pneumoniae or Chlamydia pneumoniae in older children.16 The increasing prevalence of macrolide resistance among S. pneumoniae is a cause for concern if macrolides are used in community acquired pneumonia though clinical failures have been infrequently reported.2 However, certain authorities do not recommend macrolide monotherapy for pneumonia especially if the patient has been hospitalized.6 Continuous macrolide therapy has been recommended for patients with cystic fibrosis. A Cochrane review provides evidence of improved respiratory function after six months of azithromycin. Data beyond six months were less clear, although reduction in pulmonary exacerbation was sustained. Treatment appeared safe over a six-month period; however, emergence of macrolide resistance was a concern.17 Erythromycin (or one of its derivatives) is the drug of choice for Mycoplasma pneumoniae, Legionella pneumophila, diphtheria (also for treatment of carriers and chemoprophylaxis), pertussis (also for chemoprophylaxis) and Chlamydia trachomatis.6 Clarithromycin and azithromycin also have activity against many nontuberculous mycobacteria.3 Telithromycin has a low potential for inducing resistance and has been developed specifically to target the typical (e.g. S. pneumoniae, H. influenzae, M. catarrhalis and Staphylococcus aureus) and atypical (e.g. Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Bordetella) causative pathogens that are most frequently identified in community-acquired respiratory tract infections.5

Pertussis Traditionally, erythromycin has been the first-line agent in the treatment of pertussis and Chlamydia infections in the newborn infant. Its association with an increased risk of hypertrophic pyloric stenosis, however, has prompted some clinicians to use azithromycin instead.3 A 5-day course of azithromycin or a 7-day course of clarithromycin is better tolerated and may be comparable with 14 days of erythromycin when treating pertussis.18

Skin and Soft Tissue Infections Studies have proven the efficacy of erythromycin and the newer macrolides in the treatment of pyoderma, abscesses, infected wounds, ulcers, or erysipelas. Topical erythromycin as a solution or gel has long been one of the standard treatments of acne. Resistance in up to 60% of Propionibacterium acnes has made its use less desirable. Erythromycin (1.5%–2.0%) is more effective than placebo for the treatment of inflammatory acne papules and pustules. Oral azithromycin is also effective in the treatment of acne.1 Macrolides, Azalides and Ketolides 83

Sexually Transmitted Diseases The unique pharmacokinetics of azithromycin, including high tissue concentrations and a prolonged tissue half-life, allows single-dose treatment courses, directly observed therapy, and improved patient compliance. Guidelines published by the US Public Health Service currently recommend either doxycycline, 100 mg twice a day for 7 days, or azithromycin, 1 g as a single dose, for either chlamydial infections or nongonococcal urethritis among adolescents and adults.2 A single 1 g dose of azithromycin is also one of the recommended treatments for genital ulcer disease (chancroid) caused by H. ducreyi. Azithromycin is also efficacious in the treatment of uncomplicated gonorrhea. Gastrointestinal side effects, however, occur frequently with single large doses.2

Helicobacter Pylori Infections Numerous studies have documented the efficacy of clarithromycin in the treatment of H. pylori infections associated with peptic ulcer disease. Antibiotic therapy for H. pylori associated peptic ulcer disease decreases ulcer recurrence and promotes healing.2 Regimens include a proton pump inhibitor, clarithromycin, and either amoxicillin or metronidazole; or ranitidine bismuth citrate, clarithromycin, and either amoxicillin, metronidazole, or tetracycline. Treatment courses are for 14 days and all agents are given twice daily.2

Nontuberculous Mycobacteria Clarithromycin is the most active Mycobacterium avium complex (MAC) antimicrobial agent and should be part of any drug regimen for treating active MAC disease in patients with or without AIDS.1 Clarithromycin and azithromycin have been shown to be effective in preventing and treating disseminated M. avium complex disease in HIV-infected patients.2 Clarithromycin is also the drug of choice for treating infections with rapidly growing mycobacteria including M. chelonae, M. fortuitum and M. abscessus.

Toxoplasmosis Clarithromycin or azithromycin (or clindamycin) may be used (as an alternative to sulfadiazine) in combination with pyrimethamine in the treatment of toxoplasmosis (The macrolide spiramycin is used to treat primary toxoplasmosis in pregnant women).19

Other Uses Erythromycin has a well-established role as an alternative to penicillin, e.g. in the prophylaxis of rheumatic fever and bacterial endocarditis and in the treatment of anthrax and actinomycosis.2 The role of erythromycin as an alternative drug to penicillin, particularly in the prevention of bacterial endocarditis in patients who have underlying cardiac conditions recently has been replaced because of erythromycin-associated GI intolerance and unpredictable blood levels with the various erythromycin formulations. The newer macrolides are considered alternatives.6 84 Rational Antimicrobial Practice in Pediatrics

Erythromycin evokes striking changes in gastric motor activity by its action as a motilin receptor agonist. It has been used in the treatment of gastroesophageal reflux disease for its prokinetic effects.20 Azithromycin has been proposed as effective treatment for enteric fever and shigellosis (See chapter on Antimicrobial Therapy in Enteric Fever). Azithromycin reduces the clinical failure rate and duration of hospital stay in comparison to fluoroquinolones and relapse rate in comparison to ceftriaxone, when used in the treatment of typhoid fever in populations with multidrug resistant typhoid fever.21 Azithromycin has been mentioned as an effective treatment of erythrasma and rosacea as well as in the treatment of donovanosis. It has been used in the treatment of erythema migrans (Lyme disease) but amoxicillin has been found to be superior. Treatment of patients with typical cat-scratch disease with oral azithromycin for 5 days affords significant clinical benefit. Azithromycin and clarithromycin are also effective for treating Mediterranean spotted fever in children. Azithromycin is useful in treating cyclosporine-induced gingival hyperplasia. Oral azithromycin was as effective as ocular tetracycline in treating trachoma and may be more convenient.1 Erythromycin is the drug of choice for Chlamydia trachomatis inclusion conjunctivitis.6

Dosage For erythromycin, the dose is 30–50 mg/kg/day given orally 4–6 hourly. Equivalent dosage of ethylsuccinate to erythromycin base (and the other erythromycin salts) is 400 mg to 250 mg.6 Azithromycin may be administered as 30 mg/kg single dose, 10 mg/kg once daily for 3 days, or 10 mg/kg on the first day followed by 5 mg/kg on days 2 through 5. For the treatment of pharyngitis, azithromycin should be given in the dose of 12 mg/kg per day for 5 days.2 The recommended dose of clarithromycin for streptococcal pharyngitis is 7.5 mg/kg every 12 hours for 10 days. Dosage for treatment of acute maxillary sinusitis is 7.5 mg/kg every 12 hours for 14 days.2 For management of enteric fever azithromycin is dosed as 10–20 mg/kg/day (maximum 1 gm) for 5–7 days. Telithromycin has been employed in the dose of 800 mg once daily for 5–10 days in adults. Specific guidelines for children are awaited.2

Adverse Drug Reactions The most common adverse reactions to erythromycin are gastrointestinal (GI) symptoms, including nausea, vomiting, abdominal cramps and diarrhea. These side effects are dose- related and result from erythromycin’s action on the gastric hormone motilin. Motilin activates duodenal/jejunal receptors to initiate peristalsis. There is a 25% incidence of typical GI symptoms with oral or intravenous administration.6 Antibiotic-associated colitis should be considered in patients with diarrhea that does not resolve on discontinuation of erythromycin.17 There is less GI distress with the newer macrolide.6 Allergic reactions occur rarely (most often with the estolate salt).6 Erythromycin estolate can cause cholestatic hepatitis, which manifests with nausea, vomiting, abdominal pain, jaundice, fever, liver function abnormalities and occasionally eosinophilia.1 It may be Macrolides, Azalides and Ketolides 85 confused with viral hepatitis or acute cholecystitis. It is probably an allergy and recovery is usual.19 The use of the estolate salt is not recommended.2 There have also been reports that erythromycin has been associated with cardiac conduction abnormalities, allergic reactions of a mild to severe nature, skin eruptions that range from mild to severe, and reversible hearing loss. Side-effects of topical erythromycin include erythema, scaling, tenderness, burning, itching, irritation, oiliness and dryness. It is a very weak sensitizer and only a handful of reports of contact dermatitis to it have been published.1 Although both azithromycin and clarithromycin are well-tolerated by children, azithromycin has shorter treatment regimens and improved tolerance which may improve compliance in the treatment of respiratory tract, skin, or soft tissue infections.6 Gastrointestinal intolerance is the primary adverse side effect of these agents, but occurs at a significantly reduced rate when compared with erythromycin. The most common adverse effects reported with azithromycin were diarrhea (3.6%); nausea (2.6%); abdominal pain (2.5%); and headache or dizziness (1.3%). Laboratory abnormalities were infrequent and minor including transient increases in transaminases in 1.5% of patients.22 Adverse events related to the intravenous infusion of azithromycin were pain at the injection site (6.5%) and local inflammation (3.1%).2 A recent large scale retrospective analysis of azithromycin in adults found that the risk of cardiac death was significantly increased with azithromycin compared with no antibiotics or amoxicillin.23 Deaths were more likely in patients with pre-existing risk of heart disease. It would be worthwhile to be cautious with the use of this drug especially in patients with heart disease.23 The most common adverse reactions reported with clarithromycin were similar (e.g. nausea (3.8%), diarrhea (3%), abdominal pain (1.9%), and headache (1.7%).24 There was no difference in the spectrum and frequency of adverse reactions between the extended-release or immediate-release formulations of clarithromycin. Gastrointestinal adverse events with the extended-release formulation, however, tended to be less severe and resulted in fewer discontinuations of the medication. Laboratory abnormalities were also rare and included abnormal liver function tests and decreased white blood cell counts.2 It can also induce mania, especially when given with steroids.1 The most common adverse effects of telithromycin reported were diarrhea (10.8%), nausea (7.9%), headache (5.5%), dizziness (3.7%) and vomiting (2.9%).2 Telithromycin might cause mild-to-moderate and transient visual disturbances, such as blurred vision, difficulty focusing and diplopia.5 Transient blurred vision occurred in 0.6% of telithromycin-treated patients. Clinical trials have shown a small increase in the QTc interval on the ECG with telithromycin.2

Drug-Drug Interactions Erythromycin and clarithromycin are oxidized by the cytochrome P-450 system, primarily the CYP3A4 subclass of hepatic enzymes. This converts the macrolide to a nitrosalkalane metabolite that forms an inactive metabolite-enzyme complex by binding to the iron of the CYP3A4 enzyme. This interaction inhibits the CYP3A4 enzymes resulting in decreased clearance of other agents given concurrently that are metabolized by the same enzyme system.2 Interference with the hepatic CYP3A4 enzyme system is responsible for increased 86 Rational Antimicrobial Practice in Pediatrics blood levels of benzodiazepines (triazolam, midazolam, and alprazolam), carbamazepine, cyclosporine, ergot alkaloids, pimozide, protease inhibitors, ‘statins’, i.e. 3-hydroxy- 3,methylglutaryl-coenzyme A reductase inhibitors (atorvastatin, lovastatin, and simvastatin), tacrolimus, theophylline and warfarin.3,6 Clarithromycin is a less potent inhibitor of the CYP3A4 enzymes than erythromycin. Azithromycin interferes poorly with this system and no major interactions have been reported with azithromycin.2,6 There are case reports, however, of toxicity related to coadministration of azithromycin and lovastatin, warfarin, cyclosporine, disopyramide, and theophylline.25 Erythromycin, troleandomycin and clarithromycin are the most potent inhibitors of carbamazepine metabolism by CYP3A4 enzymes; some patients have up to four times the normal plasma concentration of carbamazepine, which can cause serious toxicity. Macrolides that have reduced (e.g. roxithromycin) or absent (e.g. azithromycin, spiramycin) potential for such interaction are recommended for the treatment of patients receiving carbamazepine. Oxcarbazepine, tiagabine, and felbamate are not affected by coadministration of erythromycin.4 The concurrent use of cisapride, pimozide, terfenadine, and astemizole with clarithromycin is contraindicated because of the possible cardiotoxic effects of these agents and the occurrence of torsades de pointes. Class 1A antiarrhythmic agents (quinidine, disopyramide) too should be used cautiously when given with clarithromycin. Both clarithromycin and azithromycin have been associated with digoxin toxicity.2 A number of case reports have described the interaction of clarithromycin with cyclosporine A, resulting in cyclosporine toxicity. Rhabdomyolysis has occurred secondary to a drug interaction between simvastatin and clarithromycin.1 Clarithromycin may reduce the absorption of zidovudine (AZT) by 20%, whereas azithromycin does not. Data suggest that when the two agents are separated by at least 2 hours, no reduction in zidovudine levels is found. Clarithromycin interacts with rifabutin in such a way that co-administration of the two agents can result in a 50% decrease in the AUC of clarithromycin. The current theory points to enzyme induction secondary to rifabutin administration. When co-administered, desloratadine or fexofenadine increase levels of azithromycin.1 The potential for telithromycin to inhibit the CYP3A4 pathway is comparable with clarithromycin even though metabolism of telithromycin does not result in the formation of nitrosalkalene metabolite. Telithromycin also competitively inhibits the CYP2D6 system. Limited published data are available on potential drug interactions with telithromycin. Telithromycin, however, results in increases in the AUC values of cisapride, theophylline, digoxin, simvastin and midazolam. Caution should be used administering telithromycin with other drugs metabolized by the CYP3A4 enzymes.2

Contraindications and Special Precautions Hypersensitivity to macrolides occurs rarely. Erythromycin estolate should not be used in patients with liver disease.19 Appropriate dose reductions, clinical monitoring and therapeutic drug level monitoring are necessary when drugs metabolized by the CYP3A4 enzymes are given concurrently with macrolides.2 It is recommended that telithromycin be avoided in patients with congenital prolongation of the QTc interval; in those with Macrolides, Azalides and Ketolides 87 ongoing proarrhythmic conditions, such as uncorrected hypokalemia or clinically significant bradycardia; and in patients receiving group 1A (e.g. quinidine and procainamide) antiarrhythmic agents. Postmarketing reports show there have been several cases of exacerbations of myasthenia gravis during treatment with telithromycin, and, therefore, telithromycin is not recommended for patients with this disorder.5

CONCLUSIONS The advanced macrolides (azithromycin and clarithromycin) and ketolides (telithromycin) are structural analog of erythromycin that have similar mechanisms of action. These antimicrobials have several distinct advantages over erythromycin including improved oral bioavailability, longer half-life allowing once- or twice-daily administration, higher tissue concentrations, enhanced antimicrobial activity, and less gastrointestinal adverse effects. Clarithromycin and azithromycin have been used extensively for the treatment of upper and lower respiratory tract infections and shown to have similar clinical efficacy to many other antimicrobials. Between the two azithromycin is cheaper, allows once a day dosing and shorter therapy and has no drug interactions. Treatment guidelines have emphasized the roles of azithromycin in the treatment of certain sexually transmitted diseases, enteric fever, shigellosis and clarithromycin for the treatment of H. pylori–associated peptic ulcer disease. Azithromycin and clarithromycin have been used successfully for preventing and treating disseminated M. avium complex infections in HIV-infected patients.2 Telithromycin has been shown to be effective clinically in the out-patient treatment of respiratory diseases. Theoretically, telithromycin has an advantage over the macrolides because it remains active in vitro against most macrolide-resistant S. pneumoniae isolates.2

 REFERENCES 1. Scheinfeld NS, Tutrone WD, Torres O, Weinberg JM. Macrolides in dermatology. Dis Mon. 2004;50:350- 68. 2. Zuckerman JM. Macrolides and ketolides: azithromycin, clarithromycin, telithromycin. Infect Dis Clin North Am. 2004;18:621-49. 3. Bowlware KL, Stull T. Antibacterial agents in pediatrics. Infect Dis Clin North Am. 2004;18:513-31. 4. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol. 2003;2:473-81. 5. File TM. Telithromycin new product overview. J Allergy Clin Immunol. 2005;115:S1-13. 6. Black DJ, Ellsworth A. Practical overview of antibiotics for family physicians. Clin Fam Pract. 2004;6:265. 7. Mah FS. New antibiotics for bacterial infections. Ophthalmol Clin North Am. 2003;16:11-27. 8. Metlay JP. Antibacterial drug resistance: implications for the treatment of patients with community- acquired pneumonia. Infect Dis Clin North Am. 2004;18:777-90. 9. Kaye KS, Engemann JJ, Fraimow HS, Abrutyn E. Pathogens resistant to antimicrobial agents: Epidemiology, molecular mechanisms, and clinical management. Inf Dis Clin of North Am. 2004;18:467- 511. 10. Hyde TB, Gay K, Stephens DS, Vugia DJ, Pass M, Johnson S, et al. Macrolide resistance among invasive Streptococcus pneumoniae isolates. JAMA. 2001;286:1857-62. 11. Dagan R, Leibovitz E. Bacterial eradication in the treatment of otitis media. Lancet Infect Dis. 2002;2:593- 604. 12. Andes D, Anon J, Jacobs MR, Craig WA. Application of pharmacokinetics and pharmacodynamics to antimicrobial therapy of respiratory tract infections. Clin Lab Med. 2004;24:477-502. 88 Rational Antimicrobial Practice in Pediatrics

13. Meijvis SCA, Van de Garde EMW, Rijkers GT, Bos WJW. Treatment with anti-inflammatory drugs in community acquired pneumonia. J Internal Med. 2012;272:25-35. 14. Van Eijk AM, Terlouv DJ. Cochrane Database Syst Rev. Azithromycin for treating uncomplicated malaria. 2011;16(2):CD006688. 15. Martin JM, Green M, Barbadora KA, Ward ER. Erythromycin-resistant group A streptococci in school children in Pittsburgh. N Engl J Med. 2002;346:1200-06. 16. Thibodeau KP, Viera AJ. Atypical Pathogens and Challenges in Community-Acquired Pneumonia. Am Fam Physician. 2004;69:1699-1706. 17. Southern KW, Barker PM, Solis-MoyaA, Patel L. Cochrane Database Syst Rev. Macrolide antibiotics for cystic fibrosis. 2011;7(12):CD002203. 18. Aoyama T, Sunakawa K, Iwata S, Takeuchi Y, Fujii R. Efficacy of short-term treatment of pertussis with clarithromycin and azithromycin. J Pediatr. 1996;129:761-4. 19. Bennett PN, Brown MJ. Antibacterial Drugs. In: Clinical Pharmacology, 9thedition. Churchill Livingstone. 2003;pp.227-8. 20. Hasler WL. Pharmacotherapy for intestinal motor and sensory disorders. Gastroenterol Clin North Am. 2003;32:707-32. 21. . Shah D. Role of azithromycin in enteric fever. Indian Pediatr. 2009;46:51-2. 22. Hopkins S. Clinical toleration and safety of azithromycin. Am J Med. 1991;91:40S-5S. 23. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Eng J Med. 2012;366:1881-90. 24. Guay DR, Patterson DR, Seipman N, et al. Overview of the tolerability profile of clarithromycin in preclinical and clinical trials. Drug Saf. 1993;8:350-64. 25. Westphal JF. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol. 2000;50:285-95. Quinolones 89 99 Quinolones Indu Khosla, Vishal Mukhija, Vijay V

 INTRODUCTION The era of quinolone antibiotics began with the serendipitous discovery of the prototype quinolone antibiotic, nalidixic acid during the synthesis of the antimalarial agent chloroquine in the early 1960s.1 In the nineties, fluoroquinolones (Quinolones) had become a dominant class of antibiotics in adults because of their excellent tissue penetration and their bactericidal activity. They were however not authorized for pediatric use because of the potential for joint toxicity reported from experiments with young animals. Despite the absence of official approval of the FDA and the Indian drug regulatory authority they are widely used in pediatrics. In the USA alone, the number of annual ciprofloxacin prescriptions for patients younger than 18 years is estimated at 1,50,000; 20% for children less than 1 year of age.2 This article describes the pharmaceutical profile of fluoroquinolones with special reference to the clinical implications.

Mechanism of Action The quinolones act primarily on a group of enzymes called topoisomerases (Type I and Type II). Topoisomerases are a class of enzymes that maintain the cellular DNA molecule in a physicochemically stable and biologically active state as well as play an important role in bacterial DNA replication and safe decatenation of the subsequent daughter chromosome. Type I topoisomerases are active during the replication of single stranded DNA and Type II topoisomerases the double stranded DNA. The quinolones are strong inhibitors of type II topoisomerases (DNA gyrase and topoisomerase IV). DNA gyrase introduces negative supercoils and eliminates positive supercoils that occur ahead of the DNA replication. Topoisomerase IV separates the daughter DNA once replication is completed. DNA gyrase is the primary target of quinolones in gram negative organisms and topoisomerase IV in the gram positive organisms.1,3 Several aspects of the quinolone structure directly influence antibacterial activity (Figure 1). 90 Rational Antimicrobial Practice in Pediatrics

Figure 1: Structure activity relationships1

Spectrum of Activity (Table 1) The first and second-generation quinolones mainly act on aerobic gram-negative rods.3 The third and fourth generation quinolones have been designed to build up range of activity towards the gram-positive organisms and atypical organisms but no change in gram negative activity.

TABLE 1 Classification of quinolones Generation Example Activity First Nalidixic acid Achieves minimal serum levels Second Class 1-Norfloxacin Class 2 have higher tissue concentrations Class 2-Ciprofloxacin Ofloxacin and some action against atypical pathogens Third Sparfloxacin, Gatifloxacin, Expanded activity against gram-positive Levofloxacin, Moxifloxacin bacteria and atypical pathogens Fourth Trovafloxacin Added significant activity against anaerobes

Newer fluoroquinolones such as levofloxacin, moxifloxacin, gatifloxacin and gemifloxacin have excellent intrinsic activity against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and the atypical respiratory pathogens. With respect to penicillin resistant pneumococci, newer FQ MIC’s remain the same in both resistant and susceptible strains. Antipneumococcal activity is present in all newer quinolones with levofloxacin having highest MIC 50–MIC 90 (1-3.13 mcg/mL) and hence relatively lower activity. A recently published study in Canada (1988–1998) has however tracked a decreased susceptibility to FQ’s in S. pneumoniae probably due to increased prescriptions. Newer quinolones also have activity against group A and group B hemolytic streptococci. Both the older and Quinolones 91 newer quinolones have excellent activity against all aerobic gram negative bacilli. As far as antipseudomonal activity is concerned ciprofloxacin is the best.1, 3 All quinolones have moderate activity against Mycobacterium tuberculosis, the best being moxifloxacin. The quinolones however do not have any activity against Nocardia and Treponema. Trovafloxacin is the only quinolone specifically approved for use in the treatment of anaerobic infections; but rarely prescribed because of hepatotoxicity. Gati, moxi and sparfloxacin have demonstrated in vitro activity, but have not been studied in diseases caused by anaerobes.

Mechanisms of Bacterial Resistance4-7 Resistance to quinolones may occur via mutations in chromosomal genes or via mutations in plasmids. Mutations in chromosomal genes occur in genes that: 1. Encode the subunits of DNA gyrase and topoisomerase IV (altered target mechanism) 2. Regulate the expression of cytoplasmic membrane efflux pumps or proteins that constitute outer membrane diffusion channels (altered permeation mechanism) Plasmid mediated resistance can occur by following means K. pneumoniae, E. Coli and other enteric bacteria may express Qnr proteins which protects DNA gyrase from quinolones. These usually cause development of a low level resistance. However they may be accompanied with additional chromosomal mutations or other plasmid based resistance methods. In one study, 313 ceftazidime-resistant Enterobacteriaceae isolates collected in the United States between 1999 and 2004 were screened for the known qnr genes.5 A qnr gene was present in: • 20 percent of K. pneumoniae isolates • 31 percent of Enterobacter spp isolates • 4 percent of E. coli isolates A fluoroquinolone-modifying enzyme evolved by mutation of a plasmid-encoded gene for an aminoglycoside acetyltransferase; this mediates low-level resistance to ciprofloxacin, as well as high-level resistance to tobramycin and amikacin. This enzyme variant has been present since at least 1999 and is now widely disseminated in enteric gram-negative bacteria such as E. coli, Klebsiella spp, and Enterobacter spp in the United States. A plasmid-encoded efflux pump, QepA, which pumps fluoroquinolones such as norfloxacin and ciprofloxacin out of the cell, confers low-level resistance. Isolates encoding the QepA protein have been found in Europe, Japan, China, and North America, but usually only in low frequency. Another plasmid-encoded efflux pump, OqxAB, has been found in E. coli isolates from humans and swine.

Pharmacokinetics The pharmaco kinetic profile of the commonly used quinolones are given in Table 2. Quinolones achieve high concentrations in kidneys, lung and gall bladder. Similar concentrations are also achieved in bone and CSF. The frequently used doses of fluoroquinolones in children appear in Table 3 which have been deduced from adult doses. 92 Rational Antimicrobial Practice in Pediatrics

TABLE 2 Pharmacokinetics and pharmacodynamics of quinolones Pharmacokinetic Ciprofloxacin Norfloxacin Ofloxacin Levoflox Gatiflox Moxiflox property Oral bioavailability 60-80 35-45 85-95 99 98 90 (%) Plasma protein 20-35 15 25 40 20 50 binding (%) C max (mg/mL) 5.2 3.4 3.1 AUC (mg/h/L) 47.7 32.4 30.8 Elimination 3-5 4-6 5-8 7 9 13 half life (Hrs) Route of Oral/IV Oral/IV Oral/IV Oral/IV Oral/IV Oral/IV administration Route of Hepatic, Hepatic, Renal Renal Renal Hepatic elimination renal renal

TABLE 3 Dosages of commonly used quinolones Drug Route Dose (mg/kg/ dose) Frequency Ciprofloxacin Oral 15 Q12 hours IV 10 Q12 hours Norfloxacin Oral 5-7.5 Q12 hours Ofloxacin Oral 7.5 Q12 hours IV 7.5 Q12 hours Gatifloxacin Oral 10 Q24 hours Levoflox Oral 10 Q24 hours IV 10 Moxiflox Oral 10 Q24 hours IV 10

Clinical Pharmacology/Pharmacodynamics The FQ’s are bactericidal antibiotics. They display a concentration dependent killing effect. Schentag et al have described a relationship between the ratio of area under the curve (AUC) and the minimal inhibitory concentration (MIC) called area under the inhibitory curve. (AUIC). To achieve maximal therapeutic benefit, the peak to MIC ratio should be maintained at >8–10 and the AUIC should be  125 for gram negative organisms and 30 for gram-positive organisms. In addition, to prevent the development of resistance maintenance of peak to MIC ratio at 10 or AUIC 125 for gram negative organisms and 50 for gram-positive organisms is necessary.1 Quinolones 93

Clinical Indications8-20 Indications in which fluoroquinolones may be useful in children include those in which 1. Infection is caused by multidrug-resistant pathogens for which there is no safe and effective alternative and 2. Parenteral therapy is not feasible and no other effective oral agent is available. Appropriate uses should be limited to the following: • Exposure to aerosolized Bacillus anthracis to decrease the incidence or progression of disease (FDA licensed) (evidence grade III; see Table 4); • Urinary tract infections caused by P. aeruginosa or other multidrug-resistant, gram- negative bacteria (FDA licensed for complicated E. coli urinary tract infections and pyelonephritis attributable to E. coli in patients 1–17 years of age) (evidence grade II–2); Use of quinolones for prophylaxis though effective, is associated with risk of increased resistance • Chronic suppurative otitis media or malignant otitis externa caused by P aeruginosa (evidence grade II–3); Lang et al used ciprofloxacin to treat 21 patients with chronic suppurative otitis media and previous treatment failure: 86% were cured at the end of the treatment, but one third relapsed. Fluoroquinolones have been used to treat acute otitis media as well. The excellent microbiological, pharmacokinetic, and pharmacodynamic characteristics of the new fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin, and gatifloxacin) have encouraged their growing use, probably contributing to the emergence of fluoroquinolone–resistant pneumococci.2 Although pneumococcal resistance to new fluoroquinolones is currently low, there is still concern about the potential for widespread emergence of resistance to these agents if they are indiscriminately used. • Chronic or acute osteomyelitis or osteochondritis caused by P aeruginosa (not for prophylaxis of nail puncture wounds to the foot) (evidence grade III). • In cystic fibrosis bronchopulmonary infections with Pseudomonas aeruginosa and S. aureus are a major cause of morbidity and mortality. There is now unanimous support for the treatment of P. aeruginosa pulmonary super infections in children with cystic fibrosis by ciprofloxacin, but in higher doses (40–60 mg/kg/day). • Mycobacterial infections caused by isolates known to be susceptible to fluoroquinolones (evidence grade III); Recent data suggest that the newer quinolone moxifloxacin is superior to the older quinolones for MDR TB. • Gram-negative bacterial infections in immunocompromised hosts in which oral therapy is desired or resistance to alternative agents is present (evidence grade II–1); • Gastrointestinal tract infection caused by multi drug resistant Shigella species, Salmonella species, Vibrio cholerae, or C. jejuni (evidence grade II–2); However, strains with intermediate resistance to fluoroquinolones have also been described. Quinolones were considered as the treatment of choice in enteric fever with rates of clinical and bacteriological failure of less than 1%. However, studies from various parts of the Indian subcontinent and South East Asia show increasing resistance to quinolones 94 Rational Antimicrobial Practice in Pediatrics

with prolonged defervescence and high rates of clinical failure. Other indications include non typhoidal Salmonella osteomyelitis and meningitis particularly in patients with sickle cell anemia. • Documented bacterial septicemia or meningitis attributable to organisms with in vitro resistance to approved agents or in immunocompromised infants and children in whom parenteral therapy with other appropriate antimicrobial agents has failed (evidence grade III); and • Serious infections attributable to fluoroquinolone-susceptible pathogen(s) in children with life-threatening allergy to alternative agents (evidence grade III).

Adverse Drug Reactions21-25 The restriction of quinolone use and paucity of prospective studies has limited safety data in children. Most studies seem limited to detailing and retrospectively analyzing incidents reported to the drug monitoring agencies. However, in view of the severity of the clinical situation that leads to the prescription of a quinolones in children and the multiplicity of clinical events possible, studies should include control groups with the same disease but receiving other antibiotics. See Table 4 for summary of side effects.

Articular Side Effects in Children Quinolone induced cartilage toxicity in immature animals has been the basis for non- approval of their use in children. Experience with quinolones in children has been reported in more than 10,000 cases (many of them having cystic fibrosis). The incidence of quinolone associated arthropathy (QAA) in children remains uncertain. Arthralgia and arthropathy have been described in adults and children with cystic fibrosis. QAA has been rarely reported in children without cystic fibrosis, the overall incidence being around 1%. In most children with cystic fibrosis, concurrent joint disease has also been ascribed to hyperimmune mechanisms or the so-called cystic fibrosis arthropathy or hypertrophic pulmonary osteoarthropathy. The occurrence of arthralgia has not been reported to be greater than expected as a result of cystic fibrosis. Also none of the evaluated quinolones had a negative effect on the linear growth of children. Additionally by the mid nineties, 1795 case reports of juveniles treated with ciprofloxacin were published, of which 1.5% developed arthralgias or arthritis, but no unequivocal cases of arthropathy. Although further research is needed to clearly establish the safety of quinolone in pediatric patients, the potential therapeutic benefits should be considered in relationship to low probability of debilitating adverse effects. Tendinitis and tendon rupture are also adverse effects of quinolones. The mechanism is unclear. Pefloxacin and ciprofloxacin have a high tendency to cause tenotoxicity while ofloxacin and levofloxacin have low potential for causing this effect. The symptoms are joint pain and swelling followed by difficulty in movement. Rupture of the involved tendons has been reported and can cause permanent disability. The symptoms may start within one to two days after starting therapy. Tendinitis resolves in a few weeks but may persist over months. Quinolones 95

TABLE 4 Adverse drug effects of commonly used quinolones System Specific adverse drug reactions Prototype Drug CVS Hypotensiontachycardiaprolonged QT interval Sparfloxacin CNS Headachedizzinesssleep disturbancesmood Ciprofloxacin changesconfusionpsychosistremorsseizures Skin Rashespruritusphotosensitivityurticarias Lomefloxacin GIT Nauseavomitingdiarrheaepigastric pain Grepafloxacin Liver Increased transaminasescholestatic jaundicehepatitis Trovafloxacin Musculoskeletal Arthropathiestendonitistendon rupture Pefloxacin Renal Azotemiacrystalluriashematuriainterstitial nephritis renal failure Levofloxacin Others Feverschillsangioedemasanaphylaxis -

TABLE 5 Quality of evidence I Evidence obtained from at least 1 properly randomized controlled trial II–1 Evidence obtained from well-designed controlled trials without randomization II–2 Evidence obtained from well-designed cohort or case-control analytic studies, preferably from1 center or research group II–3 Evidence obtained from multiple time series with or without the intervention; dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence III Opinions of respected authorities that are based on clinical experience, descriptive studies, and case reports or reports of expert committees

Specific Non-articular Side Effects of Quinolones The adverse drug reactions associated with quinolones include gastrointestinal, CNS side effects, phototoxicity, renal effects, hepatic effects, mutagenicity, and cardiotoxicity. Most of these are mild and considered to be class effects. However, more serious effects that infrequently occur seem to be an idiosyncratic reaction; e.g. hemolytic uremic syndrome with temafloxacin, hepatic reactions with trovafloxacin (leading to banning of these drugs). The effects on the central nervous system are a real risk for children and are probably underestimated (incidence close to 3–6%). Intracranial hypertension is a known side effect of nalidixic acid in young children. Other side effects include dizziness, drowsiness, and headaches; sleep disorders, delirium and seizures, which occur as a result of direct action on GABA and NMDA receptors. Photo sensitive reactions caused by quinolones are predominantly phototoxic in nature, but typical photo allergic features can also be demonstrated with certain quinolones such as nalidixic acid, enoxacin and lomefloxacin. The reported incidence of phototoxicity ranges from <0.05% (ciprofloxacin)1 as high as 19% for a high dose fleroxacin. 96 Rational Antimicrobial Practice in Pediatrics

Minor gastrointestinal problems, diarrhea, nausea and abdominal pain are common at a frequency ranging from 2 to 4%. The principal cardiac risk associated with quinolones toxicity is an increased QT interval. This effect involves the entire class although the risk is higher for some compounds, such as Grepafloxacin (withdrawn in 1999). Transient renal failure with increased creatinine levels is another side effect infrequently seen in children.

Clinical Significant Drug Interactions The absorption of all quinolones can be altered by the co administration of divalent or trivalent cation containing agents. Aluminium, magnesium, iron, calcium and zinc containing products most commonly result in significant decreases in the bioavailability. Some of the quinolones inhibit the cytochrome P450 1A2 isozyme, responsible for metabolism of methyl xanthines derivatives including theophylline. Enoxacin, ciprofloxacin and grepafloxacin have been shown to reduce the total body clearance of theophylline. This may result in increase in serum levels of theophylline by 30–84% and can cause theophylline toxicity, manifested as nausea, vomiting, and seizures. Moxifloxacin does not inhibit the metabolism of theophylline.3 Quinolones also increase the levels of warfarin and other coumarin derivatives.

Contraindications Quinolones are contraindicated in persons with a history of hypersensitivity to ciprofloxacin or any member of the quinolone class of antimicrobial agents. They are also contraindicated in children with seizure disorders.

CONCLUSIONS The quinolones are a valuable addition to our armamentarium of antibiotics. The class of drugs would continue to grow with time. Each new addition would bring with it a unique spectrum of activity, safety and tolerability profile. Clinicians must remain abreast with these particular aspects so that their clinical applications are appropriate. Despite rare, specific problems associated with individual quinolones, this class of antibiotics generally is well tolerated and effective and the safety data in children seem to be similar to those in adults. A number of controversies however exist due to observations of joint toxicity in animals. The increasing use of quinolones in pediatric infections has been associated with good results with no clear demonstration of chondrotoxicity. Quinolones are indispensable in children with cystic fibrosis and multidrug resistant tuberculosis and recommended in children with complicated UTI’s, shigellosis, non-typhoidal Salmonella infections and when the isolate is nalidixic acid susceptible in enteric fever. The newer quinolones though excellent for respiratory tract infections, should be used only as second line drugs owing to fear of drug resistance and as other alternatives are available. Quinolones 97

 REFERENCES 1. O’Donnell JA, Gelone SP. The newer fluoroquinolones. Infect Diseases Clin N Am. 2004;18:691-716. 2. Nelson JD, McCracken GH. Fluoroquinolone use in children. Pediatr infect dis J. 2002;21:A7-8. 3. O’Donnell JA, Gelone SP. FluoroQuinolones. Infect Diseases Clin N Am. 2000;14:489-513. 4. Garau J, Xercavins M, Rodriguez-Carballeira M, et.al. Emergence and dissemination of quinolone resistant E Coli in the community. Antimicrob agents chemother. 1999:43:2736-41. 5. Robicsek A, Strahilevitz J, Sahm DF, et al. qnr prevalence in ceftazidime; resistant Enterobacteriaceae isolates from the United States. Antimicrob Agents Chemother. 2006;50:2872. 6. Polk RE, Johnson CK, McClish D, et al. Predicting hospital rates of fluoroquinolone-resistant Pseudomonas aeruginosa from fluoroquinolone use in US hospitals and their surrounding communities. Clin Infect Dis. 2004;39:497. 7. Hooper DC. Fluoroquinolone resistance among Gram-positive cocci. Lancet Infect Dis. 2002;2:530. 8. The Use of Systemic Fluoroquinolones Pediatrics Vol.118 No.3 pp.1287-92. 9. Gendrel D, Chalumeau M. Fluoroquinolones in pediatrics: a risk for the patient or for the community? The Lancet Infectious diseases. 2003;3:537-45. 10. Blondeau JM. Expanded activity and utility of new fluoroquinolones: a review. Clin Ther. 1999;21:3. 11. Parry CM, Hien TT, et al. Typhoid fever. N Engl J Med. 2002;347:1770-82. 12. Harish BN, Menezes GA. Antimicrobial resistance in typhoidal salmonellae. Indian J Med Microbiol. 2011;29(3):223-9. 13. Petrilli AS, Dantas LS, et.al. Oral Ciprofloxacin versus intravenous ceftriaxone administered in out patient setting for fever and neutropenia in low risk pediatric oncology patients. A randomized prospective trial. Med Pediatr Oncol. 2000:34:87-91. 14. Patrick CC. Use of fluoroquinolones as prophylaxis in patients with neutropenia. Pediatr Infect Dis J. 1997;16:135-9. 15. Alghasham AA, Nahata MC. Clinical use of FluroQuinolones in children. Annals of pharmacotherapy. 2000; 34:347-59. 16. Church DA, Kanga JF Kuhn RJ, et.al. Sequential Ciprofloxacin therapy in pediatric cystic fibrosis: comparative study versus ceftazidime /tobramycin in the treatment of acute pulmonary exacerbations. Pediatr Infect Dis J. 1997;16:97. 17. Richard DA, Nousia–Arvanitakis S, et.al. Oral ciprofloxacin vs. intravenous ceftazidime plus tobramycin in pediatric cystic fibrosis patients: comparison of anti pseudomonas efficacy and assessment of safety with ultrasonography and MRI. Pediatr Infect Dis J. 1997;16:572-8. 18. Sher L, Arguedas A, Husseman, et.al. Randomized, investigator-blinded, multicenter, comparative study of gatifloxacin versus amoxicillin/clavulanate in recurrent otitis media and acute otitis media treatment failure in children. Pediatr Infect Dis J. 2005;24:301-8. 19. Schaad UB, Wedgwood J, Ruedeberg A, Kraemer R, Stevens JC, Mampel B. Ciprofloxacin as antipseudomonal treatment in patients with cystic fibrosis. Pediatr Infect Dis J. 1997;16:97-105. 20. Centers for Disease Control and Prevention (CDC). Update to CDC’s sexually transmitted diseases treatment guidelines,2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR Morb Mortal Wkly Rep. 2007;56:332. 21. Hayem G, Carbon C. A reappraisal of quinolone tolerability: The experience of their musculoskeletal adverse effects. Drug safety. 1995;13:338-42. 22. Prieur BL. Ciprofloxacin and Tenosynovitis. The Lancet. 1988;2:162-70. 23. Pierfitte C, Royer RJ. Tendon disorders with fluoro quinolones. Therapie. 1996;1:419-20. 24. Szarfman A, Chen Mblum MD. More on FluoroQuinolones antibiotics and tendon rupture. N Engl J Med. 1995;332:193. 25. Chalumeau M, Tonneliere. Fluoroquinolones safety in pediatric patients: a prospective multicenter cohort study in France. Pediatrics. 2003;111:e714-9. 98 Rational Antimicrobial Practice in Pediatrics 1010 Glycopeptides, Oxazolidinones and Daptomycin Pallavi Bhargava, Vivek Kak, Tanu Singhal

 INTRODUCTION This chapter discusses drug therapy of gram-positive infections chiefly MRSA. While vancomycin has been the gold standard drug for the past several year, many new drugs for MRSA and resistant enterococcal infections have been introduced. Notable among these is daptomycin. Several other agents including quinipristin dalfopristin are not discussed further as they are not currently available in India.

 VANCOMYCIN Vancomycin is a large complex glycopeptide that was first isolated in 1956 from a sample of soil that contained the organism Nocardia orientalis.

Mechanism of Action The drug exerts its antimicrobial action by restricting cell wall synthesis in susceptible organisms by preventing formation of the required for the bacterial cell wall. The amino acids in these peptidoglycans terminate in D-alanyl-D-alanine residue manner and vancomycin binds to these residues and prevents elongation of the peptidoglycan backbone. Vancomycin may also impair RNA synthesis. The drug exhibits time dependent killing with moderate persistent effects and the 24 hours AUC/MIC ratio has been described the optimum PK-PD parameter.

Spectrum of Activity Vancomycin is primarily a drug with activity against gram-positive organisms. With the exception of certain Neisseria species (not gonorrhoea or meningitidis) and Flavobacterium meningosepticum, it has no gram-negative activity. Vancomycin has no activity against mycobacteria, rickettsiae or chlamydia. Glycopeptides, Oxazolidinones and Daptomycin 99

The drug is slowly bactericidal against sensitive organisms; however, enterococci are only inhibited and not killed if the drug is used alone with achievable serum concentrations. The combination of vancomycin and an aminoglycoside is bactericidal against enterococci unless high-level aminoglycoside resistance is present. Its spectrum of activity includes both methicillin-sensitive and resistant strains of S. aureus and most strains of coagulase-negative staphylococci. These organisms have vancomycin MIC’s in the range 0.25 to 4.0 mg/L. There have been case reports of coagulase-negative Staphylococcus resistant to vancomycin from the late 1980’s however these are still fairly rare. Streptococci, including viridans species, anaerobic and microaerophilic strains, and penicillin-sensitive and resistant pneumococci are all susceptible to vancomycin. The clinically achievable levels of vancomycin in serum inhibit most strains of Listeria monocytogenes, however, therapeutic failures have been reported and the authors do not recommend this drug for Listeria infections, especially of the central nervous system (CNS). The nondiphtheroid corynebacteria including C. jeikeium are susceptible in vitro to vancomycin. The anaerobic spectrum of vancomycin includes anaerobic and microaerophilic Streptococcus, and Clostridia species, including both C. perfringens and C. difficile. The susceptibility of actinomycetes is variable. The clinician should be aware of gram-positive organisms, that should be considered intrinsically vancomycin resistant unless shown to be otherwise by MIC’s. These include opportunistic pathogens like Lactobacillus, Leuconostoc, Pediococcus and often Listeria.

Drug Resistance Acquired resistance to vancomycin was unusual until the late 1980’s, when reports of enterococci resistance to glycopeptides were reported. Vancomycin resistant enterococci (VRE) usually are Enterococci faecium but vancomycin resistance has also been seen in E. faecalis, E. gallinarum, E. casseliflavus, E. avium. The mechanism of resistance in these organisms is usually due to a change in the amino acids at the site of action of vancomycin. Instead of the peptidoglycan ending in D-alanyl-D-alanine bipeptide the drug resistant organism’s bipeptide terminates in D-alanyl-D-lactate. This removes the site for vancomycin to bind and causes the organism to become resistance to the drug. Beside enterococci, over the last 5 years, this mechanism of resistance has also been recently reported in a few clinical strains of Staphylococcus aureus. These strains, the first isolates of Staphylococcus aureus truly vancomycin resistant have been labeled as VRSA, were first seen in a patient in USA who was infected with a methicillin resistant Staphylococcus aureus (MRSA) isolate and had concomitant isolation of a vancomycin resistant enterococci (VRE) from wounds and stool. The Van A gene complex, which mediated the vancomycin resistance in VRE was transferred to the MRSA isolate leading to Staphylococcus aureus isolate that was both MRSA as well as vancomycin resistant. Prior to this, there had been isolates of Staphylococcus aureus that had reduced susceptibility to vancomycin labeled as vancomycin or glycopeptide-intermediate S. aureus (VISA/ GISA). These isolates become less susceptibile to vancomycin by increasing their cell 100 Rational Antimicrobial Practice in Pediatrics wall size with increased production of D-alanyl-D-alanine bipeptides in its peptidoglycan cell wall. Vancomycin binds to these bipeptides and is unable to reach in a sufficient amount at the level of the cytoplasmic membrane leading to a decreased susceptibility. It is important to note that the major factor that has driven the rise of both methicillin/oxacillin resistance in Staphylococcus aureus as well as VRSA is the use/ overuse of vancomycin in the hospital setting. Thus, it is imperative that the drug be used carefully and if culture results show that therapy can be simplified, it be done as soon as possible.

Pharmacokinetics The drug is primarily used in intravenous form. The oral route may be effectively used for treating pseudomembranous colitis but cannot be used for treating systemic infections, as there is minimal to no absorption of the drug from the gastrointestinal (GI) tract. However, in exceptional circumstances in individuals with both inflammation in the GI tract and renal failure, administration of vancomycin orally may result in potentially high serum concentrations of vancomycin. The drug can be used intraperitoneally for treating Continuous Ambulatory Peritoneal Dialysis (CAPD) associated peritonitis. The intramuscular route of administration causes severe pain and should not be used. When treating systemic infections in critically sick patients, vancomycin is administered using a loading dose by slow intravenous therapy to avoid infusion related side effects. The duration of the dose should be longer than 1 hour. The pharmacokinetic distribution of vancomycin is consistent with two or three compartment model, with an initial distribution phase followed by an intermediate half-life of approximately one hour. The half-life varies between three to eleven hours in patients with normal renal function. The drug does have a significant post antibiotic effect, which has been demonstrated both in-vitro and in vivo. At a steady state, drug levels above 75% of serum levels are achievable in synovial, ascitic and pericardial fluid. Vancomycin also achieves good levels in pleural fluid, and in bile. It, however, does not achieve good cerebrospinal fluid (CSF) levels, except in the presence of meningeal inflammation. The degree of vancomycin penetration of the CSF increases in direct proportion to the severity of meningeal inflammation, but we suggest using higher doses of 15 mg/kg to treat patients with meningitis. When used intra-peritoneally greater than 50% of the drug can be found in the serum suggesting significant systemic absorption. The drug has good bone penetration, enough to treat osteomyelitis, however, its lung parenchymal penetration is controversial. This low penetration in lungs is suggested as a cause of vancomycin’s failure in severe MRSA (methicillin resistant Staphylococcus aureus) pneumonias. The drug is excreted primarily unchanged by the kidneys by glomerular filtration, and as renal function declines, its half-life increases and may exceed seven days in patients with no renal function. Monitoring of vancomycin drug levels is recommended in presence of renal failure, patients on hemodialysis and those with rapidly changing renal function. Glycopeptides, Oxazolidinones and Daptomycin 101

Indications Vancomycin is indicated for use for serious infections due to susceptible bacteria. As the above spectrum of activity discussion indicates, these would be infections caused by most gram-positive bacteria with the exception of those caused by Leuconostoc, Lactobacillus, Pediococcus and often Listeria. The main utility of the drug is to treat infections caused by MRSA, ampicillin-resistant enterococci and for serious infections caused by penicillin resistant pueumococci. It is also used to treat gram-positive infections in patients who are unable to tolerate beta-lactam antibiotics due to side effects. The drug can be used for infections such as endocarditis, bacteremias, brain abscesses, meningitis, ventriculitis, osteomyelitis, septic arthritis, peritonitis, renal infections and skin and soft tissue infections such as cellulitis and pyomyositis. The drug is indicated for use in meningitis but physicians using it should be aware of its poor penetration into CSF and patients should be carefully monitored for any signs of therapeutic failure. Similar caveats should be followed when using the drug for pneumonias due to its poor penetration into pulmonary tissue. The addition of a second drug such as an aminoglycoside or rifampin is often suggested by the authors when treating infections with vancomycin if the clinical response is slow especially endocarditis, osteomyelitis and or pneumonia or if prosthetic material is present. Vancomycin is used for treatment of pseudomembranous colitis caused by C. difficile. It is also used in persistent fevers in neutropenic patients especially those with central venous catheters or other invasive lines. Vancomycin is useful for the prevention of bacterial endocarditis in high risk, penicillin- allergic patients undergoing dental, oral or upper respiratory tract procedures and American Heart Association also recommends vancomycin in combination with gentamicin for gastro-intestinal and genitourinary procedures. Vancomycin is also used for surgical prophylaxis when prosthetic materials are being implanted into patients known or suspected of being colonized with MRSA.

Dosage In adult patients with normal renal function, a dose of 15–20 mg/kg every 8–12 h is the usual dose of vancomycin. The peak serum levels with a dose of 1 g every 12 h is usually between 20–40 mg/L and trough levels are between 5–10 mg/L. These are usually considered desirable therapeutic levels to treat gram-positive infections. Weight based dosing should be followed to avoid underdosing in obese individuals; maximum individual dose is 2 g. In patients who are very sick and with severe infections, a loading dose of 20–30 mg/kg may be given; the efficacy of loading dose is uncertain. In children with normal renal function, fixed dosage can be based on age as follows: < 1 week, 15 mg/kg every 12 h; 8-30 days, 15 mg/kg every 8 h; >30 days, 10 mg/kg every 6 h. Vancomycin doses in premature infants are based on gestational age as follows: < 27 weeks, 27 mg/kg every 36h; 27-30 weeks, 24 mg/kg every 24 h; 31–36 weeks, 18 mg/kg every 24 h, >37 weeks, 22.5 mg/kg every 12 h. 102 Rational Antimicrobial Practice in Pediatrics

Vancomycin is virtually completely eliminated by the kidney, and since vancomycin elimination correlates directly with creatinine clearance, the dosage can be based on creatinine clearance rather than on a simple determination of serum creatinine level. With decrease in creatinine clearance the duration of the interval between doses can be progressively increased from 12 hours based on the drop in the clearance. Thus, vancomycin dosing in the elderly usually requires dose modification based on their drop in creatinine clearance. Regardless of the dosing regimen and interval, vancomycin dose should be adjusted according to the serum levels of the drug, as there is significant inter individual pharmacokinetic variation in these age groups. In terms of monitoring serum levels, the trough of the drug should be monitored on a regular basis to adjust the interval of administration and for achieving therapeutic levels. Routine monitoring of the peak serum level is not beneficial unless treating meningitis. Patients on hemodialysis should be given 1 g IV every 4–5 days. Vancomycin dose can be repeated if necessary by monitoring serum vancomycin levels. Patients on CAPD can receive a loading dose of 30 mg/kg intraperitoneally, followed by 1.5 mg/kg in each peritoneal exchange or 7 mg/kg once daily. An option of using continuous vancomycin infusion giving a dose of around 2.5 grams a day is used in parts of Europe and has efficacy similar to traditional divided dosing. The suggested daily dose for intrathecal administration of vancomycin is 5–10 mg every 48–72 hrs. Higher initial dose of 5–10 mg/d in infants and 15–20 mg/d in children and adults for treatment of meningitis, ventriculitis and shunt infection is recommended. When used orally for treatment of C. difficile colitis the dose is generally 250 mg four times a day. The duration of treatment with the drug is dependant entirely on the nature of the infection and the infecting organism. Two weeks therapy is recommended for simple bacteremias, pneumonia, pyelonephritis. Longer duration of therapy of 4–6 weeks is necessary for endocarditis, meningitis and brain abscess and staphylococcal pneumonias.

Side Effects The initial preparations of vancomycin contained large amounts of impurities, and it was termed “Mississippi Mud” because of its brown discoloration. These impurities also led to significant side effects and thus early reports in the literature list a lot of side effects of the drug. With improvements in the manufacturing process of the drug these side effects have also decreased. The most common side effect is the so-called “Red-man syndrome”. It is an infusion rate related event and occurs 10–20 minutes after the start of infusion. The patient complains of itching and flushing of skin over the upper part of the body. This reaction occurs due to vancomycin mediated histamine release and can be minimized and prevented by slowing the infusion rate. The occurrence of this reaction does not constitute vancomycin allergy and does not preclude its use. Vancomycin allergy though rare does occur and usually manifests as hypotension and urticarial rash. Glycopeptides, Oxazolidinones and Daptomycin 103

The incidence of nephrotoxicity due to vancomycin was initially reported as high as 25% but is generally considered a vast overestimation because of confounding factors in those studies. It is estimated that in individuals receiving vancomycin alone, the rate of reversible nephrotoxicity is less than 5%. However, in individuals receiving vancomycin with an aminoglycoside the risk of nephrotoxicity is enhanced and these patients need to have both drugs carefully monitored by drug levels and estimation of renal function. A retrospective review has suggested that vancomycin nephrotoxicity is associated with serum trough > 15 mg/L. Vancomycin associated ototoxicity like tinnitus, vertigo and hearing loss are usually associated with high serum levels (> 40 mg/L) of the drug or concurrent use of ototoxic drugs or conditions such as meningitis that by themselves can cause hearing loss. Hematological toxicity has been reported with vancomycin including neutropenia and thrombocytopenia. Vancomycin induced neutropenia usually occurs after weeks of therapy and is reversible after stopping the drug. It has no relationship to serum levels. The drug can also cause phlebitis when infused via a peripheral vein. Other rare side effects reported include diarrhea, nausea, and abnormal liver function tests. It rarely can cause drug fever and two cases of hypotension and cardiac arrest due to the drug have been reported and were probably manifestations of severe allergy to the drug.

Clinically Significant Interactions The only clinically significant drug interaction of vancomycin is with aminoglycosides when used together. This use may result in increased nephrotoxicity than associated with the use of either drug alone.

Contraindications The only absolute contraindication to the drug is true vancomycin allergy. The drug should be carefully used and monitored in individuals with renal dysfunction or decreased hearing, however, the authors do not believe that these conditions constitute a contraindication to its use. Patients with these conditions should have drug levels carefully monitored and a high trough level > 15 mg/L as well as very high peak levels > 55 mg/L should be avoided. The use of aminoglycosides and other nephrotoxic agents along with vancomycin should be minimized unless absolutely necessary and if used together both aminoglycoside as well as vancomycin levels should be carefully followed along with frequent monitoring of renal function.

Availability and Cost Considerations and Comparisons Internationally vancomycin is marketed as Vancocin by Eli Lilly. Vancomycin is freely available in India under more than 7 different brand names. The MRP’s of 500 mg and 1 g are around Rs. 350 and Rs.750 respectively. There is no significant price difference between the international brand and the ones marketed by Indian pharmaceutical companies. 104 Rational Antimicrobial Practice in Pediatrics

 TEICOPLANIN Teicoplanin was first isolated through fermentation of an Actinomyces species from a soil sample from India in 1978. Teicoplanin is a mixture of different glycopeptides that are related to each other. Basic structure has a linear heptapeptide, the carbohydrates D-mannose and D-glycosamine and an acyl residue that carries fatty acids. It is a large molecule with estimated weight of about 1900 daltons.

Mechanism of Action Teicoplanin like vancomycin inhibits bacterial cell wall synthesis and has bactericidal action. It interferes with the process of building new sections of cell wall peptidoglycan by binding to the D-ala-D-ala portion subunit. This step prevents growth of the new cell wall units and final cross-binding step. The difference between vancomycin and teicoplanin is only quantitative in terms of MIC’s.

Spectrum of Activity Teicoplanin has activity against Staphylococci (S. aureus, S. epidermidis including methicillin resistant strains), Enterococci, S. pneumoniae, S. bovis and S. viridans. It also has activity against Corynebacterium species (including C. jeikeium), Listeria monocytogenes and gram-positive anaerobic bacteria namely Clostridium spp, Peptostreptococcus, Actinomycetes and Propionibacterium spp., S. aureus strains susceptible to vancomycin but resistant to teicoplanin have been described. Van-A type VRE strains are resistant to teicoplanin.

Pharmacokinetics Teicoplanin is primarily used intravenously or intramuscularly, as its oral absorption is poor. Teicoplanin at the dose of 6 mg/kg IV achieves mean peak concentration of 111.8 mg/mL and trough levels of 14 mg/mL and the volume of distribution is 800- 1600 mL/kg. It has high protein and tissue binding and it has low clearance and long half life (83–168 hours) Teicoplanin achieves adequate concentrations in heart, pericardium, mediastinal tissues, lung and synovial, pleural, peritoneal and pericardial fluid. The bone concentrations are better than that achieved with vancomycin, as shown in animal studies. Penetration into CSF and vitreous fluid is not adequate. Teicoplanin excretion is mainly through the renal route. It is dialyzable in significant quantities. Children and burn patients clear the drug faster and need higher doses for treatment.

Indications Teicoplanin is indicated perioperatively for knee or hip implant related surgeries and prevention of bacterial endocarditis in penicillin allergic patients. It can also be used perioperatively in patients known or suspected to have MRSA colonisation or are at risk for it. Teicoplanin is used frequently in following clinical situations. Intraperitoneal Glycopeptides, Oxazolidinones and Daptomycin 105 instillation in CAPD related peritonitis and intravenously for CSF shunt infection, catheter related bacteremias, neutropenic fever, lower respiratory tract infections, urinary tract infections, bone and joint and skin and soft tissue infections. Native valve endocarditis caused by viridans streptococci and enterococci, osteomyelitis with S. aureus are some of the other indications for using teicoplanin. C. difficle colitis responds just as well to teicoplanin as it does to metronidazole and oral vancomycin. The need for once daily administration, effectiveness by the intramuscular route, lack of infusion related side effects and less nephrotoxicity make it an attractive alternative to vancomycin. However, clinical experience with vancomycin use is much higher than teicoplanin and hence vancomycin is considered the gold standard agent. The drug is not FDA approved.

Dosage Dose for normal renal function is 6 mg/kg/day and for serious infections 12 mg/kg/day. It needs to be given once in 48 hours for creatinine clearance between 10 and 50 mL/min and once in 72 hours for clearance <10 mL/mim, in HD and CAPD patients. Higher maintenance dose (12 mg/kg, max 600 mg) of teicoplanin is recommended for treatment of septic arthritis. In an endocarditis case caused by S. aureus, higher trough level of > 20 mg/mL is recommended and an initial loading dose of 12 mg/kg twice daily for 3 days followed by 12 mg/kg once daily is recommended. Duration depends on the site and severity of infection and to some extent on the causative pathogen. Please refer to the suggested duration guideline in the Vancomycin section above. Intramuscular teicoplanin 400 mg/day can be given over several weeks to treat osteomyelitis caused by MRSA.

Adverse Effects The toxicity profile of teicoplanin is much superior than vancomycin, with less nephrotoxicity (4.8% versus 10.7%) and less potentiation of nephrotoxicity of aminoglycosides. Drug fever and rash are its most common side effects. There is some degree of cross sensitivity between vancomycin and teicoplanin, however, the red man syndrome described with vancomycin infusion is extremely rare with teicoplanin. Ototoxicity is rare and thrombocytopenia, leucopenia and eosinophilia are other less frequent side effects.

Drug Interactions and Contraindications The combination with rifampicin is reported as antagonistic. The only contraindication is a serious allergic reaction to teicoplanin.

Availability and Cost Considerations and Comparisons Teicoplanin is available in India under the trade name of Targocid marketed by Aventis. A 200 mg vial costs Rs. 900 while 400 mg costs Rs. 1400. Brand of Cipla introduced in the market recently costs Rs. 540 and Rs. 890 for 200 mg and 400 mg respectively. 106 Rational Antimicrobial Practice in Pediatrics

 OXAZOLIDINONES, LINEZOLID The oxazolidinones belong to a new class of antimicrobials first synthesized in 1970s. They have a unique molecular structure and mechanism of action. Linezolid is the first molecule from this class approved for clinical use in year 2000. It has antibacterial activity against a broad range of gram-positive pathogens and few other types of pathogens.

Mechanism of Action Oxazolidinones act via inhibition of initiation phase of bacterial protein synthesis. They bind to 50S ribosome and prevent synthesis of the 70S initiation complex. Because of this unique mechanism of action linezolid is not likely to develop cross-resistance with other antibacterial drugs.

Spectrum of Activity Linezolid has good activity against a variety of clinically important gram-positive organisms including strains resistant to other antimicrobial agents, a few gram-negative organisms, anaerobes and mycobacteria. Linezolid is bacteriostatic against Staphylococcus aureus (methicillin sensitive and methicillin resistant strains), coagulase negative staphylococci (CONS), E. fecalis, and fecium. It has been shown to have bactericidal activity against S. pneumoniae and S. pyogenes (Gp A strep) and a few anaerobes. There are other gram-positive bacteria against which linezolid has been shown to have activity namely, Corynebacterium spp., Listeria monocytogenes, Rhodococcus equi, Erysipelothrix rhusipathiae. Linezolid has some activity against Neisseria spp. and Haemophilus influenzae but no useful activity against enterobacteraceae. Linezolid has good activity against Mycobacterium tuberculosis and atypical mycobacteria as well as nocardia spp. Resistance to linezolid has already been reported in strains of MRSA (methicillin resistant Staphylococcus aureus and VRE (vancomycin resistant enterococci). Linezolid use or prolonged exposure to the drug is the usual scenarios where resistance has developed.

Pharmacokinetics Linezolid is rapidly and completely absorbed after oral administration achieving bioavailability of 100%. IV dose of 600 mg 12 hourly results in peak concentration of 15 mg/mL. Elimination t½ of linezolid is about 5 hours. Linezolid is metabolized by oxidation, 85% is excreted through renal route and rest fecal. 30–40% is excreted unchanged. Dosage of linezolid need not be adjusted in presence of mild to moderate renal or hepatic insufficiency. In hemodialysis patients, linezolid should be given post-dialysis as the molecule and its metabolites are removed by dialysis. Adequate levels are reached in lung, skin, pancreas and bone to inhibit pathogens of concern. CSF levels of 3-12 mg/L have been demonstrated in presence of meningitis. Children clear linezolid faster than adults and the drug may need to be given 8 hourly. Glycopeptides, Oxazolidinones and Daptomycin 107

TABLE 1 Linezolid: US FDA approved indications for clinical use Condition Caused by Infections E. faecium (VRE) Nosocomial pneumonia Staphylococcus aureus (MRSA and MSSA) Streptococcus pneumoniae Community acquired pneumonia Streptococcus pneumoniae Staphylococcus aureus Uncomplicated skin and skin structure infections Staphylococcus aureus Streptococcus. pyogenes Complicated skin and skin structure infections Staphylococcus aureus Streptococcus. pyogenes Streptococcus agalactiae (Gp B strep)

Indications Linezolid was approved 10 years ago by US FDA for treatment of infections caused by gram-positive organisms (Table 1). It is a very important addition to the list of drugs currently available to treat resistant gram-positive infections. Methicillin Resistant Staphylococcal Infections (MRSA and MRSE) In multiple multicentric randomized controlled phase 3 trials, efficacy and safety of linezolid has been found comparable to vancomycin and other standard treatment options for infections caused by gram-positive bacteria. Linezolid has been shown to be as effective as oxacillin and vancomycin for the treatment of skin and soft tissue infections caused by MSSA and MRSA. MRSA infections of skin and soft tissue, lung, urinary tract have been treated with linezolid with success rate comparable to vancomycin. Some evidence suggests that linezolid may be superior to vancomycin for treatment of ventilator associated pneumonia because of MRSA because of better lung penetration. With the rise in incidence of community acquired MRSA, the need for using linezolid is increasing further. Linezolid can also be used as a protein synthesis inhibitor in patients presenting with toxic shock syndrome because of MRSA. Linezolid is not approved for treatment of catheter associated blood stream infections. The authors have successfully treated wound infections, bone and joint infections, pneumonias and empyemas, postneurosurgical infections caused by MRSA with IV linezolid followed by oral linezolid. Authors don’t recommend use of linezolid for the treatment of bacterial endocarditis and meningitis caused by S. aureus. Vancomycin Resistant Enterococcal Infections Bacteremia, osteomyelitis, endocarditis and even postoperative CNS infections have been successfully treated with linezolid.

Streptococcus Pneumoniae Community acquired pneumonia (CAP) caused by penicillin resistant strains have been successfully treated by linezolid. Linezolid should not be used alone as a first line drug 108 Rational Antimicrobial Practice in Pediatrics for treatment of CAP as it has limited activity against other agents causing CAP namely H. influenzae, Mycoplasma and Chlamydia spp.

Others Interestingly, linezolid has been successfully used in treating both tubercular and atypical mycobacterial infections (especially because of rapid growers) as well as infections caused by nocardia species. It is now an important drug for treating XDR tuberculosis. It is dosed as 600 mg once daily for these indications. However, prolonged treatment as needed for tuberculosis is associated with significant side effects.

Dose, Frequency and Duration The recommended dose of linezolid for adults is 600 mg orally or IV and 400 mg BD for skin and soft tissue infections. In infants and children 10 mg/kg 8 hourly is recommended. Duration of administration usually depends upon the site and severity of infection and clinical response. Duration as short as 7 days for skin and soft tissue infections and as long as 6 weeks for bone and joint infections have been used. The maximum approved duration is 28 days.

Side Effects Linezolid is a well-tolerated drug. Most commonly reported side effect is GI intolerance. The authors have come across reversible tongue discoloration in many cases and candida superinfection (candida epiglotittis) in a single patient on linezolid and cefixime. Reversible thrombocytopenia has been commonly observed worldwide in patients receiving linezolid for more than 2 weeks. The drug also depresses the white and red cell line but much less often. Serial monitoring of hematologic parameters especially platelet count is recommended. The authors recommend a baseline hemogram followed by a repeat one at the end of therapy or 2 weeks, whichever comes first. Linezolid must be used cautiously in patients already at risk for bleeding, patients with preexisting low platelets and patients on other medications that cause low platelet count. Serotonin syndrome has been reported with the use of linezolid because of its MAO inhibitory activity. Optic atrophy and peripheral neuritis are rare side effects reported after prolonged use of the drug. Peripheral neuropathy is now being reported increasingly following its use in drug resistant tuberculosis; it is painful and irreversible.

Drug Interactions Owing to its MAO inhibitory activity it should not be combined with adrenergic drugs such as adrenaline, dopamine, noradrenaline, phenylpropranolamine and ephedrine, as well as with other drugs with MAO inhibitory activity including tricyclic antidepressants and selective serotonin reuptake inhibitors.

Contraindications None. Glycopeptides, Oxazolidinones and Daptomycin 109

Availability and Cost Considerations Linezolid is freely available in India in both IV and oral formulation. The MRP for a 600 mg tablet and IV is Rs. 70–95 and Rs 300 respectively. Internationally it is available as ZYVOX a research product of Pharmacia Upjohn. Tablet of 600 mg priced at $ 57 and IV solution at $ 77. Oral suspension of Zyvox is available abroad too. Linezolid is the most economic option, an IV course costs only half as much as a course of vancomycin IV or teicoplanin IV/IM. The cost of therapy of oral linezolid turns out to be nearly 1/10th of vancomycin and teicoplanin. However, because of ready availability and relatively low cost in India there exists a big potential for drug misuse and resistance.

 DAPTOMYCIN Daptomycin is a new drug belonging to the lipopeptide class effective against many gram positive organisms including MRSA and vancomycin resistant Enterococcus and is characterized by very rapid bactericidal activity.

Chemical Structure and Mechanism of Action Daptomycin, a fermentation product of Streptomyces roseosporus is a 13-member amino acid cyclic lipopeptide with a decanoyl side-chain. The proposed mechanism involves insertion of the lipophilic daptomycin tail into the bacterial cell membrane, causing rapid membrane depolarization and a potassium ion efflux. This is followed by arrest of DNA, RNA and protein synthesis resulting in bacterial cell death. The bactericidal effect of daptomycin is rapid with greater than 99.9% of both MRSA and MSSA bacteria dead in less than 1 hour. This rapid cell death does not result in rapid bacterial cell lysis. The antimicrobial activity of daptomycin like the aminoglycosides and quinolones is concentration dependent and is associated with a prolonged post antibiotic effect. The drug is inactivated by pulmonary surfactant and therefore should not be used for pulmonary infections.

Spectrum of Activity Daptomycin’s spectrum of activity includes methicillin-resistant and susceptible Staphylococcus aureus (MRSA, MSSA), glycopeptide-intermediate S. aureus (GISA), methicillin-resistant coagulase-negative Staphylococcus spp. (CoNS), and vancomycin- resistant enterococci (VRE). Daptomycin has also demonstrated potency against vancomycin-resistant S. aureus as well as linezolid and quinupristin/ dalfopristin- resistant S. aureus and E. faecium. Furthermore, daptomycin is also effective against a variety of streptococcal groups such as the -hemolytic streptococci including S. pyogenes (Group A) and S. agalactiae (Group B) as well as other Streptococcus spp. Daptomycin is also potent against Corynebacterium jeikeium, and a variety of gram positive anaerobic species including Peptostreptococcus spp., Clostridium perfringens, Clostridium difficile, and Propionibacterium acnes. It has no activity against gram-negative and atypical organisms. 110 Rational Antimicrobial Practice in Pediatrics

Resistance Daptomycin resistance appears to emerge gradually via multiple steps resulting in a heteroresistant subpopulation with elevated minimum inhibitor concentrations to daptomycin. This is due to altered cell membrane charge which leads to reduced binding of daptomycin and consequent reduced cell depolarization. Resistance is more common in those patients treated previously with vancomycin or those with high vancomycin MIC’s suggesting some cross resistance with vancomycin.

Pharmacokinetics The drug has poor oral bioavailability and hence has to be dosed parenterally. Following parenteral administration, more than 95% of the drug binds to serum albumin and distributes primarily in the vascular compartment. The penetration of various tissues including bone, lung and CSF is very low. The drug has a half life of 8 hours and is primarily excreted unchanged in urine (80%).

Therapeutic Uses The drug has received FDA approval for management of complicated skin and soft tissue infections and bacteremia with or without right sided endocarditis due to various gram-positive infections including MRSA and VRE. Randomized controlled trials that evaluated daptomycin in adults from Europe, South Africa, US patients with complicated skin and soft tissue infections showed non inferiority of daptomycin against the comparator drug. Another randomized controlled trial that compared daptomycin with a betalactam and aminoglycoside (given for the first 4 days only) combination therapy in adults with S. aureus, bacteremia with or without right sided endocarditis showed noninferiority of daptomycin to the comparator drug. Patients with left sided endocarditis were excluded from the trial. While in the case of MSSA bacteremia both groups showed equal success rates, in those with MRSA bacteremia, the outcome of the daptomycin group was superior to the comparator. The difference was most pronounced in those with uncomplicated right sided endocarditis. Excellent outcomes in patients with MSSA bacteremia (unlike with the experience with vancomycin) suggested that daptomycin may be useful empirical therapy in patients with suspected staphylococcal bacteremia where susceptibility results were pending. Several uncontrolled case series and the Cubicin Outcome and Registry Experience (CORE) database have reported successful outcomes with daptomycin in patients with diverse gram-positive infections including bacteremia and left sided endocarditis with MRSA/ VRE. Conversely there have been case reports that describe treatment failures and emergent drug resistance with use of daptomycin in MRSA and enterococcal infections. Recent data advocates use of combination therapy of daptomycin with cephalosporins, tigecycline, gentamicin, rifampicin and other drugs for serious infections including endocarditis. Data on efficacy, safety of daptomycin in children are limited. However pharmacokinetic studies recommend doses of 6–10 mg/kg/day in children. Published data indicates that when it was used daptomycin was well tolerated and efficacious. Glycopeptides, Oxazolidinones and Daptomycin 111

Dosage The recommended dosage of daptomycin is 4 mg/kg/day for skin and soft tissue infections and 6 mg/kg/day for bacteremia. It is dosed once daily. Recent studies have evaluated higher doses ranging from 8–12 mg/kg/day for endocarditis and have not noticed increased toxicity. In patients with renal failure and creatinine clearance less than 30 mL/minute, daptomycin should be given once every 48 hours.

Adverse Effects The most common side effects noted in clinical trials are nausea, constipation and injection site reactions. The most significant side effect with daptomycin is elevation of CPK, noticed in about 3% of patients treated with daptomycin at dose of 4 mg/kg/day. Occasionally it can cause rhabdomyolysis. Muscle complications usually present in the first week of starting therapy. CPK should be monitored weekly and daptomycin stopped if levels exceed 10 times normal or if there are symptoms of myopathy and CPK levels exceed 1000. The symptoms resolve quickly after stopping therapy but CPK elevation can persist for weeks. Rarely eosinophilic pneumonia can occur with daptomycin.

Drug Interactions Daptomycin is neither inducer nor stimulator of CYP450 system and hence has no significant interactions. Concomitant use of statins should be avoided because of increased risk of muscle complications.

Summary Daptomycin is a welcome addition to the armamentarium of agents for gram-positive infections. Data is limited in children. Use of the drug can be considered in certain instances of severe MRSA and enterococcal (especially VRE) infections such as endocarditis, bacteremia and infections of the skin and soft tissue. The drug should not be used for CNS, and lung infections and when other effective agents are available.

CONCLUSIONS Vancomycin is the gold standard drug for treating MRSA , MRSE and beta lactam resistant enterocwoccal infections. Teicoplanin is a useful substitute for vancomycin especially when prolonged outpatient therapy is required. Linezolid has the advantage of excellent oral bioavailability and is crucial drug for management of drug resistant tuberculosis and atypical mycobacterial infections. Daptomycin is a therapeutic option for treatment of vancomycin resistant infections.

 REFERENCES 1. Cantu TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin concentrations: reappraisal of their clinical value. Clin Infect Dis. 1994;18:533-43. 112 Rational Antimicrobial Practice in Pediatrics

2. Cooper GL, Given DB. Vancomycin: A Comprehensive Review of 30 years of Clinical Experience. 1986. Park Row Publishers, San Deigo, CA, USA. 3. Cunha BA. Vancomycin. Med Clin North Am. 1995;79:817-31. 4. Dryden MS, Jones NF, Phillips I. Vancomycin therapy failure in Listeria monocytogenes peritonitis in a patient on continuous ambulatory peritoneal dialysis. J Infect Dis. 1991;164:1239-41. 5. EORTC. European Organization for Research and Treatment of Cancer International Antimicrobial Chemotherapy Cooperative group and the National Cancer Institute of Canada-Clinical Trials Group. Vancomycin added to empirical combination antibiotic therapy for fever in granulocytopenic cancer patients. J Infect Dis. 1991;163:951-8. 6. Farber BF, Moellering RC. Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981. Antimicrob Agents Chemother. 1983;23:138-41. 7. Goetz MB, Sayers J. Nephrotoxicity of vancomycin and aminoglycoside therapy separately and in combination. J Antimicrob Chemother. 1993;32:325-34. 8. Graziani AL, Lawson LA, Gibson GA. Vancomycin concentrations in infected and noninfected human bone. Antimicrob Agents Chemother. 1988;32:1320-3. 9. Harwick HJ, Kalmanson GM, Guze LB. In vitro activity of ampicillin or vancomycin combined with gentamicin or streptomycin against enterococci. Antimicrob Agents Chemother. 1973;4:383-7. 10. Johnson AP, Uttley AH, Woodford N, George RC. Resistance to vancomycin and teicoplanin: an emerging clinical problem. Clin Microbiol Rev. 1990;3:280-91. 11. James A, Koren G, Milliken J, Soldin S, Prober C. Vancomycin pharmacokinetics and dose recommendations for preterm infants. Antimicrob Agents Chemother. 1987;31:52-4. 12. Polk RE, Healy DP, Schwartz LB, Rock WT, Garson ML, Roller OK. Vancomycin and the red-man syndrome: pharmacodynamics of histamine release. J Infect Dis. 1988;157:502-7. 13. Spitzer PG, Eliopoulos GM. Systemic absorption of enteral vancomycin in a patient with pseudomembranous colitis. Ann Intern Med. 1984;100:533-4. 14. Mandell, Douglas and Bennett’s Principals and Practice of Infectious Diseases. 15. Targocid. product synopsis by HMR Ltd. 16. Chow AW, Azar RM. Glycopeptides and Nephrotoxicity. Intensive Care Medicine. 1994;20:S23-S29. 17. Charbonneau P, Hading I, Garaud JJ, Aubertin J, et al. Targocid: a well tolerated and easily administered alternative to vancomycin for gram-positive infections in intensive care patients. Intensive Care Medicine. 1994;20:S35-42. 18. Dennis L. Stevens, Daniel Herr et al and the linezolid MRSA study group. Clin Infect Dis 2002; 34:1481- 90. 19. Linezolid versus vancomycin for the treatment of Methicillin-Resistant Staphylococcus aureus infections. Drugs. 2001;61:525-51. 20. Plouffe JF. Emerging therapies for serious Gram-Positive Bacterial infections: A focus on Linezolid. Clin Infect Dis. 2000;31:S144-9. 21. Judith N. Steenbergen*, Jeff Alder, Grace M. Thorne and Francis P. Tally. Daptomycin: a lipopeptide antibiotic for the treatment of serious gram-positive infections. Journal of Antimicrobial Chemotherapy (2005) 55, 283–288 22. Arbeit, RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin structure infections. Clinical Infectious Diseases. 2004;38:1673-81. 23. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653-65. 24. Levine DP. Clinical experience with daptomycin in bacteremia and endocarditis. Journal of Antimicrobial Chemotherapy. 2008;62(Suppl)3: iii35-39. 25. Abdel-Rahman SM, Chandorkar G, Akins RL, Bradley JS, Jacobs RF, Donovan J, Benziger DP. Single-dose pharmacokinetics and tolerability of daptomycin 8 to 10 mg/kg in children aged 2 to 6 years with suspected or proved gram-positive infections. Pediatr Infect Dis J. 2011;30:712-4. 26. Ardura MI, Mejías A, Katz KS, Revell P, McCracken GH Jr, Sánchez PJ. Daptomycin therapy for invasive Gram-positive bacterial infections in children. Pediatr Infect Dis J. 2007;26(12):1128-32. Miscellaneous Antibacterial Drugs 113 1111 Miscellaneous Antibacterial Drugs Baldev S Prajapati, Rajal B Prajapati

 SULFONAMIDES Introduction The sulfonamide drugs were the first effective chemotherapeutic agents to be employed systematically for the prevention and cure of bacterial infections in human beings. Domagk and his Colleagues (1938) while working on azo dyes demonstrated the efficacy of “Prontosil” a dye with a sulfonamide side chain in inhibiting the growth of streptococci both in vitro and vivo. Domagk subsequently used prontosil in his daughter having streptococcal septicemia, which was fatal during those days. It was found that prontosil was broken down in the body to release sulfanilamide, which was the active antibacterial agent. Later on, several sulfonamides were produced and used extensively. However, because of rapid emergence of bacterial resistance and the availability of many effective and safer antibiotics, their use declined. However, in the mid 1970’s the combination of trimethoprim and sulfamethoxazole became available, which resulted in increased use of sulfonamides for the treatment of specific microbial infections. The antimicrobial agents containing a sulfonamide group are called sulfonamides. The sulfonamide group is also present in other non-antibacterial compounds like antidiabetic agent tolbutamide, diuretics like chlorthiazide, furosemide and acetazolamide.

Classification Sulfonamides employed for the treatment of systemic infections are subdivided depending upon their duration of action. • Short acting sulfonamides (4–8 hours) include sulfadiazine, sulfadimidine, sulfafurazole, sulfisomidine. • Intermediate acting sulfonamides (8–12 hours) include sulfamethoxazole, sulfamoxole. 114 Rational Antimicrobial Practice in Pediatrics

• Long acting sulfonamides (Approximately 7 days) include sulfadoxine, sulfamethopyrazine. • Special purpose sulfonamides include sulfacetamide (ocular use), sulfasalazine (ulcerative colitis), mafenide and silver sulfadiazine (burn dressing). • Non-absorbable sulfonamides like phthalylsulfathiazole, succinylsulfathiazole, sulfaguanidine have been banned in India.

Mechanism of Action The compound sulfanilamide exhibits structural similarity to paraaminobenzoic acid (PABA) and hence, compete with and probably substitute for PABA in the bacterial mechanism. Folic acid derived from PABA is important in bacterial metabolism. Sulfonamides also inhibit the enzyme folic acid synthetase, which is involved in the conversion of PABA to folic acid. This causes folic acid deficiency resulting in injury to the bacterial cell. Such an injured or disrupted bacterial cell can be easily phagocytosed. Sulfonamides are ineffective in the presence of pus and tissue break down products that contain large amount of PABA. PABA can counter the bacteriostatic action of sulfonamides. It is also observed that sulfonamide resistant microorganisms often show enhanced PABA synthesis.

Spectrum of Activity Sulfonamides are primarily bacteriostatic against many gram-positive and gram-negative bacteria. However, bactericidal concentrations may be attained in urine. Sensitivity pattern among microorganisms have changed from time to time and place to place. In combination with other drugs that inhibit folic acid synthesis, sulfonamides are effective in malaria, toxoplasmosis and pneumocystosis.

Therapeutic Uses • Systemic use of sulfonamides alone (without combination with trimethoprim or pyrimethamine) is rare now. • Sulfadiazine has good penetration in brain and CSF. It was the preferred compound for meningitis before availability of the modern and better antimicrobial agents. • Sulfadiazine: For toxoplasmosis in combination with pyrimethamine (1 mg/kg/day) and folinic acid. Dosage of sulfadiazine is 100 mg/kg/day in 2–4 divided doses. • Sulfamethoxazole: Used in combination with trimethoprim (see later) • Sulfasoxazole: ophthalmic solution, ointment. • Sulfadoxine: Along with pyrimethamine used for malaria • Sulpha salazine: for ulcerative colitis and juvenile rheumatoid arthritis • Sulfacetamide: 10%, 20%, 30% eye drops, 6% eye ointment. For topical use in ocular infections due to susceptible bacteria and chlamydia including ophthalmic neonatorum. • Silver sulfadiazine: 1% cream. One of the most effective for prevention of infection of burn areas and chronic ulcers. Miscellaneous Antibacterial Drugs 115

Adverse Effects Common adverse effects due to sulfonamides are: • Nausea, vomiting, epigastric pain. • Crystalluria–dose related. • Hematuria and anuria may develop. • Hypersensitivity reactions. Skin rashes, urticaria, and drug fever are common. Arthritis, serum sickness and polyarteritis nodosa are infrequent. Photosensitization is known. Stevens Johnson syndrome and toxic epidermal necrolysis are common with long acting agents. These are most severe hypersensitivity reactions associated with sulfonamides, leading to death in some exposures. • Hepatitis. • Hemolysis in G-6-P-D deficiency individuals. • Neutropenia and other blood dyscrasia. • Kernicterus may be precipitated in newborns especially in premature babies.

Drug Interactions Sulfonamides inhibit the metabolism of phenytoin, tolbutamide and warfarin, thereby enhancing their actions. They displace methotrexate from binding sites and decrease its renal excretion, thus possibly increasing toxicity. Fixed dose combinations of sulfonamides and penicillin may cause serious hypersensitivity and are banned in India.

 TRIMETHOPRIM–SULFAMETHOXAZOLE The fixed dose combination of trimethoprim (TMP) and sulfamethoxazole (SMX) is called cotrimoxazole. It contains a 5:1 ratio of SMX to TMP. The potency of this combination is expressed in terms of the TMP content. It was introduced in 1969.

Mechanism of Action and Relevant Pharmacology It causes sequential block of folate metabolism. Trimethoprim is 50,000 times more active against bacterial dihydrofolate reductase than against the mammalian enzyme. Thus, human folate metabolism is not interfered at antibacterial concentrations of trimethoprim. Individually both sulfonamide and trimethoprim are bacteriostatic, but the combination becomes cidal against many organisms. Maximum synergism is seen when the organism is sensitive to both the components, but even when it is moderately resistant to one component, the action of the other may be enhanced. Sulfamethoxazole was selected for combining with trimethoprim because both have nearly the same plasma half-life. Trimethoprim adequately crosses blood brain barrier and placenta, while sulfamethoxazole has a poor entry. Moreover, trimethoprim is more rapidly absorbed than sulfamethoxazole. Trimethoprim is partly metabolized in liver and excreted in urine. Spectrum of Activity Many isolates of S. aureus, pneumococci, Group A streptococci and Nocardia are susceptible to cotrimoxazole. In general, Haemophilus, Enterobacter, E. coli, Klebsiella, 116 Rational Antimicrobial Practice in Pediatrics

Salmonella and Shigella are also susceptible. It has poor activity against P. aeruginosa. It is active against Toxoplasma gonadii, P. jirovecii and Isospora. It has no activity against strict anaerobes.

Resistance Bacteria are capable of acquiring resistance to trimethoprim mostly through mutational or plasmid-mediated acquisition of a dihydrofolate reductase having lower affinity for the inhibitor. However, resistance to the combination has been slow to develop compared to either drug alone. Widespread use of the combination has resulted in reduced responsiveness of over 40% originally sensitive strains especially pneumococci, Haemophilus and group A streptococci.

Therapeutic Uses Common therapeutic uses are: • Urinary tract infections: Cotrimoxazole is useful for treatment of community acquired acute or recurrent urinary tract infections. It is recommended as prophylaxis for recurrent UTI. • Respiratory tract infections: It is effective in treatment of acute otitis media, acute bronchitis and pneumonia due to sensitive organisms was recommended as the first line drug for community acquired pneumonia in children but now there is increasing resistance. • Infections in immunocompromised: Cotrimoxazole is the drug of choice for treatment of P. jiroveci pneumonia and isospora diarrhea in children with HIV, malignancy and recurrent neutropenia and other defects in cell-mediated immunity. It is also effective as prophylaxis against P. jiroveci, toxoplasmosis, recurrent bacterial infections and non typhoidal Salmonella infections in the immunocompromised particularly HIV. • Bacterial diarrhea and dysentery: Cotrimoxazole is effective in the treatment of gastroenteritis caused by ampicillin resistant strains of Shigella species and traveller’s diarrhea due to enterotoxigenic E. coli. However, increasing resistance has limited its usefulness in this setting and not recommended for daily practice. • Enteric fever: Cotrimoxazole was widely used in therapy of enteric fever in the past. The emergence of multidrug resistant enteric fever in the 1990’s resulted in loss of its utility. However, recently there has been a reemergence of cotrimoxazole sensitivity and this drug may be a therapeutic option for outpatient therapy. A 12-week course eradicates carrier state of sensitive strains provided gall bladder is not involved. • Other conditions: Cotrimoxazole has been useful therapy for brucellosis and nocardiosis. • With increasing antimicrobial resistance in nosocomial infections, cotrimoxazole is being used to treat nosocomial infections due to extensively drug resistant organisms including organisms like Stenotrophomonas maltophila.

Preparations and Dosage • 5–8 mg/kg of TMP or 25–50 mg/kg of SMZ/Day in two divided doses oral or IV. Miscellaneous Antibacterial Drugs 117

• 10 mg/kg/day in two divided doses of TMP for enteric fever. • 15–20 mg/kg/day in 3 to 4 divided doses of TMP for treatment of Pneumocystis jiroveci infection. • 5 mg/kg/day of TMP either single dose or in two divided doses daily for 3 consecutive days in a week or every alternate day for prophylaxis against Pneumocystis jiroveci and Toxoplasma gonadii. • 1–3 mg/kg/day of TMP in single dose for UTI prophylaxis.

 CHLORAMPHENICOL Chloramphenicol was discovered in 1948 from Streptomyces venezuelae. It was synthetically produced and marketed in 1949. The potential for aplastic anemia has resulted in marked decline of its use in current day practice.

Mechanism of Action Chloramphenicol acts by interfering with synthesis of bacterial proteins. It inhibits protein synthesis by binding to 50S sub-unit of 70S ribosomes to prevent attachment of AA + RNA or to inhibit , required for formation of the peptide bond. At high doses it can inhibit mammalian mitochondrial protein synthesis as well. Bone marrow cells are especially susceptible.

Spectrum of Activity Chloramphenicol has a wide spectrum of antimicrobial activity. It has excellent activity against group A and B streptococci, H. influenzae, N. meningitidis, B. pertussis, Shigella, Salmonellae, Rickettsia, Chlamydia, Mycoplasma, etc. It is inactive against mycobacteria, Pseudomonas, Proteus, viruses and fungi.

Resistance Intrinsic and acquired resistance occurs. Plasmid mediated resistance is important, since cross-resistance to several antimicrobial agents like aminoglycosides, sulfonamides and tetracycline is frequent. Resistance is due to hydrolyzing enzymes or target modification.

Clinical Pharmacokinetics Pharmacokinetics of chloramphenicol has been characterized in neonates, infants and children. Oral bioavailability is good, almost 80 to 90%. The drug is available as a lipid soluble base or water-soluble ester of succinate (IV use) or palmitate (oral use). Both esters require to be hydrolyzed in the body to release the active form. The palmitate form probably gets hydrolyzed in the proximal part of small intestine and free base is rapidly absorbed. In the neonate, hydrolysis is less due to limited gastrointestinal lipase activity. The succinate form is probably hydrolyzed in the liver. In the newborns the succinate ester hydrolysis is slower than in older infants and children and 36% gets excreted in the urine unchanged. When there is liver and renal dysfunction, the 118 Rational Antimicrobial Practice in Pediatrics serum chloramphenicol levels show wide variations. This has been observed especially in sick neonates. The bioavailability of orally administered chloramphenicol palmitate is superior to that of succinate given intravenously. It seems that significant therapeutic advantage is observed when chloramphenicol palmitate is orally administered in children who can tolerate the drug by mouth. The lipid solubility of chloramphenicol makes the drug diffuse widely in tissues and body fluids. CSF levels of the drug are nearly 50% of the serum concentration irrespective of the presence or absence of meningitis. In neonates and small infants when chloramphenicol is administered for meningitis, monitoring the drug levels are essential. The importance of monitoring increases when phenobarbitone or phenytoin or both are co administered.

Therapeutic Uses Therapy with chloramphenicol must be limited to infections for which the benefits of the drug outweigh the risks of the potential toxicities. When other antimicrobial drugs are available that are equally effective but potentially less toxic than chloramphenicol, they should be used. Typhoid Fever Chloramphenicol was widely used in therapy of enteric fever, By 1970’s, resistance emerged which was plasmid mediated and associated with resistance to other drugs like cotrimoxazole and ampicillin. Moreover with chances of developing blood dyscrasia and availability of modern, better and safe antimicrobials specifically and third generation cephalosporins, chloramphenicol lost its importance in therapy of enteric fever. But recently with re- emergence of chloramphenicol sensitivity, the scope for its use in enteric fever has emerged. Bacterial Meningitis Treatment with chloramphenicol produces excellent results in H. influenzae meningitis that are better than those achieved with ampicillin and equal to the third generation cephalosporins. However, with the availability of third generation cephalosporins, chloramphenicol has lost its top position in management of bacterial meningitis in young children. As it is very cheap, it can be used in non-affording patients. Intramuscular preparations of chloramphenicol have been used to control the meningococcal epidemics in Sub Saharan Africa. In partially treated or chronic bacterial meningitis when the modern cephalosporins including ceftriaxone and other antibiotics have failed, chloramphenicol has been found effective. In this situation, it can be used with consent of parents. Anaerobic Infections Wound infections, pelvic and brain abscesses caused by B. fragilis and other respond well to chloramphenicol. Excellent diffusibility of chloramphenicol is a management asset. Other therapeutic alternatives are metronidazole and clindamycin. Miscellaneous Antibacterial Drugs 119

Rickettsial Diseases The tetracyclines are usually the preferred agents for the treatment of rickettsial diseases. However, in children, patients with hypersensitivity to tetracyclines, in pregnant women and in those with reduced renal functions chloramphenicol is a suitable alternative. Miscellaneous Uses Nosocomial pathogens such as multidrug resistant Klebsiella pneumoniae and E. coli can often be treated successfully with chloramphenicol. Brucellosis, whooping cough and M. pneumoniae are other conditions in which chloramphenicol may be used as an alternative to other drugs.

Dosage • 50 to 75 mg/kg/day in 3 divided doses orally. • 100 mg/kg/day in 4 divided doses IV.

Adverse Reactions Bone Marrow Depression Two forms of bone marrow involvement in chloramphenicol toxicity are known. One form is dose related, reversible and occurs usually during the course of treatment. The pathogenesis is assumed to be due to its ability to inhibit mammalian ribosomal protein synthesis. There is anaemia, leucopenia, thrombocytopenia and increased serum iron and free erythrocyte protoporphyrin. Keeping the serum level of chloramphenicol below 25 g/mL will reduce the incidence of this toxic effect. The second type of bone marrow suppression is an idiosyncratic reaction and not dose related. It is serious and irreversible. It may even appear some time after discontinuation of the drug and may be fatal. Fortunately, the incidence of aplastic anaemia is very uncommon with an incidence of 1 in 58,000 to 1 in 75,000. To prevent deadly complications due to chloramphenicol, indiscriminate, prolonged use of the drug should be avoided. Peripheral smear should be examined atleast twice a week during therapy. The treatment should be stopped if the leucocyte count drops below 4000/Cumm or when the proportion of granulocytes is reduced below 40%. Discontinuation of chloramphenicol after the development of aplastic anaemia does not prevent the relentless progress of the disorder.

Gray Baby Syndrome This is another dangerous complication of chloramphenicol therapy with a high mortality rate, observed in neonates, especially in preterm babies, receiving large doses of the drug (100–200 mg/kg/day) and blood levels are more than 25 mg/L. The mechanism of high-level chloramphenicol toxicity is believed to be related to a disturbance of mitochondrial electron transport. Symptoms are pallid cyanosis, abdominal distension, hypothermia and circulatory failure. The factors incriminated are (i) the deficient conjugation of chloramphenicol in the liver. A low level of hepatic glucuronyl transferase enzyme 120 Rational Antimicrobial Practice in Pediatrics activity in the first 2 to 3 weeks has been demonstrated and (ii) immaturity of the renal tubules in the newborns leading to impairment of excretion of the free form of antibiotic. To avoid this complication, chloramphenicol should not be used in newborns, unless it is must and level should not exceed 25 mg/L. They should be watched for early signs of toxicity.

Intolerance This is relatively uncommon. However, skin rashes, drug fever, angioneurotic oedema, exfoliative dermatitis, atrophic glossitis and haemorrhages involving the skin, gastrointestinal tract and the bladder have been reported. Peripheral neuritis, headache, mental confusion, optic neuritis, internal ophthalmoplegia and Herxheimer reaction are other rare adverse effects of chloramphenicol.

Interactions Chloramphenicol inhibits phenytoin, tolbutamide, chlorpropamide and warfarin metabolism. Phenobarbitone, phenytoin, rifampicin enhance chloramphenicol metabolism and thereby reduces its concentration and failure of therapy may occur. Co-administration of chloramphenicol with cimetidine has been reported to increase potential for aplastic anaemia.

 TETRACYCLINES The development of was the result of systematic screening of soil specimens collected from many parts of the world for antibiotic producing micro organisms. The first of these compounds, , was introduced in 1948. All tetracyclines contain the four cyclic rings; the substitution of various groups at the R5, R6 or R7 positions of the nucleus varies antibacterial activity, absorption and protein binding. For discussion on tigecycline see Chapter 12.

Classification On the basis of chronology of development as well as for convenience of description they may be divided into 3 groups.

Group I Group II Group III • Tetracycline • • Doxycycline • Chlortetracycline • Methacycline • Minocycline • •

Mechanism of Action The tetracyclines are primarily bacteriostatic. They inhibit protein synthesis by binding to 30S ribosomes in susceptible organisms. Subsequent to such binding, attachment of aminoacyl-t-RNA to the m-RNA ribosomes complex is interfered with. As a result peptide chain fails to grow. The sensitive organisms have an energy dependent active transport process which concentrates tetracycline intracellularly. In gram-negative bacteria Miscellaneous Antibacterial Drugs 121 tetracyclines diffuse through porin channels as well. The more lipid soluble members such as doxycycline and minocycline enter by passive diffusion also. This may be the reason for their higher potency. The carrier involved in active transport of tetracyclines is absent in the host cells. Moreover, protein-synthesizing apparatus of host cells is less sensitive to tetracyclines. These two factors are responsible for the selective effect of tetracyclines on microbes. However, at very high concentrations, tetracyclines inhibit mammalian protein synthesis. The mechanism by which tetracyclines reduce lesions of acne vulgaris is not well understood, but it appears to be the result of antimicrobial activity.

Spectrum of Activity Tetracyclines have a broad spectrum of activity that includes most rickettsia, chlamydia, mycoplasma species, spirochetes and some gram-negative and gram-positive bacteria. All gram-positive and gram-negative cocci were originally sensitive, but now many Strep. pyogenes, S. aureus and enterococci have become resistant. Minocycline is still active against most N. gonorrhoea and N. meningitidis. Clostridia, Listeria, Corynebacteria, B. anthracis are inhibited by tetracyclines. V. cholerae, Yersinia Pestis, Campylobacter, Helicobacter pylori, Brucella and many anaerobes are sensitive to tetracyclines.

Resistance Intrinsic or acquired resistance to tetracyclines is due to decreased permeability as a result of mutation or presence of inducible plasmid mediated resistance factors. Nearly complete cross-resistance is seen among different members of the tetracycline group. Partial cross-resistance between tetracyclines and chloramphenicol has been noted.

Clinical Pharmacokinetics Few data are available in children. The older tetracyclines are incompletely absorbed from GI tract. They are better absorbed if taken empty stomach. Doxycycline and minocycline are completely absorbed irrespective of food.The predominant routes of excretion are renal and biliary. Therefore, any condition impairing renal or biliary functions would be expected to prolong the clearance of tetracyclines. Only doxycycline attains appreciable CSF concentrations. They are secreted in breast milk in amount sufficient to affect the suckling infant.

Therapeutic Uses Although nearly all publications cite restriction of use in children younger than 9 years of age, most experts would prescribe a short course of 7 to 10 days duration of tetracycline in young children for serious or life threatening infections in which tetracycline is a drug of choice, e.g. scrub typhus and spotted fever. Major indications for the tetracyclines are as mentioned in Table 1. 122 Rational Antimicrobial Practice in Pediatrics

TABLE 1 Major indications for tetracyclines Therapy of choice Effective therapy • Brucellosis (with streptomycin) • Acne • Chlamydial infections • Anthrax • Cholera • Bordetella pertussis • Acute epididymitis (STD) • Mycoplasma pneumoniae • Granuloma Inguinale • Rat bite fever • Leptospirosis • Tularemia • Lyme disease • Companion drug with artemisinin’s/ • Pelvic inflammatory diseases quinine for falciparum malaria • Relapsing fever • Rickettsial infections

Dosage • Tetracycline Hydrochloride: 25–50 mg/kg/day orally 6 hourly. • Oxytetracycline: 7–10 mg/kg/day 6–12 hourly. • Doxycycline: 6 mg/kg single dose upto maximum 300 mg in children > 8 years.

Adverse Reactions Irritative effects Tetracyclines especially doxycycline can cause epigastric pain, nausea, vomiting, diarrhea and esophageal ulcerations. Intramuscular injections of tetracyclines are very painful. Thrombophlebitis on intravenous route is known to occur. Hepatic Toxicity Fatty infiltration of liver and jaundice occur occasionally. Oxytetracycline and tetracycline are safer in this regard. Tetracyclines can precipitate acute hepatic necrosis in pregnant women. Nephrotoxicity This is mainly in the presence of existing kidney disease. Exposure to acidic pH, moisture and heat favors degradation of tetracyclines. Such degraded products and outdated tetracyclines can cause proximal tubular damage and reversible Fanconi syndrome like condition. Photosensitivity Sunburn like and other skin reactions on exposed parts are seen in some individuals. Distortion of nails occurs occasionally. Teeth and Bones Tetracyclines have chelating property. Calcium-tetracycline chelate gets deposited in developing teeth and bones. Brown discolouration, malformation and susceptibility to caries are known problems with teeth. Given from mid pregnancy to 5 months extrauterine life, the deciduous teeth are affected. Tetracyclines given between 3 months and 6 years Miscellaneous Antibacterial Drugs 123 of age affect permanent anterior dentition. Repeated courses are more damaging. Given during the late pregnancy or childhood tetracyclines can cause temporary suppression of bone growth. Miscellaneous Anti anabolic effect, increased intracranial pressure, vestibular toxicity etc. are other known adverse effects of tetracyclines.

Drug Interactions Aluminium, calcium, magnesium and iron containing products or food can impair the absorption of tetracyclines. Interactions of tetracyclines are known with oral contraceptive pills, digoxin, rifampin and loop diuretics. Anticoagulant effect of warfarin is enhanced while therapeutic action of penicillins is reduced.

 METRONIDAZOLE Metronidazole is the prototype nitroimidazole introduced in 1959 for trichomoniasis and later found to be highly active against several protozoa and many anaerobic bacteria.

Mechanism of Action Metronidazole is bactericidal, amebicidal, and trichomonacidal in action. After entering the cell by diffusion its nitro group is reduced by certain redox proteins operative only in anaerobic microbes to highly reactive nitro radical, which exerts cytotoxicity by damaging DNA and other critical biomolecules. DNA helix destabilization and strand breakage has been observed in susceptible organisms. Aerobic environment attenuates cytotoxicity of metronidazole by inhibiting its reductive activation. It has been found to inhibit cell mediated immunity, to induce mutagenesis and to cause radiosensitization.

Spectrum of Activity Metronidazole is active against most obligatory anaerobic bacteria and many protozoa. Susceptible anaerobic bacteria include B. fragilis, Clostridium, Peptococcus, etc. G. vaginalis is also susceptible. Facultative gram-negative bacilli, Staphylococcus and Streptococcus are resistant. Protozoa such as Entamoeba histolytica, Trichomonas vaginalis and Giardia lamblia are inhibited by metronidazole.

Clinical Pharmacokinetics Metronidazole is almost completely absorbed from the small intestine. It is widely distributed in the body, attaining therapeutic concentration in vaginal secretions, semen, saliva and CSF. It is metabolized primarily in liver by oxidation and glucuronide conjugation. It is excreted in the urine. Its clearance is reduced markedly in neonates and infants in first 2 to 3 months of life. 124 Rational Antimicrobial Practice in Pediatrics

Therapeutic Uses Metronidazole has potent bactericidal activity against anaerobic bacteria and excellent tissue penetration, making it a mainstay of therapy for brain abscess, intra abdominal infections and other anaerobic closed space infections. Metronidazole is not used as monotherapy for any infection (except protozoan) because infection involving anaerobic bacteria is typically polymicrobial. Metronidazole alone or in combination with other agents has been used successfully for prophylaxis in gastrointestinal surgery, gynaecologic surgery or emergency appendicectomy. It is the drug of first choice in management of C. difficile infections. It is also used in the management of necrotizing enterocolitis in preterm babies in dose of 15 mg/kg IV loading dose followed by 7.5 mg/kg per dose every 12 hours. Metronidazole has excellent CSF penetration and bactericidal activity. It is found effective in the treatment of anaerobic organisms causing meningitis or ventriculitis (traumatic, postsurgical or nosocomial) and treatment of anaerobic brain abscess. Metronidazole in combination with other antibiotics and proton pump inhibitors has been used in treatment of Helicobacter pylori. It has been also found effective in treatment of parapharyngeal abscess, Ludwig angina, necrotizing fasciitis and cellulitis. It is effective therapy for bacterial vaginosis, trichomoniasis, intestinal amoebiasis, anaerobic and amoebic liver abscess. Metronidazole is also effective against G. lamblia and B. coli.

Dosage • 15–20 mg/kg/day in 3 divided doses orally for 5 days for giardiasis. • 35–50 mg/kg/day in 3 divided doses orally for 10 days for amoebiasis. • 20–30 mg/kg/day in 4 divided doses orally or IV for anaerobic infections.

Adverse Reactions Side effects to metronidazole are relatively frequent but mostly non serious. • Anorexia, nausea, metallic taste (by both oral and parenteral administration) and abdominal cramps are the most common. • Less frequent side effects are headache, glossitis, dryness of mouth, dizziness, rashes and transient neutropenia. • Prolonged administration may cause peripheral neuropathy, vertigo, ataxia, seizures and other CNS adverse effects. • Thrombophlebitis if the solution is not well diluted on IV therapy. • Causes a disulfiram like reaction if co administered with alcohol. • Rare adverse effects include maculopapular skin rash, chest pain, and palpitation, discoloration of urine, gynaecomastia and acute pancreatitis. Metronidazole has been shown to be mutagenic in vitro and carcinogenic in laboratory animals.

Contraindications The drug is contraindicated in active neurological disease, blood dyscrasias, first trimester of pregnancy and chronic alcoholism. Miscellaneous Antibacterial Drugs 125

Drug Interactions • A disulfiram like intolerance to alcohol occurs among some patients taking metronidazole along with alcohol. • Enzyme inducers like phenobarbitone and rifampicin may reduce its therapeutic effect. • Cimetidine can reduce metronidazole metabolism, requiring reduction in its dosage.

 LINCOSAMIDES Although not related structurally to erythromycin or other macrolide compounds, the lincosamides have similar mechanism of action and antimicrobial activity as macrolides.

Mechanism of Action and Clindamycin appear to inhibit RNA dependent protein synthesis by binding to 50S ribosomal sub units, inhibiting peptide bond formation of susceptible organisms.

Resistance Staphylococcal resistance to clindamycin can be induced in a stepwise manner in vitro, Clindamycin resistance confers complete cross resistance with lincomycin and partial resistance with erythromycin.

Spectrum of Activity Clindamycin has the same spectrum of activity as lincomycin but is relatively more potent. Clindamycin is active against most gram-positive aerobic cocci including staphylococci, S. pneumoniae, and other streptococci, even those resistant to penicillin. It is also active against many anaerobic organisms. Clindamycin also has activity against Plasmodium, Pneumocystis and Toxoplasma species.

Therapeutic Uses Lincomycin should never be used because of adverse reactions and available alternatives. Clindamycin is effective therapy for moderate to severe infections due to aerobic gram- positive cocci and anaerobic bacteria. There is significant experience from infancy through adolescence for treatment of intra abdominal, gynaecologic, pelvic and bone and joint infections. It is a superior agent in animal models of osteomyelitis, probably related to high concentration in bone, neutrophils and macrophages. Clindamycin offers no advantage over penicillin G for treatment of uncomplicated, acute anaerobic upper and lower respiratory tract infection, but is superior to penicillin for treatment of chronic sinusitis, lung abscess, odontogenic and parapharyngeal abscess. It is used as adjunctive therapy for necrotizing fascitis due to its effect on reducing bacterial toxin production. For infections in a patient with hypersensitive to penicillin, clindamycin is an acceptable alternative drug for moderate to severe infections. The ability of clindamycin to target ribosomal protein production has led its use in treatment of toxin mediated infectious caused by Staphylococcus aureus (Toxic Shock 126 Rational Antimicrobial Practice in Pediatrics

Syndrome—TSS) and Streptococcus pyogenes (toxic shock like illness), either alone or in combination with cell wall active antibiotic agents. Other uses of clindamycin include: • Treatment of acne vulgaris, • Cerebral and ocular toxoplasmosis. • Adjunctive therapy for falciparum malaria. • Treatment of community acquired MRSA infections • Therapy for P. jiroveci resistant or intolerant to cotrimoxazole.

Dosage • 20–30 mg/kg/day in 4 divided doses PO. • 20–40 mg/kg/day in 3 divided doses IV dilute for slow infusion over 30 minutes.

Adverse Reactions Pseudomembranous colitis, initially reported to occur in upto 10% of adults with clindamycin, is much less common in children. Rapid infusion of undiluted lincosamides has led to cardiac arrest, presumably from a mechanism similar to quinidine. Other adverse effects of these compounds include increased serum hepatic enzymes, Stevens-Johnson syndrome, skin rashes and eosinophilia.

Drug Interactions Coadministration of clindamycin with gentamicin may increase nephrotoxicity. Clindamycin and lincomycin infusions potentiate effects of non-depolarizing neuromuscular blocking agents.

 NITROFURANTOIN Nitrofurantoin is one of the many synthetic S. nitrofurans derivatives, derived from pentosans obtained from corncobs, oat husks and bran. Nitrofurantoin is more soluble in urine as compared to water due to presence of urea and creatinine in urine, resulting in high urinary drug levels.

Mechanism of Action Nitrofurantoin is bacteriostatic, but may be bactericidal in high concentration in urine, following therapeutic doses. It appears that nitrofurantoin is reduced into active intermediates by bacterial enzymes, resulting in inactivation or alteration of ribosomal molecules and leading to inhibition of protein, DNA, RNA and cell wall synthesis.

Spectrum of Activity and Resistance Nitrofurantoin is active against several gram-positive and gram-negative organisms including S. aureus, Group D Streptococcus, E. coli, Salmonella and Shigella. It is inactive against Miscellaneous Antibacterial Drugs 127 most isolates of P. aeruginosa. Development of resistance has been reported rarely following prolonged therapy, cross-resistance with other agents has not been observed.

Clinical Pharmacokinetics It is well absorbed orally, rapidly metabolized in the liver and other tissues. Renal excretion accounts for 30 to 40% of elimination.

Therapeutic Uses Its use is primarily as a urinary antiseptic agent and for prevention of recurrent urinary tract infection. It may be used for treatment of cystitis where the microorganisms are resistant to other orally available agents but should not be used for treatment of tissue infection such as pyelonephritis. The drug is assuming greater importance in today’s day and age with rising incidence of ESBL production in community acquired urinary tract infections.

Dosage • 5–7 mg/kg/day in 3 to 4 divided doses. • 1–2 mg/kg/day in single bedtime dose as prophylaxis for UTI.

Adverse Reactions Nausea, epigastric pain and diarrhea are common gastrointestinal adverse effects. Acute reaction with chills, fever, leucopenia and hepatitis may occur occasionally. Pulmonary reactions in form of acute pneumonitis syndrome, subacute pulmonary syndrome with cough, dyspnea, pulmonary infiltrates and pulmonary effusions as well as chronic pulmonary fibrosis are known following prolonged use of nitrofurantoin.

Drug Interactions Nitrofurantoin antagonizes the antimicrobial effect of quinolones. Coadministration of nitrofurantoin with antacids may decrease bioavailability.

Contraindications Individuals with impaired renal functions (since the drug will not be adequately concentrated in the urine) and children less than three month of age should not receive nitrofurantoin.

 RECOMMENDED READING

1. Abramson JS, Girener LB. Should tetracycline be contraindicated for therapy of presumed Rocky Mountain spotted fever in children less than 9 years of age? Pediatrics 1990;86:123. 2. Hardman JG, Limbird LE, et al (Eds). Goodman and Gilman’s. The Pharmacological Basis of Therapeutics. 10th edition: McGraw-Hill, New York, 2001. 3. Jacobs RF, Schutz GE, Young RA, Kearns GL, James KP. Antimicrobial Agents In: Long SS, Pickering LK, Prober CG (Eds). Principle and Practice of Pediatric Infectious Diseases. New York, Churchill Livingstone. 1997:1604-43. 128 Rational Antimicrobial Practice in Pediatrics

4. Merchant SM, Vithlani NP. Current antibiotic usage II: Aminoglycosides, tetracyclines, erythromycin, vancomycin and sulphonamides. Indian J Pediatr. 1986;53:199-213. 5. Merchant SM, Vithlani NP. Current antibiotic usage. I: Penicillins, Cephalosporins and chloramphenicol. Indian J Pediatr. 1986;53:25-36. 6. Powell DA, Nahata. Chloramphenicol new perspectives on an old drug. Intell Clin Pharm. 1982;16:295- 300. 7. Sack CM, Koup JR, Smith AC. Chloramphenicol Pharmacokinetics in infants and young children. Pediatrics. 1980;66:579-84. 8. Saivin S, Houin G. Clinical Pharmacokinetics of doxycycline and minocycline. Clin Pharmacokinet. 1988;15:355. 9. Salter AJ. Trimethoprim Sulfamethoxazole: an assessment of more than 12 years of use. Rev Infect Dis. 1982;4:196. 10. Sulfonamides, cotrimoxazole and Quinolones. In: Tripathi KD (Ed). Essentials of Medical Pharmacology, 5th edition. New Delhi, Jaypee Brothers Medical Publishers (P) Ltd. 2003:641-52. 11. Tetracyclines and Chloramphenicol (Broad Spectrum Antibiotics). In: Tripathi KD (Ed). Essentials of Medical Pharmacology, 5th edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd. 2003:668- 77. Colistin and Tigecycline 129 1212 Colistin and Tigecycline Nishant Verma, Deepchand Khandelwal, Rakesh Lodha

 COLISTIN Introduction Antimicrobial resistance among gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, has become a worldwide health care crisis with many of these pathogens showing limited or no susceptibility to currently available antimicrobial treatments. This problem is further compounded by the marked decline in the discovery and development of novel antibiotics. The limited therapeutic options have forced infectious disease clinicians and microbiologists to reappraise the clinical value of older antibiotics like polymixins. Colistin, or Polymixin E, is a cationic obtained from Bacillus polymyxa subspecies colistinus. It was discovered in 1949, and was initially used therapeutically in Japan and in Europe during the 1950s and in the United States in the form of colistimethate sodium (CMS) in 1959.1 Colistin was one of the first antibiotics with significant activity against gram-negative bacteria, notably Pseudomonas aeruginosa. It exhibits rapid, concentration-dependent bactericidal activity. Colistin was largely replaced by aminoglycosides in the 1970s because of concern about nephrotoxicity and neurotoxicity.2-4 In the last 10–15 years, however, colistin has been used as a ‘salvage’ therapy for infections caused by multidrug-resistant (MDR) gram-negative bacteria.5 Because such a large gap exists between the years that colistin was used clinically, available pharmacokinetic and pharmacodynamic data are very limited. Thus, information regarding colistin toxicities and optimum dosing is not well defined, and no universal dosing for the antibiotic exists. In addition, reports have begun to surface of colistin resistance among the organisms that the drug is currently being used to treat.6 This increased rate of resistance has emphasized the need to provide adequate, effective dosing with minimal toxicity.

Chemistry Colistin consists of a cationic cyclic decapeptide linked to a fatty acid chain through an amide linkage. Based on the composition of amino acids and fatty acids, at least 30 130 Rational Antimicrobial Practice in Pediatrics different components have been isolated from colistin. Two major components are colistin A (polymyxin E1) and colistin B (polymyxin E2). The proportion of colistin A and colistin B in commercial material differs between pharmaceutical supplier sand batches.7,8 Colistin is commercially available in two forms, colistin sulfate and colistimethate sodium (CMS). Colistin sulfate is cationic and stable, whereas CMS is anionic and not stable in vitro or in vivo. Colistin sulphate has greater antimicrobial activity, but is also more toxic, so it is restricted to topical use. CMS is the form that is safer to administer parenterally because of its lower toxicity. CMS by itself has been shown to display little to no antibacterial activity and is considered an inactive prodrug of colistin. On parenteral administration, CMS is readily hydrolyzed to form partially sulfomethylated derivatives, as well as colistin sulfate, the active form of the drug.6

Mechanism of Action The mechanism behind colistin’s bactericidal ability is thought to be indistinguishable from that of , the standard of the . The target of antimicrobial activity of colistin is the bacterial cell membrane. Colistin binds with the anionic lipopolysaccharide molecules by displacing calcium and magnesium from the outer cell membrane of gram-negative bacteria, leading to permeability changes in the cell envelope. The disruption of the outer membrane leads to leakage of the cell content and subsequently cell lysis and death.8 Another characteristic of colistin which is of potential benefit is its unique anti-endotoxin activity, being able to neutralize bacterial lipopolysaccharides.9 The significance of this mechanism for in vivo antimicrobial action, namely prevention of the endotoxin’s ability to induce shock through the release of cytokines, is not clear.1

Spectrum of Activity Colistin has a narrow antibacterial spectrum of activity, with susceptibility mostly against common gram-negative aerobic bacilli. Most significantly, it displays in vitro activity against MDR gram-negative pathogens such as A. baumannii, P. aeruginosa, and K. pneumoniae. It also has considerable activity against Stenotrophomonas species.6 Colistin is not active against some gram-negative aerobic bacilli (including Pseudomonas mallei, Burkholderia cepacia, Proteus species, Providencia species, Serratia species, Edwardsiella species, and Brucella species), gram-negative and gram-positive aerobic cocci, gram-positive aerobic bacilli, anaerobes, fungi, and parasites.1

Pharmacokinetics Colistin sulfate and CMS are not absorbed by the gastrointestinal tract with oral administration. On parenteral administration, CMS is hydrolyzed and forms a complex mixture of partially sulfomethylated derivatives and colistin.10 Colistin appears in plasma soon after administration of CMS, indicating rapid conversion of CMS in to colistin. Studies in rats have shown that only 7–16% of an administered dose of CMS is converted systemically to colistin, indicating that CMS is an inefficient prodrug of colistin.11 Colistin and Tigecycline 131

CMS is eliminated predominantly by the kidneys. Following parenteral administration, ~ 60% of CMS is excreted in the urine during the first 24 hours. In renal failure, the renal excretion of CMS is decreased resulting in a greater conversion to colistin. This explains the need to decrease the dose of CMS in renally impaired patients. Colistin is eliminated predominantly by the non-renal route by means of mechanisms not yet fully understood. No biliary excretion has been reported in humans.12 The pharmacokinetics of intravenous CMS in adolescents with cystic fibrosis with a dose of 5–7 mg/kg/day in 3 divided doses has demonstrated a half-life of 3.4 hours, volume of distribution of 0.09 L/kg, and total body clearance of 0.35 mL/min/kg.13

Pharmacodynamics Most pharmacodynamic data on colistin are from in-vitro studies. Colistin displays concentration-dependent killing against susceptible strains of P. aeruginosa, A. baumannii and K. pneumoniae, including MDR strains. Colistin concentrations in the vicinity of MICs or above result in extremely rapid initial killing, with large decreases in colony forming units per ml occurring as early as 5 minutes following exposure. For the susceptible strains of P. aeruginosa, the MICs of colistin sulphate range from 1 to 4 mg/L, while the values for CMS are significantly higher and range from 4 to 16 mg/L.14 A very modest post-antibiotic effect is seen only at high concentrations against P. aeruginosa.15 It has been shown in recent studies that colistin demonstrates “inoculum effect”, i.e. both the rate and extent of killing by colistin are decreased at high compared to low inocula.16 Despite the often extensive initial killing observed against colistin-susceptible strains with exposure to colistin alone, regrowth is a common feature both in vitro and in vivo. Though the exact reason for this regrowth is not known, but it is proposed that the colistin-susceptible strains harbor a sub-population of colistin-resistant cells, which contribute to regrowth, and emergence of colistin resistance later.15 Recent studies to determine which pharmacokinetic/pharmacodynamic index best predicted the antibacterial activity of colistin found that the overall killing was best correlated with AUC/MIC (the ratio of area under curve to MIC). The identification of this index will be the key to designing optimal dosage regimens for patients.17

Dosing and Administration Systemic administration: Two formulations are commercially available for parenteral use. Both contain colistimethate sodium powder for reconstitution, but they are formulated differently and have distinct dosing recommendations. The product available in the United States is supplied in vials containing 360 mg of CMS per vial (equivalent to 150 mg colistin base activity). The product available in India and many European countries is provided in vials of 1 and 2 million international units (IU) of CMS. [One IU is defined as the amount of colistin that inhibits the growth of E. coli 95 I.S.M. in 1 mL broth at pH 7.2].18 12,500 IU CMS = 1 mg CMS = 0.42 mg colistin base activity 132 Rational Antimicrobial Practice in Pediatrics

The doses recommended by the Indian manufacturers are as follows: • For patients <60 kg : 50,000–75,000 unit/kg per day, in three divided doses. • For patients >60 kg : 3–6 million unit/day in three divided doses. In patients with renal dysfunction, the systemic dose must be modified (Table 1). In-spite of these dosing recommendations by the manufacturers, studies have shown that alternative dosing regimens including dose escalation and use of a loading dose may be more efficacious.19,20 As per this regime in adults, a loading dose of 9 million units followed 24 hours later by dosing @ 4.5 million units twice daily (in patients with normal renal function), and 4.5 million units once daily (creatinine clearance 20–50 mL/ minute) 4.5 million units every 48 hours in those with CrCl less than 20 mL/minute is recommended. This translates to a loading dose of 10 mg/kg of salt and maintenance dose of 5 mg/kg twice daily in children. Cure rates of more than 80% were achieved in patients with infections due to colistin only susceptible organisms and reversible nephrotoxicity was seen in around 15%. Though, the efficacy and safety of this regime needs to be evaluated further but it should be considered in critically sick patients.

TABLE 1 Dosing and equivalences (A) of colistimethate in adults with normal renal function, and (B) of colistimethate in adults with impaired renal function44 (A) Dosage Equivalence Equivalent dose recommended in IU# of colistin base# Colistimethate 6–12 mg/kg/day 75,000–150,000 2.5–5 mg/kg/day sodium (q6–12 h) IU/kg/day (q6 –12 h) (q6–12 h) (B) Creatinine Dose of Equivalence Equivalent dose clearance colistimethate in IU# of colistin base# 80–50 mL/h 6–9 mg/kg/day 75,000 IU–114,000 2.5–3.8 mg/kg/day (q12 h) IU/kg/day(q12h) (q12 h) 50–10 mL/h 6 mg/kg/day 75,000 IU/kg/day 2.5 mg/kg/day (q12 h–24 h) (q12 h–24 h) (q12 h–24 h) < 10 mL/h (anuria) 3.6 mg/kg/day 45,000 IU/kg/day 1.5 mg/kg/day (q36 h) (q36 h) (q36 h)

# 1 mg colistin base = 2.4 mg CMS; 1 mg colistin base = 30.000 IU; 1 mg CMS = 12.500 IU

Inhaled administration: Inhalational administration of CMS is not approved by the FDA, but is common in cystic fibrosis clinics throughout the world.21 The dosage of CMS commonly used for inhalation in adults with CF is 40–60 mg two or three times a day.5 If inhaled CMS is used it should be administered with caution. The drug breakdown products can cause direct damage to lung tissue, leading to potentially serious and life-threatening side effects. This is particularly true for the premixed, ready to use liquid Colistin and Tigecycline 133 forms of the products. If colistin is to be used for nebulized inhalation, it must be mixed immediately prior to administration.22

Clinical Uses The use of colistin should be considered for the treatment of infections caused by gram- negative bacteria resistant to other antimicrobials or when treatment with these agents has been clinically ineffective. In the last decade colistin has been used to treat of a range of infections (VAP, bacteremia, CNS infections, UTI) caused by MDR gram- negative bacteria, in particular P. aeruginosa, A. baumannii and K. pneumoniae, in critically- ill adult and pediatric patients.

Pneumonia MDR gram-negative bacilli have become a major cause of nosocomial pneumonia, especially in critically ill patients requiring mechanical ventilation. A recent systematic review by Florescu et al. evaluating the efficacy of colistin for the treatment of Ventilator-Associated Pneumonia showed that colistin is as safe and as efficacious as standard antibiotics for the treatment of VAP.23 The most recent American thoracic society guidelines also recommend colistin as a therapeutic option for the treatment of VAP caused by MDR gram-negative organisms.24 Inhaled colistin has been used as an adjunctive therapy to intravenous antibiotics for nosocomial pneumonia due to multidrug-resistant organisms. However, there is minimal evidence of benefit when used in this setting. In a recent study, aerosolized colistin resulted in no extra benefit when given as an adjunct to intravenous colistin to patients with multidrug-resistant gram-negative ventilation associated pneumonia.25 In a separate study, inhaled colistin was compared with inhaled saline in patients with ventilator-associated pneumonia caused by either A. baumannii or P. aeruginosa.26 Although, patients who used inhaled colistin had increased microbial eradication from the respiratory secretions, they had no difference in clinical outcomes and had an increased rate of bronchospasm compared with patients who used inhaled saline. If inhaled colistin is used it should be administered with caution.

Respiratory Infections in Cystic Fibrosis Pseudomonas aeruginosa frequently colonizes the airway of patients with CF, initially only intermittently, but generally evolving towards a chronic infection, almost impossible to eradicate. As infection by P. aeruginosa has been related to a significant worsening in lung function, a need for aggressive treatment of the initial cases of intermittent colonization is commonly accepted, in order to prevent it from becoming chronic. Inhalation of CMS has been used in CF over the last two decades both for the treatment of initial colonization as well as for the treatment of chronic infections. Treatment of initial colonization: For the treatment of initial colonization, different treatment regimens have been proposed including inhaled tobramycin (80 mg every 12 hours) or colistin (1–3 million IU every 12 hours) alone or associated with systemic antibiotics 134 Rational Antimicrobial Practice in Pediatrics

(oral ciprofloxacin or other IV antipseudomonal agents) for a total duration of 3 weeks to 3 months. Nevertheless, no properly designed studies have proved the superiority of any of these strategies or established their optimal duration.27 Treatment of chronic infections: CF patients with chronic P. aeruginosa infection are recommended to receive regular nebulized antipseudomonal antibiotic treatment, to avoid the development of acute exacerbations and preserve respiratory function. Nebulized tobramycin or colistin (eventually associated with oral ciprofloxacin) have been proposed, though no clinical differences have been proved so far.27 Treatment of acute exacerbations: For treatment of acute exacerbations of CF, a combination of two IV antipseudomonal agents is recommended. Antimicrobial treatment in these cases should be tailored by previous isolations, and usually includes an antipseudomonal beta lactam associated with an aminoglycoside. Colistin should be reserved as a second- line treatment in patients infected by MDR-GNB or presenting intolerance to aminoglycosides.28

CNS Infections Intravenous treatment with colistin alone is not recommended for CNS infections with GNB because colistin does not consistently cross the blood brain barrier in noninflamed or inflamed meninges. There are several case reports in the literature citing successful treatment with intraventricular or intrathecal administration of colistimethate in children and adults with gram-negative meningitis. Literature has reported doses ranging from 3.2–10 mg given once daily for intrathecal administration and 10–20 mg/day for intraventricular administration in adults.29

Blood Stream Infections No specific comparative trials have assessed the effectiveness of colistin in MDR/ carbapenem resistant gram-negative bacteraemia. However, there are multiple case reports and case series in the literature which have demonstrated successful use of colistin in treating blood stream infections with response rates ranging from 60–100%.27,30 Herein, colistin should be used in combination and never as monotherapy. Case series describing the use of colistin in patients with carbapenem resistant enterobacteriaceae have revealed high mortality (as high as that seen in patients receiving inappropriate therapy) in those patients who received monotherapy as compared to those who received dual therapy with carbapenem and colistin or triple drug therapy with carbapenem, colistin and tigecycline.31

Other Uses Good outcomes with IV colistin therapy have been reported in patients with other sites of infection like: urinary tract infections, surgical site and soft tissue infections, tracheobronchitis, intra-abdominal infections, bone and joint infections, infective endocarditis, and otitis media.27 Colistin and Tigecycline 135

Topical colistin sulphate has been used for conditions such as otitis externa and eye infections due to P. aeruginosa. Oral colistin sulphate has also been used in certain conditions for decontamination and sterilization of the gut.

Colistin Use in Children In clinical studies, colistimethate sodium has been safely and successfully administered to the pediatric population (including neonates, infants, children and adolescents).32-34 The adverse effects related to colistin in this patient population appears to be no different from that of the adult population. In a recent systematic review of the use of colistin in children without cystic fibrosis, 271 children were evaluated and 86.5% were cured of infection. Nephrotoxicity occurred in 2.8% of the children and no neurotoxicity was reported.35

Adverse Reactions The most important side effect of intravenous colistin is nephrotoxicity; neurotoxicity also occurs, although the frequency and severity is much less. Both renal and neurologic toxicity are dose-dependent and usually reversible after early discontinuation of the drug.

Nephrotoxicity Colistin has been associated with hematuria, proteinuria, and oliguria and acute renal failure due to acute tubular necrosis.36, 37 It may be difficult to determine the relative contribution of colistin to development of acute renal failure since patients who receive colistin typically have complex clinical circumstances and many may be receiving other concomitant nephrotoxins. Recent data indicate that colistin-related nephrotoxicity, may be less prominent than previously thought.29 Nephrotoxicity, if it occurs, usually occurs within the first 4 days of therapy and mainly includes acute tubular necrosis, manifested as decreased creatinine clearance and increased serum urea and creatinine levels. In recent reports, nephrotoxicity was documented in 8–19% of patients.38 Frequent monitoring of renal function is advised. Use of other nephrotoxic drugs should be avoided whenever possible.

Neurotoxicity Neurological symptoms which have been associated with the use of colistin include dizziness, weakness, facial and peripheral paresthesia, vertigo, visual disturbances, confusion, ataxia, and neuromuscular blockade, which can lead to respiratory failure or apnea. The incidence of colistin-associated neurotoxicity reported in initial studies was about 7 percent; paresthesias were the main neurotoxic adverse event.39

Other Adverse Effects Hypersensitivity reactions (including rash, pruritus, urticaria, and fever) have been reported in 2 percent of patients.39 Other rare complications related to colistin administration are ototoxicity, drug fever, and gastrointestinal disturbances. Complications related to 136 Rational Antimicrobial Practice in Pediatrics administration of aerosolized colistin are sore throat, cough, bronchoconstriction, and chest tightness bronchodilation prior to administration may be beneficial.40

Drug Interactions Other antibiotics which interfere with the nerve transmission at the neuromuscular junction (like: aminoglycosides) should not be given concomitantly with colistin. Curare-like muscle relaxants (e.g. tubocurarine) and other drugs, including ether, succinylcholine, gallamine, decamethonium potentiate the neuromuscular blocking effect. Concomitant administration of other nephrotoxic agents (gentamycin, amikacin, streptomycin, vancomycin, etc.) should be avoided.

Drug Resistance Resistance to colistin is uncommon and the mechanism of colistin resistance is poorly defined. Studies of colistin-resistant Pseudomonas aeruginosa strains have suggested that alterations of the outer membrane of the bacterial cell are related to the development of resistance. These alterations may be in the form of: • reduction in LPS • reduced levels of specific outer membrane proteins • reduction in cell envelope Mg and Ca contents • lipid alterations. Resistance is postulated to be induced by a gene (PmrA), which modifies LPS resulting in reduced binding affinity of colistin and possibly related antimicrobial peptides to the outer membrane.41 There are no standardized methods for colistin susceptibility testing. The broth microdilution method is preferred for susceptibility testing. The disk diffusion method cannot be used to test for resistance since polymyxins diffuse poorly in agar.42 Development of resistance to colistin is a serious concern. As colistin is the last line of defense against the virulent pathogens, resistance to this antibiotic may have devastating effects. Moreover, researchers have found that clinically selected colistin- resistant organisms, once emerged, have a potential to persist in the patients and the hospital environment and cause subsequent transmission.43 With the continued use of colistin for treatment of infection with various multidrug-resistant gram-negative pathogens, it is likely that we will see an increasing number of instances of both de novo emergence of resistance and nosocomial spread.

Cost of the Therapy 1 million unit vial of Colistin (XylistinTM–Cipla) costs about Rs 700. A child of 20 kg weight will require 1–2 million units daily. So the total cost for a 10 day therapy would be around Rs 7000–14000. Colistin and Tigecycline 137

CONCLUSION • Colistin, is a bactericidal drug that disrupts the outer cell membrane of gram-negative rods and is primarily used for treatment infections with MDR-GNB (especially Pseudomonas aeruginosa and Acinetobacter baumannii). • Colistin is formulated as colistimethate sodium for reconstitution for parenteral use. It is measured as grams of colistin base activity in the United States and as international units of colistimethate sodium in Europe and India. The recommended dosage varies by formulation and manufacturer. Dose adjustments should be made in the setting of renal dysfunction. • There is a dearth of information on the pharmacokinetics and pharmacodynamics of colistin in human subjects. As more data becomes available, the current dosing regimen may need to be modified including use of a loading dose and dose escalation. • Inhaled colistin should be used with caution and must be mixed immediately prior to administration. • Penetration of colistin into the cerebrospinal fluid is low when administered intravenously. • Renal toxicity is the most important side effect of intravenous colistin, and renal impairment appears to be reversible. Neurologic toxicity, mainly paresthesias, is also associated with colistin.

 REFERENCES 1. Falagas ME, Kasiakou SK. Colistin. The Revival of Polymyxins for the Management of Multidrug- Resistant gram-negative. Bacterial Infections. Clinical Infectious Diseases. 2005;40:1333-41. 2. Ryan KJ, Schainuck LI, Hickman RO, Striker GE. Colistimethate toxicity: report of a fatal case in a previously healthy child. JAMA. 1969;207:2099-101. 3. Brown JM, Dorman DC, Roy LP. Acute renal failure due to overdosage of colistin. Med J Aust. 1970;2:923-4. 4. Koch-Weser J, Sidel VW, Federman EB, Kanarek P, Finer DC, Eaton AE. Adverse effects of sodium colistimethate: manifestations and specific reaction rates during 317 courses of therapy. Ann Intern Med. 1970;72:857-68. 5. Li J, Nation RL, Turnidge JD, et al. Colistin: the re-emerging antibiotic for multidrug-resistant Gram- negative bacterial infections. Lancet Infect Dis. 2006;6:589-601. 6. Lim LM, Neang LY, Anderson D, Yang JC, Macander L, Jarkowski A, et al. Resurgence of Colistin: A Review of Resistance, Toxicity, Pharmacodynamics, and Dosing. Pharmacotherapy. 2010;30(12):1279- 91. 7. Orwa JA, Govaerts C, Busson R, et al. Isolation and structural characterization of colistin components. J Antibiot 2001;54:595–9 8. Li J, Nation RL, Milne RW, Turnidge JD, Coulthard K. Evaluation of colistin as an agent against multi- resistant gram-negative bacteria. Int J Antimicrob Agents. 2005;25:11-25. 9. Warren HS, Kania SA, Siber GR. Binding and neutralization of bacterial lipopolysaccharide by colistin nonapeptide. Antimicrob Agents Chemother. 1985;28:107-12. 10. McMillan FH, Pattison IC. Sodium colistimethate. I. Dissociations of aminomethanesulfonates in aqueous solution. J Pharm Sci. 1969;58:730-7. 11. Li J, Milne RW, Nation RL, Turnidge JD, Smeaton TC, Coulthard K. Pharmacokinetics of colistin methanesulphonate and colistin in rats following an intravenous dose of colistin methane sulphonate. J Antimicrob Chemother. 2004;53:837-40. 138 Rational Antimicrobial Practice in Pediatrics

12. Michalopoulos AS, Karatza DC, Gregorakos L. Pharmacokinetic evaluation of colistin sodium. Expert Opin Drug Metab Toxicol. 2011;7(2):245-55. 13. Reed MD, et al. The pharmacokinetics of colistin. J Clin Pharmacol. 2001;41:645- 54. 14. Li J, Turnidge J, Milne R, et al. In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother. 2001;45:781-5. 15. Bergen PJ, Li J, Nation RL. Dosing of colistin—back to basic PK/PD. Current Opinion in Pharmacology. 2011;11:464-9. 16. Bulitta JB, Yang JC, Yohonn L, Ly NS, Brown SV, D’Hondt RE, et al. Attenuation of colistin bactericidal activity by high inoculum of Pseudomonas aeruginosa characterized by a new mechanism-based population pharmacodynamic model. Antimicrob Agents Chemother. 2010;54:2051-62. 17. Dudhani RV, Turnidge JD, Coulthard K, Milne RW, Rayner CR, Li J, Nation RL. Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models. Antimicrob Agents Chemother. 2010;54:1117-24. 18. Kaye KM, Kaye D. Polymyxins (polymyxin B and colistin). In: Mandell GL, Bennett JE, Dolin R, editors, Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 6th edition. Philadelphia: Churchill Livingstone. 2005;435-6. 19. Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011;55:3284. 20. Dalfino L, Puntillo F, Mosca A, et al. High Dose, Extended-Interval Colistin Administration in Critically Ill Patients: Is this the Right Dosing Strategy? A Preliminary Study. Clin Infect Dis. 2012. 21. Linden PK, Paterson DL. Parenteral and inhaled colistin for treatment of ventilator-associated pneumonia. Clin Infect Dis. 2006;43 Suppl 2:S89-94. 22. FDA Drug Safety Podcasts—Colistimethate (marketed as Coly-Mycin M and generic products) http:/ /www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm077907.htm (Accessed on October 20, 2012) 23. Florescu DF, Qiu F, McCartan MA, Mindru C, Fey PD, Kalil AC. What Is the Efficacy and Safety of Colistin for the Treatment of Ventilator-Associated Pneumonia? A Systematic Review and Meta- Regression. Clinical Infectious Diseases. 2012;54(5):670-80. 24. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator -associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. 25. Kofteridis DP, Alexopoulou C, Valachis A, et al. Aerosolized plus intravenous colistin versus intravenous colistin alone for the treatment of ventilator-associated pneumonia: a matched case-control study. Clin Infect Dis. 2010;51:1238. 26. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, et al. Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram- negative bacteria. J Antimicrob Chemother. 2010;65:2645. 27. Molina J, Cordero E, Pachon J. New information about the polymyxin/colistin class of antibiotics. Expert Opin Pharmacother. 2009;10(17):2811-28. 28. Antibiotic treatment for cystic fibrosis. Consensus document. Report of the UK Cystic Fibrosis Trust Antibiotic Working Group, 2009. Available from: http://www.cftrust.org.uk/aboutcf/publications/ consensusdoc/. 29. Tamma PD, Lee CK. Use of Colistin in Children. The Pediatric Infectious Disease Journal. 2009;28(6):534-5. 30. Landman D, Georgescu C, Martin DA, Quale J. Polymyxins Revisited. Clin Microbiol Rev. 2008;21(3):449-65. 31. Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012;56:2108-13. 32. Iosifidis E, Antachopoulos C, Ioannidou M, Mitroudi M, Sdougka M, Drossou-Agakidou V, et al. Colistin administration to pediatric and neonatal patients. Eur J Pediatr. 2010;169:867-74. 33. Falagas ME, Sideri G, Vouloumanou EK, et al. Intravenous Colistimethate (Colistin) Use in Critically Ill Children Without Cystic Fibrosis. The Pediatric Infectious Disease Journal. 2009;28(2):123-7. Colistin and Tigecycline 139

34. Jajoo M, Kumar V, Jain M, Kumari S, Manchanda V. Intravenous Colistin Administration in Neonates. The Pediatric Infectious Disease Journal. 2011;30(3):218-21. 35. Falagas ME, Vouloumanou EK, Rafailidis PI. Systemic colistin use in children without cystic fibrosis: a systematic review of the literature. International Journal of Antimicrobial Agents. 2009;33(6):503.e1- 503.e13. 36. Kallel H, Hergafi L, Bahloul M, et al. Safety and efficacy of colistin compared with imipenem in the treatment of ventilator-associated pneumonia: a matched case-control study. Intensive Care Med. 2007;33:1162. 37. Goverman J, Weber JM, Keaney TJ, Sheridan RL. Intravenous colistin for the treatment of multi-drug resistant, gram-negative infection in the pediatric burn population. J Burn Care Res. 2007;28:421. 38. Markou N, Apostolakos H, Koumoudiou C, et al. Intravenous colistin in the treatment of sepsis from multiresistant GNB in critically ill patients. Crit Care. 2003;7:R78. 39. Koch-Weser J, Sidel VW, Federman EB, et al. Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy. Ann Intern Med. 1970;72:857. 40. Alothman GA, Ho B, Alsaadi MM, et al. Bronchial constriction and inhaled colistin in cystic fibrosis. Chest. 2005;127:522-9. 41. Groisman EA, Kayser J, Soncini FC. Regulation of polymyxin resistance and adaptation to low-Mg2 environments. J. Bacteriol. 1997;179:7040-5. 42. Gales AC, Reis AO, Jones RN. Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. J Clin Microbiol. 2001;39:183. 43. Bogdanovich T, Adams-Haduch JM, Tian G, Nguyen MH, Kwak EJ, Muto CA, Doi Y. Colistin-Resistant, Klebsiella pneumoniae Carbapenemase (KPC)–Producing Klebsiella pneumoniae Belonging to the International Epidemic Clone ST258. Clinical Infectious Diseases. 2011;53(4):373-6. 44. Amsden G. Tables of antimicrobial agent pharmacology. In: Mandell GL, Bennett JE, Dolin R (Eds). Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 6th edition. Philadelphia: Churchill Livingstone. 2005;p668-9.

 TIGECYCLINE Introduction There is a pressing need for new antibiotics to combat the worsening problem of bacterial resistance to existing agents. Strains of potentially life-threatening bacteria that are resistant to multiple antibiotics are becoming increasingly widespread. The main approach for developing new antibiotics in the past has been to modify existing drug classes to restore activity against bacteria that have become to resistant to the previous generation of drugs. But although the development of second and third generation drugs in the major antibacterial classes, including penicillins, cephalosporins, macrolides and quinolones, have helped keep antibiotic resistance at bay, success with this strategy is becoming much harder to achieve.1 Tigecycline is the first in a new generation of tetracyclines, known as , which have been developed to overcome the problems of resistance to earlier tetracyclines. It was approved by the US Food and Drug Administration for the treatment of a range of bacterial infections in June 2005. Tigecycline has in vitro activity against many gram- positive and gram-negative aerobic as well as anaerobic bacteria including MRSA, vancomycin-resistant enterococci, extended spectrum beta lactamase producing Klebsiella and carbapenem-resistant Acinetobacter. Although not yet approved for patients less than 18 years of age, its excellent safety and tolerability profile in adults suggests that it may be an important antimicrobial agent for children.2,3 140 Rational Antimicrobial Practice in Pediatrics

Chemistry Tetracyclines as a class of antibiotics were first discovered in the 1940s. Chlortetracycline was the first member to be discovered, it is a product of Streptomyces aureofaciens. Other tetracyclines soon followed, some naturally occurring molecules like tetracycline and other semisynthetic products like, doxycycline and minocycline.4 The discovery of tetracyclines represented a significant advance in the treatment of many gram-positive and gram-negative bacterial infections. However, following their initial widespread use, a high incidence of tetracycline resistance among many bacteria led to tetracyclines being relegated to second- or third-line therapy. In an attempt to restore the potential of tetracyclines as broad-spectrum antibiotics, systematic searches for tetracycline analogues with activity against both tetracycline-susceptible and tetracycline-resistant organisms were performed in the early 1990s. These efforts led to the identification of the glycylcyclines, including tigecycline.5 The tetracycline nucleus consists of four linear fused tetracyclic rings, with a variety of functional groups attached at different positions. The glycylcyclines are obtained by adding N,N-dimethylglycylamido (DMG) substituent at the 9 position of minocycline and 6-demethyl-6-deoxytetracycline. Further modification of this structure led to the discovery of tigecycline (GAR-936), which is the 9-tert-butyl-glycylamido derivative of minocycline.6 Tigecycline is the only member of the glycylcyclines group of antibiotics, which has been approved for clinical use.

Mechanism of Action Tigecycline, like the tetracyclines, acts by inhibiting bacterial protein synthesis. It binds to the A-site on 30S subunit of ribosome and blocks the entry of aminoacyl-transfer ribonucleic acid (tRNA) into the respective ribosomal binding sites. This prevents the incorporation of amino-acid residues into the elongating peptide chain. Although the mechanism of action of tigecycline is same as other tetracyclines, it has distinct advantages over the other members of the group. This is because tigecycline appears to assume a different steric conformation, owing to the large substituent at position 9. This results into high affinity of binding of tigecycline to the ribosome, and thus into evasion of the common ribosomal protection mechanisms that are associated with resistance to tetracyclines.7 Additionally, tigecycline has the property to evade common tetracycline efflux mechanisms.

Spectrum of Activity Tigecycline has a broad spectrum of antimicrobial activity, which includes aerobic and anaerobic gram-positive and gram-negative bacteria, as well as atypical pathogens. Specifically, tigecycline has been shown to possess excellent antimicrobial activity against MRSA, Vancomycin resistant Enterococci (VRE), and penicillin non-susceptible Streptococcus pneumoniae. It has also demonstrated potent antimicrobial activity against ESBL-producing Escherichia coli and Klebsiella pneumoniae. Additionally, it constitutes Colistin and Tigecycline 141 one of the few potentially active agents against carbapenem-resistant Acinetobacter baumannii, which typically exhibits resistance to all beta-lactam agents.8 Though tigecycline has a wide spectrum of activity, it shows low activity against Proteus and is not active against Providencia spp. and Pseudomonas aeruginosa, due to the production in these organisms of chromosomally encoded resistance nodulation division (RND) type efflux pumps that recognize tigecycline as a substrate. Furthermore, the activity of this agent is not optimal against Burkholderia cepacia, Stenotrophomonas maltophilia, Legionella pneumophila, and certain members of the Bacteroides fragilis group.9

Administration and Dosage In view of a limited oral bioavailability, tigecycline is currently available as an intravenous formulation. The recommended regimen for adults is an initial loading dose of 100 mg followed by 50 mg every 12 hours (Table 1). Using a loading dose followed by multiple maintenance doses, the steady state of tigecycline is reached within 3 days.10 Though the safety and efficacy of tigecycline has not been established in children < 18 year age, but it may be used with extreme caution in highly selective cases. The dosing recommended for children is: a loading dose of 1.5 mg/kg followed by 1 mg/ kg (not to exceed 50 mg) every 12 hours.3 Tigecycline is available as a lyophilized powder in 50 mg vial strength (stored at 2° to 8°C). It is reconstituted with normal saline or 5% dextrose and given as an infusion in normal saline or ringer lactate (maximum concentration 1 mg/mL) over 30–60 min. Reconstituted solution may be stored at room temperature for up to 24 hours and at 2° to 8°C for up to 48 hours.11

Pharmacokinetics

A single intravenous tigecycline dose of 100 mg results in a Cmax (peak serum concentration) of 0.85 to 1 mg/L, and an extended half-life of 27 hours. In vitro plasma protein binding ranges from 71% to 89% at concentrations observed in clinical studies. The steady-

TABLE 1 Dosing schedule of tigecycline Adults Children* Loading dose–100 mg Loading dose–1.5 mg/kg Dosage Maintenance dose– Maintenance dose–1 mg/kg 50 mg q 12 h q 12 h Dose modification in Child Pugh class A and B–None hepatic insufficiency Child Pugh class C–Reduce maintenance dose by 50% Dose modification in None renal insufficiency *Not yet approved by the US FDA for use in children < 18 years of age. Should not be used in children less than 8 years age. 142 Rational Antimicrobial Practice in Pediatrics state volume of distribution averages 7–9 L/kg.12 The large volume of distribution of tigecycline reflects the high penetration of this drug into tissues. In a study evaluating the degree of tissue penetration of tigecycline in 104 patients undergoing various types of scheduled surgical interventions or lumbar puncture, it was found that the penetration of the drug was highest in bile, followed by gallbladder, colon, and lung tissue, whereas tigecycline exposure in bone, and synovial or cerebrospinal fluid was lower compared to serum.13 Tigecycline is partially metabolized in the liver and the major elimination of unchanged drug and its metabolites is through biliary excretion into the gastrointestinal tract. The two major pathways of tigecycline metabolism in the liver consist of glucuronidation, and amide hydrolysis to t-butylaminoacetic acid and 9-aminominocycline. None of the above products of tigecycline metabolism and degradation is considered to have significant pharmacological activity.14 In patients with severe hepatic impairment (Child-Pugh class C) the systemic clearance of tigecycline is decreased by approximately 55%, and the elimination t½ is prolonged by approximately 43% compared to healthy subjects.15 So, in this group of patients (Child-Pugh class C) the maintenance doses of tigecycline should be reduced by 50% (Table 1).16 Less than 15% of tigecycline is excreted unchanged in urine and renal clearance accounts for <20% of total clearance.17 Tigecycline kinetics in subjects with severe renal failure as well as in those with end-stage renal impairment treated by hemodialysis indicates that no dosage adjustment is required.18 It has also been shown that the amount of tigecycline removed by hemodialysis is minimal and the timing of administration of tigecycline with regard to the hemodialysis procedure does not appear to influence the tigecycline pharmacokinetics considerably.17,19

Pharmacodynamics Regarding tigecycline, due to prolonged PAE against most pathogens, along with extensive volume of distribution, and prolonged elimination t½ in humans, the AUC/MIC ratio has been proposed as the most important predictor of clinical and microbiological efficacy.17 Tigecycline, similarly to tetracyclines, exhibits in general a bacteriostatic pattern of antibacterial activity. However, this depends on the pathogen and strain examined, for example: tigecycline has demonstrated bactericidal activity against S. pneumoniae in several relevant studies.21

Clinical Applications of Tigecycline Tigecycline was approved in 2005 by the US Food and Drug Administration (FDA) and in 2006 by the European Medicines Agency (EMEA) for the treatment of complicated skin and skin structure infections (cSSSIs) and complicated intra-abdominal infections (cIAIs) in adults. In March 2009, the FDA approved tigecycline for the treatment of community-acquired pneumonia (CAP) caused by S. pneumoniae (penicillin-susceptible isolates), H. influenzae (beta-lactamase negative isolates) and Legionella pneumophila.22 Tigecycline is not currently approved for infections caused by multidrug-resistant (MDR) Colistin and Tigecycline 143 or extensive drug-resistant (XDR) organisms; despite that, off-label use is increasing globally for indications such as nosocomial sepsis/septic shock, bacteremia and ventilator- associated pneumonia (VAP) in the critically ill ICU patients. This is because of the appealing in vitro spectrum of tigecycline and the lack of other active antimicrobial agents against the MDR/XDR pathogens except for colistin.16 Complicated skin/skin structure infections and Intra-abdominal infections Two phase-3, randomized, double-blind studies evaluating the efficacy of tigecycline, compared with vancomycin plus aztreonam, were conducted in hospitalized patients with complicated skin/skin-structure infections. On analyzing the results, the overall clinical cure rates were similar (86.5% for tigecycline and 88.6% for vancomycin-aztreonam) in the 2 groups. Microbiological success rates were also comparable in the 2 treatment groups (86% vs. 88%). Of note, tigecycline was as effective as vancomycin-aztreonam (78% vs. 76%) in eradicating strains of MRSA. Moreover, all 8 strains of B. fragilis isolated in the tigecycline treatment group were eradicated.23 A pooled analysis of 2 phase 3, double-blind, randomized study comparing tigecycline with imipenem-cilastatin in patients with complicated intra-abdominal infections showed that overall, clinical cure rates were similar (86%) in the 2 treatment groups. Bacterial eradication rates were also similar between groups.24 In summary, tigecycline has exhibited non-inferiority to other standard treatments for cSSSIs and cIAIs. Although there are several antibiotic combinations that can be used to treat these infections, tigecycline is unique for its ability to be used as monotherapy for empirical coverage of various drug-resistant pathogens.

Pneumonia Tigecycline has been compared with levofloxacin for the treatment of patients hospitalized for community-acquired pneumonia (CAP), requiring intravenous antibiotics, in two multicenter, randomized, double-blind clinical trials.25 At the test-of-cure evaluation (within 7 to 23 days after the completion of therapy), cure rates in the tigecycline treatment arms were not inferior compared to the levofloxacin treatment arms. In view of these positive results, tigecycline was approved for the treatment of CAP by FDA in 2009. Apart from CAP, many cases of patients with nosocomial pneumonia treated with tigecycline have been reported in the biomedical literature, including cases caused by organisms like multidrug-resistant A. baumannii, carbapenem-resistant K. pneumoniae, and MRSA.14,26 In a multicentre, randomized, double-blind study comparing tigecycline regimen (tigecycline ± ceftazidime ± aminoglycoside) with imipenem regimen (imipenem /cilastatin ± vancomycin ± aminoglycoside) in patients with nosocomial pneumonia, Freire et al found significantly lower cure rates with tigecycline in VAP patients, and also more deaths occurred in VAP patients treated with tigecycline than imipenem. In non-VAP patients, tigecycline was non inferior to imipenem.27 In view of these discrepencies, the role of tigecycline in treatment of nosocomial pneumonia remains uncertain and it is currently not approved by FDA for this indication. 144 Rational Antimicrobial Practice in Pediatrics

Other Indications In the current era of MDR organisms, tigecycline is being increasingly prescribed for off-label indications like, nosocomial sepsis, septic shock and bacteremia. However, this is of great concern because tigecycline is primarily a bacteriostatic agent with a very large volume of distribution. The steady-state serum concentrations achieved after a standard dosing with tigecycline are quite low relative to commonly used sensitivity breakpoints. So, in severe infections with high bacteremia risk, low serum levels combined with bacteriostatic rather than bactericidal activity may lead to an unfavorable microbiological response (higher non-cure rates and delayed clearance of bacteremia). Another problem with use of tigecycline for MDR infections is superinfection with organisms inherently resistant to tigecycline (i.e. Proteus spp, Providencia spp, P. aeruginosa). So, use of this drug as monotherapy should be restricted to patients with documented non-pseudomonal infections and an anti-pseudomonal agent should be added to empirical regimens in patients with risk factors for pseudomonal infections.16 There are few reports of use of tigecycline for treatment of urinary tract infections, however there are concerns regarding its effectiveness because only 10-15% of an administered dose of the drug is excreted unchanged in the urine.14

Use in Children Tigecycline is not expected to be used in children less than 8 years of age because of possible bone and tooth discoloration and therefore has not been tested in patients this young. Although the safety and effectiveness of tigecycline in pediatric patients below the age of 18 years have not been established and it is not approved by FDA for use in this age group, but, because of its excellent safety and tolerability profile in adults, tigecycline may be an important antimicrobial agent for children in selected cases. A recent Phase II, multicenter, open-label clinical trial was done in children aged 8 to 11 years with cSSSI, cIAI, and CAP to assess the pharmacokinetic properties, safety profile, and descriptive efficacy of tigecycline. The results of this trial showed that tigecycline was well tolerated in children and the clinical cure rates were acceptable. Nausea was the most frequent adverse event. This trial also suggested that tigecycline dose of ~1.2 mg/kg q 12 h be superior to the 1 mg/kg dose.28 However, further phase III trials are needed before the use of tigecycline can be established in children.

Safety Profile All-cause Mortality A meta-analysis of 13 RCTs comparing tigecycline with other active comparators demonstrated a significant increase in mortality and non-cure rates with tigecycline. Overall, tigecycline was associated with a 0.7% absolute or 30% relative increase in mortality.29 The increased unfavorable outcomes with tigecycline therapy occurred for both FDA- approved as well as non-approved indications. However, the greatest increase in risk of death with tigecycline is seen in patients with ventilator-associated pneumonia, an unapproved use. Colistin and Tigecycline 145

Based on these results, FDA has updated the Warnings and Precautions and Adverse Reactions sections of the tigecycline drug label to include information regarding increased mortality risk of this drug.30 The cause of excess death in these trials is often uncertain, but it is likely that most deaths are probably related to the severe infection for which tigecycline was used as a treatment.

Adverse Reactions Tigecycline appears to have low potentials for organ toxicity. Nausea and vomiting are the most commonly encountered adverse effects associated with this drug, and they generally occur during the first 1–2 days of therapy. The majority of cases of nausea and vomiting associated with tigecycline are either mild or moderate in severity. Food may improve the tolerability of tigecycline, but decreasing the infusion rate of the drug has not been shown to be beneficial. Antiemetics have not been shown to be beneficial in decreasing the incidence of nausea and vomiting.15 The frequent laboratory abnormalities observed in patients recieving tigecycline include thrombocythemia, hyperbilirubinemia, elevated SGOT/SGPT, hypoproteinemia, anemia, prolongation of PT and aPTT.14 Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Tigecycline is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: permanent discoloration of the teeth in children less that 8 years of age, photosensitivity, pseudotumor cerebri, and anti-anabolic action (which can lead to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of tigecycline.3

Drug Interactions Tigecycline is not a substrate, inhibitor, or inducer of common cytochrome P450 enzymes and is not highly protein bound. As a result of these properties, pharmacokinetic drug interactions are uncommon with tigecycline. Concomitant administration of tigecycline and warfarin results in a decrease in clearance and an increase in Cmax of warfarin. Though tigecycline does not significantly alter the effects of warfarin on INR but, prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is co-administered with warfarin.31

Drug Resistance There are three different mechanisms responsible for tetracycline resistance–ribosomal protection, efflux and chemical modification.9 The first two mechanisms are the most clinically significant. Tigecycline has demonstrated anti-bacterial activity against tetracycline resistant organisms which have protected ribosomes. Thought the exact mechanism by which tigecycline overcomes this resistance is not known, but it is proposed that tigecycline binds more avidly to the bacterial ribosome so that the product of the bacterial resistance gene is unable to disrupt this tight bond. Tigecycline is also active against organisms that display efflux-based resistance which may be because of the inability of tigecycline 146 Rational Antimicrobial Practice in Pediatrics to induce tetracycline efflux pumps or because the efflux pump may not be able to export tigecycline.32 Tigecycline is inherently not active against Pseudomonas spp, Proteus spp, Providencia spp. and Morganella morganii due to the production in these organisms of chromosomally encoded resistance nodulation division (RND) type efflux pumps that recognize tigecycline as a substrate.33 There have been recent reports of emerging tigecycline resistance among Acinetobacter spp. In a prospective study conducted at PGI Chandigarh which included isolates from urine of patients with complicated UTI, it was found that 14.2% isolates of Acinetobacter calcoaceticus–Acinetobacter baumannii complex were resistant to tigecycline.34 Astonishingly, a study from Israel found 66% MDR A. baumannii had resistance to tigecycline.35 The mechanisms of resistance to tigecycline in A. baumannii should be elucidated; there may be a possible role an efflux pump mechanism. The increasing resistance to tigecycline is of great concern. Microbiological documentation prior to treatment with exact determination of tigecycline MIC is very important; some organisms with borderline susceptibility are difficult to eradicate and are prone to development of resistance on treatment.16

Cost of Therapy Each 50 mg vial of tigecycline costs around Rs. 700–900. For a child weighing 10 kg, the total cost of therapy of a course of tigecycline at a dose of 1 mg/kg q 12 hour for 14 days will be approximately Rs. 4000–5000.

CONCLUSIONS • Tigecycline appears to hold promise as a novel expanded spectrum antibiotic. However, based on the limited experience and associated risks, clinicians should cautiously individualize its use on a case-by-case scenario and assessing potential risks/benefits in every candidate patient. • Tigecycline has a low potential for organ toxicity and drug-drug interactions. These properties, along with twice-daily dosing and the lack of need to monitor renal function, make the use of this antibiotic relatively uncomplicated. • Tigecycline’s lack of activity against P. aeruginosa and low serum concentrations after the approved dose regimen are major drawbacks of this novel drug. • Use of tigecycline has been associated with a relative increase in all-cause mortality to an extent of 30% over the other comparator antibiotics. Though the cause for this increase has not been established, but thus increase in all-cause mortality should be considered when selecting among treatment options. • Although generally considered safe, routine use in pediatric patients is not recommended at this time. Colistin and Tigecycline 147

 REFERENCES 1. Walsh C. Where will new antibiotics come from? Nature Rev Microbiol. 2003;1:65-9. 2. Pankey GA, Tigecycline. J Antimicrob Chemother. 2005;56:470-80. 3. Pankey GA, Steele RW. Tigecycline: A Single Antibiotic for Polymicrobial Infections. Pediatr Infect Dis J. 2007;26(1):77-8. 4. Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev. 2001;65(2):232-60. 5. Chopra I. Glycylcyclines: third-generation tetracycline antibiotics. Curr Opin Pharmacol. 2001;1:464- 9. 6. Sum PE, Petersen P. Synthesis and structure-activity relationship of novel derivatives leading to the discovery of GAR-936. Bioorg Med Chem Lett. 1999;9(10):1459-62. 7. Bergeron J, Ammirati M, Danley D, James L, Norcia M, Retsema J, Strick CA, Su WG, Sutcliffe J, Wondrack L. Glycylcyclines bind to the high-affinity tetracycline ribosomal binding site and evade Tet(M)- and Tet(O)-mediated ribosomal protection. Antimicrob. Agents Chemother. 1996;40(9):2226- 8. 8. Karageorgopoulos DE, Kelesidis T, Kelesidis I, Falagas ME. Tigecycline for the treatment of multidrug- resistant (including carbapenem-resistant) Acinetobacter infections: a review of the scientific evidence. J Antimicrob Chemother. 2008;62(1):45-55. 9. Zhanel GG, Homenuik K, Nichol K, Noreddin A, Vercaigne L, Embil J, et al. The glycylcyclines: a comparative review with the tetracyclines. Drugs. 2004;64:63-88. 10. Sun HK, Ong CT, Umer A, Harper D, Troy S, Nightingale CH, Nicolau DP. Pharmacokinetic profile of tigecycline in serum and skin blister fluid of healthy subjects after multiple intravenous administrations. Antimicrob Agents Chemother. 2005;49(4):1629-32. 11. Kasbekar N. Tigecycline: A new glycylcycline antimicrobial agent. Am J Health Syst Pharm. 2006;63:1235-43. 12. Mikels SM, et al. In vitro activities of GAR-936. In: Programs and Abstracts of the Thirty-ninth Interscience Conference on An-timicrobial Agents and Chemotherapy, San Francisco, CA. Washington, DC: American Society of Microbiology. 1999;26:Abstract 414. 13. Rodvold KA, Gotfried MH, Cwik M, Korth-Bradley JM, Dukart G, Ellis-Grosse EJ. Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose. J Antimicrob Chemother. 2006;58(6):1221-9. 14. Falagas ME, Karageorgopoulos DE, Dimopoulos G. Clinical Significance of the Pharmacokinetic and Pharmacodynamic Characteristics of Tigecycline. Current Drug Metabolism. 2009;10:13-21. 15. Townsend ML, Pound MW, Drew RH. Tigecycline: a new glycylcycline antimicrobial. Int. J Clin Pract. 2006;60(12):1662-72. 16. Giamarellou H, Poulakou G. Pharmacokinetic and pharmacodynamic evaluation of tigecycline. Expert Opin Drug Metab Toxicol. 2011;7(11):1459-70. 17. Meagher AK, Ambrose PG, Grasela TH, et al. Pharmacokinetic/pharmacodynamic profile for tigecycline - a new glycylcycline antimicrobial agent. Diagn Microbiol Infect Dis. 2005;52:165-71. 18. Meagher A, Cirincione B, Piedmonte M, et al. Pharmacokinetics of tigecycline in healthy adult volunteers and in subjects with renal impairment. Clin Microbiol Infect. 2004;10(Suppl 3):274. 19. Doan TL, Fung HB, Mehta D, Riska PF. Tigecycline: a glycylcycline antimicrobial agent. Clin Ther. 2006;28(8):1079-106. 20. Owens RC Jr, Ambrose PG. Antimicrobial stewardship and the role of pharmacokinetics- pharmacodynamics in the modern antibiotic era. Diagn Microbiol Infect Dis. 2007;57(3)(Suppl):77S- 83S. 21. Hoellman DB, Pankuch GA, Jacobs MR, Appelbaum PC. Antipneumococcal activities of GAR-936 (a new glycylcycline) compared to those of nine other agents against penicillin-susceptible and -resistant pneumococci. Antimicrob Agents Chemother. 2000;44(4):1085-8. 22. Letter to Wyeth Pharmaceuticals, Inc. Department of Health & Human Services. Available from: http:/ /www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/021821s013,021821s017,021821s018ltr.pdf [Accessed 11 October 2012]. 148 Rational Antimicrobial Practice in Pediatrics

23. Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis. 2005;41:S341-53. 24. Babinchak T, Ellis-Grosse E, Dartois N, Rose GM, Loh E. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis. 2005;41:S354–66. 25. Tanaseanu C, Bergallo C, Teglia O, Jasovich A, Oliva ME, Dukart G, et al. Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in community-acquired pneumonia. Diagn Microbiol Infect Dis. 2008; 61(3):329-38. 26. Schafer JJ, Goff DA, Stevenson KB, Mangino JE. Early Experience with Tigecycline for Ventilator- Associated Pneumonia and Bacteremia Caused by Multidrug-Resistant Acinetobacter baumannii. Pharmacotherapy: J Human Pharmacol Drug Therapy. 2007;27(7):980–7. 27. Freire AT, Melnykb V, Kimc MJ, et al. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis. 2010; 68:140-51. 28. Purdy J, Jouve S, Yan JL, Balter I, Dartois N, Cooper CA, Korth-Bradley J. Pharmacokinetics and safety profile of tigecycline in children aged 8 to 11 years with selected serious infections: a multicenter, open-label, ascending-dose study. Clin Ther. 2012;34(2):496-507. 29. Prasad P, Sun J, Danner RL, Natanson C. Excess Deaths Associated With Tigecycline After Approval Based on Noninferiority Trials. Clin Infect Dis. 2012;54(12):1699-709. 30. FDA Drug Safety Communication: Increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections. Available from: http://www.fda.gov/Drugs/DrugSafety/ ucm224370.htm#.UH8JRVgnWAE.email [Accessed 19 October 2012] 31. Stein GE, Craig WA. Tigecycline: A critical analysis. Clin Infect Dis. 2006;43:518-24. 32. Someya Y, Yamaguchi A, Sawai T. A novel glycylcycline, 9-(N,N-dimethylglycylamido)-6-demethyl-6- deoxytetracycline, is neither transported nor recognized by the transposon Tn10-encoded metal- tetracycline/H+ antiporter. Antimicrob Agents Chemother. 1995;39(1):247-9. 33. Dean CR, Visalli MA, Projan SJ, Sum PE, Bradford PA. Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1. Antimicrob Agents Chemother. 2003;47(3):972-8. 34. Taneja N, Singh G, Singh M, Sharma M. Emergence of Tigecycline & Colistin resistant Acinetobacter baumanii in patients with complicated urinary tract infections in north India. Indian J Med Res. 2011;133:681-4. 35. Navon-Venezia S, Leavitt A, Carmeli Y. High tigecycline resistance in multidrug-resistant Acinetobacter baumannii. Journal of Antimicrobial Chemotherapy. 2007;59:772-4. Antifungals 149 1313 Antifungals Tanu Singhal, Pradnya Gadgil

 INTRODUCTION With the advent of newer and even more potent chemotherapeutic, immunosuppressive and antimicrobial regimens, complications due to fungal pathogens are on the rise. Concurrently great advances have been made in the field of antifungal drugs. Newer antifungal drugs have been discovered and older drugs re-formulated. This review discusses the pharmacology and clinical use of various systemic antifungal drugs.

 CLASSES OF ANTIFUNGAL DRUGS 1. Polyenes 2. Azoles 3. Echinocandins 4. Nucleoside analogs

 POLYENES Amphotericin B The oldest antifungal class is the polyene macrolides including amphotericin B and nystatin. Amphotericin B deoxycholate has been the ‘gold standard’ for the treatment of invasive fungal infections and the yardstick to measure efficacy of new agents. New lipid formulations available are—amphotericin B colloidal dispersion (ABCD; Amphotec), the lipid complex formulation (ABLC; Abelcet) and the small unilamellar liposomal formulation (L-AmB; AmBisome, Fungisome, Phosome). However, cost of the liposomal preparations, significant toxicity and availability of the new azoles and echinocandins have reduced the use of amphotericin B and its derivatives.

Mechanism of Action The main mechanism of action is binding to ergosterol, the principal sterol in the fungal cell membrane. This binding leads to cell death by depolarization of the membrane, 150 Rational Antimicrobial Practice in Pediatrics with subsequent increase in membrane permeability. A contributory mechanism of action may be the generation of oxidative metabolites, which is implicated to cause in vitro functional stimulation of phagocytes. In addition to fungal ergosterol, amphotericin B also binds to cholesterol in human cell membranes, possibly accounting for its toxicity. Lipid formulations of amphotericin B are taken up by activated monocytes and macrophages and transported to the site of infection, where phospholipases release the free drug. They are better tolerated than the conventional deoxycholate preparation because the lipid stabilizes the drug in a self-associated state, so that it cannot interact with human cell membrane cholesterol.

Spectrum of Activity Most Candida species, Aspergillus, Cryptococcus neoformans, Zygomycetes, Blastomyces dermatidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Sporothrix schenckii and Penicillium marneffei. Does not cover: Candida lusitaniae, Scedosporium, Fusarium, Trichosporon, Pseudallescheria boydii and Scedosporium prolificans. Resistance to amphotericin B has been produced in vitro, and resistant strains have been isolated from patients who have received long-term therapy with amphotericin B deoxycholate. Fluconazole-resistant strains of Candida albicans that were cross-resistant to amphotericin B have been isolated from a few immunocompromised patients. Cryptococcus neoformans isolates resistant to fluconazole and amphotericin B have also been documented. Fungi resistant to amphotericin B deoxycholate may also be resistant to amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, and amphotericin B liposomal.

Pharmacokinetics Absorption of amphotericin B from the gastrointestinal tract is negligible. After intravenous infusion of the conventional deoxycholate formulation, the drug is released from its carrier, distributes predominantly (> 90%) with lipoproteins, and is taken up preferentially by organs of the mononuclear phagocytic system (MPS). The drug follows biphasic elimination from plasma with an initial half-life of 24–48 hours, followed by a terminal half-life of up to 15 days. Tissue accumulation and redistribution into the plasma pool apparently account for most amphotericin B disposition, since the drug is only very slowly excreted into urine and bile and since no metabolites have been identified. Cerebrospinal fluid (CSF) concentrations are only 2% to 4% of serum concentrations so this drug is a poor choice for monotherapy in meningitis. Lipid formulations of amphotericin B are important therapeutic advances because they reduce nephrotoxicity while preserving antifungal activity of the parent compound. The plasma pharmacokinetics of amphotericin B colloidal dispersion (ABCD; Amphotec) is not markedly different from those of conventional amphotericin B. The lipid complex Antifungals 151 formulation (ABLC; Abelcet) is taken up more rapidly by the MPS; the small unilamellar liposomal formulation (L-AmB; AmBisome) is characterized by comparatively higher peak plasma levels and prolonged circulation in plasma. The lipid formulations spare the kidney thus reducing nephrotoxicity but at the same time are ineffective in treating renal fungal infections.

Clinical Uses Amphotericin B is the treatment of choice for invasive and life-threatening fungal infections, including blastomycosis, coccidioidomycosis, paracoccidiodomycosis, cryptococcosis, histoplasmosis, mucormycosis and sporotrichosis. For aspergillosis, voriconazole is now preferred to amphotericin B. For candidemia in non neutropenic adults, the echinocandins/ fluconazole are preferred to amphotericin B due to similar efficacy but lower toxicity. However, in non-neutropenic children, where data on echinocandins is limited, fluconazole/ amphotericin B are the preferred drugs. Amphotericin B is also the drug of choice for neonatal candidiasis, candida meningitis, osteoarticular candida infections and candida endocarditis. Amphotericin B deoxycholate is used as an alternative agent for long-term suppressive (i.e. secondary prophylaxis) or maintenance therapy to prevent recurrence or relapse of coccidioidomycosis, cryptococcosis, or histoplasmosis in HIV infected individuals who have received adequate treatment of the infection. Amphotericin B deoxycholate may be the preferred agent for pregnant women with invasive fungal infections due to concerns regarding the use of azole antifungal agents during pregnancy. Intravenous amphotericin B (lipid formulations) has also been used for empiric therapy in febrile neutropenic patients. Amphotericin B is also used for the treatment of certain protozoal infections, including leishmaniasis and amebic meningoencephalitis.

Indications for Using Lipid Formulations Because clinical experience with newer amphotericin B formulations is limited, these formulations have generally been reserved for second-line therapy in patients with invasive fungal infections that are intolerant of or refractory to conventional amphotericin B, defined as follows: • Development of renal dysfunction (serum Cr > 2.5 mg/dL) during antifungal therapy • Severe or persistent infusion-related adverse events despite premedication or comedi- cation regimens • Disease progression after > 500 mg total dose of amphotericin B. In addition, liposomal amphotericin B is approved as initial empiric therapy for: • In patients with CNS candidiasis and candida endocarditis • The neutropenic patient who has persistent fever, despite broad-spectrum antibiotic therapy • In patients who have proven or probable systemic fungal disease but have pre-existing renal dysfunction (creatinine > 2.5 mg/dL) • In therapy of leishmaniasis. 152 Rational Antimicrobial Practice in Pediatrics

Dosage of Conventional Amphotericin B For Amphotericin B deoxycholate the initial test dose is 0.25 mg/kg body weight (minimum 1 mg) increasing gradually to 1 mg/kg body weight depending on individual response and tolerance. In emergency situations the maximum dose can be achieved over a single day as well. Within the range 0.6–1 mg/kg, the daily dose should be maintained at the highest level, which is not accompanied by unacceptable toxicity. For seriously ill patients the daily dose may be gradually increased up to an absolute maximum of 1.5 mg/kg. The higher dosage level may be given on alternate days. If medication is interrupted for more than 7 days, therapy should be resumed starting at the lowest dosage level, i.e. 0.25 mg/kg body weight, and increased gradually. The drug should be diluted in 5% dextrose (recommended concentration 10 mg/100 mL). Studies have shown that rapid infusion (over 1–2 h) is as safe and well tolerated as prolonged (over 3–6 h) infusion of conventional amphotericin B and greatly facilitates outpatient and home administration of the drug. Rapid infusion should not be used in patients with azotemia (creatinine clearance < 25 mL/min), hyperkalemia, or dose >1 mg/kg, or in patients who receive drug therapy via a central catheter that extends into the right heart. Notwithstanding the discussion above, available data does not provide definitive answers to several questions: whether a test dose of amphotericin B should be given at the start of therapy; whether the daily dose should be increased gradually to the maximum dose over several days or the maximum dose should be given on the first day; and whether the maximum daily dose or the total dose over time is most important with regard to outcome. Some authorities do not recommend a separate test dose, but do use a cautious infusion of the first dose (quasi test dose). Prediction of allergic responses to subsequent doses cannot be done on the basis of allergic response to the test dose as the two do not always correlate.

Dosage of Lipid Formulations Lipid preparations are conventionally used in dosages of 3–5 mg/kg/day, which has equivalent efficacy as 1 mg/kg/day of amphotericin B deoxycholate. However a large multicenter maximum tolerated dose study of L-Amphotericin B (ambisome) using doses of 7.5-15 mg/kg/day found a nonlinear plasma pharmacokinetic profile and no demonstrable dose-limiting nephrotoxicity or infusion related toxicity. Amphotericin B colloidal dispersion (ABCD; Amphotec): Initial test dose 2 mg over 10 minutes then 1 mg/kg daily as a single dose increased gradually if necessary to 3–4 mg/kg daily as a single dose; maximum 6 mg/kg daily Lipid complex formulation (ABLC; Abelcet): The initial test dose for is 1 mg over 15 minutes then 5 mg/kg daily. Liposomal formulation (L-AmB; AmBisome): Test dose 1 mg over 10 minutes then 1 mg/kg daily as a single dose increased gradually to 3 mg/kg daily as a single dose; maximum 5 mg/kg daily. High doses up to 10 mg/kg/day may be needed in mucormycosis. In febrile neutropenic patients, unresponsive to broad-spectrum antibacterials, initial test Antifungals 153 dose 1 mg over 10 minutes then 3 mg/kg daily as a single dose until afebrile for 3 consecutive days. A new indigenous liposomal formulation is now available (fungisome) which needs sonication perior to administration. This preparation can be dosed as 1-3 mg/kg/day (higher doses recommended for mucormycosis). For treatment of invasive aspergillosis a dose of 3 mg/kg per day has been shown to be as efficacious and less toxic than a dose of 10 mg/kg/day.

Duration of Therapy The optimal duration of amphotericin B therapy is unknown. It depends on the clinical indication, the extent of infection, degree of immunosuppression and graft function (in post-transplant patients). No specific total dose is recommended.

Adverse Effects Infusion related adverse events are fairly common with conventional amphotericin B (50–90%). These are characterized by nausea and vomiting, diarrhea, epigastric pain; febrile reactions, headache, myalgia, dyspnea and tachypnea. In 1 large comparative trial, during initial infusion without premedication, L-AmB recipients experienced significantly less fever and chills than AmBD recipients (fever, 16.9% versus 43.6%, respectively; and chill, 18.4% versus 54.4%, respectively). Infusion-related events connected with ABCD and ABLC appear to be considerably more common than those associated with L-AmB and similar in frequency to infusion-related events associated with AmBD. Fever and chills associated with the lipid-based drugs tend to occur mainly after the first two infusions and are less frequent with subsequent infusions. Infusion-related hypoxia has been documented in as many as 25% of ABCD and ABLC recipients but is usually reversible and without long-term sequelae. Prophylactic antipyretics, antihistaminics, steroids and meperidine partially ameliorate these reactions with conventional and lipid based products. Rapid infusion of amphotericin B deoxycholate has been associated with a more severe reaction consisting of hypotension, bronchospasm, hypokalemia, arrhythmias, and shock. It may be difficult to determine whether these severe reactions indicate intolerance or hypersensitivity to amphotericin B. Anaphylaxis and anaphylactoid reactions have been reported in people taking all formulations of amphotericin B. Nephrotoxicity is the other major dose-limiting toxicity of amphotericin B occuring in 30–50% cases. The manifestations of nephrotoxicity are azotemia, decreased glomerular filtration, loss of urinary concentrating ability, renal loss of sodium and potassium, and renal tubular acidosis. The renal injury reduces erythropoietin production and leads to a normochromic normocytic anemia. Nephrotoxicity associated with amphotericin B deoxycholate appears to involve several mechanisms, including direct vasoconstrictive effects on renal arterioles and lytic action on renal tubular cell membranes. Renal function usually improves within a few months of discontinuing therapy, but some impairment may remain. Sodium and water repletion (10–15 mL/kg) prior to the infusion helps in reducing nephrotoxicity. The serum creatinine should be monitored regularly at least twice a week and potassium and magnesium supplemented. A rise in serum creatinine 154 Rational Antimicrobial Practice in Pediatrics beyond 2.5 mg/dL may be an indication to switch to the lipid-based agents. Nephrotoxicity, is less common with all 3-lipid formulations of amphotericin B than with AmBD. In comparative studies the respective rates of nephrotoxicity (defined as twice baseline serum creatinine) are: ABLC ~25%, ABCD ~15%, L-AmB ~20%, and AmBD ~30% to 50%. Importantly, in open label studies, administrations of lipid-based amphotericin B drugs are reported to stabilize or even improve renal function in patients with pre-existing renal insufficiency. In addition, individuals receiving concurrent nephrotoxic agents (e.g. cyclosporine, aminoglycosides) are less likely to have renal dysfunction when receiving lipid formulations compared to AmBD. Amphotericin B intravenous infusion has also been associated with anemia, headache, thrombophlebitis, and GI effects (indigestion, loss of appetite, nausea, vomiting, diarrhea, stomach pain). Less frequently, blurred or double vision, cardiac arrhythmias, leukopenia, polyneuropathy, seizures, and thrombocytopenia have been reported. Other adverse events associated with lipid-based products have included elevations in liver transaminases, alkaline phosphatase, and serum bilirubin levels. Liver function test abnormalities have been noted in 25% to 50% of patients treated with L-AmB but these findings are reversible without drug discontinuation in the majority of patients.

Drug Interactions Close monitoring required with concomitant administration of nephrotoxic drugs or cytotoxic agents. Drugs that increase the risk of nephrotoxicity of Amphotericin B include amino- glycosides, cyclosporin, tacrolimus, vancomycin, pentamidine isoethionate and polymyxins. Drugs that increase the risk of hypokalemia due to Amphotericin B include systemic corticosteroids and ACTH, thiazide and loop diuretics. Amphotericin B may increase the toxicity of cardiac glycosides and skeletal muscle relaxants (by virtue of hypokalemia) and that of flucytosine by reducing renal excretion and increased cellular uptake of flucytosine. Concomitant administration of zidovudine and amphotericin B may be associated myelotoxicity and nephrotoxicity. Amphotericin B coadministered with blood dyscrasia- causing medications, bone marrow depressants, or radiation therapy may increase chance of anemia or other hematologic effects. Dosage reduction may be required.

Contraindications Amphotericin B deoxycholate and alternative formulations of amphotericin B are contraindicated in patients allergic to amphotericin B or any of formulation components. Extreme caution should be exercised when using amphotericin B deoxycholate in patients with renal impairment.

 AZOLES Unlike amphotericin B the antifungal azoles are synthetic compounds. The azoles are classified as imidazoles (miconazole and ketoconazole) or triazoles according to whether they contain two or three nitrogen atoms, respectively, in the five-membered azole ring. Antifungals 155

The triazoles can be further classified as first generation triazoles (itraconazole, fluconazole) and second generation (voriconazole, ravuconazole, posaconazole). The chemical structures and pharmacologic profiles of ketoconazole and itraconazole are similar. Ketoconazole is now infrequently used and will not be discussed further. Fluconazole is unique because of its comparatively small molecular size and lower lipophilicity. Voriconazole is a second-generation triazoles and a synthetic derivative of fluconazole. Voriconazole combines the broad spectrum of antifungal activity of itraconazole with the increased bioavailability of fluconazole.

Mechanism of Action The azoles inhibit ergosterol synthesis through an interaction with C-14 alpha demethylase, a cytochrome P-450 dependent enzyme that is necessary for the conversion of lanosterol to ergosterol. The depletion of ergosterol alters membrane fluidity, thereby reducing the activity of membrane-associated enzymes and leading to increased permeability and inhibition of cell growth and replication. The potential for similar interactions in mammalian cells with enzymes dependent on cytochrome P-450 also mediates some of the major toxic effects and drug interactions of the azoles. One important distinction between the triazoles and imidazoles is the greater affinity of the former for fungal as compared with mammalian cytochrome P-450 enzymes. Other antifungal effects of azoles include the inhibition of endogenous respiration, a toxic interaction with membrane phospholipids, and the inhibition of the morphogenetic transformation of yeasts to the mycelial form.

Itraconazole and Fluconazole Spectrum of Activity Principally active against dermatophytes, Candida species (exception all C. krusei, and some C. glabrata), C. neoformans, Trichosporon beigelii, dimorphic fungi (B. dermatitidis, H. capsulatum, C. immitis, P. brasiliensis, Sporothrix schenckii). Only itraconazole is active against aspergillus and dematiaceous molds and both itraconazole and fluconazole have no activity against Fusarium and Zygomycetes.

Resistance Resistance in Candida species during azole therapy is well recognized; especially in HIV positive during therapy of recurrent oropharyngeal candidiasis, breakthrough C. krusei and C. glabrata infections in individuals receiving fluconazole prophylaxis; few patients with cryptococcal meningitis receiving mantainence therapy. However, resistance is not obligate; patients will respond to higher doses of the azoles, and new generation triazoles.

Pharmacokinetics Itraconazole is a weak base and requires an acid environment for optimal solubilization and absorption. Itraconazole is available abroad as a capsule, as an oral cyclodextrin 156 Rational Antimicrobial Practice in Pediatrics formulation which has superior bioavailability and as an intravenous formulation. Only the capsule form is available in India. The bioavailability of capsular itraconazole is two to three times higher when taken with fatty food than when taken on an empty stomach. The peak plasma concentrations of itraconazole, are three to five times higher after 7 to 14 days of treatment (steady state) than after a single dose. A loading dose of 200 mg of itraconazole three times daily for three days is recommended in patients with serious infections to reduce the time until steady-state concentrations are attained. Itraconazole are extensively bound (> 99%) to plasma proteins, but unbound drug distributes well throughout most tissues including the brain but not in non proteinaceous body fluids. Itraconazole is extensively metabolized in the liver and excreted almost exclusively in the feces and the urine. The terminal elimination half-lives for itraconazole at steady- state conditions is 7 to 10 hours and 24 to 42 hours, respectively. The half-life of increases with increases in the dose from 100 to 400 mg daily, suggesting that the metabolic pathways in the liver are saturable within the therapeutic dose range. Because little itraconazole is excreted in the urine, the doses need not be changed in patients with renal impairment. In addition, drug is not removed by hemodialysis. Fluconazole is available as both an oral and intravenous formulation. In contrast to itraconazole the absorption of oral fluconazole is not altered by the presence of food or gastric acidity. Peak plasma concentrations of fluconazole are proportional to the dose, occur within two to four hours after oral administration, and are approximately 2 to 2.5 times higher at steady state (which occurs about 6 to 10 days after treatment is begun) than after single doses. As with itraconazole, the administration of a loading dose of fluconazole is recommended. Fluconazole resembles flucytosine in that both are highly water-soluble, minimally bound to plasma proteins, and distributed in a volume that approximates that of total body water. The concentrations of fluconazole in most body tissues and fluids usually exceed 50 percent of the corresponding plasma concentrations and are especially high in cerebrospinal fluid and urine. The peak cerebrospinal fluid concentrations in patients with fungal meningitis range from approximately 70 to 90 percent of peak plasma concentrations. Similarly, urinary concentrations of fluconazole may exceed 100 µg per milliliter, which is much higher than those of other oral azoles. In contrast to the imidazoles and itraconazole, fluconazole is minimally metabolized; approximately 80 percent of an administered dose is excreted unchanged in the urine. The terminal elimination half-life increases from approximately 30 hours in patients with normal renal function to 98 hours in patients with severe renal impairment (glomerular filtration rate, < 20 mL per minute). Consequently, the dose should be reduced in patients with glomerular filtration rates below 50 mL per minute. Fluconazole is effectively removed during hemodialysis and to a lesser extent during peritoneal dialysis.

Clinical Uses Fluconazole is considered the drug of choice in treatment of proven or suspected candidemia in non-neutropenic adults and children. However, in patients who are critically sick, or who have been on azole prophylaxis or when infection is acquired in units with high Antifungals 157 rates of fluconazole resistance, the echinocandins (in adults) and amphotericin B (in children) are the recommended drugs. Fluconazole is also the preferred drug in initial management of oropharyngeal and esophageal candidiasis and also in all deep seated candida infections after initial therapy with amphotericin B/echinocandins if the isolate is susceptible to fluconazole. It can also be used instead of topical therapy in management of vulvovaginal candidiasis (single dose) or as pulse therapy in tinea corporis, pityriasis versicolor and onchymycosis. It is the drug of choice for meningeal and non-meningeal coccidial infections. It is also indicated for consolidation therapy of cryptococcal meningitis, T. beigelii infections and dermatomycosis. In the prophylactic setting it is effective for preventing Candida infections in acute leukemia, bone marrow transplant, liver transplant patients, neonates and those with recurrent vulvovaginal candidiasis, in primary prevention of cryptococcosis and histoplasmosis in AIDS patients and in secondary prevention of cryptococcosis and coccidiomycosis in HIV infected patients. Itraconazole is a useful agent for dermatophytic infections, pityriasis versicolor and all forms of cutaneous and mucosal Candida infections, but its clinical efficacy for invasive Candida infections has not been evaluated. It is an approved second line agent for invasive Aspergillus infections and therapy of choice for non-meningeal and non-life threatening paracoccidiodomycosis, blastomycosis, sporotrichosis and histoplasmosis. Intravenous itraconazole is at least as effective and safer than conventional amphotericin B in persistently febrile neutropenic patients. The non-availability of the cyclodextrin and the intravenous formulation in India limits its usefulness in a lot of settings.

Dosage Fluconazole: 6–12 mg/kg/day • Oropharyngeal candidiasis—oral or IV 3–6 mg/kg on first day then 3 mg/kg daily for 7–14 days • Esophageal candidiasis—3–6 mg/kg/day for 14–21 days • Invasive candidiasis and cryptococcal infections—oral or IV 12 mg/kg daily; max. 400 mg daily • Antifungal prophylaxis in immunocompromised patients—oral or IV 6–12 mg/kg/day; maximum 400 mg daily; commence treatment before anticipated onset of neutropenia and continue for 7 days after neutrophil count in desirable range • Neonates—3–6 mg/kg given IV three times a week till IV access is present Itraconazole: The recommended dose of the capsule formulation is 5–8 mg/kg/day (100– 400 mg/day) with a loading dose of 4 mg/kg three times daily for the first 3 days in serious infections. • Oropharyngeal candidiasis—100 mg daily (200 mg daily in immunocompromised) for 15 days • Vulvovaginal candidiasis—200 mg twice daily for 1 day • Pityriasis versicolor, 200 mg daily for 7 days • Tinea corporis and tinea cruris, either 100 mg daily for 15 days or 200 mg daily for 7 days 158 Rational Antimicrobial Practice in Pediatrics

• Tinea pedis and tinea manuum, either 100 mg daily for 30 days or 200 mg twice daily for 7 days • Onychomycosis, either 200 mg daily for 3 months or course (‘pulse’) of 200 mg twice daily for 7 days, subsequent courses repeated after 21-day interval; fingernails 2 courses, toenails 3 courses • Histoplasmosis, 200 mg 1–2 times daily • Systemic aspergillosis, candidiasis and cryptococcosis including cryptococcal meningitis where other antifungal drugs inappropriate or ineffective, 200 mg once daily (candidiasis 100–200 mg once daily) increased in invasive or disseminated disease and in cryptococcal meningitis to 200 mg twice daily • Maintenance in AIDS patients to prevent relapse of underlying fungal infection and prophylaxis in neutropenia when standard therapy inappropriate, 200 mg once daily, increased to 200 mg twice daily if low plasma-itraconazole concentration • Systemic aspergillosis, candidiasis and cryptococcosis including cryptococcal meningitis where other antifungal drugs inappropriate or ineffective—IV 200 mg every 12 hours for 2 days, then 200 mg once daily for maximum 12 days

Adverse Reactions Fluconazole: It is a well tolerated drug even in doses as high a 1200 mg/day in adults and 12 mg/kg/day in children. In adults, receiving 100–400 mg/day, the incidence of serious adverse effects or laboratory abnormalities leading to discontinuation of the drug is 2.8%. Nausea, vomiting, diarrhea and other gastrointestinal symptoms are seen in less than 5%, skin rash and headache in less than 2% and reversible asymptomatic elevations of hepatic transaminases in less than 7%. Severe side effects including liver failure and exfoliative dermatitis have been reported anecdotally. Itraconazole: It is well tolerated like fluconazole (discontinuation needed in only 4% of those receiving up to 400 mg/day). Nausea vomiting (10%), hypertriglyceridemia (9%), hypokalemia (6%), elevated liver enzymes (5%), rash or pruritus (2%). There are rare reports of heart failure and hence prescribe with caution to patients at high-risk of heart failure, with poor ventricular function and those being treated with negative inotropic drugs.

Drug Interactions These are a major problem with the use of azoles. See Table 1 for details (adapted from 2).

Voriconazole Spectrum of Activity Effective against a wide variety of fungi including most Candida species (mainly fungistatic) including many Candida krusei except Candida glabrata, T. beigelii, C. neoformans, Aspergillus species (fungicidal), Fusarium species and most dimorphic fungi. It is not effective against Zygomycetes. Antifungals 159

Pharmacokinetics Voriconazole is almost completely absorbed after oral administration. It is distributed well with tissue and CSF levels several times the plasma levels. It is extensively metabolized by the liver and is both an inhibitor and substrate of enzymes CYP2C19, CYP2C4 and CYP2C4. As a result of point mutation in the genes encoding these enzymes, patients are either poor or extensive metabolizers of voriconazole. The levels can be up to 4 times higher in patients who are deficient in this gene as compared to homozygous subjects. 20% non-Indian Asians and 5% of whites are deficient. Owing to problems in voriconazole metabolism, therapeutic drug monitoring of voriconazole levels is recommended. Voriconazole metabolism is nonlinear in adults with an approximately 3-fold increase in its area under the concentration-time curve after a 33% increase in dosage. In contrast, in children the elimination of voriconazole seems to be linear with doses of 3 mg/kg and 4 mg/kg every 12 hours.

Clinical Use It is the drug of choice for invasive aspergillosis (superior to conventional amphotericin B). Though it is approved for management of Candida infections, it does not offer any significant advantage over the cheaper fluconazole. As per guidelines, voriconazole should not be used for fluconazole resistant Candida and echinocandins or amphotericin used instead. Its niche use is in oral step down therapy for Candida krusei if it demonstrates susceptibility to voriconazole. Other indications include fusariosis, scedosporiasis and as salvage therapy for invasive and refractory fungal infections (excluding zygomycetes). In patients with fever and neutropenia, it is slightly though not statistically inferior to liposomal amphotericin B in efficacy but shows less breakthrough infections and lesser toxicity.

Dosage The dosage in adults is 6 mg/kg/dose BD for 1 day followed by maintenance of 4 mg/kg/dose BD. In children, drug elimination is quicker and doses of 7 mg/kg twice daily with no loading is recommended. In patients with renal insufficiency no dosing changes are required for the oral preparation; because of renal clearance of the IV carrier, individuals with creatinine clearances of less than 50 mL/min should receive the oral preparation. Those with mild to moderate hepatic dysfunction should receive half the mantainence dose.

Adverse Effects Well tolerated drug. Important side effects include transient dose related visual disturbances such as altered enhanced perception of light, blurred vision (25–45%), hallucinations or confusion (10%), skin reactions (10%) and transient liver enzyme abnormalities (10–20%).

Drug Interactions See Table 1. 160 Rational Antimicrobial Practice in Pediatrics

TABLE 1 Drug interactions of triazoles2 Mechanism and drug involved Triazole involved Comment Decreased absorption of triazole Itraa Take them at least Anatacids, H2 antagonists, omeprazole, 2 hours apart sucralfate, didanosine, grapefruit juice Increased metabolism of triazole Itraa, flu, vori a Potential for therapy INH, rifampicin, rifabutin, phenytoin, failure, increased potential phenobarbital, carbamazepine for hepatotoxicity Increased concentration of coadministered drug through inhibition of its metabolism by triazole Terfenadine, astemizole, cisapride, Itra, flu, vori Concomitant use prohibited pimozide, quinidine Lovastatin, simvastatin, atorvastatin Itra, flu, vori Concomitant use prohibited Phenytoin Itra a, flu a, vori a Monitor levels Benzodiazepines Itra, flu, vori Monitor closely Carbamazepine flu Monitor closely Haloperidol itra Monitor closely Rifampicin, rifabutin Itra, flu Monitor closely Clarithromycin itra Monitor closely Indinavir Itra Monitor closely Ritonavir, NNRTI vori Monitor closely Vinca alkaloids Itra, vori Avoid concomitant use Busulfan itra Avoid concomitant use All-transretinoic acid flu Monitor closely Nifedipine, felodipine Itra, flu Monitor closely Cyclosporin A, tacrolimus Itra, flu, vori Monitor serum levels Sulfonyl urea drugs, warfarin, prednisolone Itra, flu, vori Monitor closely Digoxin, quinidine itra Monitor levels Zidovudine, theophylline flu Monitor closely a Major significance

Posaconazole Posaconazole is a new expanded spectrum triazole agent with a spectrum as wide as amphotercin B.

Spectrum of Activity Posaconazole is active against all Candida species, Aspergillus, Zygomycetes and cryptococci. Additonally, it is effective against less common fungal pathogens with intrinsic Antifungals 161 resistance to other antifungal agents including Fusarium, chromoblastomycosis, cocciodioidomycosis and other fungi.

Pharmacokinetics The drug is available as an oral suspension. It is absorbed well, especially if given along with food or nutritional supplements. Dividing the daily oral dose increases total exposure to the drug. The drug is extensively distributed in all body tissues and has a long half-life of 35 hours. Age, race, gender, renal and hepatic function do not affect its elimination and no dosage adjustments are required.

Indications Posaconazole has received approval for prevention of fungal infections in neutropenic patients. In a trial in patients with acute myeloid leukemia and myelodysplastic syndrome, prophylaxis with posaconazole reduced incidence of fungal infections and all cause mortality at 100 days compared to fluconazole/itraconazole. In patients who have undergone hematopoetic stem cell transplant and graft versus host disease, posaconazole was as effective as fluconazole in reducing invasive fungal infections and also reduced the incidence of probable and proven aspergillosis and mortality due to fungal infections. Posaconazole has also demonstrated efficacy in treatment of those invasive fungal infections including aspergillosis, fusariosis, chromoblastomycosis, candida and coccidioidomycosis where previous antifungal agents had failed. The mortality in patients with refractory aspergillosis treated with posaconazole lower as compared with in an external control group. Posaconazole has also demonstrated efficacy in management of oropharyngeal candidiasis.

Dosage Posaconazole is approved in patients older than 18 years of age where the prophylactic dose is 200 mg thrice daily and the therapeutic dose is 400 mg twice daily (or in patients who have poor oral intake it should be given as 200 mg four times daily). No dose adjustments are needed for patients with renal or hepatic dysfunction; the drug is not removed by hemodialysis.

Adverse Effects Nausea, vomiting and diarrhea and mild elevation of liver enzymes are common side effects. Rarely the drug can cause severe hepatic dysfunction and liver failure.

Drug Interactions Posaconazole only inhibits the cytochrome P 450 3A4 enzyme and none of the other cytochrome P450 enzymes and thus has limited potential for drug interactions as compared to other azoles. Its use is contraindicated with certain cytochrome P 450 3A4 substrates 162 Rational Antimicrobial Practice in Pediatrics such as ergot alkaloids, quinidine, astemizole, terfenadine, cisapride, halofantrine, pimozide due to effect on prolongation of the QT interval. Use of anticonvulsants and rifampicin reduce posaconazole exposure and hence, their concomitant use should be avoided.

 ECHINOCANDINS The echinocandins are a new class of antifungal lipopeptides. Three echinocandin compounds are now licensed for use including caspofungin, micafungin and anidulafungin and commercially available. These agents have similar pharmacologic properties; they possess potent, broad-spectrum, fungicidal in vitro activity against Candida species and potent inhibitory activity against Aspergillus species and have demonstrated antifungal efficacy against these organisms in various animal models and in patients.

Mechanism of Action They inhibit the synthesis of 1,3-ß-D-glucan, a polysaccharide in the cell wall of many pathogenic fungi. Along with chitin, rope like glucan fibrils are responsible for the cell wall’s strength and shape; are essential in maintaining osmotic integrity of the fungal cell and play an important role in cell division and cell growth. As 1,3-ß-D-glucan is a selective target present only in fungal cell walls and not in mammalian cells, echinocandins have few adverse effects.

Spectrum of Activity Candida (fungicidal), Aspergillus (fungistatic). Not C. neoformans, Fusarium, Zygomycetes.

Pharmacokinetics Echinocandins are available only in parenteral form, have favorable pharmacokinetic properties and are targeted for once-daily dosing. They are distributed well into all tissues including the brain but not in CSF and urine. The pharmacokinetics of the echinocandins are compared in Table 1.

Clinical Use All echinocandins have been approved for management of invasive candidiasis. In studies comparing caspofungin with liposomal amphotericin B for candidemia, caspofungin was as efficacious with lower toxicity. In a comparative trial with fluconazole in invasive candidiasis in mainly non neutropenic, anidulafungin was superior to fluconazole. Micafungin in comparative trials with liposomal amphotericin B and caspofungin was non inferior. Hence, in candidemia in adults in both neutropenic/non-neutropenic patients, echinocandins have supplanted amphotericin B as drugs of choice due to similar efficacy and lower toxicity. All the echinocandins are similar in efficacy in management of candidemia. Anidulafungin has the lowest MICs, however, the clinical benefit of this phenomenon has still to be demonstrated. Antifungals 163

Echinocandins have been demonstrated as noninferior to fluconazole in management of oropharyngeal candidiasis. However, anidulafungin has been seen to be associated with higher relapse rates as compared to fluconazole. Caspofungin is approved for salvage treatment of Aspergillus infections either alone or in combination with other agents like amphotericin B and voriconazole. It has also been approved for empirical therapy of febrile neutropenia. Studies with micafungin and anidulafungin for these two indications are underway. Micafungin has also been approved as prophylaxis for fungal infections in patients who have undergone stem cell transplant.

Dosage and Administration See Table 2.

TABLE 2 Pharmacokinetics and dosage of the echinocandins Caspo Mica Anidula T ½ in hours 09-11 11-17 24-26 Protein binding 96-97 99.8 84 Metabolism Metabolized, Via COMP Slow degradration spontaneous degradation Dose change in liver disease Mild None None None Moderate Dec dose None None Severe No data No data None Loading Dose Required Not required Required Infusion times 60 minutes 60 minutes 91-182 minutes Storage after reconstitution 48 hours Can be used Used within 24 hours upto 48 (96) hours Protection from light Not required Required Not required Volume of diluent 250 mL 100 mL 115 (100+15) for 50 mg 280 (250+30) mL for 100 mg 560 (500+60) mL for 200 mg Adult dose 70 mg loading 100 mg OD 200 mg loading and then and then 50 mg 100 mg od OD Pediatric dose 70 mg/m2 2–4 mg/kg od Not approved, but 1.5 mg/kg loading and then 50 mg/m2 Neonatal dose 25 mg/m2 10–12 mg/kg Not approved (some have used up to 5 mg/kg) 164 Rational Antimicrobial Practice in Pediatrics

Adverse Reactions Well tolerated drug with side effects serious enough to cause discontinuation seen only in 5%. The most frequently reported side effects include elevated transaminases, GI upset, headaches and ocasionally histamine mediated symptoms. Injection site reactions may be seen and are more common with caspofungin. Micafungin can cause benign liver tumors in rats.

Drug Interactions Caspofungin levels are decreased by carbamazepine, dexamethasone, efavirenz, nevirapine, phenytoin and rifampicin (initially increased and then reduced). Hence, consider increasing the dose of caspofungin. The plasma concentration of caspofungin is increased by cyclosporin. Micafungin and anidulafungin have fewer drug interactions as compared to caspofungin. Cyclosporin increases anidulafungin levels but the significance of this is not known. Micafungin can increase nifedipine and cyclosporine levels.

Cost Echinocandins are expensive drugs and treatment costs range from 8000–12000 per day for adults.

Conclusions and Summary The echinocandins are valuable addition in the armamentarium of antifungal drugs due to their excellent efficacy and lower toxicity and fewer drug interactions. More pediatric data is awaited. Cost of these drugs is also a major impediment against their use.

Flucytosine Flucytosine (5-fluorocytosine; 5-FC) is a low-molecular-weight, synthetic, fluorinated pyrimidine-analog. Its advantage lies in the fact that it has the least drug interactions as compared to all the other classes of anti-fungal drugs.

Mechanism of Action 5-FC is rapidly converted into 5-Fluorouracil (5-FU) in susceptible fungal cells. 5-FU inhibits fungal protein synthesis after getting incorporated within fungal DNA in place of uridylic acid as well as inhibits fungal DNA synthesis by inhibiting thymidylate synthetase. The toxicity of flucytosine seems to be due to its conversion to 5-FU.

Spectrum of Activity Candida, C. neoformans. 5-FC has little or no anti-aspergillus activity. Organisms develop resistance very quickly, if used as monotherapy.

Pharmacokinetics Flucytosine is readily absorbed from the gastrointestinal tract, has negligible protein binding, and distributes evenly into tissues and body fluids. It undergoes negligible hepatic Antifungals 165 metabolism and is eliminated predominantly in active form in urine. Based on an elimination half-life of 3–6 hours in patients with normal renal function, flucytosine usually is administered in three to four equally divided doses. It is available in oral and parenteral forms.

Clinical Use When flucytosine is used in combination with amphotericin B the chances of resistance developing to flucytosine are less. Also the antifungal activity of amphotericin B is enhanced especially in sites where penetration of amphotericin B is poor (CSF, heart valves and vitreal body). It is indicated as a companion to AmB in induction therapy of cryptococcal meningitis and in invasive deep-seated Candida infections (particularly non-Candida) in the critically ill patient.

Dosage It is 100 mg/kg/day in 3–4 divided doses. Monitoring of plasma concentration is essential to avoid toxicity and blood sample should be taken 2 hours post-dosage. Levels of 40-60 g/mL are desirable.

Adverse Reactions Nausea, vomiting, diarrhea, rashes, hallucinations, convulsions, headache, sedation, vertigo, alterations in liver function tests (hepatitis and hepatic necrosis reported); blood disorders including thrombocytopenia, leukopenia, and aplastic anemia reported.

Drug Interactions Renal excretion of flucytosine decreased and cellular uptake increased by amphotericin (toxicity possibly increased). Close monitoring required with concomitant administration of nephrotoxic drugs or cytotoxics. Plasma concentration of flucytosine possibly reduced by cytarabine.

TABLE 3 Antifungal agents at a glance Flucon AMB-D L AMB Vori Posa Echino C. albicans Yes Yes Yes Yes Yes Yes Candida species + +++ +++ ++ ++ ++++ Aspergillus No Yes Yes Yes Yes Yes Mucor No Yes Yes No Yes No Cryptococcus Yes Yes Yes Yes Yes No Route available IV, PO IV IV IV, PO PO IV Adverse effects + ++++ ++ ++ ++ + Drug Interactions +++ + + +++ +++ + Dose (mg/kg/day) 12 0.7–1.5 3–5 7 200 TDS Varies Cost/day/adult 200 300 8000- 12,000 IV 2,200 10,000 33000 2500 oral 166 Rational Antimicrobial Practice in Pediatrics Contd... involvement in neonates needed recommended or in whom there ishistory of azole exposure catheters intravascular all Remove brain barrier suppressive therapy with fluconazole is needed. For prosthetic joint infection, removal of joint is required deoxycholate amphotericin B not and flucytosinefluconazoleby Followed 5 FC or AmB-D with without 5 FC orechinocandin once patient stable with strongly recommended. negative blood culture andfluconazole or If valve replacement is replacement alonefluconazole organism susceptible do not cross the blood not possible, life-long fluconazole or recommended as they followed by fluconazole followed by fluconazolealone joint is necessary. and radiologic resolution 6-12 months is needed and For hip joint open drainage surgical debridement is often TABLE 4 Treatment of fungal infections Type of fungal infectionchoiceof Drug Candida Suspected/confirmedincandidiasis invasive adults OR Fluconazole Alternative drug EchinocandinSuspected/confirmedincandidiasis invasive children/neonatesOR Fluconazole B Amphotericin CommentsB Amphotericin Pyelonephritis EchinocandinCNS candidiasisechinocandin Choose Fluconazoletherapy of Duration Treat for 2 weeks after last Endocarditis Lipid Amphotericin B Amphotericin B preferred In neonates treat for 3 weeks Fluconazole in a very sick patient Amphotericin B LFAmB with or withoutOsteomyelitis as limited data on negative culture Step down to fluconazole Echinocandins and lipid Echinocandins notisreplacement Valve Septic arthritisweeks 2 after last negative culture byfollowed LFAmB 6 weeks treatment after valve Treat till complete clinical, CSF echinocandinor AmB-D echinocandins in children LFAmB followed by Look closely for CNS and eye echinocandinor AmB-D Drainage of affected 6 weeks therapy Prolonged treatment of up to Antifungals 167 Contd... period of immunosuppression is over immunosuppressed Use other drugs in flucona- zole refractory disease intervention to agent of another classDose of posaconazole notestablished in pediatrictreated successfully For patients, resume antifungal patients. Anidulafungindata not available therapy once immunosuppression recommences Itraconazole/echinocandin/AmB-D fluconazole severe disease use Voriconazole or itraconazole or micafungin orposaconazole itraconazole Role of combination therapy patients continue till not defined. If failure, switchover. is immunosuppression For sick patients LFAmBpatients sick For or AmB-D followed by fluconazole echinocandin or AmB-D Posaconazole/ treatment of choice Treatment should continue till TABLE 4 Contd... Type of fungal infectionchoiceof Drug disseminatedChronic candidiasis Fluconazole alone for Alternative drugfollowed Echinocandin Oropharyngealcandidiasis Transition to fluconazole, stable patients Comments Several months till all lesions ororally Fluconazole Esophageal candidiasisfluconazole by suspension clotrimoazole Voriconazole/ Fluconazole or Posaconazole/Candida fromtherapy of Duration respiratory secretionsFebrile neutropenia once patient is stable Itraconazole/Empirical therapy not recommended Mild disease use topical therapy and moderate to Treatment generally Aspergillosis days 7-14 radiologically. resolved have aspergillosisInvasive LFAmB or caspofungin Oral fluconazolevoriconazole AmB-D, Voriconazole 14-21 days LFAmB or caspofunginsurgical Consider At least 6-12 weeks, in 168 Rational Antimicrobial Practice in Pediatrics 4 weeks and then to continue secondary prophylaxis with fluconazole predisposing factor suchas control of diabetes lesions and underlying risk factor is corrected, at least Fluconazole and flucytosine uncertainmaximallyin LFAmB tolerated doses–D/posaconazole AmB voriconazole Surgical resection important Treat till clinical resolution and followed by fluconazole of choice fluconazole pressure and treatment of underlyingradiologic of stabilization then fluconazole for 10 weeks TABLE 4 Contd... Type of fungal infectionchoiceof Drug AspergillomaAllergic bronchopulmonary Itraconazoleaspergillosis Alternative drugMucormycosis Role of medical therapy Itraconazole or Comments Voriconazole orCryptococcosis meningitisCryptococcal therapy resction Surgical flucytosineand AmB–D Corticosteroids are byfollowed LFAmB therapy of Duration Manage intracranial posaconazole Initial therapy for 2 weeks and mainstay of therapy Antifungals 169

 ANTIFUNGAL AGENTS AT A GLANCE See Table 3.

 TREATMENT OF FUNGAL INFECTIONS See Table 4.

CONCLUSIONS The prognosis of several serious fungal infections has improved substantially as newer, less toxic antifungal drugs have become available, but still the invasive mycoses have remained difficult to treat. As new antifungal drugs are released and more data about combination regimens become available, we can look forward to more effective and better-tolerated treatments for candidiasis, aspergillosis, and other invasive mycoses.

 RECOMMENDED READING 1. Como JA, Dismukes WE. Oral Azole Drugs as Systemic Antifungal Therapy; New Eng J Med. 1994;330:263-72. 2. Craig J, Hoesley, William E, Dismukes WE. New Antifungal Agents: Emphasis on Lipid Formulations of Amphotericin B; Clinical updates National Foundation for Infectious Diseases Volume II, Issue 2 - June 1999. 3. Groll AH, Gea-Banacloche JC, Glasmacher A, Just-Nuebling G, Maschmeyer G, Walsh TJ. Clinical pharmacology of antifungal compounds. Infect Dis Clin North Am. 2003;17:159-91,ix. 4. Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr., Calandra TF, Edwards JE Jr, et al. Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases. 2009;48:503-35. 5. Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, Sobel JD, Dismukes WE. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. 2000;30:710-8. 6. Steinbach W. Antifungal agents in children. Paed Clin North Am. 2005;52:895-915. 7. Walsh TJ, et al. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America. Clinical Infectious Diseases. 2008;46:327-60. 170 Rational Antimicrobial Practice in Pediatrics 1414 Antivirals Vijay N Yewale

 INTRODUCTION The number of antiviral drugs has increased dramatically over the past decade, largely due to human immunodeficiency virus (HIV) infection. This chapter deals with the agents available for treatment of infections due to DNA and RNA viruses excluding retroviruses such as HIV. The first antiherpes compound, Idoxuridine was synthesized in 1959 and was approved for topical treatment of herpetic keratitis in 1962. Amantadine was discovered in 1964 and was approved for prophylaxis and treatment of influenza A virus. Vidarabine was approved for the treatment of herpes encephalitis in 1972. Ribavirin was introduced as a broad-spectrum antiviral agent (active against both DNA and RNA viruses) in 1972. The aerosolized form was used for RSV bronchiolitis in 1985. Acyclovir, with a selective activity against HSV and VZV with high safety profile, was introduced in 1977. The antiviral spectrum against herpes viruses was expanded with introduction of ganciclovir and bioavailability was improved with introduction of valacyclovir and valganciclovir. The close relationship between the viral replicative cycle and host-cell metabolism is primarily the reason why development of safe and effective antiviral agents has lagged behind development of other antimicrobial agents such as antibiotics.

 AMANTADINE AND RIMANTADINE These drugs act on the M2 protein in the cell membrane of the influenza A virus, inhibiting replication, uncoating and assembly of the virus. Resistance is frequent and rapid and occurs by change in the M2 viral protein by mutation. These drugs have almost become redundant in the treatment of influenza as the currently circulating influenza viruses including novel H1N1 and H3N2 are almost always resistant to these drugs. Highly pathogenic avian influenza virus (H5N1) is also resistant. Antivirals 171

These drugs are no longer recommended by the WHO in management of current day influenza infections.

 OSELTAMIVIR AND ZANAMAVIR (NEURAMINIDASE INHIBITORS) These drugs are the cornerstone in management of current day influenza virus infections.

Mechanism of Action and Resistance Potent and specific inhibitors of the neuraminidase of influenza A (including H5N1) and B viruses. It acts by inhibition of influenza virus neuraminidase. Influenza virus neuraminidase is responsible for virus assembly and release and oseltamivir inhibits this process. Resistance is by mutation in the hemagglutinin and/or neuraminidase. Resistance has not been recognized in influenza B virus to date, but is being reported in influenza A virus.

Pharmacokinetics Zanamavir: inhaled dry powder. About 4% to 17% of drug is absorbed systemically. Oral bioavailability is very low. IV preparation is under trial. Oseltamivir: Good oral bioavailability—70% to 80% absorbed. Prodrug form is metabolized by the liver esterases to active parent compound, carboxylate. No interaction with P450 system. Food does not decrease bioavailability but reduces the risk of gastrointestinal intolerance. Eliminated unchanged in urine.

Dosage Zanamavir: 5 mg/dose, two such inhalations bid for 5 days. Not FDA approved but effective for prophylaxis in the dose of 5 mg od per day. Oseltamivir: (75 mg capsule or 12 mg/mL liquid). For treatment dose for > 13 yrs/>35 kg is 75 mg BD. For <15 kg 30 mg BD, 15–24 kg 45 mg BD, 25–34 kg 60 mg BD. Therapy needs to be continued for 5 days. For severe illness, double the usual recommended dose may also be used and treatment continued for 10 days. For prophylaxis oseltamivir is approved as a once-daily-dose (i.e. half the therapeutic dose) dose of 75 mg once daily for at least 7 days. The drug should be started within 2 days of exposure. The duration of protection lasts for as long as dosing is continued and therefore in community outbreaks and can be safely given for up to 6 weeks.

Adverse Effects Oseltamivir is known to cause neurologic and GI side effects. Occasional bronchospasm has been reported following inhalation of Zanamavir. 172 Rational Antimicrobial Practice in Pediatrics

Indications for Use Therapeutic Neuraminidase inhibitors are known to reduce morbidity and duration of influenza related illness. They reduce infectivity and slow down virus transmission. More importantly, they reduce the incidence of complications and improve outcome, once complications have occurred. They are most beneficial when given within the first 48 hours of illness. Recent data, however, suggests that they are useful if given late during the course of disease even when complications have occurred. For any patient presenting with influenza like illness, the treatment strategy depends on two factors: the severity of illness and the likelihood of complications. In patients with mild disease who are not at risk for complications, only symptomatic treatment is indicated. Antibiotics and antivirals should not be prescribed. Patients should be counseled about the red flag signs and asked to seek medical care in the event these occur. These patients should be asked to stay at home till they are afebrile to prevent disease transmission to others. Patients with ILI who are at high risk for complications should be started on antiviral therapy irrespective of the severity of disease. The use of antivirals in all children below the age of 5 with flu-like illness, is however debatable. These children may present with multiple episodes of flu-like illness, in the season and how many episodes would one use antivirals? Hence, some discretion in use of antivirals in children below the age of 5 with mild illness is advised and watchful waiting is definitely an option. For patients who present with symptoms of severe illness or who have complications, antiviral treatment with oseltamivir should be started without delay. Definitive diagnosis of influenza by molecular tests is not a prerequisite to start antiviral treatment. This is because by the time, results are available in real life settings the disease has already recovered or progressed and also because negative molecular tests do not rule out influenza.

Prophylactic Prophylactic antivirals are indicated in patients who are exposed to influenza and have high risk of developing complications. These include the immunocompromised, pregnant women, those with chronic comorbid conditions and the morbidly obese. Risk of developing resistance is a danger of this approach.

 RIBAVIRIN Mechanism of Action and Resistance Interferes with viral mRNA synthesis. Resistance is rare. Spectrum of Activity Broad-spectrum antiviral active against Orthomyxoviruses (Influenza A and B), Paramyxo- viruses (Parainfluenza, RSV, measles), Arenaviruses (Lassa fever virus), bunyavirus (encephalitis), hantavirus, togaviruses (HCV), enteroviruses (polio, coxsackie B) and adenoviruses. Antivirals 173

Pharmacokinetics Administered by aerosol, orally or intravenously. Absorbed when used as aerosol. Bioavailability 33% to 45% after oral dose. CSF levels 70% of plasma levels. Metabolized by liver and 40% excreted by kidney. Concentrated in erythrocytes and t½ in RBCs is 40 days.

Clinical Indications • Aerosol for treatment of RSV bronchiolitis/pneumonia in specific children including age less than 6 weeks, congenital heart disease, chronic lung disease, preterm infants, immunocompromised children, cystic fibrosis and children with neurologic or neuromuscular disorders. No benefit in mild disease or when started late. • As oral treatment of HCV when combined with interferon-alfa; produces a sustained decrease in HCV RNA levels, improves systemic symptoms and improves liver histology. • As intravenous therapy for hemorrhagic fevers including Lassa fever, hemorrhagic fever renal syndrome (hantavirus) and adenovirus disease. Oral ribavirin may be of benefit prophylactically in individuals exposed to hemorrhagic fevers • Tried in SSPE in combination with interferon- benefits but does not cure.

Dosage Bronchiolitis: 6 g dissolved ion 300 ml sterile water and administered by a small particle aerosol generator (SPAG-2) over 18 hours for 3 to 7 days. Can be delivered by mask, oxygen hood or through ventilator. HCV: 600 mg bid for 24 to 48 weeks Lassa fever: 2 g loading (25 to 33 mg/kg) followed by ½ the dose qid for 4 days and then ½ of this dose tid for 3 days.

Adverse Effects Aerosolized ribavirin can cause anorexia, nausea and bronchospasm. Environmental exposure to aerosolized ribavirin by health workers can cause headache, conjunctivitis, bronchospasm. Ribavirin may get precipitated in ventilator tubings. Oral and intravenous ribavirin can cause dose related hemolytic anemia. Very highly teratogenic (category X) and pregnant health care workers should take care while caring for a patient on inhalation ribavirin therapy.

 ACYCLOVIR Spectrum of Activity Antiviral spectrum limited to herpes viruses. Most potent against HSV type 1, two-fold less active against HSV type 2. Less potent against VZV and EBV and least active against CMV or HHV-6. 174 Rational Antimicrobial Practice in Pediatrics

Mechanism of Action and Resistance Acyclovir is phosphorylated to monophosphate form by viral TK (Thymidine kinase) and to triphosphate form by cellular enzymes. This triphosphate form inhibits DNA polymerase and viral replication. It also is incorporated into the viral DNA and acts as a chain terminator to inhibit replication. Resistance is by one of the three mechanisms 1. Absence or partial production of thymidine kinase—HSV 2. Altered thymidine kinase substrate specificity—VZV 3. Altered viral DNA polymerase—VZV Prevalence of acyclovir resistant HSV is 1% but as high as 10% to 20% in immunocompromised hosts. Acyclovir resistant VZV is unusual.

Pharmacokinetics Oral bioavailability is 10% to 30% and decreases with increasing dose. Peak plasma concentration of 0.4 to 0.8 µg/mL after 200 mg dose and 0.8 to 1.6 after 800 mg dose. Bioavailability is less with liquid preparation. Peak plasma levels after 5 mg/kg IV over 1 hour is 9.8 µg and 20 µg after 10 mg/kg dose. Acyclovir is distributed widely in body fluids including vesicular fluid, aqueous humor, CSF, salivary and vaginal secretions. Also concentrated in breast milk, amniotic fluid and placenta. The mean plasma ½ life (t½) of elimination is 2.5 hours. It is 4 hours in neonates and increases to 20 hours in anuric patients. Excreted almost unchanged in urine. Dose modification required in renal failure.

Clinical Indications Topical acyclovir: Decreases slightly healing time and viral shedding in mucocutaneous lesions in primary infection with HSV. No clinical benefit except mild soothing effect in patients with recurrent herpes simplex lesions. Has mild clinical benefit in immunocompromised patients with VZV lesions. Oral acyclovir HSV: Reduces viral shedding, clinical symptoms and time until lesion healing in normal and immunocompromised individuals with mucocutaneous lesions associated with primary HSV infection. Recurrent HSV disease improves with oral acyclovir. Oral acyclovir reduces recurrence of genital herpes during pregnancy and decreases the need for cesarean section but since it is a category C drug, it is not FDA approved for this indication. Continuous suppressive therapy with oral acyclovir reduces cutaneous recurrences after neonatal infection when given after 14 to 21 days of intravenous therapy has been completed. Bells palsy associated with HSV infection can be treated with oral acyclovir and prednisone. VZV: Reduces duration of fever, mean number of lesions and the time to crusting by 2 days in children, adolescents and adults with primary VZV infection if started within the first 24 hours after appearance of the lesions. Postexposure prophylaxis with oral Antivirals 175 acyclovir reduces risk of varicella in close and household contacts if given 7 to 9 days after exposure. Infectious mononucleosis: Reduces viral shedding but does not change the course of the disease. Intravenous acyclovir Severe or life-threatening disease caused by HSV and VZV, including encephalitis, acute retinal necrosis syndrome, hepatitis, neonatal disease, widespread mucocutaneous disease, widespread zoster with or without visceral dissemination in a normal immunocompetent individual. Any primary VZV infection, widespread herpes zoster and disseminated HSV in an immunocompromised individual. Zoster ophthalmicus with complications like keratitis, anterior uveitis or contralateral hemiplegia as well as retinal necrosis.

Dosage Topical acyclovir—5% ointment every 3 to 4 hours for 7 days. Oral acyclovir—200 mg capsule or 800 mg tablet or 400 mg/5 mL suspension For primary HSV, in adolescents 200 mg 5 times a day for 10 days and in children 15 mg/kg/dose (max 200 per dose) 5 times a day for 10 days. Recurrent HSV 800 mg tid for 2 days or 400 mg tid for 5 days. Suppressive therapy 400 mg bid. Post-IV therapy in neonate—300/m² per dose tid for 6 months. VZV 20 mg/kg/dose (max 800 mg) qid for 5 days or until lesions have crusted. IV acyclovir For HSV encephalitis: 10 mg/kg or 500 mg/m2 8 hourly for 14–21 days (20 mg/kg 8 hourly in children less than 12 years) For neonatal HSV disease: 10–20 mg/kg/dose every 8 hours for 21 days For varicella: 10–12 mg/kg (500 mg/m2) 8 hourly for 7 days For herpes zoster: 10–12 mg/kg (500 mg/m2) 8 hourly for 7–14 days

Adverse Effects Topical acyclovir: Pain, local irritation or local rash due to polyethylene glycol base. Systemic acyclovir: Nausea, diarrhea, rash or headache. Neutropenia in neonates put on oral after IV acyclovir treatment. Extravasations can cause inflammation, ulceration and necrosis of surrounding tissue. Neurotoxicity associated with lethargy, tremors, seizures and coma. Renal toxicity in patients with poor hydration, rapid IV infusion, in those with prior renal disease and in those on other nephrotoxic drugs. Renal toxicity including renal tubular damage, crystalline nephropathy or interstitial nephritis may occur in 5% patients. 176 Rational Antimicrobial Practice in Pediatrics

 VALACYCLOVIR Hydrochloride salt of the ester of acyclovir. After oral administration valacyclovir is absorbed rapidly and is metabolized by first pass through intestinal tract and by liver into acyclovir and L-valine. The relative bioavailability of acyclovir increases 3 to 5 times to 70% following valacyclovir administration. Valacyclovir is converted rapidly and virtually completely to acyclovir and therefore has the same mechanism of action and resistance as acyclovir. Used as an alternative to oral acyclovir as better bioavailability and less frequent dosing needed for treatment of primary (1000 mg bid for 7–10 days) and recurrent HSV infections (500 mg bid), herpes labialis (2 gm bid for 1 day) primary VZV and zoster (1000 mg tid for 5 days). Liquid formulation not available and pediatric dosing not standardized.

 PENCICLOVIR Spectrum of Activity Selective activity against herpes viruses similar to that of acyclovir. Inhibits HSV–1, HSV–2, VZV at increasing concentration in plasma. Negligible activity against CMV. Inhibits HBV also.

Mechanism of Action and Resistance Like acyclovir, phosphorylated to triphosphate and inhibits viral DNA polymerase. It is 100 times less potent than acyclovir triphosphate in inhibiting DNA polymerase but an antiviral effect is achieved because of its presence in high concentrations for a prolonged period in virus-infected cells. Resistance is minimal and is by production of deficient or altered TK activity.

Pharmacokinetics Poorly absorbed after oral administration. Information on intravenous use in pediatric patients is not available. Penciclovir 1% cream is not absorbed systemically.

Clinical Indications Cream for the treatment of herpes labialis lesions on lips and face. At the onset of lesions every 2 hours while awake for 3 to 5 days.

 FAMCICLOVIR It is the prodrug of penciclovir. Famciclovir undergoes rapid transformation to penciclovir and then acts like penciclovir.

Pharmacokinetics Absorbed rapidly after oral administration. Excellent bioavailability of 77%. Administration with food reduces peak plasma levels but does not alter bioavailability. Metabolized Antivirals 177 in liver by deacetylation and oxidation to form penciclovir. Elimination t ½ is 2 to 3 hours. Excreted by filtration and active tubular secretion by kidneys. Nonrenal clearance by fecal excretion of one-third drug.

Clinical Indications For treatment of primary HSV (250 mg tid/500 mg bid for 7 days), treatment of recurrent HSV (125 mg tid/250–500 mg bid for 7 days) and suppression of recurrent HSV (250 mg bid) and in both normal and immunocompromised patients. Treatment of herpes zoster in immunocompetent host (500 mg tid for 7–10 days). In chronic HBV infection and for prophylaxis against recurrent HBV infection in liver transplant recipients. No clinical trials in pediatric population and pediatric dosing not standardized. Occasional headache, dizziness and GI intolerance.

 GANCICLOVIR Spectrum of Activity Ganciclovir has selective activity against herpesviruses, with uniquely potent antiviral activity against CMV at a very low concentration. HSV 1, HSV 2, VZV, EBV, HHV 6, HHV 7 and HHV 8 are also inhibited. In vitro activity against HBV and adenoviruses.

Mechanism of Action and Resistance Phosporylated by TK in HSV infected cells and by protein kinases encoded by UL97 gene in CMV infected cells. The active form, i.e. ganciclovir triphosphate is incorporated into viral DNA, where it slows and stops viral DNA chain elongation and produces short, noninfectious viral DNA fragments. It also inhibits DNA polymerase. Resistance is seen in 8% to 38%. Resistant strains emerge either quickly after a few weeks of therapy or slowly after therapy. There are 2 mechanisms 1. Point mutation or deletion in UL97 gene reducing phosphorylation of ganciclovir— common and the strains remain susceptible to foscarnet and cidofovir. 2. Point mutation in viral polymerase UL54 gene. They are resistant to foscarnet and cidofovir as well.

Pharmacokinetics After IV administration widely distributed. CSF (levels up to 70% of plasma) and brain (38%). Aqueous, vitreous and subretinal fluid levels are like serum levels. Excreted by kidneys. Oral bioavailability is poor; 5% and is better if administered with food.

Clinical Indications • Treatment of immunocompromised patients with invasive CMV disease such as retinitis, pneumonia, esophagitis, colitis, myocarditis, encephalitis, persistent fever and leukopenia syndrome and viral sepsis syndrome. However, treating CMV pneumonia in bone marrow and stem cell transplant patients is difficult and may not respond to ganciclovir. 178 Rational Antimicrobial Practice in Pediatrics

• Early or pre-emptive therapy in immunocompromised patients with virologic markers (PCR or antigen) of CMV but no active disease. Pre-emptive therapy now favored over prophylaxis in high-risk patients and well established for high-risk hemopoetic stem cell transplant (GVHD, or history of active CMV disease), high-risk lung, liver, heart and kidney transplant patients. • Prophylaxis of transplant recipients who have received transplants from CMV seropositive donors. Recipients who are seronegative and have received antithymocyte globulin are at greatest risk. Risk of hematopoetic stem cell transplant greater than solid organ transplant. • Newborns congenitally infected with CMV with CNS involvement.

Dosage Solution for IV use 10 mg/mL over 1 hour; also available as 250 mg, 500 mg capsule. Therapy involves induction and maintenance. Induction—5 mg/kg/dose bid for 2 to 3 weeks and then maintenance dose of 5 mg/kg/day (Valganciclovir is a more convenient oral alternative for maintenance). 6 mg/kg/dose bid for 6 weeks to treat neonatal CMV disease. Pre-emptive treatment—5 mg/kg/dose bid for 7 to 14 days followed by maintenance for 2–5 weeks till Ag/PCR negative. Prophylaxis—5 mg/kg/day for 3–6 months (Valganciclovir may be more convenient).

Adverse Effects Local phlebitis, irritation, blistering or ulceration. Dose dependent reversible neutropenia seen in 1/3 to 1/2 patients who receive treatment for over 2 weeks. Thrombocytopenia especially in AIDS patients on antiretroviral therapy. Monitor CBC 2–3/wk and discontinue if ANC < 500–750 or platelets < 25,000. G CSF can be used to treat neutropenia. Headache, behavioral changes, psychosis, seizures and coma.

 VALGANCICLOVIR Prodrug of ganciclovir, metabolized rapidly to ganciclovir in the body. Well absorbed after oral administration and hydrolyzed in intestine and liver to ganciclovir. Bioavailability is high 60% as compared to 6% to 9% of ganciclovir. Absorption is enhanced with ingestion of food. Excreted by kidneys. It is FDA approved and a more convenient alternative to IV ganciclovir for therapy in CMV retinitis in AIDS patients and for prophylaxis and pre-emptive therapy in transplant patients (except liver transplant). Also useful for maintenance therapy once induction therapy with IV ganciclovir is complete. Adult doses are 900 bid for 3 weeks and then 900 mg qd. Available as 450 mg tablets. The tablets have to be swallowed whole and cannot be crushed or broken. A liquid pediatric formulation is not available in India, though it is available abroad. The pediatric dose for prophylaxis is calculated on the Antivirals 179 basis of body surface area and creatinine clearance and is 7 × BSA in m2 × creatinine clearance. Side effects are similar to IV ganciclovir and there is complete cross-resistance with ganciclovir.

 FOSCARNET Spectrum of Activity Selectively inhibits herpes viruses as well as most but not all acyclovir resistant HSV and VZV and most but not all ganciclovir resistant CMV. When combined with ganciclovir has a synergistic effect against CMV and with zidovudine synergistic against HIV. Also active against HIV and HBV.

Mechanism of Action Does not require phosphorylation and directly inhibits viral DNA polymerase.

Pharmacokinetics Cerebrospinal fluid (CSF) levels are 60% of plasma levels. Vitreous concentration same or slightly higher than plasma. 80% excreted unchanged by kidney. 20% deposited in bones and teeth and remains for months. Oral foscarnet has poor bioavailability

Clinical Indications Used as a second line agent for therapy of ganciclovir resistant CMV infections and acyclovir resistant HSV infections. Not used as primary therapy due to unfavorable side effect profile.

Dosage • For HSV: 60 mg/kg/dose tid for 3 weeks for induction • For CMV: 90 mg/kg IV 12 hourly for 14 days and then 90 to 120 mg/kg/day for maintenance • Infusions should be given slowly over 1–2 hours (no faster than 1 mg/kg/min).

Adverse Effects Renal toxicity in 1/3 of patients. After 1st week of therapy and is reversible. Monitor serum creatinine 1 to 3 times/week and stop if > 2.9 mg/dL. Concomitant nephrotoxic drugs increase risk of nephrotoxicity. Hypocalcemia, hypercalcemia, hypophosphatemia, hyperphosphatemia, hypokalemia, hypomagnesimia (Monitor electrolytes 1 to 2/ week). Other side effects include perioral tingling, numbness, paresthesia of the limbs and tetany or seizures, cardiac dysarrhythmias. 180 Rational Antimicrobial Practice in Pediatrics

 CIDOFOVIR Spectrum of Activity Broad spectrum against all DNA viruses. Most specific and potent against CMV especially ganciclovir reistant strains. Very active against VZV and HSV-1 and acyclovir resistant, TK deficient strains of HSV-1.

Mechanism of Action and Resistance Selectively inhibits viral DNA polymerase. Phosphorylated by cellular enzymes and does not need TK. Resistance by mutation in viral DNA polymerase.

Pharmacokinetics Not well absorbed orally (bioavailability is 5%). Alkoxyalkyl esters of cidofovir, with better absorption will be available soon. Aerosolized form is being developed. Poor CSF concentration. Mainly excreted by kidney unchanged. T½ is short but intracellular t½ is long (17 to 65 hours).

Clinical Indications As a second line agent for ganciclovir and foscarnet resistant CMV, HSV and VZV infections.

Dosage It is 5 mg/kg once weekly for 2 weeks for induction and 5 mg/kg once in 2 weeks for maintenance. Probenecid given 3 hours before and then 2 hours and 8 hours after completion of IV cidofovir to reduce the risk of nephrotoxicity. Hydrate with normal saline before cidofovir.

Adverse Effects Nephrotoxicity is frequent (proteinuria, azotemia, proximal tubular dysfunction). It is dose dependent, increased with other nephrotoxins and reduced with hydration and probenecid. Use of cidofovir is contraindicated with other nephrotoxic drugs such as aminoglycosides, amphotericin B, foscarnet, NSAIDs. One week washout period is recommended before cidofovir is given. Other side effects are neutropenia and metabolic acidosis.

 LAMIVUDINE Spectrum of Activity Active against HIV and HBV. Antivirals 181

Mechanism of Action and Resistance It is a nucleoside analog that inhibits HIV reverse transcriptase and HBV DNA polymerase. Resistance occurs by mutation in the HBV DNA polymerase.

Pharmacokinetics Following oral administration, it is rapidly absorbed with a bioavailability of 80%. It is widely distributed in a volume comparable to total body water. Plasma half-life is 9 hours. 70% is excreted unchanged in urine. 3 mg/kg per day provides plasma levels comparable to adults.

Clinical Indications Chronic hepatitis B—It suppresses HBV DNA levels and is associated with biochemical normalization and histological improvements in inflammation and progression of fibrosis. A minority of patients develop HBeAg seroconversion, i.e loss of HBeAg and development of anti-HBe antibodies. In most patients viremia returns to pretreatment levels after discontinuation of lamuvudine, sometimes in association with hepatitis flare. A major limitation with use of lamivudine is rapid emergence of mutations (YMDD mutants). Lamivudine therapy can benefit patients with decompensated cirrhosis and extend the transplantation free time. Combined use of interferon- with lamivudine generally shows no greater efficacy than monotherapy with interferon-, although combination therapy may be associated with higher HBe seroconversion. HIV—See section on antiretroviral therapy.

 ADEFOVIR DIPIVOXIL Adefovir dipivoxil has recently been approved for the treatment of CHB. Adefovir dipivoxil is the oral prodrug of adefovir, a nucleotide analog of adenosine monophosphate. In vivo, adefovir dipivoxil is converted to the parent compound, adefovir, and through two phosphorylation reactions, to adefovir diphosphate, the active intracellular metabolite that interacts with the HBV polymerase. Adefovir diphosphate acts as a competitive inhibitor and chain terminator of HBV replication. Two large randomized controlled trials have demonstrated that adefovir dipivoxil in a dose of 10 mg per day is effective in patients with HBeAg-positive or HBeAg-negative CHB. Also, adefovir dipivoxil effectively suppresses lamivudine-resistant HBV in patients with CHB after liver transplantation, compensated or decompensated liver disease, and co-infection with HIV. Adefovir is well tolerated, reduces HBV DNA levels and normalizes ALT levels. But sustained response with HBeAg to anti-HBe seroconversion is rarely obtained and HBsAg loss is exceptional. The response is maintained during therapy which needs to be continued indefinitely in the majority of patients since withdrawal of treatment is generally followed by a rapid reactivation of hepatitis B. 182 Rational Antimicrobial Practice in Pediatrics

CONCLUSIONS Several new antiviral agents are under development. Identification of agents with improved pharmacokinetics, greater potency, and/or improved toxicity profile will make antiviral therapy more satisfactory. Prodrugs can be used to improve bioavailability. Newer drug delivery techniques are being identified. Combination therapy is being studied to increase antiviral activity, reducing drug dosage and toxicity.

 RECOMMENDED READING 1. Bryson YJ. Antiviral Agents. In Feigen RD, Cherry JD, (Eds). Textbook of Pediatric Infectious Diseases. 4th edition. Philadelphia: WB Saunders Company. 1998:2660-90. 2. Gani R, Hughes H, Fleming D, Griffin T, Medlock J, Leach S. Potential impact of antiviral drug use during influenza pandemic. Emerg Infect Dis. 2005;11:1355-6. 3. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Clinical Aspects of Pandemic 2009 Influenza A (H1N1) Virus Infection. NEJM. 2010;362:1708-19. Section 2: AntimicrobialGeneral Principles Therapy of Antimicrobial of Infections Therapy 183 1515 General Principles of Antimicrobial Therapy YK Amdekar

Antibiotics are ideally prescribed for treating bacterial infections. In practice, it amounts to diagnosing bacterial infection reasonably correctly to ensure rational use of antibiotics. Antibiotics are also used for prophylaxis of bacterial infections in selective situations. It is important to strictly follow the standard protocols for prophylaxis, though in practice it is unfortunately loosely employed. However, in clinical practice, antibiotics are most commonly used empirically. Empirical use is based on personal observation and practical experience. Empirical use of antibiotics may be scientifically acceptable if few prerequisites are judiciously met with. Therefore, it should be an endeavor of every physician to justify antibiotic prescription in general and specially in case of empirical use.

Diagnosing Acute Bacterial Infection It is not easy each time to be sure about presence or absence of acute bacterial infection. However, if few principles are strictly followed, antibiotic misuse can be minimized to a great extent, if not totally avoided. Fever is the hallmark of acute bacterial infection and hence antibiotic therapy is not justified in any acute symptom that is unaccompanied with fever. Neonate and shock state may be an exception to this rule. However, the converse is not true in that fever may not represent every time an acute bacterial infection; it may be due to viral or parasitic infection, or it may result from a non-infective condition such as malignancy or collagen vascular disease. Central fever, heat fever or drug fever may be other conditions leading to acute onset fever. Hence, it is important to differentiate acute bacterial infection from other causes of acute onset fever. Most of the times, clinical differentiation is possible between acute bacterial and viral infection. Acute viral infection is disseminated throughout the system (URTI and LRTI), may affect multiple systems (respiratory and gastrointestinal), spreads from and to other 184 Rational Antimicrobial Practice in Pediatrics family members. Fever is usually high at onset, settles by D3–4 and child is comfortable and not sick during inter febrile state. As against, acute bacterial infection is localized to one part of the system (acute tonsillitis does not present with running nose or chest signs). Fever is generally moderate at the onset and peaks by D3–4 and child often continues to be sick even during inter febrile state. In malaria, fever is often erratic and child looks normal during inter febrile period. Classical rigors are often absent. Paucity of other symptoms and physical signs is common though splenomegaly and pallor, if present, is a strong clinical marker. It is important to realize that definitive diagnosis of acute bacterial infection is generally not possible for the first 2–3 days with the exception of tonsillitis, otitis media, acute lymphadenitis and bacillary dysentery. Hence, antibiotic prescription for fever of acute onset is not justified on the first couple of days unless one of the above mentioned conditions are evident on physical examination. In the absence of definitive diagnosis during first 2–3 days of fever, serious bacterial infections must be ruled out, which is possible on careful physical examination. Serious bacterial infections where delay in instituting antibiotics would result in poor outcome include meningitis, pneumonia, sepsis and diphtheria. In case of suspicion of any of these serious bacterial infections, suitable action is necessary in the form of appropriate tests and/or hospitalization prior to antibiotic therapy. Every pediatrician must document absence of physical signs of these serious infections and then observe further course of febrile illness without antibiotic therapy. If fever persists beyond 3–4 days without any obvious localization, one must consider urinary tract infection (UTI) or typhoid fever. It is important to order relevant laboratory tests before instituting antibiotic therapy, lest correct diagnosis is missed with dire consequences, Delay in starting an antibiotic by a day or two in these infections will not harm the patient. Routine urinalysis would point to UTI and ideally urine culture is ordered before starting antibiotic. It is important not to miss the diagnosis of UTI as it may recur with possibility of irreversible renal damage. Similarly typhoid fever demands reasonably definite diagnosis, as therapy may have to be continued for longer period to ensure cure. In suspected case of typhoid fever, leucopenia with neutrophilia and eosinopenia favor the diagnosis and blood culture must be sent before starting antibiotic therapy so as to confirm the diagnosis retrospectively. With increasing prevalence of drug resistant typhoid fever, confirmation of diagnosis has assumed far greater importance.

Diagnosing Chronic Bacterial Infection Chronic bacterial infection such as tuberculosis, chronic UTI or chronic sinusitis is not easy to diagnose clinically and demands relevant investigations. Such chronic infection is not likely to worsen over next few days and there is always enough time on hand to confirm the diagnosis before starting antibiotic therapy. Antibiotic trial is not rational in these cases, as therapy may have to be continued for longer period even if patient becomes asymptomatic within few days. Ideally bacteriological diagnosis must be attempted in chronic infection. General Principles of Antimicrobial Therapy 185

Prophylactic Antibiotic Therapy Prerequisites for prophylactic antibiotic therapy include two key factors—knowledge of specific infection against which prophylaxis is planned and increased susceptibility of the host against that particular infection. Penicillin prophylaxis for rheumatic fever is a classical example of rational prophylactic therapy and so also is a neonate exposed to open tuberculosis in the mother. A person in immediate contact with meningococcal disease is another example of ideal prophylaxis. In all these conditions, prophylaxis is planned against specific infecting agent and hence choice and duration of prophylactic antibiotic therapy is clear. Perioperative administration of a narrow spectrum antibiotic to prevent surgical site infections is another example of ideal prophylaxis. Routine prophylaxis using broad-spectrum antibiotics is irrational as it may lead to development of drug resistant organisms.

Empirical Antibiotic Therapy There is a place for empirical antibiotic therapy in clinical practice. However, one must ensure that such a therapy does not harm the patient by delaying correct diagnosis. Stringent prerequisites must be followed before considering empirical antibiotic therapy. Young infants < 3 months of age with high fever, undiagnosed fever in an immuno- compromised patient, fever in a patient in the intensive care unit and unaccounted fever in a child with heart defect (probability of subacute bacterial endocarditis) are high risk situations for bacterial infection and should be treated with antibiotics but only after relevant investigations including bacteriological tests are sent to the laboratory. Minimum investigations include CBC, urinalysis, blood culture and chest X-ray. Other tests may be considered in relevance to the probability of clinical diagnosis and include CSF examination. Viral infection with atypical progress such as persistent fever well beyond the appearance of skin rash in a child with measles may suggest secondary bacterial infection and necessitate an antibiotic.

Choice of Antibiotic It is based on probability of gram-positive or gram-negative bacterial infection as suggested by the age of the patient and site of infection. Drug resistance may not be the initial consideration in the treatment of community-acquired infections unless local epidemiology demands such a consideration. Multidrug resistant typhoid fever or shigellosis are likely in the current scenario and an appropriate antibiotic may be chosen on the basis of antibiotic sensitivity pattern noted in the community. Most of the other community-acquired infections would respond to almost any antibiotic. It is important to choose an antibiotic, which has low potential to develop resistance such as amoxycillin for oral use or cefotaxime for parenteral use. Oral drug is always preferred unless patient’s condition demands use of parenteral drug. In such a case, antibiotic available with both formulations may be the best choice so that one could shift to oral therapy with the same drug, once patient’s condition stabilizes. Change from one parenteral drug to another oral drug is not ideal. 186 Rational Antimicrobial Practice in Pediatrics

Drug resistance plays heavily in the minds of the physician; however, it should not be a serious contender in routine community acquired infections. In stable conditions, there would always be time available to monitor response to an antibiotic and hence choice of antibiotic should be restricted to first line of drugs. Addition of enzyme inhibitor to an antibiotic may be a theoretical proposition to safeguard against beta-lactamase producing organisms as no single enzyme inhibitor is known to take care of several enzymes that organism may produce. Thus it may give a false sense of security. Besides, the cost of therapy increases considerably by addition of enzyme inhibitor. For example, cost of amocycillin in combination with enzyme inhibitor is five times that of parent drug. In general, first line of antibiotics is adequate for most of the common community acquired infections and other antibiotics should be reserved for specific usage such as nosocomial infections. Broad-spectrum antibiotics are not the best for simple community acquired infections and in fact, narrow-spectrum antibiotic hits the organism the hardest.

Change of Antibiotic In case of failure of anticipated response, change of antibiotic may be considered after adequate trial for 3-4 days. Second antibiotic must be rationally chosen, as it should widen the bacterial cover beyond that offered by the first antibiotic. For example, if amoxycillin is used as a first antibiotic for community acquired respiratory infection and has failed, second choice should essentially cover atypical organisms such as mycoplasma/ chlamydia that are not covered by amoxycillin. Macrolide would be the antibiotic of choice in such a case. Thus higher generation or newer antibiotic is not necessarily the choice for a change. If second antibiotic fails, it is best to review the diagnosis. Invariably, wrong diagnosis is the cause of antibiotic failure and not the drug itself. Addition of another antibiotic when first one fails is not rational in acute bacterial infection. If first one has failed, it should be replaced.

Combination Antibiotic Therapy It is irrational to use two antibiotics for a single infection in office practice. It may be necessary only in selective situations wherein unstable condition of the patient demands quick control and there is no clue to bacteriological diagnosis as happens in neonatal sepsis or suspected infection in immunocompromised patient. In such cases, time is the crucial factor to save life and it would be irrational not to use two antibiotics to widen the bacterial cover, synergy and also take care of probable drug resistance. Use of fixed drug combinations such as an antibiotic with antiparasitic drug is irrational. In children, acute dysentery is caused by bacterial infection and there is generally no coinfection with amoebiasis. Similarly, antibiotic combined with lactobacillus or co prescription with vitamin B complex is an exaggerated claim by pharmaceutical companies. General Principles of Antimicrobial Therapy 187

Duration of Antibiotic Therapy Duration of therapy depends upon the age, type of organism and site of infection. Younger the age, more serious or disseminated the disease is and is often caused by gram- negative organisms. Such a disease would require treatment for 2–3 weeks while therapy for a week may suffice for community acquired infection in an older child. Deep-seated infection such as bone or joint infection may justify longer therapy.

Increasing Prevalence of Antibiotic Resistance Multiple factors are responsible for increasing drug resistance. Poor patient compliance, aggressive marketing practices of pharmaceutical industry, self medication, easy availability of antibiotics across the counter, substitution by chemists, substandard quality of drugs and non-existent control of drug regulation authorities are all responsible for increasing drug resistance. However, irrational use by medial professionals is probably the main contributing factor for the current scenario. Most of the antibiotic misuse by medical professionals comes from diffidence and fear of missing serious bacterial infection and its dire consequences. Every practitioner is concerned with his or her individual patient and considers it safe to use antibiotic in almost every case. Fear of legal action makes many physicians prefer an error of commission to error of omission and hence, an antibiotic prescription gives them false sense of security. It is important to realize that such narrow vision in favor of an individual patient leads to spread of drug resistant infections in the community, of which every individual patient is also a part. It is not the wrong clinical judgment as much as it is the negligence that is punished in the court of law. Poor communication with the patient and relatives and poor documentation of clinical opinion are the main reasons for legal problems. It is also the main factor contributing to irrational practices. It is of utmost necessity that every physician documents his probable diagnosis and the basis for such a diagnosis before writing a prescription. If this is meticulously followed, irrational use of antibiotics would be minimal. In the court of law, such documentation would help in favor of the physician even in case of complications or poor outcome. Hence, legality should not be an excuse for irrational antibiotic use and “defensive” practice is not warranted. If physicians do not follow such an ideal practice, the time is not far when no antibiotic would work and community will be in danger of life even with so called “benign” common infections.

CONCLUSIONS In conclusion, if general principles of antimicrobial therapy were strictly followed, it would do immense good to the community. Problem of drug resistance is a result of our own wrong doing and before the situation gets out of control, we need to act seriously. We all owe it to the community. Protocols and guidelines formulated by an official scientific organization would go a long way to give an impetus to rational use of antibiotics, as it would serve the community the best and also protect physicians from legal hassles. 188 Rational Antimicrobial Practice in Pediatrics

 RECOMMENDED READING

1. Dancer SJ. How antibiotics can make us sick: less obvious side effects of antimicrobial therapy. Lancet Infect Dis. 2004;4:611-9. 2. Leone M, Bourgoin A, Cambon S, Dubuc M, Albanese J, Martin C. Empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome. Crit Care Med. 2003;31:462-7. 3. Long: Principles and Practice of Pediatric Infectious Diseases, 2nd edition, Copyright © 2003 Elsevier. 4. Mandell: Principles and Practice of Infectious Diseases, 5th edition, Copyright © 2000 Churchill Livingstone, Inc. 5. Niederman MS. Appropriate use of antimicrobial agents—challenges and strategies for improvement. Crit Care Med. 2003;31:608-16. 6. Safdar N, Handelsman J, Maki DG. Does combination antibiotic therapy reduce mortality in gram- negative bacteremia? A meta-analysis. Lancet Infect Dis. 2004;4:519-27. 7. Warren DK, Hill HA, Merz LR, Kollef MH, Hayden MK, Fraser VJ et al. Cycling empirical antimicrobial therapy to prevent emergence of drug resistance. Crit Care Med. 2004;32:2450-6. 8. Weinstein L. Common sense (clinical judgment) in the diagnosis and antibiotic therapy of etiologically undefined infections. Pediatr Clin North Am. 1968;15:141. Antimicrobial Therapy in Acute Gastroenteritis 189 1616 Antimicrobial Therapy in Acute Gastroenteritis Shinjini Bhatnagar, Keya Mariam Kunnekel, Pankaj Vohra

 INTRODUCTION Antimicrobial therapy is required in only a small percentage of children with acute gastroenteritis. However, as maintenance of hydration and correction of dehydration take precedence over all other modes of therapy in the management of childhood diarrhea it is also discussed.

 REVISED RECOMMENDATIONS FOR TREATMENT OF ACUTE DIARRHEA The revised WHO and IAP recommendations for treatment of acute diarrhea are use of reduced osmolarity ORS for treating dehydration and maintaining hydration, and twice required daily allowance (RDA) of elemental zinc for at least 14 days.1,2

Reduced Osmolarity ORS The new improved reduced osmolarity ORS recommended for all ages and all types of diarrhea by the WHO, Government of India and the Indian Academy of Pediatrics contains 75 mmol/L of sodium and 75 mmol/L of glucose with an osmolarity of 245 mosmol/l.1-4 These recommendations are based on a recent meta-analysis which included 12 large randomized controlled trials. Use of reduced osmolarity ORS was associated with a significant 39% reduction in need for intravenous fluids, 19% reduction in stool output and 29% lower incidence of vomiting as compared with the standard WHO ORS (sodium 90 mEq/L glucose 110 mmol/L, osmolarity 311 mOsm/L).2-4 The need for intravenous fluids is considered an important outcome measure as in many peripheral health facilities, where IV therapy may not be available; reducing the need for unscheduled IV therapy would reduce the risk of death from dehydration. It was also found to be as effective in adults and children with cholera. The safety data in patients with cholera, whereas limited, is reassuring. 190 Rational Antimicrobial Practice in Pediatrics

Zinc in the Treatment of Diarrhea Based on studies in India and other developing countries there is sufficient evidence to recommend zinc in the treatment of acute diarrhea as adjunct to oral rehydration.3-10 Studies have shown that zinc supplemented children had 16% (95% CI 11% to 22%) faster recovery from diarrhea with a 34% (95% CI 17% to 48%) reduction in the odds of acute episodes lasting more than 7 days and the total stool output was reduced by 24% (95% CI 2% to 41%) as compared to the placebo group. Importantly, zinc supplementation has shown to reduce the incidence and severity of diarrhea in the subsequent two to three months after supplementation has been stopped.2,6-10 All studies showed that the effect of zinc did not vary significantly with age, nutritional status assessed by anthropometry or the type of zinc salt used—zinc sulfate, zinc acetate or zinc gluconate. The results of the most recent meta-analyses are consistent with the previous data.11,12 Therapeutic benefits of zinc administration during diarrhea are biologically plausible because of its effects on various components of the immune system and its direct gastrointestinal effects. Zinc is said to improve absorption of water and electrolytes by helping in early regeneration of intestinal mucosa, restoration of enteric enzymes and enhancing humoral and cellular immunity. Zinc has been also shown to have antisecretory properties in malnourished guinea pigs. WHO recommends that 20 mg per day of zinc supplementation should be given once or twice daily for 10–14 days starting as early as possible after onset of diarrhea in children older than 6 months. Although more evidence is required, it is recommended that infants less than 6 months should be given 10 mg per day. These recommendations have been endorsed by the Indian Academy of Pediatrics and the pharmaceutical industry has responded positively by marketing formulations that contain only zinc. Iron containing formulations should not be used with zinc as it may interfere with zinc absorption.

 ANTIMICROBIAL DRUGS Antimicrobial drugs are not required for routine treatment of acute diarrhea because most episodes are caused by pathogens for which antimicrobial drugs are not effective (Table 1). Rotavirus is responsible for 20 to 25% of diarrhea episodes in children aged 6-24 months visiting treatment facilities and for 15% of cases in the same age group in the community. It causes patchy blunting of intestinal villi with some reduction of mucosal disaccharidases, which return to normal within 2–3 weeks. The diarrhea is watery, and is usually associated with vomiting and low-grade fever. Antimicrobials are not recommended as the diarrhea is self-limiting with the median duration being about 8 days and can be effectively treated with oral rehydration fluids and continued feeding. Enterotoxigenic E. coli (ETEC) is another major cause of diarrhea and is responsible for up to 25% of all diarrheas in children from developing countries. ETEC does not invade the mucosa or damage the brush border but manifests with watery diarrhea by producing heat labile (LT) and/or heat stable (ST) enterotoxins that induce secretion of fluids and electrolytes. Antibiotic therapy does not offer any significant clinical benefit, as the diarrhea is self- limiting. The mainstay of treatment is oral rehydration fluids and continued feeding. Antimicrobial Therapy in Acute Gastroenteritis 191

TABLE 1 Etiology of acute diarrhea Pathogen Incidence Rotavirus 25–30% Enterotoxigenic E. coli (ETEC) 20% Shigella 5–10% Enteropathogenic E. coli (EPEC), 5–7% Locally adherent E. coli, Campylobacter, Salmonella G. lambia, E. histolytica <2% V. cholerae 5–10%

When should Antimicrobials be given for Treatment of Acute Diarrhea? The only specific clinical indications for use of antimicrobial agents where they have been found to be useful include: • Suspected cholera with severe dehydration • Bloody diarrhea (probably shigellosis) • Serious associated nongastrointestinal infections, e.g. pneumonia, septicemia, meningitis, urinary tract infection, etc.

 CHOLERA The mainstay of therapy for cholera is rehydration with oral rehydration solution (for some dehydration) or intravenous Ringer’s lactate (for severe dehydration). Antimicrobials may be used as an adjunct to oral rehydration therapy for severely purging cholera patients to reduce the rate of stool output, minimize fluid requirement and stop excretion of Vibrio cholerae in the stool. Antibiotics like tetracycline (12.5 mg/kg four times a day for a period of 3 days), erythromycin (12.5 mg/kg given four times a day for 3 days), co-trimoxazole (trimethoprim 5 mg/kg or sulphamethoxazole 25 mg/kg twice a day for three days) and furazolidone (1.25 mg/kg four times a day for 3 days) have been used effectively in the past. Doxycycline (6 mg/kg or 300 mg in adults given as a single dose) has been found to be as effective as multiple doses of tetracycline in treatment of cholera.13 In children <8 years of age tetracyclines have been found to cause discolouration of teeth and delay in bone growth and hence alternative therapy is preferred. The major concern is that resistance to the above drugs has been reported. Studies in adults with V. cholerae 01 and 0139 have shown that single dose (1 g) ciprofloxacin is effective in the treatment of cholera and is better than single dose doxycycline in the eradication of the pathogen from the stool.14-16 Treatment with norfloxacin (400 mg given twice a day for three days) in adults has been reported to decrease stool output, diarrheal duration and need for intravenous fluids.17 There is preliminary evidence to suggest that fluoroquinolones can be safely used in children as an adjunct to oral rehydration therapy.18 Extensive experience of the use of these drugs in children with 192 Rational Antimicrobial Practice in Pediatrics typhoid, cystic fibrosis and dysentery has shown no evidence of bone or joint toxicity, and impairment of linear growth.19-23

 BLOODY DIARRHEA Definition The episode is termed bloody diarrhea or dysentery when visible blood is present in the stool. Terms like bloody diarrhea, dysentery, bacillary dysentery and invasive diarrhea are often used interchangeably. Bloody diarrhea refers to any episode of diarrhea with visible red blood and does not include melena or episodes where blood streaks are present on the surface of formed stool. Episodes where blood is identified by microscopic examination or biochemical tests are not defined as bloody diarrhea.1 Classical textbook definition of dysentery means bloody diarrhea accompanied with fever, abdominal cramps, tenesmus and mucoid stools. However, in clinical practice all these accompanying features may not always be present. Bacillary dysentery is used for dysentery caused by Shigella and distinguishes shigellosis from amoebic dysentery (not a common cause of dysentery in children). Invasive diarrhea refers to diarrhea caused by bacteria like Shigella, some Salmonella, E. coli and Campylobacter jejuni that invade the bowel mucosa causing inflammation and mucosal damage. Thus, episodes of invasive diarrhea are called dysentery or bloody diarrhea when visible blood is present.

Shigellosis The genus Shigella belongs to the family Enterobacteriacae and includes four species S. dysenteriae, S. flexneri, S. boydii and S. sonnei. These are gram-negative, non-motile bacilli, which are responsible for most episodes of bloody diarrhea. S. sonnei and S. boydii usually cause relatively mild illness in which diarrhea may be watery or bloody. S. flexneri is the commonest cause of endemic shigellosis in developing countries and results in significant morbidity and mortality. The most severe prolonged and fatal disease is produced by Shigella dysenteriae type 1 also known as the Shiga bacillus (Sd1), which produces a potent cytotoxin known as Shiga toxin. It is responsible for large regional epidemics and is resistant to antimicrobials more frequently than other species. Shigella causes patchy destruction of the colonic epithelium resulting in micro-ulcers and inflammatory exudates. Case-fatality in patients among patients with Sd1 requiring hospitalization can be as high as 15%. This can be further increased by delayed hospitalization or treatment with ineffective antimicrobials.

Antimicrobial Therapy in Bloody Diarrhea Rationale for Antimicrobial Therapy Antimicrobial therapy is the mainstay of treatment in bloody diarrhea and is targeted towards Shigella as it is the commonest cause of bloody diarrhea. Prompt antimicrobial therapy decreases associated mortality, reduces the duration of anorexia and malabsorption and hastens elimination of Shigella from the stool. It is recommended that absorbable, Antimicrobial Therapy in Acute Gastroenteritis 193 systemically effective antimicrobials agents should be used as Shigella invades the intestinal mucosa and multiplies within the submucosa. The choice of antimicrobial should, if possible, be based on recent susceptibility data from Shigella strains isolated in the area. If information on local strains is not available, data from nearby areas or from recent regional epidemics should be used. Effective antimicrobial therapy should produce improvement within 48 hours by decreasing the blood in stools, the frequency of stools and fever. If no improvement is seen then antimicrobial resistance should be suspected.

Choice of Antimicrobials In recent years, strains of Shigella resistant to several antimicrobials like ampicillin, co- trimoxazole have emerged and these are no longer recommended for treatment of infection.24-33 Nalidixic acid has been the drug of choice for the last several years but over the last decade nalidixic acid resistant Shigella dysenteriae type 1 has been reported from several regions of South and Middle-east Asia, Eastern and Southern Africa.29-39 In addition there has been a recent outbreak of nalidixic acid resistant Shigella sonnei from Israel.32,40 Widespread use of nalidixic acid may reduce the efficacy of ciprofloxacin as nalidixic-acid resistant Shigella strains are reported to show some degree of cross- resistance to ciprofloxacin. Further the cost of treatment with nalidixic acid is about three times that of ciprofloxacin. Based on evidence from randomized controlled trials, WHO recommends ciprofloxacin, as the drug of choice for all patients with bloody diarrhea, irrespective of age (Table 2).41,42 Single dose of norfloxacin in adults has also found to be effective.44 Norfloxacin (20 mg/kg/day × 5 days) has been found to significantly reduce the duration of diarrhea and presence of blood in stools in children when compared to nalidixic acid. No joint problem was encountered in this study at up to 4 months follow-up.45 Ofloxacin (total dose 15 mg/kg/day) has been compared to nalidixic acid (55 mg/kg/day × 5 days) in a RCT and shows significantly lesser proportion of treatment failures.46 However, now fluoroquinolone-resistant Sd1 infection have been reported.47,48

TABLE 2 Antimicrobials for treatment of bloody diarrhea Antimicrobial Dose Duration First Line Ciprofloxacin 15 mg/kg twice a day 3 days

Second line 1. Ceftriaxone 50–100 mg/kg once a day intra muscular 2–5 days 2. Azithromycin 6–20 mg/kg/1–1.5 g once a day orally 1–5 days 3. 20 mg/kg four times a day 5 days 4. Cefixime 8 mg/kg/day 5 days 194 Rational Antimicrobial Practice in Pediatrics

Alternative Therapy Newer quinolones, pivmecillinam, ceftriaxone and azithromycin are currently the alternative antimicrobials that are usually effective for treatment of multi-resistant strains of Shigella in all age groups (see Table 2).41,42,46,49-52 Higher cost and no pediatric formulation for pivmecillinam, injectable doses of ceftriaxone, limited efficacy data on ceftriaxone and azithromycin and rapid development of resistance with azithromycin limit their widespread use.53,55 Randomized clinical trials conducted comparing cefixime (8 mg/kg/day) with a placebo,54-56 ampicillin-sulbactum or trimethoprim-sulphamethoxazole in the treatment of shigellosis have shown significantly higher clinical and bacteriological cure rates. It is recommended that these second line drugs used only when local strains of Shigellaare known to be resistant to ciprofloxacin. Antimicrobials that are not effective against Shigella and should not be used to treat patients with bloody diarrhea are listed in Table 3. Other uncommon causes of bloody diarrhea are Campylobacter jejuni, Schistosoma, Salmonella, enteroinvasive and entero-haemorrhagic E. coli. All these pathogens require special laboratory procedures for isolation. Infection with Campylobacter jejuni responds to early treatment with an effective antimicrobial, e.g. erythromycin, but most episodes recover by the time the laboratory diagnosis is made. Antimicrobial therapy in Salmonella infection may prolong the carriage of the pathogen.

TABLE 3 Antimicrobials not effective against Shigella • Ampicillin, chloramphenicol, cotrimoxazole, tetracycline • Nitrofurans, aminoglycosides, first- and second-generation cephalosporins, amoxycillin • Nalidixic acid

Algorithm for Treatment of Bloody Diarrhea If sensitivity patterns are not available treatment should be started with oral ciprofloxacin (15 mg/kg given two times a day for a total period of three days). The patient should be called back after 2 days to look for signs of improvement which are: • Disappearance of fever • Less blood in stool • Passage of fewer stools • Improved appetite • Decreased abdominal pain • Return to normal activity It is important to note that diarrhea takes 2–3 days to cease after disappearance of blood. If there is minimal or no improvement after 2 days, resistance to the initial antimicrobial is assumed and it should be stopped. A second antimicrobial, for example, Antimicrobial Therapy in Acute Gastroenteritis 195 ceftriaxone at the dose of 50–100 mg/kg once (intra-muscular) or twice (intravenously) a day or cefixime (8 mg/kg/day 12 hourly) should be given for 2 to 5 days.

High-Risk Cases of Dysentery Risk factors for death are greatest among infants, non-breastfed, dehydrated or malnourished children. History of convulsions or measles and presence of unconsciousness, hypo or hyperthermia at first contact are indicators of severe illness and these children are at greater risk of dying. Such children should be referred to the hospital for treatment. Those with severe malnutrition should be additionally screened and treated for associated sepsis.

When to Consider Amoebic Dysentery? Young children should not be routinely treated for amoebiasis, as it is an infrequent cause of bloody diarrhea in children. The incidence of disease with Entamoeba histolytica increases with age and most episodes are in adults. Amoebiasis should be considered only if two different antibiotics usually effective for Shigella in the area have been given sequentially without showing signs of clinical improvement, or if a microscopic examination of fresh stool done in a reliable laboratory shows trophozoites of E. histolytica containing RBC. Amoebic dysentery should be treated with metronidazole given at 10 mg/kg/dose three times a day for 5–10 days. Presence of cysts of Entamoeba histolytica is not an indication for treatment as usually these are non pathogenic E. dispar cysts.

Supportive Care Supportive care is very essential while treating dysentery. This includes treating dehydration, associated fever, other systemic infections (such as pneumonia or urinary tract infection), convulsions, metabolic complications, and rectal prolapse. Adequate calorie dense feeding should be continued. WHO and Indian Academy of Pediatrics recommend daily dose of 20 mg of elemental zinc (as zinc sulfate, or zinc acetate or zinc gluconate) once daily for 10 to 14 days (10 mg per day for infants below six months) in children up to five years of age.2 Drugs for symptomatic relief, abdominal and rectal pain should not be used, as they can increase severity of illness.

 GIARDIASIS Treatment for Giardia is definitely indicated if Giardia trophozoites are identified in stool or duodenal fluid. Giardiasis is treated with 5 mg/kg/dose of metronidazole given three times a day for five days.1 Tinidazole can also be given as a single dose (50 mg/ kg orally; up to a maximum of two doses). The adverse effects and treatment failures to these drugs have given rise to the need for alternative anti-giardial agents. There is some evidence to suggest that albendazole and mebendazole are equally effective and better tolerated than metronidazole.58-62 There is recent preliminary evidence from a randomized controlled trial in Egypt that nitazoxanide (nitrothiazolyl-salicylamide derivative, 196 Rational Antimicrobial Practice in Pediatrics dose 12–47 months 100mg 12 hourly x 3 days; 4–11 years 200mg 12 hourly x 3 days) was significantly better in achieving earlier recovery from diarrhea as compared to a placebo.57 However, there was no clinical difference when 110 children were randomly treated with nitazoxanide or metronidazole.58 There is presently limited evidence from randomized controlled trials to recommend routine treatment with nitazoxanide for giardiasis. Additionally the cost of treatment with nitazoxanide is almost seven times higher than that with metronidazole.

 INFECTION WITH UNUSUAL PATHOGENS Cryptosporidium Cryptosporidium parvum is an intracellular protozoa causing watery, non-bloody diarrhea often accompanied with fever, vomiting and anorexia. In children with normal immune function the disease is self-limiting with a mean duration of diarrhea of 10 days. Chronic high volume diarrhea leading to malnutrition, extra intestinal manifestations and sometimes death are features of immunocompromised children with cryptosporidiosis. Supportive therapy is the mainstay of treatment of cryptosporidium infection in immuno- competent children. Nitazoxanide is presently the only FDA approved treatment available for children 1 to 11 years of age with normal immune function. The role of nitazoxanide in treating cryptosporidiosis in immunocompromised children is not clear.64,66 Parmomycin has shown to have potential benefits in immunocompromised individuals but needs further evaluation.67-69

Clostridium Difficile Colitis Infection with C. difficile (due to Toxin A and B) though uncommon may be considered in children on prolonged antimicrobial therapy and hospitalization. Clinical symptoms range from mild to severe consisting of bloody diarrhea, abdominal cramps and fever. While use of nearly any antibiotic may result in C. difficile toxin production, -lactam antibiotics (e.g. cephalosporins and penicillins) and clindamycin are most commonly implicated. Clinical data obtained mostly from adults shows that almost 25% of the patients respond favorably to discontinuation of the offending antibiotics. Specific antimicrobials may be indicated for those with moderate to severe disease or with when the initial symptoms persist even after the offending antibiotic has been discontinued. Metronidazole and vancomycin have shown more than 90% efficacy rates in controlled trials70 in adults. Treatment should be initiated with metronidazole (orally or intravenously) and vancomycin (orally) should be reserved for second line therapy to prevent or minimize development of vancomycin resistant bacterial pathogens (i.e. Enterococcus and Staphylococcus aureus). Relapses of infection are seen in up to 33% and should be treated as initial therapy, with metronidazole as the preferred drug.

Associated Non-gastrointestinal Infection, e.g. Pneumonia, Septicemia, Meningitis, Urinary Tract Infection All children, particularly infants less than 3 months of age or those severely malnourished, Antimicrobial Therapy in Acute Gastroenteritis 197 should be carefully screened for non-gastrointestinal infection, e.g. pneumonia, septicemia, meningitis, urinary tract infection. Early detection and appropriate treatment of associated systemic infection in malnourished children can reduce the mortality significantly.

 OTHER DRUGS FOR DIARRHEA Antidiarrheal Agents Agents like adsorbents (kaolin, pectin, activated charcoal, bismuth subcarbonate), motility suppressants (opiates, opiate-like compound tincture of opium, camphorated tincture of opium or paregoric, codeine, diphenoxylate with atropine, loperamide hydrochloride) are not indicated in the routine treatment of acute diarrhea Motility suppressants decrease intestinal peristalsis and delay the elimination of the causative organisms. Their use in infants can be particularly dangerous causing paralytic ileus, respiratory depression, abdominal distension, bacterial overgrowth and sepsis. The anti secretory properties of the new synthetic enkephalinase inhibitor, Racecadotril, are attributed to inactivation of endogenous enkephalins, secreted by myenteric and submucus plexus in the digestive tract.71,72,74 This compound differs from -opiate receptor agonists like loperamide and diphenoxylate because its anti-secretory mechanisms are independent of effects on intestinal motility.73,74 This drug has been evaluated in a small number of children and adults with diarrhea in randomized controlled trials with varying results.75-77 The benefit of this drug for treatment of acute diarrhea has not been documented to an extent and in a manner that is required minimally to recommend its use. We need more evidence of its efficacy and safety from well-designed randomized controlled studies done in our settings.78

Combination Therapy Several combinations of antibacterial agents and of antibacterials with antidiarrheals are available. They offer no extra clinical benefit as compared to a properly selected single antibacterial agent for the small proportion of diarrheal illness where indication for their use exists. Combination therapy can promote overgrowth of harmful resistant bacteria and the antimotility agents that are often a part of these combinations may delay excretion of invasive pathogens. Some drug combinations containing metronidazole group of drugs can induce further vomiting.

Probiotics There is currently insufficient evidence to recommend probiotics in the treatment of acute diarrhea in our settings as almost all studies reported till now are from developed countries.2 It may not be possible to extrapolate the findings of these studies to our setting where the breast feeding rates are high and the microbial colonization of the gut is different. The earlier studies have documented a beneficial effect on rotavirus diarrhea, which was present in more than 75% of cases in studies from the west while it constitutes about 25% of diarrhea in hospitalized children and 15% in outpatient practice in India. 198 Rational Antimicrobial Practice in Pediatrics

The more objective parameter of stool output has not been evaluated. Because the efficacy of probiotics is dependent on the formulation and the host factors it is rational to invest in randomized controlled trials to gather evidence of benefit before they are recommended for routine use in diarrhea.

CONCLUSIONS In conclusion ORS remains the mainstay of therapy during acute diarrhea and zinc as an adjunct as an additional modest benefit in the reducing the stool volume and duration of diarrhea. Antimicrobials should be restricted to children with bloody diarrhea, cholera with severe dehydration, for associated non-gastrointestinal infections especially malnourished children or infants less than 3 months and for definitely proven amoebiasis and giardiasis.

 REFERENCES 1. The treatment of diarrhea. A manual for physicians and other senior health workers. 2005 WHO/CDD/ SER/80.2 2. Bhatnagar S, Bhandari N, Mouli UC, Bhan MK. Consensus Statement of IAP National Task Force: Status Report on Management of Acute Diarrhea. Indian Pediatr. 2004;41:335-48. 3. Reduced osmolarity oral rehydration salts (ORS) formulation. A report from a meeting of experts jointly organized by UNICEF and WHO. UNICEF HOUSE, New York, USA, 18 July 2001. WHO/FCH/ CAH/0.1.22. 4. Hahn SK, Kim YJ, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration due to diarrhea in children: systematic review. BMJ. 2001;323:81-5. 5. Fontaine O. Effect of zinc supplementation on clinical course of acute diarrhea. J Health Popul Nutr 2001;19:339-46. 6. Zinc Investigators Collaborative Group. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries; pooled analysis of randomized controlled trials. Am J Clin Nutr. 2000;72:1516-22. 7. Bhatnagar S, Bahl R, Sharma PK, Kumar GK, Saxena SK, Bhan MK. Zinc treatment with oral rehydration therapy reduces stool output and duration of diarrhea in hospitalized children; a randomized controlled trial. J Pediatr Gastroenterol Nutr. 2004;38:34-40. 8. Bahl R, Bhandari N, Saksena M, Strand T, Kumar GT, Bhan MK, et al. Efficacy of zinc fortified oral rehydration solution in 6-35 month old children with acute diarrhea. J Pediatr. 2002;141:677-82. 9. Baqui AH, Black RE, El Arifeen S, Yunus M, Chakraborty J, Ahmed S, et al. Effect of zinc supplementation started during diarrhea on morbidity and mortality in Bangladeshi children: community randomized trial. BMJ. 2002;325:1059. 10. Effect of zinc supplementation on clinical course of acute diarrhea. Report of a Meeting, New Delhi, 7- 8 May 2001. J Health Popul Nutr. 2001;19:338-46. 11. Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev. 2008;3:CD005436. 12. Lukacik M, Thomas RL, Aranda JV. A meta-analysis of the effects of oral zinc in the treatment of acute and persistent diarrhea. Pediatrics. 2008;121:326-36. 13. Alam AN, Alam NH, Ahmed T, Sack DA. Randomized double blind trial of single dose doxycyline for treating cholera in adults. BMJ. 1990;300:1619-21. 14. Usbutun S, Agalar C, Diri C, Turkyilmaz R. Single dose ciprofloxacin in cholera. Eur J Emerg Med. 1997;4:145-9. 15. Khan WA, Bennish ML, Seas C, Khan EH, Ronan A, Dhar U, et al. Randomized controlled comparison of single-dose ciprofloxacin and doxycycline for cholera caused by Vibrio cholerae 01 or 0139. Lancet. 1996;348:296-300. Antimicrobial Therapy in Acute Gastroenteritis 199

16. Gotuzzo E, Seas C, Echevarria J, Carrillo C, Mostorino R, Ruiz R. Ciprofloxacin for the treatment of cholera: a randomized, double-blind, controlled clinical trial of a single daily dose in Peruvian adults. Clin Infect Dis. 1995;20:1485-90. 17. Dutta D, Bhattacharya SK, Bhattacharya MK, Deb A, Deb M, Manna B, et al. Efficacy of norfloxacin and doxycycline for treatment of vibrio cholerae 0139 infection. J Antimicrob Chemother. 1996;37:575-81. 18. Moolasart P, Eampokalap B, Supaswadikul S. Comparison of the efficacy of tetracycline and norfloxacin in the treatment of acute severe diarrhea. Southeast Asian J Trop Med Public Health. 1998;29: 108-11. 19. Schaad UB, abdusSalam M, Aujard Y, Dagan R, Green SD, Peltola H, et al. Use of fluoroquinolones in pediatrics: consensus report of an International Society of Chemotherapy commission. Pediatr Infect Dis J. 1995;14:1-9. 20. Pradhan KM, Arora NK, Jena A, Susheela AK, Bhan MK. Safety of ciprofloxacin therapy in children: magnetic resonance images, body fluid levels of fluoride and linear growth. Acta Paediatr. 1995;84: 555-60. 21. Bethell DB, Hien TT, Phi LT, Day NP, Vinh H, Duong NM, et al. Effects on growth of single short courses of fluoroquinolones. Arch Dis Child. 1996;74:44-6. 22. Doherty CP, Saha SK, Cutting WA. Typhoid fever, ciprofloxacin and growth in young children. Ann Trop Paediatr. 2000;20:297-303. 23. Gendrel D, Chalumeau M, Moulin F, Raymond J. Fluoroquinolones in paediatrics: a risk for the patient or for the community? Lancet Infect Dis. 2003;3:537-46. 24. Ahmed K, Shakoori FR, Shakoori AR. Aetiology of shigellosis in northern Pakistan. J Health Popul Nutr. 2003;21:32-9. 25. Dutta S, Rajendran K, Roy S, Chatterjee A, Dutta P, Nair GB, et al. Shifting serotypes, plasmid profile analysis and antimicrobial resistance pattern of Shigellae strains isolated from Kolkata, India during 1995-2000. Epidemiol Infect. 2002;129:235-43. 26. Anh NT, Cam PD, Dalsgaard A. Antimicrobial resistance of Shigellaspp isolated from diarrheal patients between 1989 and 1998 in Vietnam. Southeast Asian J Trop Med Public Health. 2001;32:856-62. 27. Iwalokun BA, Gbenle GO, Smith SI, Ogunledun A, Akinsinde KA, Omonigbehin EA. Epidemiology of shigellosis in Lagos, Nigeria: trends in antimicrobial resistance. J Health Popul Nutr. 2001;19:183-90. 28. Mache A. Antibiotic resistance and sero-groups of Shigella among paediatric outpatients in southwest Ethiopia. East Afr Med J. 2001;78:296-9. 29. Lee JC, Oh JY, Kim KS, Jeong YW, Cho JW, Park JC, et al. Antimicrobial resistance of Shigellasonnei in Korea during the last two decades. APMIS 2001;109:228-34. 30. Aysev AD, Guriz H. Drug resistance of Shigella strains isolated in Ankara, Turkey, 1993-1996. Scand J Infect Dis. 1998;30:351-3. 31. Legros D, Ochola D, Lwanga N, Guma G. Antibiotic sensitivity of endemic Shigella in Mbarara, Uganda. East Afr Med J. 1998;75:160-1. 32. Ashkenazi S, May-Zahav M, Sulkes J, Zilberberg R, Samra Z. Increasing antimicrobial resistance of Shigella isolates in Israel during the period 1984 to 1992. Antimicrob Agents Chemother. 1995;39: 819-23. 33. Bennish ML, Salam MA, Hossain MA, Myaux J, Khan EH, Chakraborty J, et al. Antimicrobial resistance of Shigella isolates in Bangladesh, 1983-1990: increasing frequency of strains multiply resistant to ampicillin, trimethoprim-sulfamethoxazole, and nalidixic acid. Clin Infect Dis. 1992;14:1055-60. 34. Panhotra BR, Saxena AK, Al-Mulhim K. Emergence of nalidixic acid resistance in Shigellasonnei isolated from patients having acute diarrheal disease: report from eastern province of Saudi Arabia. Jpn J Infect Dis. 2004;57:116-8. 35. Ghosh AR, Sugunan AP, Sehgal SC, Bharadwaj AP. Emergence of nalidixic acid-resistant Shigellasonneiin acute-diarrhea patients on Andaman and Nicobar Islands, India. Antimicrob Agents Chemother. 2003;47:1483. 36. Jesudason MV. Shigella isolation in Vellore, south India (1997-2001). Indian J Med Res. 2002;115: 11-3. 37. Hoge CW, Bodhidatta L, Tungtaem C, Echeverria P. Emergence of nalidixic acid resistant Shigelladysenteriae type 1 in Thailand: an outbreak associated with consumption of a coconut milk dessert. Int J Epidemiol. 1995; 24:1228-32. 200 Rational Antimicrobial Practice in Pediatrics

38. Ashraf MM, Ahmed ZU, Sack DA. Unusual association of a plasmid with nalidixic acid resistance in an epidemic strain of Shigelladysenteriae type 1 from Asia. Can J Microbiol. 1991;37:59-63. 39. Datta P, Sen D. Outbreak of dysentery due to nalidixic acid resistant S. dysenteriae 1 at Agartala, Tripura: a hospital based study. Indian J Public Health. 1990;34:11. 40. Dagan D, Orr N, Yavzori M, Yuhas Y, Meron D, Ashkenazi S, et al. Retrospective analysis of the first clonal outbreak of nalidixic acid-resistant Shigellasonnei shigellosis in Israel. Eur J Clin Microbiol Infect Dis. 2002;21:887-9. 41. Leibovitz E, Janco J, Piglansky L, Press J, Yagupsky P, Reinhart H et al. Oral ciprofloxacin vs. intramuscular ceftriaxone as empiric treatment of acute invasive diarrhea in children. Pediatr Infect Dis J. 2000;19:1060-7. 42. Pocket book of Hospital Care for Children. Guidelines for the management of common illnesses with limited resources. WHO 2005. 43. Zimbabwe, Bangladesh, South Africa (Zimbasa) Dysentery Study Group. Multicenter, randomized, double blind clinical trial of short course versus standard course oral ciprofloxacin for Shigelladysenteriae type 1 dysentery in children. Pediatr Infect Dis J. 2002 Dec;21:1136-41. 44. Gotuzzo E, Oberhelman RA, Maguina C, Berry SJ, Yi A, Guzman M, et al. Comparison of single dose treatment with norfloxacin and standard 5-days treatment with trimethoprim sulfamethoxazole for acute shigellosis in adults. Antimicrob Agents Chemother. 1989;33:1101-4. 45. Bhattacharya K, Bhattacharya MK, Dutta D, Dutta S, Deb M, Deb A, et al. Double-blind, randomized clinical trial for safety and efficacy of norfloxacin for shigellosis in children. Acta Paediatr. 1997; 86:319-20. 46. Vinh H, Wain J, Chinh MT, Tam CT, Trang PT, Nga D, et al. Treatment of bacillary dysentery in Vietnamese children: two doses of ofloxacin versus 5-days nalidixic acid. Trans R Soc Trop Med Hyg. 2000;94:323-6. 47. Bhattacharya SK, Sur D. An Evaluation of current shigellosis treatment. Expert Opin Pharmacother. 2003;4:1315-20. 48. Pazhani GP, Sarkar B, Ramamurthy T, Bhattacharya SK, Takeda Y, Niyogi SK. Clonal Multidrug- Resistnt Shigelladysenteriae Type 1 Strains Associated with Epidemic and Sporadic Dysenteries in Eastern India. Antimicrobial Agents Chemo. 2004;48:681-4. 49. Alam AN, Islam MR, Hossain MS, Mahalanabis D, Hye HK. Comparison of pivmecillinam and nalidixic acid in the treatment of acute shigellosis in children. Scand J Gastroenterol. 1994;29:313-7. 50. Varsano I, Eidlitz-Marcus T, Nussinovitch M, Elian I. Comparative efficacy of ceftriaxone and ampicillin for treatment of severe shigellosis in children. J Pediatr. 1991;119:841. 51. Kabir I, Butler T, Khanam A. Comparative efficacies of single intravenous doses of ceftriaxone and ampicillin for shigellosis in a placebo-controlled trial. Antimicrob Agents Chemother. 1986;29:645-8. 52. Basualdo W, Arbo A. Randomized comparison of azithromycin versus cefixime for treatment of shigellosis in children. Pediatr infect Dis J. 2003;22:374-7. 53. Khan WA, Seas C, Dhar U, Salam MA, Bennish ML Ann. Treatment of shigellosis: Comparison of azithromycin and ciprofloxacin. A double blind, randomized, controlled trial. Intern Med. 1997;126:697- 703. 54. Martin JM, Pitetti R, Maffei F, Tritt J, Smail K, Wald ER. Treatment of shigellosis with cefixime: two days vs. five days. Pediatr Infect Dis J. 2000;19:522-6. 55. Helvaci M, Bektaslar D, Ozkaya B, Yaprak I, Umurtak B, Ertugrul A. Comparative efficacy of cefixime and ampicillin-sulbactam in shigellosis in children. Acta Paediatr Jpn. 1998;40:131-4. 56. Ashkenazi S, Amir J, Waisman Y, Rachmel A, Garty BZ, Samra Z, et al. A randomized, double-blind study comparing cefixime and trimethoprim-sulfamethoxazole in the treatment of childhood shigellosis. J Pediatr. 1993;123:817-21. 57. Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Giardia intestinalis and Entamoebahistolytica or E. dispar: a randomized, double blind, placebo-controlled study of nitazoxanide. J Infect Dis. 2001;184:381-4. 58. Ortiz JJ, Ayoub A, Gargala G, Chegne NL, Favennec L. Randomized clinical study of nitazoxanide compared to metronidazole in the treatment of symptomatic giardiasis in children from Northern Peru. Aliment Pharmacol Ther. 2001;15:1409-15. Antimicrobial Therapy in Acute Gastroenteritis 201

59. Yereli K, Balcioglu IC, Ertan P, Limoncu E, Onag A. Albendazole as an alternative therapeutic agent for childhood giardiasis in Turkey. Clin Microbiol Infect. 2004;10:527-9. 60. Sadjjadi SM, Alborzi AW, Mostovfi H. Comparative clinical trial of mebendazole and metronidazole in giardiasis of children. J Trop Pediatr. 2001;47:176-8. 61. Pengsaa K, Sirivichayakul C, Pojjaroen-anant C, Nimnual S, Wisetsing P. Albendazole treatment for Giardia intestinalis infections in school children. Southeast Asian J Trop Med Public Health. 1999;30: 78-83. 62. Misra PK, Kumar A, Agarwal V, Jagota SC. A comparative clinical trial of albendazole versus metronidazole in children with giardiasis. Indian Pediatr. 1995;32:779-82. 63. Dutta AK, Phadke MA, Bagade AC, Joshi V, Gazder A, Biswas TK, et al. A randomized multicentre study to compare the safety and efficacy of albendazole and metronidazole in the treatment of giardiasis in children. Indian J Pediatr. 1994;61:689-93. 64. Amadi B, Mwiya M, Musuku J, Watuka A, Sianongo S, Ayoub A, et al. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial. Lancet. 2002;360:1375-80. 65. Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double blind, placebo-controlled study of nitazoxanide. J Infect Dis. 2001;184:103-10. 66. Rossignol JF, Hidalgo H, Feregrino M, Higuera F, Gomez WH, Romero JL, et al. A double-’blind’ placebo-controlled study of nitazoxanide in the treatment of cryptosporidialdiarrhoea in AIDS patients in Mexico. Trans R Soc Trop Med Hyg. 1998;92:663-6. 67. White AC Jr, Chappell CL, Hayat CS, Kimball KT, Flanigan TP, Goodgame RW. for cryptosporidiosis in AIDS: a prospective, double blind trial. J Infect Dis. 1994;170:419-24. 68. Hewitt RG, Yiannoutsos CT, Higgs ES, Carey JT, Geiseler PJ, Soave R, et al. Paromomycin: no more effective than placebo for treatment of cryptosporidiosis in patients with advanced human immunodeficiency virus infection. Clin Infect Dis. 2000;31:1084-92. 69. Kosek M, Alcantara C, Lima AA, Guerrant RL. Cryptosporidiosis:an update. Lancet Infect Dis. 2001;1:262-9. 70. Wenisch C, Parschalk B, Hasenhundl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. 1996;22:813-8. 71. Farthing MJ. Introduction. Enkephalinase inhibition: a rational approach to antisecretory therapy for acute diarrhea. Aliment Pharmacol Ther. 1999;13(Suppl 6):1-2. 72. Marcais-Collado H, Uchida G, Costentin J, Schwartz JC, Lecomte JM. Naloxone-reversible antidiarrheal effects of enkephalinase inhibitors. Eur J Pharmacol. 1987;144:125-32. 73. Turck D, Berard H, Fretault N, Lecomte JM. Comparison of racecadotril and loperamide in children with acute diarrhoea. Aliment Pharmacol Ther. 1999;13(Suppl 6):27-32. 74. Prado D; Global Adult Racecadotril Study Group. A multinational comparison of racecadotril and loperamide in the treatment of acute watery diarrhea in adults. Scand J Gastroenterol. 2002;37: 656-61. 75. Alam NH, Ashraf H, Khan WA, Karim MM, Fuchs GJ. Efficacy and tolerability of racecadotril in the treatment of cholera in adults: a double blind randomized controlled clinical trial. Gut. 2003;52:1419- 23. 76. Cezard JP, Duhamel JF, Meyer M, Pharaon I, Bellaiche M, Maurage C, et al. Efficacy and tolerability of racecadotril in acute diarrhea in children. Gastroenterology. 2001;120:799-805. 77. Hamza H, Ben Khalifa H, Baumer P, Berard H, Lecomte JM. Racecadotril versus placebo in the treatment of acute diarrhea in adults. Aliment Pharmacol Ther. 1999;(13 Suppl 6):15-9. 78. Bhan MK, Bhatnagar S. Racecadotril–Is there enough evidence to recommend it for treatment of acute diarrhea? Indian Pediatr. 2004;41:1203-4. 202 Rational Antimicrobial Practice in Pediatrics 1717 Antimicrobial Therapy in Upper Respiratory Tract Infections Saheli Misra, Ritabrata Kundu, Nupur Ganguli

 INTRODUCTION Upper respiratory tract infections are the most common illnesses affecting children. The upper respiratory tract infection can broadly be classified into: • Rhinosinusitis • Pharyngitis • Otitis media • Croup/Epiglottitis They can be caused both by virus and bacteria. The main bacterial etiologic agents of upper respiratory tract infections in children are S. pneumoniae, H. influenzae and M. catarrhalis. Increasing resistance to antimicrobials is a growing concern both nationally and globally. Inappropriate use of antibiotics for upper respiratory tract infections (URTIs), many of which are viral, adds to the burden of antibiotic resistance. Antibiotic resistance is increasing in Streptococcus pneumoniae, responsible for most cases of acute otitis media (AOM) and acute bacterial sinusitis (ABS).

Antimicrobial Resistance in Pathogens Causing URTI Streptococcus pneumoniae develops resistance to (e.g. amoxicillin) by altering the penicillin binding proteins. These proteins serve as a docking port for the drug and if altered, help the bacterium to avoid interaction with the drug. This mechanism of resistance can be overcome if the drug bacterial interaction is overwhelmed: then the drug is able to penetrate. This is the basis of high dose aminopenicillin for treatment of suspected drug resistant S. pneumoniae. Recent use of beta lactam antibiotics (within 3 months), extremes of age (< 2 years and >65 years) and day care center attendance are risk factors for drug resistant S. pneumoniae (DRSP). Though in the western countries about 25% to 50% of Streptococcus pneumoniae are penicillin resistant, most Indian isolates are still sensitive to penicillin.1 Antimicrobial Therapy in Upper Respiratory Tract Infection 203

With H. influenzae and M. catarrhalis there is alternate mechanism of resistance to aminopenicillin. They produce  lactamase, which directly degrades the  lactam ring of aminopenicillin. Here increasing the dose will be of no help but adding lactamase inhibitor like clavulanate can overcome the resistance. Alternatively using a  lactamase stable antibiotic like cefuroxime/cefpodoxime will be able to kill these organisms. A significant proportion of H. influenzae (25–30%) and most Moraxella isolates (95%) are beta lactamase producing and resistant to amoxicillin.2

 RHINOSINUSITIS Rhinosinusitis is an URTI that predominantly affects the nasal part of the respiratory mucosa. Common cold infections are caused mainly by viruses are self limiting and last for a short duration. Most children have 3 to 8 colds per year. Such an URTI is the trigger for acute sinusitis; 0.5–5% of common colds become complicated by development of acute sinusitis.3 Acute sinusitis is defined pathologically by transient inflammation of the mucosal lining of the paranasal sinuses lasting less than 30 days. It can be both viral or bacterial in origin. The viral infections are self limiting. The diagnosis of bacterial sinusitis is made on clinical criteria: symptoms of nasal or postnasal discharge, daytime cough that lasts more than 10 but fewer than 30 days; a temperature of at least 102°F; and purulent nasal discharge present for at least three to four consecutive days. Mere presence of purulent nasal discharge in the first few days of an URTI can occur with viral etiology and does not merit antibiotics. The principal bacterial pathogens implicated in bacterial sinusitis include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Early identification of bacterial sinusitis is beneficial to prevent the rare but life threatening complications such as meningitis, subdural empyema, cavernous sinus thrombosis and orbital cellulitis.4

Choice of Antibiotic In Disease of Mild to Moderate Severity Approximately 80 percent of children with acute bacterial sinusitis will respond to treatment with amoxicillin. Use of amoxicillin as first-line therapy in suspected cases of acute bacterial sinusitis is desirable because of its general effectiveness, safety, tolerability, low cost, and narrow spectrum. The usual starting dosage in children younger than two years with mild to moderate uncomplicated acute bacterial sinusitis is 45 mg per kg per day in two divided doses or a high dose of 90 mg per kg per day in two divided doses in patients with risk factors for drug resistant S. pneumoniae.5 It must be mentioned here that drug resistant S. pneumoniae is uncommon in India and with the revision of breakpoints by the Clinical Laboratory Standard Institute (CLSI) where the new susceptibility breakpoint of non meningeal isolates is 2 µg/mL unlike 0.06 earlier, the prevalence of resistant pneumococci has declined further. Hence the need to use high doses of amoxicillin is likely to be infrequent. 204 Rational Antimicrobial Practice in Pediatrics

For patients who are allergic to amoxicillin, • cefdinir (14 mg per kg per day in one or two doses) or • cefuroxime (30 mg per kg per day in two divided doses) or • cefpodoxime (10 mg per kg once daily) can be used (only if the allergic reaction was not a type 1 hypersensitivity reaction). In cases of serious allergic reactions, • clarithromycin (15 mg per kg per day in two divided doses) or • azithromycin (10 mg per kg per day on day 1, 5 mg per kg per day for four days as a single daily dose) Most patients who are appropriately treated will respond within 48 to 72 hours. If the patient does not improve, the antimicrobial is ineffective or the diagnosis of sinusitis is incorrect. In case of Severe Disease or Patients who do not Respond to Initial Therapy with Amoxicillin In this setting we need to cover for beta lactamase producing H. influenzae and Moraxella. The drug of choice is coamoxiclav dosed as 30–40 mg/kg of the amoxicillin component per day in 2-3 divided doses. If drug resistant Pneumococcus is suspected then plain amoxicillin @ 30–40 mg/kg/day may be added to coamoxiclav. Other oral options include cefuroxime, cefpodoxime or cefdinir. In patients who are acutely ill with vomiting or poor oral intake, ceftriaxone may be given @ 75 mg/kg/day.

Duration of Therapy A lot of controversy exist as there is no consistent evidence that a longer course of treatment (>7 days) is more effective than a shorter course. Adjuvant therapies such as saline nasal irrigation, antihistamines, and decongestants to supplement antimicrobial therapy have not been thoroughly investigated, and the American Academy of Pediatrics makes no recommendations for their use. Likewise, the use of antibiotic prophylaxis to prevent recurrent episodes of acute bacterial sinusitis has not been evaluated and no recommendations are made for its use.

 PHARYNGITIS Pharyngitis is an acute URTI that affects the respiratory mucosa of the throat resulting in a predominant symptom of pain that may be associated with headache, fever and general malaise. Clinically it is difficult to differentiate between viral and bacterial aetiology (Table 1). Viral pharyngitis is much more gradual in onset and usually fever is absent. Other findings of viral pharyngitis include conjunctivitis, cough, hoarseness, coryza, anterior uveitis, discrete ulcerative lesions, viral exanthema, diarrhea and often a history of a similarly sick contact in the family. Goup A  hemolytic streptococcal pharyngitis (GABHS) is the only commonly occurring form of bacterial pharyngitis for which antibiotic therapy is definitely indicated. In other words with the exception of very rare infection caused by other bacterial pathogens, e.g. Corynebacteriam diptheriae and Neisseria gonorheae, antibacterial therapy is of Antimicrobial Therapy in Upper Respiratory Tract Infection 205

TABLE 1 Causes of pharyngitis Virus Bacteria • Rhinovirus • Strep pyogenes 15–20% • Coronavirus • GpC/G strep • Adenovirus • N. gonorrhoea • HSV • Corynbacterium diphheriae • Parainfluenza • Arcanobacterium haemolyticum • Influenza • Mycoplasma • Coxasackievirus • C. pneumoniae • EBV • Yersinia enterocolitica no proven value for other acute pharyngitis. Most children who have pharyngitis improve spontaneously within 14 days. Streptococcal pharyngitis is uncommon before 2–3 years of age, primarily a disease of children between 5 and 15 years of age and spread by close contact. Studies have found that tonsillar or pharyngeal exudates, tender cervical lymphadenopathy and recent exposure to streptococcal throat infection are useful predictors of bacterial infection. The likelihood of bacterial pharyngitis is pesent in 50% children if 3 of the following features are present:3 • fever higher than 100°F; • tonsillar swelling or exudates • tender cervical lymphadenopathy • absence of cough

Diagnostic Dilemma: Clinical vs Laboratory The diagnosis of GABHS pharyngitis can be done by a throat culture or rapid antigen diagnostic test (RADT) for GABHS. The culture is the gold standard for diagnosis but requires time causing a delay in identification of GABHS. This delay often causes an overuse of antibiotics that provokes a rise in the drug-resistant bacterial strains. RADTs allow the identification of GABHS on a throat swab in a matter of minutes. American Academy of Pediatrics recommends laboratory confirmation of the presence of GABHS. The decision to obtain a throat swab specimen is based on clinical criteria (age >3 years, clinical signs and symptoms of pharyngitis, the season and the community epidemiology). Children with signs or symptoms suggesting viral infection like coryza, conjunctivitis, hoarseness, cough, stomatitis or diarrhea should not be tested.7 English experts state that, depending on clinical assessment of severity, patients presenting acute pharyngitis can be considered for an immediate antibiotic prescribing strategy. In case a RADT test is done as the primary investigation, we need to confirm negative RADT results with a throat culture as advised also by American Academy of Pediatrics.7 On the contrary, because of the high specificity, it is not necessary to confirm a positive RADT test.8 Unfortunately RADT is not available in most parts of our country so in most cases our decision is based on clinical criteria. 206 Rational Antimicrobial Practice in Pediatrics

Drug of Choice Penicillin is the drug of choice for GABHS with its narrow spectrum and few adverse effects. Although penicillin V is the drug of choice, ampicillin or amoxicillin are equally effective and, due to the good taste, represent a suitable option in children.7 Prompt administration of penicillin therapy shortens the clinical course, decreases the incidence of suppurative sequelae, the risk of transmission and prevents acute rheumatic fever even when given within 9 days after onset of illness. Recommendations for antimicrobial therapy for Group A streptococcal pharyngitis are shown in Table 2.7,9

TABLE 2 Therapeutic options for GABHS pharyngitis recommended by American Hearth Association and American Academy of Pediatrics AAP7,9 Drug Dose Duration Penicillins Penicillin V (oral) Children <27 kg: 400 000 U (250 mg) 10 days 2 to 3 times daily; Children >27 kg, adolescents, and adults: 800 000 (500 mg) 2 to 3 times daily Amoxicillin (oral) 30-50 mg/kg once daily (maximum 1 g) 10 days Benzathine Penicillin Children <27 kg: 600 000 U (375 mg); Once (intramuscular) Children >27 kg, adolescents, and adults: 1 200 000 U (750 mg) For individuals allergic to penicillin Narrow-spectrum According to preparation need 10 days cephalosporin (cephalexin, cefadroxil) (oral)* Clindamycin (oral) 20 mg/kg per day divided in 3 doses 10 days (maximum 1.8 g/d) Azithromycin (oral) 12 mg/kg once daily (maximum 500 mg) 5 days Clarithromycin (oral) 15 mg/kg per day divided BID 10 days (maximum 250 mg BID) * Patients with immediate or type I hypersensitivity to penicillin should not be treated with a cephalosporin4

Duration of Therapy The standard duration of antibiotic therapy is 10 days. Recurrent pharyngitis may represent a relapse or may result from new exposure.8 In case of relapse cephalosporins/coamoxiclav have been proposed to be more effective than penicillin.10 Antimicrobial Therapy in Upper Respiratory Tract Infection 207

 ACUTE OTITIS MEDIA Otitis media is an acute URTI that affects the respiratory mucosa of the middle ear cleft. In developed countries otitis media is the most common indication for antibiotic prescribing and surgery in young children. Otitis media is best regarded as a spectrum of disease. The most important conditions are: • Otitis media with effusion (OME)11—OME is a condition with presence of fluid in the middle ear for at least 8 weeks in the absence of signs and symptoms of acute infection. • Acute otitis media (AOM)12 is defined as the presence of middle ear effusion plus the presence of symptoms (pain) or sign (bulging of tympanic membrane or fresh discharge or acute inflammation). It can be with perforation (AOMwiP) or without perforation (AOM). • Chronic suppurative otitis media (CSOM)3 is defined as discharge through a perforated tympanic membrane for longer than 2 to 6 weeks. OME is the most common form of otitis media. It can occur spontaneously as a component of rhinosinusitis or following an episode of AOM. Most children experience at least one episode of AOM peaking between 6 and 12 months of age. Pathogenesis in OME and AOM is multifactorial, both bacterial and viral. Bacterial infection with common respiratory pathogens (S. pneumoniae, H. Influenzae and Moraxella catarrhalis) often preceded by viral illness. Viral aetiology is respiratory syncytial virus and influenza virus. The pain associated with AOM resolves within 24 hours in 60% cases and within 3 days in 80%. But AOM is less likely to resolve spontaneously in children younger than 2 years. Complications include CSOM, mastoiditis, labyrinthitis, facial palsy, meningitis, intracranial abscess and lateral sinus thrombosis. These complications have reduced with the use of antibiotics. Complications are uncommon with OME. A major challenge is to distinguish between AOM and OME as antimicrobial treatment for OME is usually not indicated.13 Purulent ear discharge of recent origin is most likely to be AOM, but the difficulty arises in AOM without perforation. To support the diagnosis of AOM in a child with middle ear effusion it should be accompanied by ear pain, fever, hearing loss and discharge. Establishment of diagnosis of AOM depends on symptomatic criteria or otoscopic criteria or both. Bulging opacity and immobility of the tympanic membrane in otoscopic finding are highly predictive of AOM.3

Indications for Antibiotics • Children less than 2 years with bilateral AOM. • Children older than two years with severe infection (defined as moderate to severe otalgia or temperature greater than 102.2°F). • Children who have AOM with perforation. • Children at high risk of complication (immunodeficiency, craniofacial abnormality like left palate). • Children who did not improve after 48 hours of watchful waiting. 208 Rational Antimicrobial Practice in Pediatrics

Antibiotics may be deferred in otherwise healthy with mild symptoms or in whom the diagnosis is uncertain.16 In such cases it is necessary to follow-up the child.

Drug of Choice (Table 3) Principles of therapy are same as for acute bacterial sinusitis with amoxicillin @ 30-40 mg/kg/day being the preferred drug for non severe disease and coamoxiclav being the drug of choice for severe disease. Single dose ceftriaxone @ 50 mg/kg may be used in children who are vomiting or where compliance is an issue.

Progress Persistent Acute Otitis Media If there is no clinical improvement within 48 to 72 hours, the patient must be reassessed to confirm the diagnosis, exclude other causes of illness, and initiate antibiotic therapy in those on symptomatic treatment alone. Patients who are already taking antibiotics should be changed to second-line therapy.12 Options include high-dose amoxicillin/ clavulanate, cephalosporins, and macrolides. Parenteral ceftriaxone administered daily over three days is useful in children with emesis or resistance to amoxicillin/clavulanate. For children who do not respond to second-line antibiotics, clindamycin and tympanocentesis are appropriate options. Although it is not approved for use in children, levofloxacin is effective in children who have persistent or recurrent acute otitis media.15

Recurrent Acute Otitis Media Most children with recurrent acute otitis media improve with watchful waiting. Although antibiotic prophylaxis may reduce recurrence, there are no widely accepted recommendations for antibiotic choice or prophylaxis duration.16

Duration of Treatment The optimal duration of treatment of AOM is uncertain. There are 2 schools of thought. One advocates treatment for ten days and the other for 1 to 7 days. Studies comparing these 2 durations of treatment are inconclusive.12 For younger children and for children with severe disease standard treatment for 10 days is recommended.17 For children 6 years or older with mild to moderate disease a 5 to 7 days course is appropriate.

 CROUP/EPIGLOTTITIS Croup is a common clinical illness in preschool children. The incidence peaks in the second year of life. Viral agents are the principal factors responsible for laryngotrcheobronchitis. Of these parainfluenza virus heads the list, followed by influenza A and B, respiratory syncytial virus (RSV), adenovirus and measles. Croup can be due to involvement of the structures surrounding the vocal cord. When it involves structures above the cord, i.e. epiglottis then the condition is known as acute epiglotitis. Involvement of the vocal cord and structures below it is termed laryngitis, laryngotracheitis or laryngotracheobronchitis depending upon the extent of inflammation. Antimicrobial Therapy in Upper Respiratory Tract Infection 209

TABLE 3 Antibiotics used in acute otitis media and their doses16 Drugs Dosage Comments Amoxicillin 40–50 mg/kg/day, given First-line drug. Safe, effective, orally in two divided doses and inexpensive Amoxicillin/clavulanate 40 mg of amoxicillin Second-line drug. For patients with per kg per day; 6.4 mg of recurrent or persistent acute otitis clavulanate per kg per day, media, those taking prophylactic given orally in two divided amoxicillin, those who have used doses antibiotics within the previous month, and those with concurrent purulent conjunctivitis Azithromycin (one dose) 30 mg per kg, given orally For patients with penicillin allergy. One dose is as effective as longer courses Azithromycin 20 mg per kg once daily, For patients with recurrent acute (three-day course) given orally otitis media Azithromycin 5–10 mg per kg once For patients with penicillin allergy (five-day course) daily, given orally (type 1 hypersensitivity) Cefdinir 14 mg per kg per day, For patients with penicillin allergy, given orally in one or excluding those with urticaria or two doses anaphylaxis to penicillin (i.e. type 1 hypersensitivity) Cefpodoxime 30 mg per kg once daily, For patients with penicillin allergy, given orally excluding those with urticaria or anaphylaxis to penicillin (i.e. type 1 hypersensitivity) Ceftriaxone 50 mg per kg once daily, For patients with penicillin allergy, given intramuscularly or persistent or recurrent acute otitis intravenously. One dose media, or vomiting for initial episode of otitis media, three doses for recurrent infections Cefuroxime 30 mg per kg per day, For patients with penicillin allergy, given orally in two divided excluding those with urticaria or doses anaphylaxis to penicillin (i.e. type 1 hypersensitivity) Clarithromycin 15 mg per kg per day, For patients with penicillin allergy given orally in three (type 1 hypersensitivity). May divided doses cause gastrointestinal irritation Clindamycin 30–40 mg per kg For patients with penicillin allergy per day, given orally in (type 1 hypersensitivity) four divided doses 210 Rational Antimicrobial Practice in Pediatrics

Presentations include a barking cough and inspiratory stridor. The diagnosis is based on clinical assessment. Traditionally the most important differential diagnosis has been acute epiglottitis though incidence of this condition has fallen dramatically with the widespread use of vaccination against type b. Haemophilus influenzae in western countries. It is still important to consider the possibility because of vaccine failure and poor vaccine coverage in developing countries. In epiglottitis lateral neck radiograph shows enlarged epiglottitis (thumb sign), ballooning of the hypopharynx and normal subglottic structures.18 X-ray has moderate sensitivity and specificity. The best method of diagnosis is to visualize the epiglottis after intubation. Intubation many precipitate laryngeal spasm and hence laryngoscopy should be performed in suspected cases only when facilities for intensive care are available. As laryngotracheobronchitis is primarily viral in origin, antibiotics have no role; main stay of therapy includes airway management, nebulized epinephrine and corticosteroids. In case of airway obstruction stabilization of airway is critical.

Role of Antibiotics In epiglottitis, ceftriaxone in a dose of 80–100 mg/kg/day in 2 divided doses or cefotaxime 50–180 mg/kg/day in 4 divided doses is given parenterally till culture reports are available. Some authorities recommend ampicilin (200 mg/kg/day in 4 divided doses) with chloramphenicol (75-100 mg/kg/day in 4 divided doses). Combined ampicillin and sulbactum/ clavulanic acid may be used as another alternative. The patient should improve immediately following intubation with disappearance of respiratory distress and cyanosis.

Duration of Therapy Antibiotics should be continued for 7–10 days.

CONCLUSIONS Most upper respiratory tract infections are viral and do not merit antibiotics. Antibiotics do not prevent bacterial superinfection. Antibiotics are indicated for acute bacterial sinusitis, ASOM and streptococcal sore throat. Amoxicillin is the drug of choice for all; in severe or non responsive sinusitis and otitis media coamoxiclav may be used. Third generation cephalosporins should be used sparingly.

 REFERENCES 1. Song JH Lee NY, Chiyanmas S. Spread of drug resistant Streptococcus pneumoniae in Asian Countries: Asian Network for Surveillance of Resistant Pathogens (ANSORP) study. Clin Infect Dis. 1999;28: 1206-11. 2. Barnett ED, Klein JO. The problem of resistant bacteria for the management of acute otitis media Pediatr Clin North Am. 1995;42:509-17. 3. Morris PS. Upper Respiratory tract Infections (including Otitis Media).Pediatr Clin N Am. 2009;56:101- 17. 4. Behrman RE. Textbook of Pediatrics, 19th edition. Philadelphia: WB Saunders Company, 2011. Antimicrobial Therapy in Upper Respiratory Tract Infection 211

5. Elaine Kierl Gangel. Practice Guidelines. AAP Issues Recommendations for the Management of Sinusitis in Children. Am Fam Physician. 2002;65(6):1216-20. 6. Marta Regoli, Elena Chiappini, Francesca Bonsignori, Luisa Galli, Maurizio de Martino Update on the management of acute pharyngitis in children Ital J Pediatr. 2011; 37: 10. Published online 2011 January 31. doi: 10.1186/1824-7288-37-10. 7. American Academy of Pediatrics, Committee on Infectious Diseases. Red Book: Report of the Committee on Infectious Diseases. 27. Elk. Grove Village; 2006. 8. Gerber MA. Nelson, Textbook of pediatrics, International editions. 18 Vol. 182. Group A Streptococcus. 2007. pp. 1135–9. 9. Gerber MA, Baltimore RS, Eaton CB, Gewitz M, Rowley AH, Shulman ST, Taubert KA. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association endorsed by the American Academy of Pediatrics Circulation. 2009. pp. 1541-51. 10. Casey JR, Pichichero ME. Symptomatic relapse of group A beta-hemolytic streptococcal tonsillopharyngitis in children. Clin Pediatr (Phila) 2007;46(4):307–10. doi: 10.1177/0009922806293919. 11. Stephen M, Weber, Kenneth M, Grundfast. Modern management of acute otitis media. Pediatr Clin North Am. 2003;50:399-411. 12. American Academy of Pediatrics and American Academy of Family Physicians Subcommittee on Management of Acute Otitis Media. Clinical practice guidelines: Diagnosis and management of acute otitis media. Pediatr. 2004;113:1451-65. 13. Wald ER. Acute Otitis Media:more trouble with the evidence . Pediatr Infect Dis J. 2003;22:103-4. 14. Piglansky L. Leibovitz E, Raiz S. Bacteriologic and clinical efficacy of high dose Amoxicillin for therapy of acute otitis media in children. Pediatr Infect Dis J 2003,22:405-13. 15. Arguedas A, Dagan R, Pichichero M, Leibovitz E, Blumer J, McNeeley DF, et al. An open-label, double tympanocentesis study of levofloxacin therapy in children with, or at high-risk for, recurrent or persistent acute otitis media. Pediatr Infect Dis J. 2006;25:1102–9. 16. Ramakrishnan K, Sparks RA, Berryhill WE. Diagnosis and Treatment of Otitis Media. Am Fam Physician. 2007;76(11):1650-8. 17. Dowell SF, Butler JC, Giebink SG. Acute otits media; management and surveillance in an era pneumococcal resistance a report from the drug resistant streptococcal pneumonia therapeutic working group. Pediatr Infect Dis J. 1991;18:1-9. 18. Lieber JJ, Epiglotoitis. In; Ferri’s Clinical Advisor: Instant Diagnosis and Treatment London: Mosby. 2005;295. 212 Rational Antimicrobial Practice in Pediatrics 1818 Antimicrobial Therapy in Community Acquired Pneumonia Poonam Mehta, Prawin Kumar, SK Kabra

 INTRODUCTION Pneumonia is the leading cause of mortality and a common cause of morbidity in children below five years of age. The estimated incidence of pneumonia is 0.29 and 0.05 episodes per child-year in low-income and high-income countries, respectively. It is estimated that a total of around 156 million new episodes occur each year and most of these occur in India (43 million), China (21 million), Pakistan (10 million) and Bangladesh, Indonesia and Nigeria (six million each).1 In 2010 out of 7.6 million deaths in children below 5 years of age, 1.396 million (18.3%) deaths were because of pneumonia.2

 ANTIMICROBIAL THERAPY FOR CAP Administration of appropriate antibiotics in the early course of pneumonia alters the outcome of illness particularly when the causative agent of pneumonia is a bacterium. Antibiotics may not have any role in pneumonia caused by viruses. Unnecessary antibiotic administration in children may lead to selection of resistant organisms and thus may promotes serious illness in the future.3 However, in view of the public health implications of better outcome of pneumonia by early administration of antibiotics and inability to clinically differentiate between bacterial and viral pneumonia, antibiotics are administered to all children with pneumonia. Differentiation between viral and bacterial pneumonia is also not possible by complete blood counts, acute phase reactants like CRP and CXR. In view of the difficulty and cost associated with identification of etiological agents, the choice of antibiotic in most cases of CAP is empiric. In children with severe disease requiring hospitalization, in those with poor response, underlying disease and immuno- compromised status, an attempt should be made to identify the etiological agent. Antimicrobial Therapy in Community Acquired Pneumonia 213

Factors that may help in selection of appropriate empirical antibiotics include: knowledge of etiological agents, sensitivity of pathogens to antibiotics, severity of the disease, immune status, nutritional status, previous antimicrobial usages, history of hospitalization, duration of illness, associated complications and cost and safety of antibiotics.

Likely Etiological Agents Gram-negative enteric bacteria are the most common pathogens in neonates and are obtained via vertical transmission from the mother during birth.4 In children between the ages 2 months to 5 years, western data show that viruses are the most frequent cause of community acquired pneumonia (CAP), respiratory syncytial virus (RSV) being the most common. In developing countries, bacterial infections are the most common cause in this age group. The commonest bacterial pathogens isolated in under five children with pneumonia are Streptococcus pneumoniae (S. pneumoniae) (30% to 50%) and Haemophilus influenzae (H. influenzae) (10% to 30%)5 and 50% of deaths due to pneumonia in this age is attributed to these two organisms.6 Apart from bacterial pathogens, viral pathogens have been isolated in nasopharyngeal aspirates of children below five years of age with pneumonia in 44–49% cases.7,8 In children older than 5 years S. pneumoniae is the predominant pathogen. Atypical organisms like Mycoplasma pneumoniae and Chlamydia pneumoniae are emerging pathogens for CAP in preschool-aged children and are common causes of CAP in older children and adolescents.9-13 There are very few studies that have looked for all possible etiological agents in children.14-20 Table 1 gives summary of etiological agents based on published studies in literature. Coinfection with two or more microbial agents is 10–40% in hospitalized patients, which is more common than previously thought. Pertussis should be considered in all children with CAP, especially if immunizations are not complete. Mycobacterium tuberculosis also may cause CAP in children who have been exposed to an adult patient with sputum positive tuberculosis.

Sensitivity of Pathogen Common etiological agents including S. pneumoniae and H. influenzae are sensitive to wide range of antibiotics including semisynthetic penicillins (amoxicillin, ampicillin), cephalosporins (cefuroxime, cefpodoxime, cefdinir), macrolides (erythromycin, roxythromycin, azithromycin and clarithromycin), cotrimoxazole and chloramphenicol. First generation cephalosporins and cefaclor are not very effective against H. influenzae and cefixime does not cover S. pneumoniae. Antibiotic resistance in pneumococci is an emerging problem all over the world. The mechanism of drug resistance is by changing the cell wall protein which is the binding site for beta lactam antibiotics. Higher levels of beta lactams can overcome this type of resistance in many strains. Addition of beta lactamase antagonist (like clavulanic acid) has no effect as production of beta lactamase is not the basis for resistance. In India, pneumococci have a low but increasing incidence of resistance to penicillin,21 214 Rational Antimicrobial Practice in Pediatrics G. negativespp Chlamydia M. pneumoniae Viruses Mixed inf H. influenzaepneumoniae S. Positive No of patients bacilli (Hospitalized) (Hospitalized) 16 years(Ambulatory) (Hospitalized) 13 years (Ambulatory) (Ambulatory) (Hospitalized) (35/129) 20 15 16 19 18 21 17 TABLE 1 Etiological agents for acute lower respiratory infection in children Person, place Age group Forgie et al(Gambia) alet Wubbel (USA) 1–9 yearsalet Ishiwada 6 months to(Japan) 74alet Gendreal 168(France) years <15 18 months tokoimaHeiskanen 60 (81%)et al (Finland) 596 73 (43%) <15years 104alet Kabra 11 (15%)(India) 389 (64.4%) 201 117 (19.6%)(85%) 87 45 (61%) 2–60 months 51 (8.6%) 95 133 (66%) 35 (27%) 3 (6%) ?? 93 (94%) 14 (13.3%) 0 57 (28%) 9 (12%) ?? 6 (3%) 10 (6%) 3 (4%) (5%) 5 89 (14..9%) 29 (14%) 9 (12%) 12 (7%) 179 (29.9%) 6 (6%) 44 (22%) 34 (20%) 51 (25%) 10 (11%) 43 (41.3%) 18 (9%) 30 (28.8%) 23 (24%)(25%) 26 36 (38%) 8 (9%) Ngeow et alet Ngeow 30 (40%) (Malaysia) 2 months to 3 years 87 41 (47%) 12 (13.8%) 7 (8.1%) 1 (1.2%) 8 (9.1%) 9 (10.3%) Antimicrobial Therapy in Community Acquired Pneumonia 215 but high incidence of resistance to cotrimoxazole (56%), and chloramphenicol (17%). However, there is no co relation between in vitro resistance and response to cotrimoxazole therapy in community-acquired pneumonia.22 Approximately 10–15% of Streptococcus pneumoniae are macrolide-resistant, and up to 40% of penicillin-resistant strains are also macrolide–resistant.23 Macrolide resistance among Streptococcus pneumoniae is emerging worldwide. Macrolide resistance among pneumococci is primarily due to genetic mutations affecting the ribosomal target site (ermAM) or active drug efflux (mefE). Antibiotic resistance of Hemophilus influenzae is reported up to 20–50% of isolates from nasopharyngeal cultures from healthy school going children from various parts of India. High resistance to chloramphenicol, ampicillin, co-trimoxazole, and erythromycin are reported. No resistance was found to the third generation cephalosporins.24-26 Invasive bacterial infection surveillance study group enrolled 3441 patients from Delhi, Lucknow, Chennai, Nagpur, Trivendrum and Vellore and reported 40% resistance to ampicillin, 53% to chloramphenicol, 41% to cotrimoxazole and 35% to erythromycin in 58% H. influenzae isolates.27-28 Atypical organisms such as Chlamydia and Mycoplasma are sensitive to macrolides and tetracycline. The latter is not used in children below 8 years of age due to dental staining later in life. Thus macrolides are the drug of choice for pneumonia due to atypical organisms. Newer quinolones such as gatifloxacin and levofloxacin have an advantage of good coverage for S. pneumoniae, H. influenzae and atypical organisms. However, the experience of these antimicrobials in children is limited and more studies are needed before they can be used as first line drug in CAP. Severity of Illness In most circumstances microbial etiology of pneumonia remains similar despite varying degree of severity of illness.29 However, it is logical to select the most appropriate antibiotics that have lesser chance of failure in more severe disease (See Tables 2 and 3 for categorization of severity of illness).

Underlying Disease Identification or knowledge of underlying disease is also important for selection of antibiotics. Some underlying diseases predispose a patient to pneumonia due to specific organisms. Children with hemoglobinopathies or nephrotic syndrome are more susceptible to pneumococcal infections. A child with cystic fibrosis is likely to have infections due to Staphylococcus, H. influenzae or Pseudomonas. Immune deficiency whether primary or secondary predisposes a child to infections due to unusual opportunistic organisms. Pneumonia in HIV infection may be due to gram-negative bacilli, Pneumocystis carinii (PCP) and fungi in addition to usual pathogens. The progression of disease is rapid in immunodeficient patients hence most efficient antibiotics combination are used as first line treatment in immunocompromised host. In a neutropenic child with pneumonia causative organisms include gram-negative bacilli (especially Pseudomonas, Ataphylococcus, Aspergillus, Pneumocystis in addition to common pathogens such as S. pneumoniae and H. influenzae. 216 Rational Antimicrobial Practice in Pediatrics

TABLE 2 Diagnosis and assessment of severity of pneumonia in children aged two months to 5 years with cough or difficult breathing Clinical Category Essential features Very severe pneumonia Central cyanosis, or Not able to breastfeed or drink, or Convulsions, or Lethargy or unconsciousness, or Severe respiratory distress (e.g. head nodding) Severe pneumonia Lower chest in drawing, or Nasal flaring, and no signs of very severe pneumonia Pneumonia Fast breathing e.g. Age RR/min 2 m up to 12 m > 50 12 m up to 5 y > 40 and No indicators of severe or very severe pneumonia No pneumonia No fast breathing, and no indicators of severe or very severe pneumonia

TABLE 3 Criteria for respiratory distress in children with pneumonia Signs of respiratory distress 1. Tachypnea, respiratory rate , breaths/min Age 0–2 months > 60 Age 2–12 months >50 Age 1–5 years > 40 Age > 5 years > 20 2. Dyspnea 3. Retraction (Suprasternal, intercostals or subcostal) 4. Grunting 5. Nasal flaring 6. Apnea 7. Altered mental status 8. Pulse oximetry measurement < 90% room air

Nutritional Status The etiology of pneumonia in malnourished children is generally similar to that in well- nourished children, with an added predisposition for gram-negative organisms.30 Malnourished children are predisposed to more frequent and severe episodes. Pneumonia in malnourished children may progress to severe disease rapidly. The symptoms of pneumonia may be masked in severely malnourished children possibly because of a blunted inflammatory response. In a study on malnourished children with pneumonia, fast breathing had a sensitivity of 61% and specificity of 79% compared to sensitivity of 79% and specificity of and 65% in well-nourished children. The required respiratory rate for malnourished children stood about 5 breaths/minute less than that for well-nourished Antimicrobial Therapy in Community Acquired Pneumonia 217 children. Since they are a high-risk group, malnourished children with severe malnutrition with non-severe pneumonia by definition should be treated as severe pneumonia or should have respiratory rate cut off of 5 breaths/min less than that is defined for pneumonia in children less than five years by WHO.31

Previous Antibiotics History of antibiotics in the current episode or in the recent past (previous 2–4 weeks) may give an idea about possible resistant organisms. If a patient had received repeated courses of antibiotics; patient’s microbial flora may be resistant to those antibiotics and a different set of antibiotics may be chosen.32

Duration of Illness A short duration of the illness suggests a possible bacterial etiology. A longer duration of the illness (>2 weeks) suggests a possibility of infection due to mycobacterium tuberculosis or atypical organisms or certain viral infections like adenovirus.

Indications for Intravenous Antibiotic Therapy Intravenous antibiotic therapy is warranted if the child has very severe or severe pneumonia, disturbed consciousness, improper swallowing, frequent vomiting, suspected drug malabsorption. Switch to oral when the child starts accepting orally and shows significant clinical improvement. Complete intravenous therapy is needed if the patient is newborn.

Treatment of Pneumonia (Table 4) For treatment purposes pneumonia may be classified as (a) Community acquired, without risk factors, and (b) pneumonia with risk factors. Both these can be further classified as nonsevere and severe illness.

Community Acquired Pneumonia without Risk Factors Children Less than 3 Months They should be hospitalized and treated with intravenous antibiotics usually a third generation cephalosporin and an aminoglycoside. If Chlamydia is suspected than a macrolide may be given. Children 3 Months 5 Years Nonsevere pneumonia can be managed on ambulatory basis. Antimicrobials choices include: amoxicillin, cotrimoxazole or oral second-generation cephalosporins (cefuroxime). Second generation cephalosporins are, however, considerably expensive. For drug resistant S. pneumoniae infection higher doses of amoxicillin is indicated. Large surveillance data for S. pneumoniae are not available. Available data suggest that India has low or intermediate penicillin resistant to S. pneumoniae. Therefore, routine use of higher dose of amoxicillin in community acquired pneumonia is not indicated. If the child has received beta lactams in the previous three months or is attending a day care center the possibility of infection 218 Rational Antimicrobial Practice in Pediatrics with drug resistant S. pneumoniae and use of high dose amoxicillin (60–80 mg/kg/day) may be considered. The usual duration of therapy is 5 days. A Cochrane review have demonstrated that 3 day oral amoxicillin is as effective as 5-day therapy.33 It is suggested that nonsevere community acquired pneumonia diagnosed by clinical features may be treated with 3 days of amoxicillin. The child should be reassessed after 3 days. Mother or attendant may be explained to bring the child to health care facility if there is deterioration in the condition. The deterioration may be identified by appearance of chest in-drawing, difficulty in feeding or cyanosis. The attending pediatrician may assess the child by asking the parents about the general condition, feeding, fever, vomiting, sleep, etc. The child may be examined for tachypnea, air entry in chest, chest in drawing, crepitations/ rhonchi, bronchial breathing, etc. If the assessment suggest deterioration child may be treated with second line drugs (amoxicillin–clavulanate, third generation cephalosporins including cefdinir/cefpodoxime or chloramphenicol). If the child’s condition remains same then the primary drug may be continued for another 2 days and reassessed. Deterioration at any time or no response on day 4 requires second line drugs (Table 4). A skiagram of chest is indicated in children not responding to antibacterials. Children with severe or very severe pneumonia need hospitalization. The first-line antibiotics include injection ampicillin, cefuroxime, or amoxicillin clavulanic acid given by intravenous route. If Staphylococcus is suspected then cloxacillin should be added. The antibiotics can be given orally when the child starts accepting orally and shows significant clinical improvement. The optimal duration of antibiotics for severe pneumonia is unclear. Conventionally antibiotics are continued for a total of 7–10 days. Systematic reviews of studies that used oral amoxicillin in children with severe pneumonia without hypoxia suggests that such patients can be managed on ambulatory basis with oral antibiotics.34 Two cluster randomized controlled trials also suggest that oral amoxicillin may be equal or superior to standard treatment (referral and injectable antibiotics in hospital) for children with severe pneumonia without hypoxia.35,36 Therefore, children with pneumonia with chest indrawing without hypoxia can be managed with oral antibiotics on ambulatory patients provided that parents are willing to bring the child to health care facility on deterioration in clinical condition. Children More than 5 Years The etiology of pneumonia above 5 years of age includes Mycoplasma pneumoniae, Chlamydia pneumoniae and S. pneumoniae. A recent retrospective cohort study compared beta lactam monotherapy with combination of beta lactam and macrolide antibiotics. Results suggest that children receiving combination (Beta lactam and macrolide antibiotics) had lesser duration of hospital stay but no difference in relapse rates in children above 5 years of age. There are no large studies documenting etiology of pneumonia in children above 5 years of age from India. Till we have more studies that document burden of pneumonia due to Mycoplasma, treatment of nonsevere pneumonia for this age group may be similar to that of children below 5 years of age. If a patient does not improve with antibiotics or there are clinical features pointing towards infections due to atypical organism a course of macrolide antibiotics may be given to these patients. Antimicrobial Therapy in Community Acquired Pneumonia 219 Inj Cepha cefuroxime iaxone 3rd gen Vancomycin/ Co-amoxyclavulanic acid Cefuroxime with oral Cefuroxime Cefuroxime Second line Vancomycin/ Teicoplanin/ Linezolid + Inj 3rd Gen Cephalosporins Second line: Vancomycin/ Teicoplanin + Inj 3rd Gen Cephalosporins Inj Co-amoxyclavulanic acid Second line: Teicoplanin + Inj 3rd Gen Cephalosporins eftriaxone Inj eftriaxone Inj 3rd Gen Cephalosporins: OR Aminoglycoside OR May be replaced acid Cefotaxime/Ceftriaxone + clavulanic acid+ Cefotaxime/Ceftriaxone Pneumonia Notes Co-amoxy OR Cloxacillin Cefuroxime OR Cephalosporins:Cefotaxime/Ceftriaxone + Cefotaxime/Ceftr +Aminoglycoside(Gent/Amika) (Gent/Amika) Inj OR Inj Cefopodoxime or clavulanic acid Inj 3rd Gen Cephalosporins: OR Staphylococcaldisease Staphylococcal disease CefuroximeOR Cefuroxime clavulanic acid ORORCo-amoxyclavulanic acid Inj OR Cefuroxime OR OR Cloxacillin OR OR Inj Co-amoxy Cefotaxime/C AND OR Cefotaxime/C Cloxacillin CefpodoximeOR Cefdinir Co-amoxy Inj clavulanic acidCefdinirORCefpodoxime Co-amoxy clavulanic acid Macrolides AND Macrolides Inj Co-amoxyclavulanic acid OR monia Severe Usually severe, treated as inpatients Inj 3rd Gen Co-amoxy clavulanic acid Inj 3rd Gen Cephalosporins: On disch AmoxycillinOR Co-amoxy Amoxycillin+ clavulanic acid Cloxacillin Inj AmpicillinAmoxycillin OR Macrolide Inj Co-amoxy Amoxycillin+ Inj Ampicillin Inj 3rd Gen Cephalosporins: Inj Co-amoxy clavulanic Inj 3rd Gen Cephalosporins: Cotrimoxazole OR OR Inj 3 mo Up to Setting DomicilliaryAGE First Line Second Line Suspected First Line In-patient Second Line Suspected TABLE 4 The choice of antibiotics in pneumonia Disease Pneu 3 mo to 5 years 5 years plus of age 220 Rational Antimicrobial Practice in Pediatrics

For severe or very severe disease in children older than 5 years: it may be safer to use a combination of intravenous beta lactam agent (co-amoxiclav, ceftriaxone, cefotaxime) and a cover for atypical organism (macrolide/new fluoroquinolone) at the outset itself.

Community Acquired Pneumonia with Presence of Risk Factors The antibiotics are decided on basis of individual patient’s characteristics and have been discussed earlier. Broadly speaking a child with nonsevere pneumonia may be treated with oral cefuroxime/cefpodoxime/cefdinir/amoxicillin clavulanic acid for a period of 7–14 days. Monitoring, follow-up and assessment remain similar to community-acquired pneumonia. In case of deterioration or failure of therapy the second line antibiotic for these patients may be intravenous third generation cephalosporins. For severe disease in this group patients may be treated with third generation cephalosporin (antipseudomonal cephalosporin if Pseudomonas is suspected) with aminoglycoside with or without cloxacillin/vancomycin.

Response to Antimicrobial Therapy Clinical improvement may take up to 48–96 hours; fever can last 2–4 days, leucocytosis usually resolves by day 4, abnormal physical findings may persist > 7 days. Most non- severe CAP shows clinical resolution of symptoms in 2–3 days. Radiographs may worsen even though clinical picture is improving and chest X-ray usually returns to normal (occasionally leaving some haziness) within 6 weeks in patients. The possible causes of failure to respond adequately are inadequate therapy, which may be due to inappropriate antibiotic selection, inappropriate dosing, and poor compliance. It can also be due to development of complications like empyema or lung abscess. If there is impaired host defense mechanism, or there is development of drug resistance in the community there may be delayed response or poor response. Nonbacterial community acquired pneumonia have longer course than expected.

Shifting from Parenteral to Oral Antibiotics Child should be shifted to oral antibiotics once respiratory distress improved, tachypnea settled and child has started accepting orally to complete the desired course of antibiotics (i.e. 7 days for non staphylococcal pneumonia (Streptococcal pneumonia, H. influenzae), 2 week for staphylococcal pneumonia and 4 weeks for empyema). The choice of oral antibiotics will depend on the parenteral antibiotics which the child is receiving. If child is on intravenous penicillin the child should be shifted on oral amoxi clav, if receiving iv cephalosporin then shift to oral first and second generation cephalosporin (Cefpodoxime, cephalexin, cefuroxime), if IV vancomycin then shift to oral Linezolid.

Supportive Therapy Indications for hospitalization/intensive care treatment are listed in Tables 5 and 6. Children with pneumonia may have fever, poor intake, vomiting, electrolyte abnormalities, hypoxia Antimicrobial Therapy in Community Acquired Pneumonia 221

TABLE 5 Factors determining the need for admission • Age younger than 2 months • Toxic appearance • Hypoxemia • Oxygen saturation less than 92 percent • Cyanosis • Respiratory difficulty • Apnea • Grunting • Flaring of the nostrils • Dehydration, vomiting, or poor feeding • Immunocompromised status • Failure to respond to oral antibiotics • Inadequate observation or supervision by family

TABLE 6 Indications for ICU admission

• PaO2/FiO2 < 250 • Mechanical ventilation • CXR showing bilateral, multilobar pneumonia with increase in the size of the opacity > 50% in the 48 hours prior to admission • Hypotension • Vasopressors requirement • Acute renal failure

and respiratory failure. The antibiotics require some time to produce a response. All patients need supportive care. Fever should be treated with paracetamol in doses of 10–15 mg/kg/dose. It can be repeated every 4–6 hourly. Cough is common symptom associated with pneumonia. Cough suppressants should be avoided. Common household remedies like tulsi, ginger and honey may be given to the child. If there is bronchospasm, inhaled bronchodilators can be prescribed. Most of the vomiting may be associated with cough and does not require specific treatment. Persistent vomiting may be managed with antiemetics. However, before starting antiemetics, it is advisable to rule out other causes of vomiting including CNS infection, acidosis, or intestinal problems. Associated comorbid conditions like diarrhea, congenital heart diseases, and immunodeficiency are associated with high case fatality. Children with congenital heart diseases require careful monitoring for fluid and electrolyte balance as these patients may develop congestive heart failure. Children with diarrhea may need more fluids for correction of dehydration and ongoing losses. In malaria endemic area a possibility of malarial infection presenting as pneumonia or malaria as comorbid condition should be kept in mind. There may be hyponatremia due to SIADH. A careful monitoring and restriction of fluid is the intervention required in most cases. 222 Rational Antimicrobial Practice in Pediatrics

Hypoxia may be present in children with severe pneumonia. Hypoxia if untreated may be associated with increased case fatality rates.37 It is difficult to identify hypoxia by clinical features alone.38 Oxygen should be administered to children with tachypnea (RR > 70 per minute), chest in drawing, poor feeding or cyanosis. Oxygen may be administered by nasal prongs, nasopharyngeal tubes (Low flow, i.e. 1-2 L/min); or oxygen hood or facemask (both high flow 4-8 L/min). Small children tolerate oxygen with hood better than nasal or nasopharyngeal cannula or facemask. Nasal cannula after cutting the prongs is also well tolerated by children.39 Noninvasive monitoring of hypoxia by saturation monitoring is well-accepted method. However, it should be kept in mind that oxygen saturation gives idea about oxygenation and does not give any idea about CO2. Even with respiratory failure saturation may be normal with high flow oxygen inhalation. Therefore, it is advised that in critically sick children with pneumonia, a baseline arterial blood gas should be done and subsequently monitored with oxygen saturation. With clinical deterioration a repeat arterial blood gas for documentation of rising CO2 is desirable.

Need for Empirical Antiviral Drug Oseltamivir Some Indian studies have shown that influenza contributes towards 5–10% of all acute respiratory infections.40 The percentage contribution of influenza towards community acquired pneumonia increases during an influenza outbreak as was seen during the novel H1N1 epidemic 2009.41 Antivirals are known to reduce the mortality due to influenza pneumonia especially if administered during the first 48 hours of the illness.42 Hence during an influenza outbreak, early use of empirical antiviral drug oseltamivir along with antibacterials in children presenting with community acquired pneumonia should be considered. For details about oseltamivir dosing refer to Chapter 14.

CONCLUSIONS Pneumonia is the leading cause of mortality and common cause of morbidity in children below five years of age. In developing countries bacterial infections are the most common cause of pneumonia, Streptococcus pneumoniae and Hemophilus influenzae being common bacterial pathogens identified. Administration of appropriate antibiotics in the early course of pneumonia alters the outcome of illness. Oral amoxicillin is the drug of choice in non- severe pneumonia and pneumonia with chest indrawing without hypoxia. All children with severe pneumonia with hypoxia and severe pneumonia need to be hospitalized and treated with parenteral antibiotics.

 REFERENCES 1. Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H. Epidemiology and etiology of childhood pneumonia. Bulletin of the World Health Organization 2008;86:408-16. 2. Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, et al. Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000.. Lancet. 2012;379:(9832):2151-61. Antimicrobial Therapy in Community Acquired Pneumonia 223

3. Hamid M, Qazi SA, Khan MA. Clinical, nutritional and radiological features of pneumonia. J Pak Med Assoc. 1996;46:95-9. 4. The WHO Young Infant Study Group. Bacterial etiology of serious infections in young infants in developing countries: results of multicentre study. Pediatr Infect Dis J. 1999;18 (suppl):S17-22. 5. Falade AG, Ayede AI. Epidemiology, aetiology and management of childhood acute community-acquired pneumonia in developing countries—a review. Afr J Med Med Sci. 2011;40(4):293-308. 6. Shann F. The management of pneumonia in children in developing countries. Clin Infect Dis. 1995;21:S218-25. 7. Maitreyi R.S, Broor S, Kabra S K, Ghosh M, Seth P, Dar L. et al. Rapid detection of respiratory viruses by centrifugation enhanced cultures from children with acute lower respiratory tract infections. J Clin. Virol. 2000;16:41-7. 8. John TJ, Cherian T, Steinhoff MC, Siemoes EAF, John M. Etiology of acute respiratory tract infection in children in tropical southern India. Rev Infect Dis. 1990;13(suppl6): S463-9. 9. Pandey A, Choudhary R, Nisar N, Kabra SK. Acute respiratory tract infections in Indian children with special reference to Mycoplasma pneumoniae. J Trop Pediatrics. 2000;46:371-4. 10. Chaudhary R, Nazima N, Dhawan B, Kabra SK. Prevalence of mycoplasma preumonia and Chlamydia pneumoniae in children with community acquired pneumonia. Indian J Pediatr. 1998;65:717-1. 11. Normann E, Gnarpe J, Gnarpe H, Wettergren B. Chlamydia pneumoniae in children with acute respiratory tract infection. Acta Paediatr. Scand. 1998;87:23-7. 12. Flack G, Gnarpe J, Gnarpe H. Prevalence of Chlamydia pneumoniae in healthy and ill children with respiratory tract infections. Pediatr Infect Dis J. 1997;16:549-54. 13. Pandey A, Chaudhry R, Kapoor L, Kabra SK. Acute lower respiratory tract infection due to Chlamydia species in children under five years of age. Indian J Chest Dis Allied Sci. 2005;47:97-101. 14. Ngeow YF, Weil AF, Khairullah NS, Yusof MY, Luam L, Gaydos C. et al. Young Malaysian children with lower respiratory tract infections show low incidence of Chlamydial infection. J Paediatr Child H. 1997;33:422-5. 15. Forgie IM, O’Neill KP, Lloyd-Evans N, Leinonen M, Campbell H, Whittle HC, et al. Etiology of acute lower respiratory tract infections in Gambian children: II. Acute lower respiratory tract infection in children ages one to nine years presenting at the hospital. Pediatr Infect Dis J. 1991;10:42-7. 16. Wubbel L, Muniz L, Ahmed A, Trujillo M, Carubelli C, McCoig C, et al. Etiology and treatment of community acquired pneumonia in ambulatory children. Pediatr Infect Dis J. 1999;18:94-104. 17. Ishiwada N, Kurosaki T, Toba T, Niimi H. Etiology of pediatric inpatients with pneumonia. Kansenshogaku Zasshi. 1993;67:642-7. 18. Gendrel D, Raymond J, Moulin F, Iniguez JL, Ravilly S, Habib F, et al. Etiology and response to antibiotic therapy of community-acquired pneumonia in French children. Eur J Clin Microbiol Infect Dis. 1997;16:388-91. 19. Heiskanen-Kosma T, Korppi M, Jokinen C, Kurki S, Heiskanen L, Juvonen H, et al. Etiology of childhood pneumonia: serologic results of a prospective, population-based study. Pediatr Infect Dis J 1998;17: 986-91. 20. Kabra SK, Lodha R, Broor S, Chaudhary R, Ghosh M, Maitreyi RS. Etiology of acute lower respiratory tract infection. Indian J Pediatr. 2003;70:33-36. 21. Invasive Bacterial infection Surveillance (IBIS) Group, INCLEN. Prospective multicentric hospital surveillance of Streptococcus pneumoniae disease in India. Lancet. 1999;353:1216-21. 22. Awasthi S, Agarwal G, Singh JV, Kabra SK, Pillai RM, Singhi S, et al. Effectiveness of 3-day amoxycillin vs. 5-day co-trimoxazole in the treatment of nonsevere pneumonia in children aged 2-59 months of age: a multi-centric open labelled trial. Journal Tropical Pediatrics. 2008;54:382-9. 23. Bartlett JG. Empirical therapy of community acquired pneumonia: macrolides are not ideal choices. Semin Respir Infect. 1997;12:329-33. 24. Steinhoff MC. Invasive Haemophilus influenzae disease in India: a preliminary report of prospective multihospital surveillance. Pediatr Infect Dis J. 1998;17:S172-5. 25. Nag VL, Ayyagari A, Venkatesh V, Ghar M, Yadav V, Prasad KN. Drug resistant Haemophilus influenzae from respiratory tract infection in a tertiary care hospital in north India. Indian J Chest Dis Allied Sci. 2001;43:13-7. 224 Rational Antimicrobial Practice in Pediatrics

26. High nasopharyngeal carriage of drug resistant Streptococcus pneumoniae and Haemophilus influenzae in North Indian school children. Trop Mde Int Health. 2005;10(3):234-9. 27. Invasive Haemophilus influenzae disease in India: a preliminary report of prospective multihospital surveillance. Pediatr Infect Dis Journal. 1998;17(9):S172-5. 28. Piscitelli SC, Danziger LH, Rodvold KA. Clarithromycin and azithromycin: new macrolide antibiotics. Clin Pharm. 1992;1:137-52. 29. Juven T, Mertsola J, Waris M, et al. Etiology of pneumonia in 254 hospitalized children. Ped Infect Dis J. 2000;19:293-98. 30. Adegbola RA. The etiology of pneumonia in malnourished and well nourished Gambian children. Pediatr Infect Dis J. 1994;13:975-82. 31. Falade AG, Tschappeler H, Greenwood BC, Mulholand EK. Use of simple clinical signs to predict pneumonia in young Gambian children, the influence of malnutrition. Bull World Health Organ. 1995;73:299-304. 32. Jacobs RF. Judicious use of antibiotics for common pediatric respiratory infections. Pediatr Infect Dis J. 2000;19: 938-43. 33. Haider BA, Saeed MA, Bhutta ZA. Short-course versus long-course antibiotic therapy for non-severe community-acquired pneumonia in children aged 2 months to 59 months. Cochrane Database Syst Rev. 2008;16;(2):CD005976. 34. Kabra SK, Lodha R, Pandey RM. Antibiotics for community-acquired pneumonia in children. Cochrane Database of Systematic Reviews 2010, Issue 3. Art. No.: CD004874. DOI: 10.1002/14651858. CD004874.pub3. 35. Soofi S, Ahmed S, Fox MP, MacLeod WB, Thea DM, Qazi SA, et al. Effectiveness of community case management of severe pneumonia with oral amoxicillin in children aged 2-59 months in Matiari district, rural Pakistan: a cluster-randomised controlled trial.. Lancet. 2012;379:729-37. 36. Bari A, Sadruddin S, Khan A, Khan Iu, Khan A, Lehri IA, et al. Community case management of severe pneumonia with oral amoxicillin in children aged 2-59 months in Haripur district, Pakistan: a cluster randomised trial. Lancet. 2011;378:1796-803. 37. Duke T, Graham SM, Cherian MN, Ginsburg AS, English M, Howie S, et al. Union Oxygen Systems Working Group. Oxygen is an essential medicine: a call for international action. Int J Tuberc Lung Dis. 2010;14(11):1362-8. 38. Lodha R, Bhadauria PS, Verghese Kuttikat A, Puranik M, Gupta S, et al. Can clinical symptoms or signs accurately predict hypoxemia in children with acute lower respiratory tract infections? Indian Pediatr. 2004;41:129-36. 39. Kumar RM, Kabra SK, Singh M. Efficacy and acceptability of different modes of oxygen administration in children: implications for a community hospital. J Trop Pediatr. 1997;43:47-9. 40. Mathew JL. Influenza vaccination for children in India. Indian Pediatrics. 2009;46:304-7. 41. Parakh A, Kumar A, Kumar V, Kumar A Datta, Khare S. Pediatric hospitalizations associated with 2009 pandemic influenza virus (H1N1). An experience from a tertiary care center in North India. Indian J Pediatrics. 2010. epub 42. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Clinical Aspects of Pandemic 2009 Influenza A (H1N1) Virus Infection. NEJM. 2010;362:1708-19. Antimicrobial Therapy and Drainage of Empyema Thoracis 225 1919 Antimicrobial Therapy and Drainage of Empyema Thoracis Rasik Shah, Pradnya Gadgil

 INTRODUCTION Empyema thoracis complicates underlying pneumonia and is a serious problem despite recent advances in management. It is reported to occur in up to 28% children hospitalised for community acquired pneumonia.1 In developing countries empyema is associated with significant morbidity and consumption of scarce hospital resources.

 MICROBIOLOGY With the advent of more and more new antibiotics with different spectra, the microbiological epidemiology has altered significantly over the last decade. Moreover, the chances of identifying the causative organism from pleural fluid using cultures has decreased as most children would have received antibiotics prior to obtaining pleural fluid specimen. However, with newer techniques such as PCR can aid in diagnosis; in a recent UK trial 75% pneumococcal culture negative specimens were pneumococcal DNA positive.2 S. pneumoniae, S. aureus and H. influenzae (in unvaccinated children) are the most common causes of empyema in children. Prior to easy availability of antibiotics, S. pneumoniae, beta-hemolytic streptococci and S. aureus were the most common organisms causing empyema thoracis. With the advent of sulphonamides and then penicillins, the incidence of pneumococcal infections is decreased, with relative increase in staphylococcal infections (especially penicillinase producing). Following the introduction of penicillinase stable antibiotics the incidence statistics reversed again to pneumococcal predominance.3 Other bacteria include S. pyogenes, Pseudomonas aeruginosa, other streptococcal species (including viridans streptococci and streptococci of Lancefield group F), mycobacteria. Rare bacterial organisms isolated include Klebsiella, Enterobactor, Proteus species, Legionella, Salmonella and Yersinia. Anaerobic organisms such as Bacteroides species and Peptostreptococcus are rarely isolated in children but may be associated 226 Rational Antimicrobial Practice in Pediatrics with aspiration pneumonia or foreign bodies. Mycoplasma pneumoniae and respiratory viruses may causes pleural effusions but rarely cause empyema. Recently, Torque Teno Mini Virus (TTMV) is isolated from parapneumonic effusions, suggesting the potential role of the virus in the pathogenesis of pneumonia.4

 EMPIRICAL ANTIMICROBIAL THERAPY All cases should be admitted to hospital and treated with IV antibiotics. Initial empirical antibiotic selection should take into consideration the likeliest causative organism, history of Hib vaccination, whether the infection is community acquired or nosocomial, any predisposing factors such as underlying immunodeficiency, is it following trauma or postoperative and any likelihood of aspiration. The possibility of mycobacterial infection should also be kept in mind. Empirical treatment must cover S. pneumoniae, S. pyogenes, S. aureus and H. influenzae (in unvaccinated children). If pneumatoceles are present antistaphylococcal cover is mandatory. A reasonable choice for initial therapy would be IV coamoxiclav alone or IV cefotaxime/ceftriaxone and cloxacillin. If anaerobic infection is suspected IV clindamycin may be used. If community acquired MRSA is suspected options include cefotaxime/ ceftriaxone with IV clindamycin/IV linezolid/IV vancomycin. For nosocomial empyemas where multidrug resistant gram-negative pathogens and MRSA are possible etiologic agents, therapy with BL-BLI’s (piperacillin tazobactam/cefoperazone sulbactam) or carbapenems with vancomycin/linezolid may be needed.

 DRAINAGE Drainage is an integral part of empyema management and hence is being addressed in this book. Various option for drainage include recurrent thoracocentesis, insertion of chest drain alone or with addition of fibrinolytics, open decortications, video assisted thoracic surgery (VATS) and finally rib resection/thoracoplasty/lobectomy. In most patients presenting with early disease and few or no loculations insertion of an intercostal drainage tube usually suffices. However, the tube has a tendency to get blocked with thick pus and fibrino-purulent material leading to inadequate drainage and persistent collection of thick pus and fibrino-purulent material. Milking of ICD at regular intervals is important to ensure the patency of tube as this maneuver dislodges the small fragment of fibrino-purulent material. In addition it is necessary to ensure that the level of the water column is kept low (2 to 3 cm) for good drainage. The use of fibrinolytics is controversial, however, in stage II empyema use of fibrinolytics in conjunction with the insertion of ICD improves the success rate, though the hospitalisation is longer when compared with the VATS.5 The resolution of fever and leucocytosis with almost complete re-expansion of the lung as seen on X-ray and/or sonography are favorable indicators of success of the conservative management. The chest drainage should be continued till drainage decreases to less than 15 ml/day, which usually takes 7–14 days. Persistence of fever along with inadequate lung expansion beyond 48–72 hours are early indicators of failure of this modality and indicate intervention by video assisted thoracoscopic surgery (VATS). Delay in drainage by VATS or thoracotomy where indicated Antimicrobial Therapy and Drainage of Empyema Thoracis 227 is associated with higher mortality rate and intervention where indicated should not be delayed beyond 7 days.6 In patients presenting with advance disease (>7 days), with thick pus and multiple loculations, standard management with intercostal tube drainage is likely to fail. These patients should be referred for primary VATS, VATS allows determination of the stage of the diseases, breaking of all loculi with complete evacuation of thick pus and fibrino- purulant material. In addition, VATS gives visual impression of condition of underlying lung, its capacity to expand, and presence, site and size of broncho pleural fustula (BPF). As thick pus and fibrino-purulent material is removed thoroughly, the fever resolves quickly (usually in 48–72 hours), ICD is required for short duration (usually for 48-72 hours) and post procedure hospitalization is reduced to 6–7 days.7 VATS carries the advantages of early recovery and resolution of empyema comparable to open decortications. However, if thick fibrotic peel does not allow dissection to proceed to create enough space for VATS or if VATS is unavailable then open decortications by minithoracotomy with or without rib resection should be performed.  MODIFICATION AND DURATION OF ANTIBIOTIC THERAPY The antibiotics should be changed according to microbiological results if any. If etiological agent is identified down grading should be sought especially if broad-spectrum antibiotics are being used. It is increasingly difficult to get microbiological diagnosis and hence the initial antibiotics are usually continued especially if there is evidence of clinical improvement. In case of clinical failure and no microbiologic diagnosis the possibility of poor and inadequate drainage should be considered before considering possible drug resistance and upgrading antibiotics. The intravenous antibiotics should be continued till the child is afebrile and till the chest drain is in situ. Postdischarge from the hospital oral antibiotics may continued for a total duration of 2–4 weeks depending on the causative organism (longer for S. aureus) and the amount of residual disease.3

 REFERENCES 1. Byington CL, Spencer LY, Johanson TA, et al. An epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations. Clin Infect Dis. 2002;34:434-40. 2. Eastham KM, Freeman R, Clark J, et al. Clinical features, aetiology and outcome of empyema in the North East of England. Thorax. 2004;59:522-5. 3. Balfour-Lynn I M, Abrahamson E, Cohen G, Hartley J, King S, Parikh D, et al. BTS guidelines for the management of pleural infection in children; on behalf of the Paediatric Pleural Diseases Subcommittee of the BTS Standards of Care Committee; Thorax. 2005;60:i1-i21. 4. Galmès J, Li Y, Rajoharison A, Ren L, Dollet S, Richard N, Vernet G, et al. Potential implication of new torque teno mini viruses in parapneumonic empyema in children. Eur Respir J. 2012 Oct 11. [Epub ahead of print]. 5. Cobanoglu U, Sayir F, Bilici S, Melek M. Comparison of the methods of fibrinolysis by tube thoracostomy and thoracoscopic decortication in children with stage II and III empyema: a prospective randomized study. Pediatr Rep. 2011;3 (4):e29. 6. Goldin AB, Parimi C, LaRiviere C, Garrison MM, Larison CL, Sawin RS. Outcomes associated with type of intervention and timing in complex pediatric empyema. Am J Surg. 2012; 203(5):665-73. 7. Merry CM, Bufo AJ, Shah RS, et al. Early definitive intervention by thoracoscopy in Pediatric Empyema. J Pediatr Surg. 1999;34:170-4. 228 Rational Antimicrobial Practice in Pediatrics 2020 Chemotherapy of Childhood Tuberculosis Varinder Singh, Md Umar Tak, Soumya Tiwari

 INTRODUCTION Tuberculosis is still the most frequent infectious cause of death in the world even though 100 years have elapsed since the disease and six decades since anti tuberculosis drugs were discovered. India accounts for more than 25% of incident cases of tuberculosis in the world. About 40% of the Indian population is infected with TB bacillus; every year 1.8 million Indians develop TB, of which 0.8 million are infectious. The death rate for all forms of TB in India (excluding HIV) in the year 2010 was 26 (confidence interval, 17-39) per 100,000 population.1 Almost 3.4 million Indian children have TB disease of which 40% contract disease by the age of 6 and 80% by the age of 16 yrs.2 It has been assumed that 10% of the actual total TB caseload in India is amongst children.3 Childhood TB is an indicator of recent transmission and thus serves as a sentinel event.4 Reliable and adequate data on the burden of all forms of TB, amongst children in India, is not available. Children are not only at higher risk of developing the disease but also are more likely to develop the severe form of the disease.5 Proper identification and treatment of infectious cases in a community will reduce burden of childhood TB. Till such time, the profession shall need to focus on proper management of pediatric cases to prevent morbidity and handicap due to the disease.6

 HISTORICAL BACKGROUND Since Ehrlich’s original concept of chemotherapy based on selective staining by dyes, attempts had been made to find chemotherapeutic agents for tuberculosis. Sanocrysin– a gold salt, sulphones, vitamin D and nicotinamide (from which several current anti- tuberculosis drugs, including (INH) and ethionamide, were subsequently developed as analogs) were used. During this phase, treatment approaches included rest for the patient in sanatorium and rest for the affected portion of the lung by collapse therapy Chemotherapy of Childhood Tuberculosis 229 through operative procedures on the chest wall (thoracoplasty) and the injection of air into the pleural cavity (artificial pneumothorax).7 This was followed by the advent of INH, streptomycin and other drugs in the 40’s and later. A combination of these drugs for as long as 18 months was used till as recently as the early 1980’s. Although these regimens were effective if properly used, the actual failure rates are quite high because of poor compliance among patients. The TB armamentarium has largely not undergone major changes in the past 3– 4 decades since the availability of rifampin in the 1970’s and the reutilization of pyrazinamide ushered in the era of ‘Short Course’ chemotherapy enabling tuberculosis to be cured in six months time. Rifampin, in combination with Isoniazid and Streptomycin for 9 months led to cure rates of almost 100% with relapse rates of less than 5% in patients with pulmonary tuberculosis.8 However, the impact of this new approach was not merely the shortening of duration alone but also the capability of the intensive initial multi- drug therapy to effectively manage existing resistance to INH and many other non-rifampin drugs.8 However, this initial advantage has been lost to an extent due to usage of unregulated and poor TB regimes with these potent drugs. Both, the medical profession as well as mankind has not learnt from past mistakes and the nonchalant use of the short course drug therapy has led to complex problems and issues surrounding the treatment of tuberculosis infection and disease. We are already at a point when no new significant anti-TB drug has been made available for regular use while resistance to existing drugs including rifampin is increasing. The threat of increasing INH and polydrug resistance has necessitated a 4 drug regime using Rifampin (R), INH (H), Pyrazinamide (Z) and Ethambutol (E) as the front line therapy. Treatment of tuberculosis in the setting of multi drug resistance (INH and Rifampin), co-infection with HIV/ transplantation can be challenging. This chapter shall focus on the basic principles and current regimes for treating children using short course chemotherapy.

 PRINCIPLES OF CHEMOTHERAPY FOR TUBERCULOSIS Several biologic characteristics of M. tuberculosis have led to a hypothesis concerning the action of various drugs and drug combinations. M. tuberculosis, the causative organism of TB, is a slow growing bacterium with doubling time of about 20 hours, and it can also enter a phase of dormancy, that is drug refractory. The tubercle bacilli can be killed only in the replication phase when they are metabolically active. Mitchison described four sub-populations of bacilli in a host, depending upon their metabolic activity.9-12

Bacilli Sub-population (Mitchison Hypothesis) The postulated differences in the metabolism of these bacilli present in different lesions make them variably susceptible to the various front line drugs despite having no true resistance. The proportion of these sub-populations of bacilli differ with the type of lesion and there, probably, is a constant shift between these subpopulations. 230 Rational Antimicrobial Practice in Pediatrics

These sub-populations include: 1. Rapidly growing/multiplying bacilli: Because M. tuberculosis is an obligate aerobe, activity rates vary with oxygen supply. Bacilli are active and replicate freely where oxygen tension is high. A neutral or alkaline pH also promotes metabolic activity and growth. Environmental conditions for growth are optimal in cavities, leading to a very large bacterial population. 2. Slow growing (Intracellular): This represents the bacilli present within the macrophages at inflamed sites where pH is low. 3. Spurters: These represent the group of bacilli in the caseous material, which are slowly dividing due to low oxygen concentration and neutral pH. 4. Dormant: This represents the bacilli, which are dormant due to adverse environment. This period of dormancy can be very prolonged. As drugs largely do not act upon these types of bacteria, they are the usual cause of subsequent relapse. Children with primary pulmonary tuberculosis and patients with only extrapulmonary tuberculosis are infected with a much smaller numbers of tubercle bacilli, because the cavitary population is not present. Another important bacteriologic consideration for the treatment of tuberculosis is the presence of naturally occurring drug-resistant mutants (primary resistance) in bacillary populations, even before chemotherapy is started.12 Although the population of bacilli as a whole may be considered ‘drug susceptible’, a sub-population of drug resistant mutants occurs at a fairly predictable mean frequency of about 10-6 bacterial replications, but varies among drugs: Streptomycin 10-5 Isoniazid 10-8 to 10-9 Ethambutol 10-6 Rifampin 10-8 A cavity containing 109 tubercle bacilli has thousands of drug-resistant organisms; a closed caseous lesion with 106 bacilli has few or none. Cross-resistance does not occur naturally. Fortunately, the chance occurrence of resistance to one drug is unrelated to that for any other drug. Thus, when three to four effective drugs are used in combination for treatment of TB, there are negligible chances of emergence drug resistance. For an organism to be ‘naturally’ resistant to two drugs (primary multi drug resistance) the population size would have to be 1011 to 1016, which is rare in clinical practice. Most clinical cases of multi drug resistance are due to sequential selection of resistant organisms on sequential poor therapy or else due to transmission of MDR infection from an infectious case, as is more common in children. The combination of bacterial population size and drug resistant mutations explains why a single antitubercular drug cannot cure multibacillary disease like cavitary tuberculosis. The major biologic determinant of antitubercular therapy is the size of the bacillary population. In adults with pulmonary cavities and children with extensive pulmonary infiltrates there are many bacilli that are resistant to at least one of the first lines drugs mandating the use of more than two antituberculosis drugs. A single effective drug would select for emergence of a dominantly resistant population. Children with limited primary pulmonary tuberculosis and patients with extrapulmonary tuberculosis have lower bacterial load where Chemotherapy of Childhood Tuberculosis 231 the presence of significant numbers of drug resistant mutants shall be more reflective of the prevalence of resistance in the infectious pool rather than the occurrence of natural mutants. In case the prevalence of resistance in the community is low then therapy with two bactericidal drugs may suffice while in the presence of high drug resistance one may need to use more numbers of bactericidal drugs. This is an important issue in order to prevent amplification of drug resistance. The first line antitubercular drugs and their currently recommended dosages are out lined in Table 1. Antitubercular drugs may have several different activities as some drugs are bactericidal while others are bacteriostatic. Their action on various sub-populations of bacilli also differs thus accounting for differences in their sterilizing activity, bactericidal activity and prevention of emergence of resistance. On the basis of animal experiments and clinical trials, Mitchison classified and graded antitubercular drugs into three categories.9-10 1. Drugs with sterilizing activity: The sterilizing activity is the ability to kill all the bacilli in tubercular lesions as rapidly as possible. Because the speed of killing becomes progressively slow during chemotherapy, sterilizing activity really measures the speed with that the last few viable bacilli are killed. In general, sterilizing activity indicates the suitability of an agent for use in intensive therapy of short course regimens. Rifampin and pyrazinamide have the greatest sterilizing activity. 2. Drugs with early bactericidal activity: The bactericidal action refers to the ability of the drug to kill dividing M. tuberculosis. These drugs induce a rapid decrease in the number of living bacilli in the sputum at the beginning of treatment, rapidly reduce the bacillary load and quickly convert the sputum cultures to negative, thus reducing the infectivity of the patient. Isoniazid is the most effective drug in this category as it kills 90% of the bacilli in the first few days of treatment. Rifampin has also good early bactericidal activity. 3. Drugs with resistance prevention activity: These agents when combined with others can prevent the emergence of resistant mutants to the companion drug. This is dependent on the ability of the agent to inhibit growth, analogous to bacterio-static activity. Isoniazid and rifampin are the most effective in this category. Ethambutol has been shown to potentiate this action of other drugs like isoniazid.

TABLE 1 Currently recommended doses of antitubercular drugs (mg/kg) Frequency of Rifampicin Isoniazid Ethambutol Pyrazinamide administration IAP-RNTCP 2012 (unpublished) Thrice weekly 15 (12-17) 15 (12-17) 30 (25-30) 35 (35-40) IAP RNTCP 2012 Daily 10-12 10 20-25 30-35 WHO 2010(13) Daily 15 (10-20) 10 (10-15) 20 (15-25) 35 (30-40) 232 Rational Antimicrobial Practice in Pediatrics

Short Course Chemotherapy (SCC) The short course regimens usually consist of two phases: an initial intensive phase of 2 months using three or more drugs, followed by a continuation phase of two drugs given for several months. The intensive initial phase is designated to eliminate quickly many logs of tubercle bacilli in all three populations, whereas the continuation phase slowly eliminates the several logs that remain. Rifampin and pyrazinamide form the backbone of modern chemotherapy. Rifampin is particularly effective against mycobacteria in closed caseous lesions, which are active in intermittent short spurts of only a few hours. Pyrazinamide was discovered to have very potent activity against organisms coated in an acid environment, especially those inside macrophages. Clinical studies indicate that it contributes to early sterilization and extends its maximum effect during the initial phase of therapy rather than throughout the full course of treatment. Isoniazid and rifampin are most commonly used in the continuation phase because they kill bacilli in all three populations. All regimes shorter than 12 months are called as short course and always have Rifampin and INH as their basic components; and to bring down this treatment period to under 9 months pyrazinamide needs to be added in the initial period called intensive phase. Shorter duration of antituberculosis chemotherapy is desirable as it improves adherence, decreases period of exposure to potentially toxic drugs and being potent it increases the likelihood of early bacteriologic killing thus decreasing period of infectiousness on therapy. Regimens using isoniazid, rifampin, pyrazinamide and streptomycin during the initial (2 months), followed by Isoniazid and Rifampin in the continuation phase (4 months), (2SHRZ/4HR) routinely yielded cure rates of greater than 98% and relapse rates less than 3%.13 This regimen was pioneered for adults with TB in Singapore and its efficacy and low toxicity confirmed by later studies in other countries.14-20 SCC has also been shown in clinical trials to be effective in treating extra-pulmonary tuberculosis in adults.21-23

Chemotherapy of Childhood Tuberculosis Childhood tuberculosis differs from adult tuberculosis in several ways that have treatment implications, viz. 1. Lack of cavitary lesions in primary disease. 2. Smaller bacterial population, hence less chances of secondary resistance while receiving therapy, even if compliance is poor. 3. Propensity for extrapulmonary disease especially disseminated disease and meningitis. 4. Higher dosage of medication tolerated. 5. Low rates of adverse reactions to medications and therefore, fewer interruptions in therapy. 6. Pediatric dosage forms not always available. 7. Noncompliance rate as high as 50%. Before 1980, guidelines for the treatment of tuberculosis in children were derived mainly from studies of adults with tuberculosis.24 Subsequently various short course Chemotherapy of Childhood Tuberculosis 233 chemotherapy trials for childhood tuberculosis were undertaken with different chemotherapy regimens.25-29 Most of the currently recommended regimens lay stress on short course chemotherapy for children as well. This usually includes an intensive initial phase of 2 months with 3 or 4 drugs to be followed by a continuation phase containing 2 drugs. Rifampin, isoniazid and pyrazinamide form the backbone of initial regimens. The current consensus amongst experts is to use an additional fourth drug if the prevalence of initial INH resistance in a community is 5% or more (as is the case in India). Ethambutol is usually recommended as the fourth drug though some still use streptomycin. With increasing experience in usage of ethambutol in pediatric cases, confidence has now been reposed in this drug as oral formulation makes it safer, easier and cheaper than injectable streptomycin. Continuation phase usually contains rifampin and isoniazid for duration of 4 months except for patients with like meningeal, disseminated or bone tuberculosis where the current recommendation is 7–10 months of continuation phase. Few studies suggest that 6 months of treatment for CNS tuberculosis and 9 months of treatment in spinal tuberculosis is adequate in achieving high cure rates.29-32 Usually all the antitubercular drugs are given orally as there are only limited choices for parenteral administration. Aminoglycosides and quinolones are the only drugs currently available for parenteral administration. However, all the oral forms of drugs can be given through nasogastric tubes. Suspension form of drugs can be made and are available for the ease of administration. The emergence of newer pharmacokinetic data has led to an upward revision of the drug dosages for childhood TB.13

Intermittent Regimens for Tuberculosis Few key events in the early 90’s resulted in global awakening to resurgence of TB and prompted intensification of global efforts for control and management of tuberculosis with the impetus coming largely from the observation of epidemiological anomalies in the USA, where there were increasing notification rates and reports of serious outbreaks of MDR-TB from hospitals in New York City and Miami.33 This acted as a strong stimulus to WHO and other International agencies to focus attention on the global tuberculosis problem. Also, problems with adherence to chemotherapy regimens and drug-resistance prompted the need for simple, shorter, more effective and compliant regimens and thus, began rediscovery of short course intermittent regimens that could be given under observation. The scientific basis of intermittent chemotherapy is the long generation time (18–21 hours) of the tubercle bacilli and lag period after chemotherapy when a culture of Mycobacterium tuberculosis was exposed to an anti-tubercular drug. When the drug was washed out after 24 hours, the organisms did not begin multiplying immediately.34-35 Their numbers continued to fall for some time before re-multiplication began. This period when the drug was not available and before organisms begin multiplying is called “Lag Phase”. It is variable with the type of drug and the length of exposure to drug. It is possible to prevent further growth of bacilli if the next dose is given before the end of the lag period and this is the basis of intermittent therapy. Most of the antituberculosis 234 Rational Antimicrobial Practice in Pediatrics drugs except thiacetazone, have a lag phase and can be given intermittently. Intermittent therapy should always be given under supervision and not as self-administration, simply because there is no scope for any further decrease in the doses received by the patient. Directly observed therapy (DOT) under which the patient actually consumes the drug in front of treatment supervisor, as is being followed currently under Revised National Tuberculosis Program, becomes easier with intermittent therapy. WHO and the Government of India recommend thrice weekly DOT regimens under Revised National Tuberculosis Program for the country.36 It must be reiterated that self-administered intermittent therapy is strongly discouraged.

Role of Corticosteroids as Adjunctive Therapy in TB In acute overwhelming TB there is significant host response associated with tissue inflammation and fibrous proliferation. The heightened host response can lead to a poor clinical outcome in cases with acute respiratory failure, acute respiratory distress syndrome, and involvement of extra pulmonary sites such as meninges, pericardium, adrenals, and peritoneum. Corticosteroid agents are beneficial in the management of tuberculosis in children when the host inflammatory response contributes significantly to tissue damage or impaired function. The addition of systemic corticosteroid therapy to TB regimens has been found useful in some clinical settings. This has been shown to reduce morbidity in patients with severe paradoxical response to drugs, miliary disease with alveolar- capillary block, pericarditis and pericardial effusion, endobronchial TB with localized emphysema or collapse-consolidation lesions, central nervous system TB, and occasionally, those with peritonitis or massive pleural effusions. Corticosteroids can also be used to suppress severe drug related hypersensitivity reactions. Corticosteroid agents reduce mortality rates and long-term neurologic sequelae in patients with tuberculous meningitis by reducing vasculitis, inflammation, and intracranial pressure. It may be useful to mention that although corticosteroid is helpful in certain patients, they should not be prescribed injudiciously due to its potential to cause dissemination of TB. For most situations, prednisolone 2-4 mg/kg/day for the initial 4 weeks and tapering doses for the next 2-4 weeks may be sufficient. The duration may be shorter in cases with pleural effusion.37

Routine Use of B6 The principal toxic effects of INH are peripheral neuritis and hepatitis. Peripheral neuritis resulting from competitive inhibition of pyridoxine utilization is a rare event in children on INH therapy. Therefore, the use of supplementary pyridoxine is not necessary routinely. However, special consideration should be given to those who have one or more of the following conditions: HIV co-infection, severely malnourished, chronic renal or liver disease, pre-existing peripheral neuropathy and exclusively breast fed babies. In such situations pyridoxine is used to prevent and treat central and peripheral nervous system side effects of INH in a dose of 25–50 mg/day. Chemotherapy of Childhood Tuberculosis 235

Establishing a Microbiologic Diagnosis of Tuberculosis The revised guidelines stress the need to establish a microbiologic diagnosis of tuberculosis in all children. This is to ensure accurate diagnosis and also to enable susceptibility testing in case drug resistance is suspected. This can be done by sputum examination in older children, induced sputum following nebulization with hypertonic saline or bronchodilators or gastric aspirate. Bronchoalveolar lavage may be done if resources permit. Patients with extrapulmonary tuberculosis should undergo fluid examination and biopsies. The material obtained should be processed for ZN stain and if resources permit for AFB culture. Various molecular methods including GeneXpert aand line probe assay are now available for rapid confirmation of a smear positive specimen as Mycobacterium tuberculosis and rapid detection of rifampicin and isoniazid resistance. These techniques can be asked for in children with suspected drug resistant tuberculosis.

Steps in Starting Appropriate Treatment Having decided the need for anti-TB treatment in a patient, it is extremely important to define the patient’s status so as to determine the regimen of chemotherapy to be used and its duration. A patient is considered as “new” case (having received treatment for less than 4 weeks) or a retreatment case (previously treated completely or, partially but for more than 4 weeks—in other words—relapse, failure and defaulters). It is equally important to decide the form of TB—pulmonary or extrapulmonary. For the purpose of notification, the pulmonary cases are further classified as smear-positive pulmonary or smear-negative pulmonary TB. A recent systematic review on the impact of initial drug resistance on treatment outcome with standardized first line treatment showed that the risk of failure as well as relapse was higher in the presence on initial resistance to INH.38 WHO now recommends against the omission of ethambutol in intensive phase for any new patient in countries where the elevated levels of primary isoniazid (INH) resistance (> 4%) have been reported and there is lack of routine testing for INH resistance.13 The RNTCP in India has, therefore, now done away with the 3 drug regime (category III).36 While in countries where the initial INH resistance in new cases is 4% or below, the paucibacillary cases like EP and Smear negative pulmonary are still given 3 drug (RHZ) initial regime. This has made the hitherto differentiation between smear negative and smear positive pulmonary cases (or an effort to differentiate paucibacillary cases from others) less relevant for treatment categorization. For the programmatic purposes, the cases are defined as smear negative and smear positive Pulmonary TB as detailed in Table 2. Relapse rate has been demonstrated to be lower with 6 months SCC with initial 4 drug regime even in countries where initial INH resistance is over 4%. Disease of organs where the penetration of drugs may not be so adequate like in bones or across meninges, require prolonged continuation phase.

 RECOMMENDED REGIMES Although several recommendations including consensus protocols have been made in the past, the newest recommendations now approved are discussed. Table 2 details 236 Rational Antimicrobial Practice in Pediatrics

TABLE 2 Treatment categories and regimens for childhood tuberculosis Category of Type of patients TB treatment regimens treatment Under RNTCP Unsupervised DOTS-intermittent regime therapy Intensive phase/ Intensive phase/ Continuation phase Continuation phase

New cases • New smear-positive 2H3R3Z3E3*/4H3R3 2HRZE/4HR pulmonary tuberculosis (PTB) • New smear-negative PTB • New extra-pulmonary TB.

Previously • Relapse, failure to 2S3H3R3Z3E3 + 2SHRZE + 1HRZE/ treated cases respond or treatment 1H3R3Z3E3/ 5H3R3E3 5HRE after default • Re-treatment Others H=Isoniazid, R= Rifampicin, Z= Pyrazinamide, E= Ethambutol, S= Streptomycin *The number before the letters refers to the number of months of treatment. The subscript after the letters refers to the number of doses per week. Pulmonary TB refers to disease involving lung parenchyma. Extrapulmonary TB refers to disease involving sites other than lung parenchyma. If both pulmonary and extra pulmonary sites are affected, it will be considered as pulmonary for registration purposes. Extrapulmonary TB involving several sites should be defined by most severe site. Smear positive: Any sample (sputum, induced sputum, gastric lavage, broncho-alveolar lavage) positive for acid fast bacilli. New Case: A patient who has had no previous ATT or for less than 4 weeks. Relapse: Patient declared cured/completed therapy in past and has evidence of recurrence. Treatment after Default: A patient who has taken treatment for at least 4 weeks and comes after interruption of treatment for 2 months and has active disease. Failure to respond: A case of pediatric TB who fails to have bacteriological conversion to negative status or fails to respond clinically or deteriorates after 12 weeks of compliant intensive phase shall be deemed to have failed response, provided alternative diagnoses/reasons for non-response have been ruled out. Others: Cases who are smear negative or extrapulmonary but considered to have relapse, failure to respond or treatment after default or any other case which do not fit the above definitions. In patients with TB meningitis on Category I treatment, the four drugs used during the intensive phase can either be HRZE or HRZS. The present evidence suggests that Ethambutol should be preferred in children.Children who show poor or no response at 8 weeks of intensive phase may be given benefit of extension of IP for one more month. In patients with TB Meningitis, spinal TB, miliary/disseminated TB and osteo-articular TB, the continuation phase shall be extended by 3 months making the total duration of treatment to a total of 9 months. A further extension may be done for 3 more months in continuation phase (making the total duration of treatment to 12 months) on a case to case basis in case of delayed response and as per the discretion of the treating physician.Under Revised National Tuberculosis Program (RNTCP, all patients shall be covered under directly observed intermittent (thrice weekly) therapy. The supervised therapy is considered as the most optimal treatment and is followed under RNTCP. It is important to ensure completion of treatment in every case put on treatment to prevent emergence of resistance, particularly to Rifampicin. In the uncommon circumstances where a patient is given daily therapy, observation and completion of therapy remains as important. It is the duty of the prescriber to ensure appropriate and complete treatment in all cases. Chemotherapy of Childhood Tuberculosis 237 the recommended regimes for management of various forms of childhood tuberculosis. Routinely no other adjunct treatment is required in most cases. IAP and RNTCP do advise use of streptomycin instead of ethambutol for new cases. It is important to note that under the revised strategy as endorsed by the government and WHO, all patients should be put on observed therapy given thrice a week. However, the same combination of drugs can be used on a daily basis if observation is not possible. It may not be out of place to emphasize that the provider should ensure adherence to treatment through proper interventions in all cases. As per current Government guidelines, the sick patients on indoor DOTS may be given a benefit of daily DOTS therapy as daily observation is possible and easy.

Monitoring of Patient on Treatment It is important to monitor the patient for: 1. Response to treatment 2. Treatment adherence 3. Occurrence of side effects

Monitoring for Response to Therapy Clinical: The clinical improvement in a patient on ATT is the mainstay of assessing the response to therapy. Symptomatic improvement should be assessed on each clinic visit especially at the end of the initial phase and in subsequent follow up, by judging the improvement of fever, decrease in cough, weight gain, improved appetite and subjective well-being, and decrease in lymph node size. Majority of the patients show clinical improvement in symptoms and signs within a few weeks time. In the presence of poor response or worsening of clinical condition, it has to be ensured that the diagnosis of TB was correct and tenable; the patient was adherent to therapy; there are no other co morbid conditions or secondary infections to explain the persistence of symptoms; in addition to investigating for the possibility of drug resistant tuberculosis. Follow-up visits need to be scheduled every 4 weeks for the duration of treatment and subsequently every 3–6 months for next 2 years particularly in children with serious disease such as congenital tuberculosis or meningitis, or those with extensive residual chest radiographic findings at the end of chemotherapy. Radiological: The patients should be assessed for resolution of the radiological abnormalities at the end of initial phase. In cases where the radiological improvement is in combination with clinical response, no further X-rays may be required. In patients, who show increase or little change in radiological shadows coupled with inadequate clinical response, the intensive phase should be extended by 4 more weeks. All efforts need to be made to isolate and determine the drug sensitivity of the mycobacteria from the patient. The patients showing improvement after extended intensive therapy can be put on continuation phase or else the patient is investigated for treatment failure and drug resistant tuberculosis. Normal chest radiograph appearance is not a necessary 238 Rational Antimicrobial Practice in Pediatrics criterion for discontinuation of therapy in children treated for primary pulmonary disease. After completion of therapy, hilar adenopathy may be present for months to few years. Microbiological: To monitor treatment outcome, it is recommended by RNTCP that all patients with pulmonary tuberculosis should have repeat sputum/gastric aspirate smears performed at the end of initial phase of treatment to detect conversion to negative status among those who were initially positive and to detect early failures in those who were AFB negative. To verify treatment success, additional sputum examinations are recommended at least once before stopping treatment.36 Where facilities are available, the cultures should be obtained at the start of treatment. Sensitivity tests for all available drugs if possible need to be performed for any new patient whose sputum is still positive at the end of the intensive phase of treatment, and for any patient suspected to be at risk of being drug resistant, e.g. relapsed cases, defaulters.

Treatment Adherence A simultaneous check on treatment adherence along with response to treatment is needed. It could be undertaken by asking the patient directly, by a pill count or prescription check and by asking for the color of the urine. Patients should be evaluated monthly and should be given only enough medicine for the interval between evaluations. As far as possible, all patients must be on Directly Observed Treatment, Short course (DOTS). The arrangements for observation of therapy must be arranged either at the nearby health facilities, family practitioner or by a responsible person/relative. The patients not on directly observed therapy should be followed up more regularly and must be made aware of his follow up appointments to ensure compliance with treatment. To strengthen patient adherence, the patient and the caregiver should always be educated about the illness and treatment, and regularly motivated during the course of treatment. Efforts should be made for prompt defaulter tracing. Often the complete treatment of a patient may entail socioeconomic assistance and advice for the family. It must be emphasized that routine hospitalization of tuberculosis patients is not required to ensure completion of treatment while those with serious sickness and complications may need to be admitted. One of the reasons for poor adherence is drug stock outs or inability to buy drugs. RNTCP in India introduced the unique feature of the free patient-wise drug boxes (PWB) for all adult and pediatric cases registered with them. These ‘‘ready-to-use’’ PWBs containing a patients’ complete course of standardized drug therapy are made available to every registered patient with TB with the patient’s name on it. This improves patient care, adherence, and ensures complete treatment of every registered patient as the drug outages on treatment are obviated. The anti-TB drugs for pediatric patients are available in the form of two generic PWBs and the different weight bands are covered by mixing and matching these PWBs. The boxes contain strips of blister combipacks with each combi- pack containing all the drugs to be consumed by the patient on a given visit. This mechanism of drug delivery ensures that the treatment of a registered case gets never interrupted due to drug outages and the risks for drug errors are few. Chemotherapy of Childhood Tuberculosis 239

Drug Toxicity Monitoring and Management Rates of adverse reactions to antituberculous drugs among children are low. The important side effects, that have clinical implications, include hepatotoxicity, ocular toxicity, and skin hypersensitivity reactions. All patients should be monitored clinically for adverse reactions during the period of chemotherapy. They should be informed about symptoms of common adverse reactions to the medications they are receiving. Children taking ethambutol require regular monitoring of visual acuity and color discrimination. Routine biochemical monitoring is usually not required Minor side effects Minor side effects, such as gastrointestinal intolerance, mild skin rash, pruritus or flushing are best managed by reassurance and symptomatic treatment and the patient should be encouraged to continue anti tuberculosis treatment. Nonsteroidal anti-inflammatory drugs (NSAID) provide symptomatic relief for pyrazinamide related arthralgia. Skin rashes can usually be managed by withholding the causative drug and if it is really necessary to reintroduce the drug, the patient should undergo desensitization.

Major side effects Physicians must manage severe skin reaction and Steven-Johnson syndrome. Other common serious drug toxicity is hepatitis.39 The factors that may decide hepatotoxicity include acetylator phenotype, doses and combination of ATDs, malnutrition, and severity of disease. As the anti-TB drugs are hepatic enzyme inducers, asymptomatic biochemical derangement without increase in billirubin level may be tolerated till the enzymes remain up to 5 times the normal range. However, if patient develops jaundice or other signs of liver dysfunction during therapy, it’s prudent to stop ATT immediately irrespective of enzyme levels. The drugs are withheld till the serum billirubin becomes normal and the enzymes also start touching the normal range. Although, many patients with drug- induced hepatotoxicity can be successfully rechallenged, this is best done in a place where liver function can be carefully monitored. The drugs should be re introduced in the order of rifampicin, followed by isoniazid and then pyrazinamide. If the period without drugs is likely to be prolonged, and the patient is sick and requires treatment, at least two other drugs (e.g., streptomycin, ethambutol, fluoroquinolones) should be given until it is determined whether the offending drug can be resumed. Drugs causing severe intolerance are best avoided and substituted with other drugs. All patients who require alteration from the standard regimen should be referred to experienced physicians. Clinical manifest neuritis in children on INH therapy due to pyridoxine deficiency is very rare. If at all it occurs, it manifest as pins and needles sensation in hands and feet. It is treated with pyridoxine 25–50 mg/day. Ocular toxicity due to ethambutol may occur in up to 5% of patients if doses are between 25-50 mg/kg/day. However, it is rare in doses of 15-20 mg/kg/day.40 The toxicity results in reversible optic neuritis, blurred vision, and alteration in colour vision. In young children if ethambutol toxicity is suspected they should be monitored by electroretinogram (ERG) in consultation with an eye specialist. However, in older patients regular monitoring of color vision is sufficient. 240 Rational Antimicrobial Practice in Pediatrics

The development of the following conditions contraindicates further use of the offending drug: • Thrombocytopenia, shock and/or renal failure due to rifampicin. • Visual impairment due to ethambutol • Eighth nerve damage from streptomycin. • Steven-Johnson syndrome.

Interruption of Treatment Patient compliance is crucial factor in treatment failure and the development of acquired drug resistance. It is very important to realize that the emergence of MDR TB is always a man made problem and failure of the patient to complete the prescribed course completely and adequately is one of the reasons. In general, if it is certain that the patient was taking all medications correctly prior to interruption, then she/he can be managed as per the guidelines for treatment after interruption shown in Table 3. Whenever treatment is interrupted for more than 2 weeks, the child should be reassessed clinically and radiologically, with bacteriological examination, wherever possible. In all such cases the resumption of treatment must be preceded by evaluation for activity and investigating the causes for nonadherence. The pediatrician should not merely restart the treatment but also enable the completion of treatment by addressing issues related to nonadherence in the first instance. Addressing issues like side effects of the therapy (real or perceived), cost involved as well as educating about the need for a complete treatment even after the symptoms abate may help adherence. Both the child as well as the caregivers must be involved in decision making for re-initiating treatment.

Drug Resistant Tuberculosis Drug resistance in tuberculosis has become an important public health problem because of selection of strains resistant to potent drugs like rifampin and INH leading to failure

TABLE 3 Managing patients with interruptions in treatment Duration of therapy Duration of interruption Decision Up to 4 weeks <2 weeks Resume original regime > 2 weeks Reassess and start treatment again 4–8 weeks <2 weeks Resume original regime 2–8 weeks Extend intensive phase by 1 month more >8 weeks Consider Cat II if diagnosis is still TB. > 8 weeks <2 weeks Resume original regime >2 weeks. Review • No Active disease: activity Continue same treatment • Active disease: Category II therapy Chemotherapy of Childhood Tuberculosis 241 of first line drugs. It is primarily a microbiological diagnosis. Documentation of the level of drug resistance in the community is important in order to monitor the impact of RNTPC program over time and to ensure that the treatment regimens are appropriate.2 Various types of drug resistance are described below: • Multidrug-resistant tuberculosis (MDR TB). It is caused by strains of Mycobacterium tuberculosis that are resistant to at least isoniazid (INH) and rifampicin (RMP) with or without resistance to other first line drugs. • Polyresistance: Strains of Mycobacterium tuberculosis that are resistant to combination of drugs other than both isoniazed and rifampic in are called polyresistant. • Extensively resistant tuberculosis (XDR TB). Infection by multidrug resistance (MDR) strains of Mycobacterium with additional resistance to any fluoroquinolone and one of the three second line injectable drugs amikacin, kanamycin or capreomycin, is labelled as XDR-TB. • Pan-drug or totally drug resistant tuberculosis (TDR-TB) is caused by strains of Mycobacteria resistant to all known antitubercular drugs. The treatment of drug resistant tuberculosis is challenging because of the complexity of the drug regimens, adverse drug reactions secondary to second line antitubercular drugs and social and financial constrains to treatment. Furthermore, in the absence of any new potent anti-tubercular drug being discovered in the last 4 decades, the resistant strains are difficult to manage and treat with the use of the existing armamentarium. Drug resistant tuberculosis in children is usually a sentinel event. It reflects on poor management of the infectious pool, usually the adult patients. This results not only in an increase in number of childhood cases but also an increase in infection with drug resistant bacilli. In general, the pattern of drug resistance in children tends to mirror that found in the adult patients in the same population.41,42

When to Suspect Drug Resistance The sputum of disease caused by drug resistant organism is not different from that caused by drug susceptible bacilli. The only certain way of diagnosing resistant tuberculosis is by isolating the infective strain and assessing its susceptibility pattern despite the difficulties. It is imperative to attempt to isolate the bacteria with all the possible modalities viz. induced sputum, concentrated smears, BAL, or direct FNAC of the involved areas, etc. because many cases referred as MDR TB may not be showing any response to anti-TB drugs because of a faulty diagnosis rather than a nonresponse due to resistance. The specimen should be cultured and if AFB are grown on culture, they should be sent foir susceptibility testing to a standardized lab. At present, new genotypic methods such as GeneXpert and line probe assay are available that can determine susceptibility to isoniazid and rifampicin in a matter of hours in smear positive samples. History of prior antitubercular therapy with persistent sputum positivity is an epidemiological pointer towards the high-risk of drug resistance in any individual. Children, who are contacts of such adult patients can, therefore, be suspected to harbor resistant bacilli and should be watched diligently for any lack of response or deterioration on treatment with first line drugs. 242 Rational Antimicrobial Practice in Pediatrics

Chemotherapy of Drug Resistant Cases Second line drugs are very expensive and the response to treatment is much poorer among those who are susceptible to first line drugs. Because of the relative poorer efficacy (about 50–60% cure rates), they are generally prescribed for about 18 to 24 months that not only adds to the cost but also increases the default rate. Even though the children tolerate the second line drugs better than the adults, yet the adverse effects with these are much higher than with the first line drugs. The average cost of treatment in children would approximate to more than sixty times the cost of treatment with the first line drugs, and this is one of the biggest hurdles in treatment of drug resistant cases. Table 4 gives the relevant details regarding the second line drugs available in our country, their dosage, formulation, and side effects. The choice of antitubercular drugs to be used should ideally be based on the sensitivity pattern of the isolate from the patient or it may be feasible to identify the source case, and the isolate from this adult case can be used to assess the drug susceptibility pattern. Most initial regimens should contain at least two or three new bactericidal drugs (which commonly includes an injectable drug) to that the organism is susceptible. The selection of drugs is also dependent upon the agents to that the patient has already been exposed. When drug resistance is suspected, at least three, and often four or five drugs should be given initially until the exact susceptibility pattern is determined and a more specific regimen can be designed. In designing a regimen do not aim to keep drugs in reserve. This last battle must be won. However, it must be mentioned that such cases should only be managed by or in consultation with those having experience in the field because the therapy is difficult, has lots of side effects, needs regular assessment for efficacy and it is the final battle. Strategies to improve treatment adherence, such as directly observed therapy–DOTS- Plus, should be used.2

Extrapulmonary Tuberculosis Controlled trials of various forms of extrapulmonary tuberculosis are virtually nonexistent.15,43 In most reports extrapulmonary forms have been combined with pulmonary cases and are often not analyzed separately. Extrapulmonary tuberculosis is associated with lower bacillary burden than pulmonary disease, therefore, extrapulmonary disease generally can be treated with standard short-course regimens that are effective for pulmonary disease. Owing to the serious implication of relapsed disease at sites of potentially limited drug penetration, most clinicians treat miliary, meningeal, and skeletal tuberculosis for 9 to 12 months using 3 or 4 drugs in initial phase of treatment.13 Adequate surgical debridement and stabilization of bone and joint tuberculosis should be considered in addition to chemotherapy.

Congenital Tuberculosis Congenital tuberculosis is defined as tuberculosis occurring in an infant as a result of infection with M. tuberculosis during intrauterine life. It can occur after maternal Chemotherapy of Childhood Tuberculosis 243

TABLE 4 Reserve drugs available for treatment of MDR-Tuberculosis in India49 Drug Daily dose Cross CSF Adverse effects / and route Resistance penetration comments Ethionamide 10–20 mg/kg/d, INH Good Gastric Intolerance, Oral, qod Hepatitis, hypothyroidism Prothionamide 10-20 mg/kg/d, INH Good Gastric Intolerance, oral, qod Hepatitis Kanamycin 15-20 mg/kg/d, Amikacin Poor Auditory and IM Inj, qod vestibulo-toxicity Amikacin 15-20 mg/kg/d, Kanamycin Poor Auditory and IM Inj, qod vestibulo-toxicity, Nephrotoxic Capreomycin 15 mg/kg/ IM qod Kanamycin, Poor Audiotoxicity, amikacin nephrotoxicity 15 mg/kg/d, None Good Psychosis, Oral, qod depression, seizures, pyridoxine deficiency Ciprofloxacin 15–20 mg/kg/d, Partial cross Poor Not generally Oral, qod/bd resistance approved for pediatric with other use but can be used quinolones in MDR TB, Risk of arthropathy in children Ofloxacin 15–20 mg/kg/d, Partial cross Poor oral, qod/bd resistance with other quinolones Levofloxacin 10 mg/kg/d qod moxifloxacin Good Moxifloxacin 10 mg/kg/day qod levofloxacin Good Para amino- 150-300 mg/kg/d, None Inflamed Gastric intolerance, salicylic acid oral, qod/bd meninges Hepatitis, (PAS) hypothyroidism Clofazimine 1–2 mg/kg/d qod None Poor Hyperpigmentation Linezolid 10 mg/kg/d qod None Good Peripheral neuropathy thrombocytopenia Clarithromycin 15 mg/kg/d bd None Poor GI side effects Coamoxiclav 20 mg/kg/d bd None Poor GI side effects *These drugs are more difficult to use then the drugs listed in Table 1. They should be used only when they are necessary, and they should be given and monitored by health providers experienced in their use. 244 Rational Antimicrobial Practice in Pediatrics bacteremia at different stages in the course of tubercular disease. Postnatal tuberculosis, on the other hand, is usually acquired from a mother, other close family member, or caregiver with cavitary tuberculosis. In 1935, Beitzke suggested criteria for distinguishing congenital from postnatally acquired tuberculosis.44 Cantwell and coworkers45 revised this criteria making it more appropriate. According to them, the infant with congenital tuberculosis must have proven tuberculous lesions and at least one of the following: 1. Lesions in the first week of life; 2. A primary hepatic complex or caseating hepatic granulomas; 3. Tuberculous infection of the placenta or the maternal genital tract; or 4. Exclusion of the possibility of postnatal transmission by a thorough investigation of contacts, including the infant’s hospital attendants. Usually these infants should be treated as severely sick patients using 4-drug regime discussed earlier. Although the optimal duration of therapy has not been established, many experts treat infants with congenital tuberculosis for about 9 to 12 months because of the decreased immunologic capability of the young infant. Clinical experience suggests that the drugs in usual doses are effective and safe in young infants.

Tuberculosis and HIV Patients with severe malnutrition, hematological and reticuloendothelial malignancies, chronic renal failure, and HIV infection, as well as those taking immunosuppressive drugs, are all at greater risk for developing tuberculosis disease if infected. Furthermore, in these patients with cell mediated immune defects there are increased chances of extra- pulmonary and disseminated tuberculosis. Impact of co-infection with HIV and TB is, however, more complex as it is bi-directional. HIV and TB intersect each other at various levels and fuel each other.47 As a consequence of co-infection, TB accelerates the natural history of HIV, leading to early death. This supported by the evidence that HIV bDNA levels are higher in the involved segments of lung and decline with treatment. Thus, patients not on ART may be at disadvantage if tuberculosis treatment or diagnosis is delayed due to enhanced HIV replication. On the other hand HIV infection greatly increases the risk of active TB in children co-infected with M. tuberculosis by 10 times as compared to those without co infection (~10%per yr).48 Chemoprophylaxis is thus an important strategy for prevention of disease in such individuals. Clinical presentation of TB co-infection is similar to as in non-HIV infected children, though extrapulmonary involvement is more common. Severely immunocompromised children are more likely to have extensive/-disseminated disease. The diagnosis is more difficult as the disease is more often AFB negative and tuberculin skin test positivity is very low. The possibility of paradoxical reactions on drugs as a cause of clinical deterioration in HIV infected children with TB should be kept in mind. There are other issues in the management of coinfected patients due to drug interaction. Rifampin and protease inhibitors like Saquanavir, Ritonavir, and Non-nucleoside reverse transcriptase inhibitors (NNRTIs) like Nevirapine have appreciable pharmacologic interaction in the hepatic p450 system. This could lead to significant reduction of the serum levels Chemotherapy of Childhood Tuberculosis 245 of ARV and hence an increased risk of resistant HIV. Choosing instead to treat without Rifampin, has greater complexity as there can be difficulties due to poorer adherence and prolonged duration. In treatment of the co-infection in severely compromised, neither the nonuse of PIs and/or NNRTIs in the ARV regimen nor the non-inclusion of Rifampin in the treatment ATT is acceptable. Even if alternative treatment is devised like use of Abacavir and/or NRTIs with Rifampin, there are problems due to large number of drugs that need to be taken, side effects, bitter taste, lack of pediatric formulations and cost. Often a trade off is made for isolated treatment of tuberculosis in coinfected patients as it also reduces the plasma viral load as a matter of course without ARV. Postponing commencement of the antiretroviral treatment for patients with HIV/ tuberculosis co-infection, particularly in those patients who have less serious immunodeficiency levels from a clinical and laboratorial point of view is often resorted to.

Regime to Use 3 WHO recommends that ART in a patient with CD4 count less than 200/mm , to be started 2 weeks to 2 months after starting of tuberculosis therapy. However, if CD4 count is higher and there is no pressing need to start ART, such treatment can wait until induction phase or complete treatment of tuberculosis is completed, to have better adherence.47 However, if the patient is in advanced stage of the illness (usually with CD4 count <50–100/mm3) and needs ART urgently or if a patient develops TB while on ART then concurrent ATT and ART cannot be avoided. In such a situation, modification of ATT and/or ART regimen is required. Non-rifampin based ATT is no longer recommended, as it has been associated with an increased incidence of severe cutaneous hypersensitivity reactions, lower rates of bacillary conversion, higher treatment failure and relapse rate, and increased mortality. Rifabutin can be substituted for rifampin, and suitable dosage adjustments in ATT and/or ART made, especially in patients undergoing protease inhibitor antiretroviral therapy. The recommended regime for TB preventive therapy in HIV infected children is daily isoniazid at 10 mg/kg for 9–12 months. The AAP currently recommends a 9-month course of isoniazid with Pyridoxine supplementation.48,49 BCG administration to all symptomatic HIV infected children should be continued and surveillance to detect BCG adverse effects strengthened.

Preventive Therapy of Tuberculosis Chemoprophylaxis of tuberculosis involves usage of one or more antitubercular drugs in persons already infected or suspected of being infected with tuberculosis in order to prevent occurrence of active disease in future. Thus, it prevents occurrence of disease in already infected individual and thereby decreasing the potential future source of infection. The children and adults in close contact with an adult suspected of having infectious pulmonary tuberculosis should be tuberculin skin tested and examined as soon as possible. On average, 30–50% of household contacts to infectious cases will be tuberculin skin 246 Rational Antimicrobial Practice in Pediatrics test positive, and 5% of contacts already have overt disease. The lifetime risk of developing disease in an individual with tuberculosis infection is 10%. Risk is 10 times more in HIV infected individuals. The subject of preventive therapy is fraught with controversies regarding the number of drugs to be used, the ideal duration of treatment and the age and conditions under which the therapy is indicated. The risk of development of disease is highest just after the infection has occurred and gradually decreases with time. Recent converters are usually defined as individuals whose tuberculin test reaction increased by at least 6 mm, from <10 mm to >10 mm within past 2 years. Children, particularly those with a history of a recent contact with an infectious case or recent tuberculin convectors are at special risk of developing full- blown disease. Therefore, children form a major group requiring preventive treatment. Isoniazid therapy for latent tubercular infection appears to be more effective for children than adults, with several large clinical trials demonstrating risk reduction by 70% to 90%. Also, the risk of isoniazid-related hepatitis is minimal in infants, children and adolescent, who generally tolerate the drug better than adults. The dosage is 10 mg/kg body weight daily therapy. It’s vital to rule out disease in all cases before prophylactic INH therapy is started in any individual. Among patients with average compliance, 6-month treatment appears to yield the best benefit risk ratio. Snider et al showed that the 24-week regimen is most cost effective.50 The AAP currently recommends a 9-month course of isoniazid with effectiveness of over 90%.49 The WHO and RNTCP India recommend that all children less than 6 years of age who are in contact of an infectious case should be put on isoniazid therapy. This includes all asymptomatic contacts (under 6 years of age) of a smear positive case, after ruling out active disease and irrespective of their BCG, TST or nutritional status. Chemoprophylaxis is also recommended for (a) all HIV infected children who either had a known exposure to an infectious TB case or are Tuberculin skin test (TST) positive (>=5 mm induration) but have no active TB disease. (b) All TST positive children who are receiving immunosuppressive therapy (e.g. Children with nephrotic syndrome, acute leukemia, etc.), (c) A child born to mother who was diagnosed to have TB in pregnancy should receive prophylaxis for 6 months, provided congenital TB has been ruled out. BCG vaccination can be given at birth even if INH chemoprophylaxis is planned.

Management of a Neonate Born to a Mother with Tuberculosis Prophylactic INH (10 mg/kg/day) for newborns born to mother with tuberculosis has been so efficacious that separation of the mother and infant is no longer considered mandatory once therapy is started. BCG vaccine should be given at birth. Separation should occur only if the mother is ill enough to require hospitalization, if she has been or is expected to become non-adherent to her treatment, or if she is infected with a drug resistant strain of M. tuberculosis. INH therapy should be continued in the infant at least until the mother has been shown to be culture negative for 3 months. At that time, a tuberculin skin test (TST) can be done on the child, and prophylaxis stopped if TST is negative. Many prefer to continue INH prophylaxis for a total of 6–9 months irrespective of TST and therefore may not even ask for any TST once INH therapy Chemotherapy of Childhood Tuberculosis 247

Figure 1: The hypothesis on the action of drugs according to their speed of growth at the start of treatment. INH kills multiplying bacilli. Rifampin (RMP) kills bacilli when there are spurts of metabolism. PZA is the only drug, which kills dormant bacilli. is started. If the mother with contagious tuberculosis has been suspected of being infected with a MDR stain or has poor compliance to treatment and better supervision of therapy for the adult and infant is not possible, the Centers for Disease Control and Prevention recommends that the infant should be separated from the mother and vaccination with BCG may be considered. Vaccination with BCG appears to decrease the risk of tuberculosis in exposed infants, but the effect is variable.

CONCLUSIONS 1. The aim of antituberculosis treatment is to: cure the patient in as short a time as possible; prevent death or late effects from disease; prevent relapse; prevent emergence of drug resistance; and to protect community from infection. 2. Intensive short course chemotherapy is better than traditional two-drug regimens due to faster sterilization and bactericidal action, shorter duration over which patient noncompliance can occur, less expensive on monitoring of treatment, lower failure and relapse rate, and broader coverage of possible drug-resistant M. tuberculosis. 3. The best-studied 6-month regimen for pulmonary tuberculosis in children is an intensive phase of 2-month of daily HRZE, followed by 4-months of HR, given supervised daily or thrice weekly. 4. In general extrapulmonary tuberculosis in children should be treated in the same way as pulmonary tuberculosis, except bone and joint disease and meningitis for which there are inadequate data to support 6-month therapy at present. 5. Routine biochemical monitoring is not required, however, monthly physician-patient contact is required to ensure compliance and assess for toxicity and efficacy of therapy. 6. Patient compliance is a crucial factor in treatment failure and the development of acquired drug resistance. Whenever possible, TB treatment should be administered as directly observed therapy. 7. Both the physician and the patient share responsibility for successful treatment. 248 Rational Antimicrobial Practice in Pediatrics

 REFERENCES 1. Global tuberculosis control: WHO Report 2011. 2. RNTPC Status Report Central TB Division, Ministry of Health and Family Welfare, Delhi: TB India; 2012. 3. Singh V. Tuberculosis in children: Some issues. Health for Millions. 1995;21:27-8. 4. Bloch AB, Snider DJ. How much tuberculosis in children must we accept? Am J Pub Hlth. 1986;76:14- 5. 5. Infectious Disease and Immunization Committee, Canadian Pediatric Society: Childhood tuberculosis: Current concepts in diagnosis. The Canadian Journal of Pediatrics. 1994;1:97-100. 6. Starke JR. Childhood tuberculosis: Ending the neglect. Int J Tuberc Lung Dis. 2002;6:373-74. 7. Mitchison DA. The diagnosis and therapy of tuberculosis during the past 100 years. Am J Respir Crit Care Med. 2005;171:699-706. 8. Starke JR. Multidrug therapy for tuberculosis in children. Pediatr Infect Dis J. 1990;9:785-93. 9. Mitchison DA. Mechanism of drug action in short course chemotherapy. Bull Intern Union Against Tuberc. 1985;60:34-7. 10. Mitchison DA. The action of antituberculous-drugs in short course chemotherapy. Tubercle. 1985;66:219-25. 11. Grosset J. Bacteriologic basis of short course chemotherapy for tuberculosis. Clin Chest Med. 1980;1:231-41. 12. Grosset JH. Present status of chemotherapy for tuberculosis. Rev Infec Dis. 1989;11(suppl 2):342-7. 13. World Health Organization. Rapid advice: treatment of tuberculosis 1 in children. Geneva, Switzerland: WHO Press; 2010. Available at http://whqlibdoc.who.int/publications/2010/9789241500449_eng.pdf. [Accessed 26th ep 2012] 14. D’Esopo ND. Clinical trials in pulmonary tuberculosis. Am Rev Respir Dis.1982;125(Suppl):85. 15. Dutt AK, Moers D, Stead WW. Short-course chemotherapy for extrapulmonary tuberculosis: nine years experience. Ann Intern Med. 1986;104:7-12. 16. Snider DE, Graczyk J, Bek E, et al. Supervised six-months treatment of newly diagnosed pulmonary tuberculosis using isomiazid, rifampin and pyrazinamide with and without streptomycin. Am Rev Respir Dis. 1984;130:1091-6. 17. Singapore Tuberculosis Service/British Medical Research Council. Long-term follow-up of a clinical trial of six-month and four-month regimens of chemotherapy in treatment of pulmonary tuberculosis. Am Rev Respir Dis. 1986;133:779-83. 18. East and Central African/British Medical Council Fifth Collaborative Study. Controlled clinical trial of 4 short course regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis: final report. Tubercle. 1986;67:5-15. 19. Baba H, Shinkai A, Izuchi R, Azuma Y. Controlled clinical trial of 4–6 months regimens of chemotherapy for pulmonary tuberculosis. Bull Int. Union Tuberc. 1984;59:26-9. 20. British Thoracic Society. A controlled trial of 6-month chemotherapy in pulmonary tuberculosis. Final Report: results during the 36 months after the end of chemotherapy and beyond. Br. J Dis Chest. 1984;78:330-6. 21. British Thoracic Research Committee. Short-course chemotherapy for tuberculosis of lymph nodes: A controlled trial. Br Med J. 1985;290:1106-8. 22. Gon JG. Genitourinary tuberculosis: a 7-year review. Br J Urol. 1979;51:239-47. 23. Medical Research Council Working Party on Tuberculosis of the Spine. A controlled trial of six-month and nine-month regimens of chemotherapy in patients undergoing radical surgery for tuberculosis of the spine. Tubercle. 1986;67:243-59. 24. Smith MHD. What about short course and intermittent chemotherapy for tuberculosis in children? Pediatr Infect Dis J. 1982;1:298-303. 25. Dingley HB. Short-term chemotherapy in tuberculosis in children. Ind J Tub 1981; 29: 48. 26. Kulkarni, Vidyagouri, et al. Proceedings of the 21st National Conference of Indian Academy of Pediatrics, Bombay, December 1984; 104. 27. Francisco JC, Reis, Maria BM, Bedran, Jose AR, et al. Six month Isoniazid–Rifampicin Treatment for Pulmonary Tuberculosis in Children. Amer Rev of Resp Dis. 1990;142:996. Chemotherapy of Childhood Tuberculosis 249

28. Varudkar BL. Short course chemotherapy for tuberculosis in children. Indian J Pediatr. 1985;52: 593-7 29. Van Loenhout–Rooyackers JH, Keyser A, Laheij KJ, Verbeek aL, van der Meer JW. Tuberculous meningitis: is a 6-month treatment regimen sufficient? Int J Tuberc Lung Dis. 2001;5:1028-35. 30. Donald PR, Schoeman JF, van Zyl LE, De Villiers JN, Pretorius M, Springer P. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis. 1998;2:704-11. 31. Rajeshwari R, Balasubramaniam R, Venkatesan P, Siva Subramaniam S, Soundarapandian S, Shanmugasundaram TK, et al. Short course chemotherapy in the treatment of Pott’s paraplegia: report on five year follow-up. Int J Tuberc Lung Dis. 1997;1:152-8. 32. Jacobs RF, Sunakorn P, Chotpitayasunonah T, Pope S, Kelleher K. Intensive short course chemotherapy for tuberculous meningitis. Pediatr Infec Dis J. 1992;11:194-8. 33. Centers for Disease Control. Nosocomial transmission of multidrug-resistant tuberculosis among HIV- infected persons–Florida, New York, 1988-91. MMWR 1991;40: 585-91. 34. Dickinson JM, Mitchison DA. Short-term intermittent chemotherapy of experimental tuberculosis in the guinea pig. Tubercle. 1966;47:381-93. 35. Grumbach F, Canetti G, Grosset J, Lirzin ML. Late results of long-term intermittent chemotherapy of advanced, murine tuberculosis: Limits of the murine model. Tubercle. 1967;48:11-26. 36. Training module for Medical practitioner. TBC India accessed from http://www.tbcindia.nic.in/pdfs/ TrainingModuleforMedicalPractitioners.pdf on 15 Sep 2012. 37. Moore DP, Schaaf HS, Nuttall J, Marais BJ. Childhood tuberculosis guidelines of the Southern African Society for Paediatric Infectious Diseases. South Afr J Epidemiol Infect. 30 2009;24(3):57-68. 38. Lew W, Pai M, Oxlade O, Martin D, Menzies D. Initial drug resistance and tuberculosis treatment outcomes: systematic review and meta-analysis. Ann Intern Med. 2008 Jul 15;149(2):123-34. 39. O’brien RJ. Hepatotoxic reaction to antituberculous drugs: adjustments to therapeutic regimen. JAMA. 1991;265:3323. 40. Graham SM, Daley HM, Banerjee A, Salanipon FM, Harries AD. Ethambutol in tuberculosis: time to reconsider. Arch Dis Child. 1998;79:274-8. 41. Iseman, M.D. Treatment of multidrug-resistant tuberculosis. New Engl J Med. 1993;329:784-91. 42. Mukherjee JS, Rich ML, Socci AR, et al. Programmes and principles in treatment of multidrug resistant tuberculosis. Lancet. 2004;363:474-81. 43. Reider HL, Snider DF, Cauthen GM. Extrapulmonary tuberculosis in United States. Am Rev Respir Dis. 1990;141:347-51. 44. Beitzke H. Ueber die angeborene tuberkuloese infection. Ergeb Gesamte Tuberkuloseforsch. 1935;7:1- 30. 45. Cantwell MF, Shehab ZM, Costello AM. et al. Brief report: congenital tuberculosis. N. Eng J Med 1994;330:1051-54. 46. Cotton MF, Schaff HS, Hesseling AC, Madhi SA. HIV and childhood tuberculosis: the way forward. Int J Tuberc Lung Dis. 2004;8:675-82. 47. Kaplan JE, Masur H, Holmes KK, USPHS, Infectious Diseases Society of America. Guidelines for preventing opportunistic infections among HIV-infected persons –2002. Recommendations of the U.S. Public Health Service and the Infectiuos Diseases Society of America. MMWR Recomm Rep. 2002;51:1- 52. 48. Centers for Disease Control and Prevention. Treatment of Tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR. 2003;52:1-74. 49. American Academy of Pediatrics. Tuberculosis. In Pickering LK (ed): 2000 Red Book: Report of the committee on infectious diseases. 25th edition Elk Grove Village, IL: American Academy of Pediatrics. 2000:593-613. 50. Snider DE, Caras GJ, Koplan JP. Preventive therapy with isoniazid: cost effectiveness of different duration of therapy. JAMA. 1986;25:1579-83. 250 Rational Antimicrobial Practice in Pediatrics 2121 Antimicrobial Therapy in Enteric Fever Tanu Singhal, Nitin K Shah

 INTRODUCTION Enteric fever results from infection with Salmonella typhi/paratyphi A/B/C (now termed as Salmonella enterica serotype typhi or Salmonella enterica serotype paratyphi). Infections due to Salmonella typhi (typhoid fever) are the commonest, but with increasing immunization with the typhoid Vi vaccine, cases of paratyphoid fever (Salmonella paratyphi A) are on the rise.1,2 It is estimated that globally there were 21.65 million new cases of typhoid fever in 2000, with an estimated 216, 510 deaths.3 Paratyphoid illnesses were estimated to be 5.14 million in the same year.3 With increasing multidrug and quinolone resistance in Salmonella typhi/paratyphi, therapy of enteric fever is becoming more complicated and expensive.4 This chapter attempts to discuss currently available therapeutic options for enteric fever. It must be remembered that these recommendations are likely to change in future with change in antimicrobial susceptibility of S. enterica.

 ANTIMICROBIAL RESISTANCE IN SALMONELLA TYPHI/PARATYPHI Before deliberating on therapeutic options it is important to discuss the antimicrobial sensitivity of Salmonella typhi/paratyphi. The introduction of chloramphenicol in the 1940’s was followed by development of resistance within the next two years.4 However, it was not until 1972 that chloramphenicol-resistant typhoid fever became a major problem.4 Chloramphenicol resistance was associated with high-molecular-weight, self-transferable, HI plasmids. These S. typhi strains were also resistant to sulfonamides, tetracycline, and streptomycin, but amoxicillin and trimethoprim–sulfamethoxazole remained effective alternative drugs.4 Towards the end of the 1980s and the 1990s, S. typhi developed resistance simultaneously to all the drugs that were then used as first-line treatment Antimicrobial Therapy in Enteric Fever 251

(chloramphenicol, trimethoprim, sulfamethoxazole, and ampicillin). Outbreaks of infections with these strains occurred in India, Pakistan, Bangladesh, Vietnam, the Middle East and Africa.4 Fluoroquinolones were introduced in the late 1980’s and early 1990’s and produced very good results. However, the past decade has seen a progressive increase in the MIC’s of ciprofloxacin in Salmonella typhi and paratyphi.1,4 Since the current MIC’s are still below the NCCLS susceptibility breakpoint, laboratory reports will continue to report Salmonella typhi/paratyphi as ciprofloxacin/ofloxacin sensitive.5 However, use of fluoroquinolones in this scenario is associated with a high incidence of clinical failure as drug levels needed to kill organisms with such high MIC’s are definitely not achieved with standard doses and even with highest tolerated doses.1,4,5 It has also been demonstrated that resistance to nalidixic acid is a surrogate marker for high ciprofloxacin MIC’s, predicts fluoroquinolone failure and can hence be used to guide antibiotic therapy (i.e. if culture results show resistance to nalidixic acid irrespective of the results of ciprofloxacin/ ofloxacin sensitivity, quinolones should not be used or if used high doses should be given).6 Since MIC testing is not within the scope of most laboratories, nalidixic acid susceptibility testing is mandatory to help guide choice of antibiotics. The 2012 CLSI guidelines have lowered the break points for quinolones in Salmonella enterica as a result of which most strains will be reported as resistant and this discrepancy between in vivo and in vitro susceptibility will be resolved. With the emergence of quinolone resistance there has also been a return in sensitivity to first line antibiotics such as chloramphenicol, cotrimoxazole and ampicillin.1 However, concerns of toxicity have precluded their widespread use and beta lactams such as ceftriaxone and cefixime are now used as first line agents for therapy of enteric fever. Increase in MIC’s to ceftriaxone in Salmonella has been reported and so has been high-level resistance to ceftriaxone (minimal inhibitory concentration [MIC], 64 mg per liter).4,7,8 Additionally, there are recent publications reporting ESBL production in large percentage of Salmonella paratyphi isolates from Nepal and also Amp C production.9,10 Fortunately however, as of now most Salmonella enterica isolates remain susceptible to the third generation cephalosporins. Table 1 shows data on antimicrobial susceptibility of S. typhi at Hinduja Hospital, Mumbai and reflects the evolution of antimicrobial resistance in Salmonella typhi/paratyphi (unpublished data). Another point worth mentioning is discordance between in vitro and in vivo susceptibility in Salmonella enterica. Though Salmonella shows in vitro susceptibility to aminoglycosides and 2nd generation cephalosporins, these agents are not associated with good in vivo responses and should not be used to treat enteric fever.11

 THERAPEUTIC OPTIONS FOR ENTERIC FEVER (TABLE 2) Cephalosporins Ceftriaxone This is currently the preferred drug for inpatient therapy and severe enteric fever. Salmonella is at present almost always susceptible to this drug.4 The recommended dose is 75-100 mg/kg/day (maximum 4 gm/day) as single or two doses. The average fever clearance time is around 1 week.4 Clinical failure defined as persistent symptoms or 252 Rational Antimicrobial Practice in Pediatrics

TABLE 1 Antimicrobial sensitivity data of S. typhi at PD Hinduja National Hospital and Medical Research Centre, Mumbai Year No of isolates MDR* (%) MIC of Cipro (g/ml) Nalidixic resistance (%) 1990 101 74 0.002–0.0039 0 1992 96 66 0.0039–0.032 0 1994 110 40 0.032–0.064 2 1996 98 54 0.032–0.125 7 1998 106 52 0.125–1a 0.032–0.094b 67 2000 240 46 0.5–1a 0.032–0.094b 82 2002 277 17 0.19–1.5a 032–.094b 92 2003 167 7 0.19–2.0a 032–.094b 92 *Resistance to Chloramphenicol, Ampicillin, Cotrimoxazole a Nalidixic acid resistant strains b Nalidixic acid sensitive strains

TABLE 2 Therapeutic options for enteric fever4 Drug Dose (mg/kg/day) Time to Clinical failure* Relapse rate and duration defervescence* % (95% CI) %(95% CI) in days (95% CI) Ceftriaxone 75–100 ×14 days 6.1 (5.9–6.3) 8.7 (6.1–12) 5.3 (3.7–8.2) Cefixime 20 × 14 days 6.9 (6.7–7.2) 9.4 (5.5–15.3) 3.1 (1.2–7.5) Aztreonam 50–100 × 14 days 5.8 (5.7–5.9) 6.9 (3.1–14.2) 1 (0.05–6.2) Ampicillin 200 × 14 days 6.4 (6.3–6.6) 7.9 (5.1–11.9) 2.2 (0.9–5.0) Amoxicillin 100 × 14 days Chloramphenicol 50–75 × 14 days 5.4 (5.3–5.5) 4.8 (3.7–6.3) 5.6 (4.3–7.2) Cotrimoxazole 10 (TMP) × 14 days 6 (5.8–6.2) 9.3 (6.3– 13.4) 1.7 (0.5–4.6) Azithromycin 10–20 × 7 days 4.4 (4.2– 4.5) 3.2 (1.2–7.7) 0 (0–3) Ciprofloxacin/ 20 × 7 days 3.9 (3.8–3.9) 2.1 (1.4–3.2) 1.2 (0.7–2.2) Ofloxacin • Strains fully susceptible in vitro to the antibiotic used with the exception of quinolones wherein 4% of the strains were nalidixic acid resistant development of complications necessitating further antimicrobial treatment (in spite of the strain being susceptible) has been reported in 5–10%.4 Occasional cases of microbiologic failure (positive cultures at end of therapy) have also been reported. The relapse rate is around 5–10% and depends on duration of therapy. A randomized controlled trial Antimicrobial Therapy in Enteric Fever 253 by Bhutta et al demonstrated relapse rates of 15% with 7 days treatment versus 5% with 14 days therapy.12 Hence 14 days therapy is recommended. However, the course of therapy may be completed with oral third generation cephalosporins/outpatient parenteral therapy once complications have resolved, defervescence is achieved and oral intake is satisfactory. The main limitations of ceftriaxone include cost, need for parenteral therapy and hospitalization, prolonged time to defervescence and significant relapse rates. In some patients biliary sludging can occur during therapy and if symptomatic may warrant change in treatment. Cefotaxime in a dose of 200 mg/kg/day in 3 divided doses and cefoperazone in a dose of 100 mg/kg/day in two/three divided doses can be used instead of ceftriaxone but there is no added advantage over ceftriaxone, experience is limited and more frequent administration is required.4,13

Cefixime This oral third generation cephalosporin is used for outpatient therapy of enteric as well as a switch over drug to ceftriaxone. Trials have shown superior efficacy to quinolones and chloramphenicol in areas where there is high prevalence of resistance to these antibiotics and comparable efficacy to ceftriaxone.14-16 The dose of cefixime is not standardized and doses ranging from 10-20 mg/kg/day have been used in various trials. Since Salmonella is an intracellular pathogen and has high MIC’s to cefixime higher doses (20 mg/kg/day, max 1200 mg/day) are preferred. The mean fever clearance time is around 1 week with rates of clinical failure and microbiologic failure range from 5-15% and 0.5 -5% respectively.4 Relapse rates range from 1–10% in various studies. At least 2 weeks of treatment should be given. The main limitation of cefixime is the cost of therapy, need for compliance and since this is a 3rd generation cephalosporin, promotion of drug resistance.

Cefpodoxime This is a relatively new oral third generation cephalosporin with similar gram-negative coverage as cefixime but superior gram-positive activity than cefixime. A single open labeled study from Pakistan demonstrated 86% clinical efficacy in children with typhoid fever.17 Experience is limited, the dose is yet not standardized (probably higher doses in the range of 10–20 mg/kg would be required). For a drug more expensive than cefixime, it is uncertain what advantage it will have over cefixime.

Ampicillin/Cotrimoxazole and Chloramphenicol These were the first line antibiotics against enteric fever till widespread drug resistance made them redundant. However, with the return of sensitivity to first line drugs they are now potential therapeutic options.

Ampicillin/Amoxicillin4,18 High doses (ampicillin 200 mg/kg/day and amoxicillin 100 mg/kg/day) in 3–4 divided doses have to be administered for a total of 14 days or at least 5–7 days after defervescence 254 Rational Antimicrobial Practice in Pediatrics has occurred. Defervescence takes at least 1 week and failure rates (in spite of strain being susceptible) range from 5-12%. Relapse rates reported are 1-5%. Problems with ampicillin/amoxicillin include the high pill burden, poor oral tolerability and high incidence of diarrhea. Ampicillin/ amoxicillin in a dose of 100 mg/kg/day along with proben acid 30 mg/kg/day for 6-12 weeks is the preferred drug to treat chronic intestinal carriers and is associated with a success rate of 80%.

Chloramphenicol This was considered the gold standard for treatment of enteric fever in the past. In patients with susceptible strains, 50-75 mg/kg/day in four divided doses produces rapid defervescence (mean fever clearance time 5 days). Recommended duration of therapy is 14 days or at least 5-7 days after defervescence has occurred. Relapse and fecal carriage rates are higher with chloramphenicol as compared to other drugs and range from 4–8% in various studies.4 The main limitation with use of chloramphenicol is the fear of aplastic anemia. This non-dose dependent, non-reversible and idiosyncratic reaction occurs at an incidence rate of 1 in 20,000 to 1 in 40,000 treatment courses.19 This rare but often fatal adverse effect is responsible for reluctance to use this drug even though there is return of sensitivity to chloramphenicol since when other effective/less toxic drugs are available.

Cotrimoxazole4,18 This is the cheapest of all therapeutic options. The recommended dose and duration is 10 mg/kg/day of TMP for 14 days. The mean time to defervescence is 6 days and relapse rates are low (0.5–5%). However, clinical failure rates range from 5–15% despite susceptible strains. This is the cheapest drug for enteric; however, the concern is adverse skin reactions especially Steven Johnson’s syndrome.

Aztreonam This monobactam with exclusive gram-negative activity has been reported to be effective in therapy of enteric in a dose of 50–100 mg/kg/day in 3 divided doses for 7/014 days.22 Experience is limited; the average defervescence time is 6 days with very low relapse and fecal carriage rates. However clinical failure rates can be as high as 5–15%.4 Trials have reported longer time to defervescence as compared to ceftriaxone and chloramphenicol.20,21 It is also a much more expensive option. The main role of aztreonam is in management of severe/ complicated enteric in patients with serious allergy to the cephalosporins.

Quinolones In the era of quinolone susceptibility, quinolones produced the most dramatic responses in patients with enteric with average time to defervescence being 4 days and almost 0 relapse and fecal carriage rates.4 Ciprofloxacin and ofloxacin were used in doses of 10–20 mg/kg/day and 5-7 days therapy was sufficient. The usual MIC’s of Salmonella Antimicrobial Therapy in Enteric Fever 255 to ciprofloxacin in this era were 0.0004 to 0.004 g/mL (Table 1). However with rising MIC’s (currently around 0.2–1 g/mL) and increasing quinolone resistance, clinical failure with quinolones is common.1,4,5 Therefore, quinolones in standard doses most not be used as empirical therapy for enteric in these areas. It has been suggested that resistance may be partly overcome by increasing the dose of quinolones but there is prolonged time to defervescence and high incidence of treatment failure.20 For quinolones to be effective it is essential that the AUC/MIC ratio be more than 125 in gram-negative bacteria.21 Pharmacokinetic studies have shown that with standard adult doses of 500 mg of ciprofloxacin twice a day the maximum acceptable MIC is 0.1 g/mL. By increasing the dose of ciprofloxacin to 750 mg twice a day (30 mg/kg/day) the maximum acceptable MIC is 0.25 g/mL.22 Since the current MIC’s of many strains of Salmonella are around 1 g/mL high dose quinolones will also fail. Using high doses also raises issues of toxicity in children. There is insufficient data on the efficacy of newer quinolones (levofloxacin, gatifloxacin, moxifloxacin) against Salmonella typhi/paratyphi. Conversely if the isolate is nalidixic acid sensitive the quinolones are the most effective drugs and should be used as the drugs of first choice for both inpatient/ outpatient therapy.4 Use of quinolones is not permitted in India by the Drug Controller General of India (DCGI) due to fear of theoretical cartilage toxicity. However, IAP has recommended DCGI to allow use of quinolones in children in selected indications like typhoid fever and bacillary dysentery.

Azithromycin This newer macrolide with very high intracellular penetration has been recently evaluated in therapy of enteric fever. Randomized controlled trials have shown efficacy equal to intravenous ceftriaxone and superior to chloramphenicol and ofloxacin in patients with Salmonella resistant to these drugs.25-29 The dose used in various studies has ranged from 10 mg/kg/day (max 500 mg) to 20 mg/kg/day (max 1 gm/day) for 5–7 days. Average time to defervescence is reported as 4.4 days with very low fecal carriage and relapse rates (0-3%).4 All this makes azithromycin a promising drug for enteric fever. Possible limitations of azithromycin include no information on efficacy in severe typhoid/ inpatient therapy and marked variability in the doses used in various clinical trials. Another issue is duration of therapy. If defervescence occurs by day 6 can therapy be stopped by day 7? The proponents of azithromycin believe that because of high tissue penetration, stopping azithromycin will still ensure adequate intracellular levels for a long time; many clinicians would however be uncomfortable stopping the drug immediately after defervescence.

 TREATMENT OF ENTERIC FEVER Choice of Empirical Therapy This applies to those cases where enteric is clinically suspected but where cultures have not been sent, or results are as yet not available or when cultures are negative. 256 Rational Antimicrobial Practice in Pediatrics

TABLE 3 Choice of empirical therapy for enteric fever Situation Local susceptibility Ist line 2nd line patterns Severe illness/ High prevalence of Ceftriaxone Cefotaxime inpatient/ nalidixic acid Aztreonam complications resistance & Low (penicillin allergy) prevalence of Ampicillin resistance to Chloramphenicol amp/chloro/cotrimox Outpatient therapy Cefixime Chloramphenicol Azithromycin Amoxicillin Cotrimoxazole High dose quinolones

Choice of empirical therapy is guided by various factors including the severity of the illness, inpatient/outpatient therapy, presence of complications and local sensitivity patterns of S typhi./paratyphi chiefly sensitivity to quinolones and first line drugs including ampicillin/ cotrimoxazole/chloramphenicol.

Empirical Therapy in Severe Illness/ Presence of Complications/Inpatient Treatment The drug of first choice here is ceftriaxone. In patients with history of severe penicillin/ cephalosporin allergy aztreonam may be used. Parenteral treatment should be continued till defervescence has occurred, oral intake has improved and complications resolved. Thereafter, therapy can be switched to oral cefixime to complete a total duration of 14 days. Other oral drugs may theoretically be also used for switch over therapy but limited experience (cefpodoxime) and a different class (azithromycin, cotrimoxazole, amoxycillin) are potential disadvantages. If cultures are positive and show nalidixic acid sensitivity then therapy should be changed to ciprofloxacin as quinolones are associated with faster defervescence and lower relapse rates as compared to ceftriaxone. If cultures are positive and show nalidixic acid resistance as well as sensitivity to the first line drugs (ampicillin, chloramphenicol, cotrimoxazole) it is probably prudent to continue with ceftriaxone alone rather than change as the older drugs do not offer any advantage over ceftriaxone and are more toxic.

Empirical Outpatient Therapy If enteric is a fair diagnostic possibility and patient is stable enough to be treated on an outpatient basis and culture results are awaited/negative or cannot be sent empirical therapy may be started. Here, therapeutic options in light of high nalidixic acid resistance and > 80% sensitivity to first line drugs are oral cefixime/azithromycin/chloramphenicol/ amoxicillin/cotrimoxazole. As discussed earlier, clinical efficacy is more or less the same with all these drugs with each drug having its own advantages and limitations. Choice Antimicrobial Therapy in Enteric Fever 257 would hence depend on individual preference, experience, level of comfort (especially with chloramphenicol) and cost considerations. In areas, where nalidixic acid resistance is infrequent (rare at the moment in India) quinolones may be considered the drugs of first choice. If both nalidixic acid resistance and resistance to first line drugs (amoxicillin, chloramphenicol, cotrimoxazole) is widespread then only options are oral cefixime/azithromycin. If the local resistance pattern is unknown then chances of failure are likely to be least if either cefixime/azithromycin are used. Once culture results are available therapy can be suitably modified on basis of principles discussed earlier.

Combination Therapy Increasing resistance and prolonged time to defervescence is prompting several clinicians to use combination therapy for enteric fever in hope of bringing about early defervescence and possibly preventing relapses. Amikacin is often used as an adjunct to ceftriaxone for this purpose. Despite in vitro susceptibility, aminoglycosides do not have in vivo efficacy against S. typhi/paratyphi due to poor intracellular penetration of aminoglycosides and inability to work in acidic pH and hence are not recommended.11 In a retrospective review of culture proven cases of enteric fever at PD Hinduja National Hospital, as many as 25% patients (including adults) received a combination of antibiotics mostly ceftriaxone and azithromycin.30 But the period for defervescence was not different from when a single agent was used. Therefore, till more evidence is available it is probably wise to refrain from using combination therapy for enteric.

Failure to Respond Failure to attain defervescence within a week of starting antimicrobial therapy for enteric fever is a relatively common clinical problem. Approach to this phenomenon depends on the certainty of diagnosis. If blood cultures are positive then the course of action is simple. The antimicrobial susceptibility of the isolate reviewed and drug treatment modified if the initial drug was inappropriate. If the patient was on ceftriaxone, the laboratory should be asked to recheck for possible beta lactamase production. If the isolate is sensitive and fever persists, but toxicity is less and general condition is improving then treatment with the same drug continued since defervescence in some cases may take 10 days and fever may persist due to immunologic mechanisms. Co-infections and complications such as intrabdominal abscesses should be looked for. Other reasons for persistent fever with clinical improvement are phlebitis and drug fever. Rarely hemophagocytic syndrome may complicate Blood cultures should be repeated to demonstrate bacterial clearance. If fever persists beyond 10–14 days and all the above are negative and patient is non toxic, then treatment may be shifted to an alternate drug preferably oral to obviate the possibility of drug fever. Replacement and not addition should be done. Azithromycin is a good alternative as it has better intracellular penetration than beta lactams and also has 258 Rational Antimicrobial Practice in Pediatrics anti-inflammatory activity. Steroids should not be used as they may mask any evolving illness and increase the risk of relapse. If the diagnosis of enteric fever is not by cultures and fever is not subsiding despite use of appropriate empirical therapy than the diagnosis should be reviewed again before switching or adding new drugs.

Use of Steroids Steroid therapy has been recommended for severe enteric defined as presence of shock, delirium, coma, stupor or obtundation.31 A loading dose of dexamethasone 3 mg/kg followed by 1 mg/kg every 6 hours for 8 additional doses. The need and efficacy of such high dose steroid therapy has not been confirmed in any recent trials.

Therapy of Relapses4 The relapse rate varies with the type of drug and is most common with beta lactams (ceftriaxone, cefixime) especially if shorter duration of therapy is used. Relapses are, however, generally milder and respond well and quickly to the same drug as used for primary therapy. Hence, broadly speaking relapses may be satisfactorily treated with the same drug as used for primary therapy but in right doses and for the right duration. However, if the isolate is nalidixic acid sensitive and quinolones were not used for primary therapy, they should be used for treatment of the relapse. Azithromycin may also be a good therapeutic option for relapse treatment.

Therapy of Carriers4 The carrier state is uncommon in children and testing for chronic carriage 3 months after an episode of enteric in children is not routinely recommended. However, if chronic

CONCLUSIONS Enteric fever is an important cause of morbidity in Indian children. Resistance in Salmonella typhi/paratyphi is very dynamic and changes with changing patterns of drug use. In most parts of India at present there is a high prevalence of quinolone resistance and fair sensitivity to the first line drugs such as ampicillin/cotrimoxazole and chloramphenicol. Resistance to third generation cephalosporins is anecdotal. In this scenario, choice of empirical therapy for severe illness/inpatients is ceftriaxone. For outpatients various options for empirical therapy include cefixime, azithromycin, cotrimoxazole, chloramphenicol and amoxicillin. Equally important is to inculcate the “culture of sending blood cultures” so that diagnosis of enteric is unequivocal, antimicrobial susceptibility of the isolate is known and local resistance patterns (which guide choice of empirical therapy) are available. All laboratories should update themselves with the new CLSI guidelines so that they don’t erroneously report quinolone resistant isolates as susceptible. A close watch should be kept for development of resistance to 3rd generation cephalosporins. Antimicrobial Therapy in Enteric Fever 259 carriage is demonstrated then treatment with amoxicillin 100 mg/kg/day with proben acid 30 mg/kg/day or cotrimoxazole 10 mg/kg/day of TMP for 6–12 weeks is recommended. If the strain is nalidixic acid sensitive then quinolones for 28 days is a better option.

 REFERENCES 1. Rodrigues C, Shenai S, Mehta A. Enteric fever in Mumbai, India: the good news and the bad news. Clin Infect Dis. 2003;36:535. 2. Tankhiwale SS, Agrawal G, Jalgaonkar SV. An unusually high occurrence of Salmonella enterica serotype paratyphi A in patients with enteric fever. Indian J Med Res. 2003;117:10-2. 3. Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ. 2004;82:346-53. 4. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid Fever. N Eng J Med. 2002;347:1770-82. 5. Crump JA, Barrett TJ, Nelson JT, Angulo FJ. Reevaluating fluoroquinolone breakpoints for Salmonella enterica serotype typhi and for non-typhi Salmonellae. Clin Infect Dis. 2003;37:75-81. 6. Kapil A, Renuka, Das B. Nalidixic acid susceptibility test to screen ciprofloxacin resistance in Salmonella typhi. Indian J Med Res. 2002;115:49-54. 7. Sekar U, Srikanth P, Kindo AJ, Babu VP, Ramasubramanian V. Increase in minimum inhibitory concentration to quinolones and ceftriaxone in Salmonellae causing enteric fever. J Commun Dis. 2003;35: 162-9. 8. Saha SK, Talukder SY, Islam M, Saha S. A highly ceftriaxone-resistant Salmonella typhi in Bangladesh. Pediatr Infect Dis J. 1999;18:387. 9. Pokharel BM, Koirala J, Dahal RK, Mishra SK, Khadga PK, Tuladhar NR. Multidrug resistant and extended spectrum beta lactamase producing Salmonella Enterica (serotypes typhi and Paratyphi A) from blood isolates in Nepal: surveillance of resistance and a search for newer alternatives. Int J Infect Dis. 2006;10:434-8. 10. Kumarasamy K, Krishnan P. Report of a Salmonella enterica serovar typhi isolate from India producing CMY-2 Amp C beta lactamase. J Antimirob Chemother. 2011;67:12. 11. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 15th Supplement. PLSI document. M700-S15; 2005;25(7):34-8. 12. Bhutta ZA, Khan IA, Shadmani M. Failure of short-course ceftriaxone chemotherapy for multidrug- resistant typhoid fever in children: a randomized controlled trial in Pakistan. Antimicrob Agents Chemother. 2000;44:450-2. 13. Soe GB, Overturf GD. Treatment of typhoid fever and other systemic salmonelloses with cefotaxime, ceftriaxone, cefoperazone, and other newer cephalosporins. Rev Infect Dis. 1987; 9: 719-36. 14. Cao XT, Kneen R, Nguyen TA, Truong DL, White NJ, Parry CM. A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group. Pediatr Infect Dis J. 1999;18:245-8. 15. Rabbani MW, Iqbal I, Malik MS. A comparative study of cefixime and chloramphenicol in children with typhoid fever. J Pak Med Assoc. 1998;48:163-4. 16. Bhutta ZA, Khan IA, Molla AM. Therapy of multidrug-resistant typhoid fever with oral cefixime vs. intravenous ceftriaxone. Pediatr Infect Dis J. 1994;13:990-4. 17. Dhanjee A, Sheikh MA, Yabub M, Alam SE. Orelox (cefpodoxime) in typhoid fever. J Pak Med Assoc. 1999;49:148-9. 18. Enteric fever. In: Behrman RE, Kliegman RM, Jenson HB (Eds). Nelson Textbook of Pediatrics. 17th edition. India: Saunders. 2004;916-18. 19. Feder HM Jr, Osier C, Maderazo EG. Chloramphenicol: A review of its use in clinical practice. Rev Infect Dis. 1981;3:479-91. 20. Gotuzzo E, Echevarria J, Carrillo C, Sanchez J, Grados P, Maguina C, et al. Randomized comparison of aztreonam and chloramphenicol in treatment of typhoid fever. Antimicrob Agents Chemother. 1994;38:558-62. 260 Rational Antimicrobial Practice in Pediatrics

21. Girgis NI, Sultan Y, Hammad O, Farid Z. Comparison of the efficacy, safety and cost of cefixime, ceftriaxone and aztreonam in the treatment of multidrug-resistant Salmonella typhi septicemia in children. Pediatr Infect Dis J. 1995;14:603-5. 22. Parry CM. The treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever in Viet Nam. Trans R Soc Trop Med Hyg. 2004;98: 413-22. 23. O’Donnell JA, Gelone SP. Fluoroquinolones. Infect Dis Clin North Am. 2000;14:489-513. 24. Cipro Tablets Drug Information Cipro Tablets Available from: http://www.drugs.com/PDR/ Cipro_Tablets.html. Accessed 18/4/2006. 25. Frenck RW Jr, Mansour A, Nakhla I, Sultan Y, Putnam S, Wierzba T, et al. Short-course azithromycin for the treatment of uncomplicated typhoid fever in children and adolescents. Clin Infect Dis. 2004;38:951-7. 26. Frenck RW Jr, Nakhla I, Sultan Y, Bassily SB, Girgis YF, David J, et al. Azithromycin versus ceftriaxone for the treatment of uncomplicated typhoid fever in children. Clin Infect Dis. 2000;31:1134-8. 27. Chinh NT, Parry CM, Ly NT, Ha HD, Thong MX, Diep TS, et al. A randomized controlled comparison of azithromycin and ofloxacin for treatment of multidrug-resistant or nalidixic acid-resistant enteric fever. Antimicrob Agents Chemother. 2000;44:1855-9. 28. Butler T, Sridhar CB, Daga MK, Pathak K, Pandit RB, Khakhria R, et al. Treatment of typhoid fever with azithromycin versus chloramphenicol in a randomized multicentre trial in India. J Antimicrob Chemother. 1999;44:243-50. 29. Girgis NI, Butler T, Frenck RW, Sultan Y, Brown FM, Tribble D, et al. Azithromycin versus ciprofloxacin for treatment of uncomplicated typhoid fever in a randomized trial in Egypt that included patients with multidrug resistance. Antimicrob Agents Chemother. 1999;43:1441-4. 30. S Jog, R Soman, T Singhal, C Rodrigues, A Mehta, FD Dastur. Enteric Fever in Mumbai–Clinical Profile, Sensitivity Patterns and Response to Antimicrobials. JAPI. 2008;56:237-40. 31. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone. N Engl J Med. 1984;310:82-8. Antimicrobial Therapy in Urinary Tract Infections 261 2222 Antimicrobial Therapy in Urinary Tract Infections Kumud P Mehta, Uma Ali

 INTRODUCTION Urinary tract infection is one of the most common bacterial infections in children. Urinary tract infection (UTI) is due to invasion and multiplication of uropathogenic strains of bacteria in the kidney and urinary tract. The commonest causative organism is E. coli (80-90% of first time UTI); next to it are Proteus mirabilis and Klebsiella; Aerobacter, Pseudomonas aeruginosa, enterococci and streptococci are rare. Demonstration of significant number of bacteria (105/mL of urine) with pyuria is diagnostic of UTI in symptomatic patients. Diagnosis should not be made on basis of pyuria alone or bacteriuria alone. Clinical manifestations of UTI differ according to age and site of infection. Acute pyelonephritis or upper UTI presents in neonates and young infants with nonspecific symptoms like refusal of feeds, failure to gain weight, vomiting, irritability, seizures, jaundice, anemia, hypothermia or fever. Common clinical features in older children upto 5 years of age are febrile seizures, fever of unknown cause, diarrhea, vomiting, failure to thrive, and anemia. In children between 5-15 years presenting features include fever with chills and rigors, abdominal or back pain and vomiting. Delay in diagnosis of acute pyelonephritis and delay in starting antimicrobial therapy is responsible for renal damage. A high index of suspicion should, therefore, be maintained in every infant and child with nonspecific symptoms such as fever, poor weight gain, anemia, recurrent diarrhea, etc. Urine culture should be done from urine collected under strict aseptic conditions in a sterile bottle by clean catch technique. If urine cannot be collected by this method, suprapubic aspiration or catheter insertion (these are invasive methods and need to be done with caution). First line antimicrobial drug should be started within 48–72 hours of fever especially in a sick infant even before urine culture report is available.1-4 Cystitis or lower UTI presents with painful micturition or dysuria, urgency, precipitancy, enuresis, foul smelling urine, suprapubic pain/tenderness and fever. It is difficult to distinguish 262 Rational Antimicrobial Practice in Pediatrics between upper and lower UTI in young infants and children below 5 years of age. Hence, all UTI’s in this age should be treated as upper UTI. Simple or uncomplicated UTI is defined as urinary infection without any abnormality of kidneys/urinary tract such as congenital malformations, calculi, obstructive lesions, etc. Uncomplicated UTI responds to antimicrobial therapy quickly and recurrence of UTI is less common. Complicated UTI is associated with anatomical or functional abnormalities of kidney/ urinary tract such as vesicoureteral reflux, obstructive uropathy, calculi, meningomyelocele/ lipomeningocele with neurogenic bladder or non-neurogenic bladder dysfunction. Complicated UTI is difficult to eradicate and leads to recurrences after initial improvement. Investigations to detect underlying cause are crucial in children especially those below three years of age and include ultrasonography, micturating cystourethrography and Tc99 DMSA renal scan. Antimicrobial treatment should be continued till significant abnormalities are ruled out and many cases require long term chemoprophylaxis to prevent recurrent UTI. Recurrent UTI occurs within a month of apparently successful treatment of initial or first attack of UTI. Isolation of same organism by urine culture with fever and or recurrence of symptoms of upper or lower UTI require prompt institution of drug therapy or change in drug if patient is already on first drug.

 TREATMENT OF UTI1-4 This depends on age of the child, site of infection (upper or lower), organisms (expected or isolated). Cost of the drug and adverse effects also should be taken into consideration. UTI occurs due to ascending infection of bacterial flora that colonize bowel or peiurethral region and hence, in most community acquired cases is due to E. coli. The choice of first drug (started empirically soon after urine is collected for culture) should be based on experience and expertise of the pediatrician, supported by data from the microbiology department as regards drug sensitivity to uropathogenic E. coli in community and institution. Drug resistant strains of E. coli occur in neonates and children admitted in PICU or in those who have undergone multiple urologic procedures or surgery or in those with obstructive lesions, etc. Hence, here the choice of empirical therapy depends on previous antibiotic therapy, locally prevalent flora and its antimicrobial sensitivity. When drug sensitivity results of the pathogen grown on urine culture are available, another drug may be substituted. In neonates and infants less than 3 months with community acquired UTI, initial parenteral therapy in hospital with a third generation cephalosporin or aminoglycoside is recommended. The mortality from acute UTI is high in neonates if treatment is delayed. Once the acute symptoms of fever, vomiting, irritability subsides therapy can be completed with oral antibiotics as per culture sensitivity. The duration of treatment is for 14 days. Since the chances of an underlying urinary tract anomaly are high in neonates with a UTI, drug therapy should be continued till diagnostic tests are completed. Oral amoxycillin or cephalexin may be used as suppressive therapy as per the drug sensitivity. Antimicrobial Therapy in Urinary Tract Infections 263

In older children for uncomplicated UTI choices include amoxycillin + clavulanic acid, cotrimoxazole or oral cephalosporins (cephalexin, cefuroxime, cefixime) as outpatient therapy. High fever, associated nausea and vomiting and other features suggestive of upper UTI merit IV antibiotics (3rd cephalosporins, amoxicillin + clavulanic acid, or aminoglycosides). Treatment should be modified based on culture reports. The success of antimicrobial therapy of acute UTI is observed firstly as control of fever and clinical symptoms, which occur within 2–3 days. Pyuria and urine culture may take 4–5 days to resolve. CRP and ESR normalize after 7–10 day.1,2 The main objective of antimicrobial therapy is not only to eliminate bacteria from urine but to treat the infection in the renal parenchyma. This is achieved by ensuring adequate concentration of the drug in the tissues as well as in urine. The drug must be used in adequate dose and for adequate periods. In acute pyelonephritis or upper UTI the duration of the treatment should be 10–14 days, while for cystitis or lower UTI 3-4 days treatment should be adequate. Since it is difficult to distinguish between cystitis and pyelonephritis in infants and young children (below the age of 5 years), all urinary tract infections should be treated as if they are pyelonephritis, i.e. for 14 days. As per recent guidelines, routine alkalinization of urine is not recommended. Frequent voiding every 2–3 hours helps in reducing bacterial count in the urine. Dilute urine reduces the growth of bacteria in urine and helps the drug to clear the urinary infection. Recurrent UTI and complicated UTI are main causes of renal scars, which may progress to chronic renal failure or hypertension after many years. Evaluation and management of this entity is discussed later.

 STATUS OF VARIOUS ANTIBIOTICS FOR TREATMENT OF UTI Cotrimoxazole This combination of sulfamethoxazole and trimethoprim is highly potent and a cost effective drug against common urinary tract pathogens predominantly E. coli and Proteus species but not Pseudomonas. Its importance has increased further in the current era with the increase in prevalence of ESBL producing gram-negative infections wherein cotrimoxazole is often the only oral drug to which the isolate is susceptible. In acute uncomplicated UTI the dose recommended is 5–7 mg/kg bid orally for 14 days. In smaller doses of 2 mg/kg at nighttime as a single dose it is used to eliminate chronic bacteriuria esp. in children with vesicoureteral reflux. For 2–3 years of long-term treatment trimethoprim alone is preferred to cotrimozaxole to prevent complications such as blood dyscrasias, allergies and gastrointestinal upsets. Serious complications are rare, cost of the drug is low and availability good; however not to be used in infants below 3 months of age. Cotrimoxazole should not be used if GFR is below 15 mL/min and if GFR is between 15–30 mL/min the interval between 2 doses should be increased from 12–24 hours. 264 Rational Antimicrobial Practice in Pediatrics

Ampicillin/Amoxycillin/Amoxycillin Clavulanic Acid Ampicillin is effective both orally and parenterally. It is bactericidal for E. coli, Aerobacter and certain strains of proteus. Pseudomonas is resistant to it and it is ineffective again against penicillinase producing strains of bacteria. It produces good tissue levels and is excreted unchanged in urine in high concentrations. Except mild diarrhea, there are no major side effects. Amoxicillin has less gasrointenstinal side effects. Unfortunately because of its extensive use in out patient practice, many infections with E. coli especially those acquired in the hospital have become resistant to ampicillin/amoxycillin. To improve the spectrum it may be combined with clavulanic acid (cost of therapy is increased) or with aminoglycosides.

Aminoglycosides Gentamicin and amikacin are the two aminoglycosides widely used as first drugs for acute UTI especially in the newborn. They are effective against E. coli, Proteus, Pseudomonas and certain strains of Klebsiella including many of the community acquired ESBL producing organisms. The disadvantage is that they have to be given parenterally. The side effects of ototoxicity and renal toxicity need close monitoring if use is extended beyond 14 days or if sequentially two aminoglycosides are used inadvertently. The use of aminoglycosides should best be reserved for infections in neonates, nosocomial UTI’s, infections with drug resistant organisms and complicated UTI’s. Single parenteral dose of amikacin/gentamicin for 10 days is used by many pediatricians. In adult patients single dose is found to be as effective as 6-8 hourly doses. The dosage of aminoglycoside should be carefully modified according to level of renal insufficiency in acute or chronic renal failure. Although, nomograms of the drug dosage according to renal functional status are available, it is advisable to refer these cases to a pediatric nephrologist.

Cephalosporins The first generation cephalosporins–cephalexin and cefadroxil and cefuroxime a second generation cephalosporin and cefixime have been useful in treating community acquired UTI in children. They are not the recommended for initial therapy for serious infections in young infants. Cephalexin is used in neonates to prevent bacteriuria in antenatally diagnosed hydronephrosis due to vesicoureteral reflux or posterior urethral valves, etc. Third generation cephalosporins are active against gram-negative bacilli. More than 80% of the drug is excreted in urine when ceftazidime, cefotaxime, are used. These drugs can be used only parenterally. Their main indication in treatment is serious upper UTI, complicated UTI, drug resistant UTI or UTI in neonatal or pediatric ICU. Ceftazidime when combined with aminoglycoside can be life saving in serious gram- negative infection due to Pseudomonas or Klebsiella. Use of oral cefixime after 2–3 days of IV therapy is recommended to shorten the stay in hospital and to complete 10–14 days of treatment of acute UTI.1,2,4-6 However with the advent of extended spectrum beta lactamase producing strains of E. coli and Klebsiella in various ICU’s and even Antimicrobial Therapy in Urinary Tract Infections 265 the community, third generation cephalosporins are no longer effective in management of nosocomial UTI’s and some community acquired UTI’s. Most of these strains are resistant to quinolones and aminoglycosides as well. Combination of broad spectrum beta lactams with beta lactamase inhibitors (piperacillin tazobactam, ticarcillin clavulanate) or carbapenems may be required for some of these UTI’s.

Quinolones Fluoroquinolones are broad-spectrum antimicrobials and have an advantage of being effective when given orally, allowing normal activity and preventing hospitalization in children. Commonly available compounds are norfloxacin, ciprofloxacin, pefloxacin, ofloxacin and newer compounds (levofloxacin and gatifloxacin). These compounds have excellent activity against E. coli, Klebsiella and Proteus mirabilis and Pseudomonas. Ciprofloxacin is most active quinolone against Pseudomonas. Quinolones diffuse well into purulent areas and are very effective in treatment of pyonephrosis or renal abscesses. Use of quinolones in young infants and children was restricted because of the adverse effects on growing cartilage observed in experimental animals. However, recent reports on long term follow up of children receiving quinolones in cystic fibrosis and other infections reveal no adverse effects on linear growth. There are no major safety considerations and ciprofloxacin can be used even with reduced renal function.9 Hence although quinolones are not recommended as the drug of first choice in acute UTI, they are recommended in complicated UTI, or multi drug resistant hospital acquired infection especially due to Pseudomonas. Extensive use of quinolones for undetermined fevers, gastrointestinal infections etc. are responsible for increasing antimicrobial resistance. Nalidixic acid is a 4-quinolone derivative effective against E. coli and many strains of Proteus. Bacteria can develop resistance to this compound rapidly hence, not a drug of choice for chronic suppressive therapy. It is contraindicated in neonates and young infants because of the adverse reaction in the form of increased intracranial pressure (pseudotumor cerebri).

Nitrofurantoin This is an excellent drug for chronic suppressive therapy and can be administered in a single night time dose for several weeks to months in patients with vesicoureteral reflux, obstructive uropathy or those with recurrent UTI or those who are resistant to other common drugs like cotrimoxazole, penicillins etc. When compared with cotrimoxazole nitrofurantoin is superior in preventing recurrence of UTI when used for long-term prophylaxis.5,6 It is rapidly absorbed from gastrointestinal tract and its urinary concentration is high but it gives poor tissue levels. Therefore, it is unsuitable for treatment of acute pyelonephritis. It is mainly bacteriostatic against common urinary pathogens like E. coli. Most strains of Pseudomonas and many strains of Proteus are resistant to nitrofurantoin. It is not recommended in severe renal insufficiency (creatinine clearance of 20 mL/min or less). 266 Rational Antimicrobial Practice in Pediatrics

Methenamine Mandelate or Mandelamine This drug is a salt of mandelic acid and methenamine and combines antibacterial properties of both the drugs. Its action is due to liberation of formaldehyde in acidic pH less than 5.5. It acts against many gram-negative bacilli and C. albicans. It is not effective against Proteus and Pseudomonas species. It should not be used in upper UTI or acute infections as it is washed down too rapidly for therapeutic amounts of formaldehyde to be generated.7,10 It is of some value in chronic suppressive treatment when no other drug is working. It may also be a useful agent for some nosocomial UTI’s due to carbapenem resistant Pseudomonas infections.

Pyridium This azodye is used to give symptomatic relief when pain, burning, urgency and frequency is associated with cystitis or urethritis. It does not act as an antibacterial agent.

 OTHER ISSUES IN TREATMENT OF UTI Follow-up of a Child with UTI Revised guidelines from the Indian Academy of Pediatrics, Nephrology chapter have been recently published and discuss this in detail.12 Though there is controversy in international literature about the utility of intense radiologic evaluation and antimicrobial prophylaxis in children with UTI, the IAP continues to recommend this given the socio- logistic issues in our country. After first UTI: All children below 1 year should undergo USG, DMSA and MCU. In those aged between 1 and 5 years, an USG and DMSA should be performed and in those aged above 5 years an USG alone is enough for initial evaluation. Those children with abnormalities on USG or DMSA should undergo an MCU. After recurrent UTI: All children with recurrent UTI should undergo USG, DMSA and MCU. The USG can be done immediately, the MCU 2-3 weeks later and DMSA after 2-3 months. Patients with acute UTI should be followed up for at least 1 year. Recurrence of UTI is maximum in first 6 months after first UTI. Urine cultures should be done during febrile episodes to detect urinary tract infections.

Prevention of Recurrent UTI General Measures Adequate fluid intake and frequent voiding is advised; constipation should be avoided. In children with VUR who are toilet trained, regular and volitional low pressure voiding with complete bladder emptying is encouraged. Double voiding ensures emptying of the bladder of post void-residual urine. Circumcision reduces the risk of recurrent UTI in infant boys, and might, therefore, have benefits in patients with high grade reflux. Antimicrobial Therapy in Urinary Tract Infections 267

Bowel Bladder Dysfunction Children presenting with recurrent UTI or persistent VUR often have an associated voiding disorder, which is termed as bowel bladder dysfunction. These children should be evaluated for the same. The management of voiding disorders should be carried out in collaboration with an expert. This includes the exclusion of neurological causes, institution of structured voiding patterns and management of constipation. In patients with an overactive bladder, therapy with anticholinergic medications (e.g. oxybutinin) is effective. Patients with bowel bladder dysfunction and large post-void residues, benefit from timely voiding, bladder retraining, and clean intermittent catheterization.

Prophylactic Antimicrobial Therapy While recent guidelines from the AAP do not advocate routine antimicrobial prophylaxis in children with anatomic abnormalities of the urinary tract or those with recurrent UTI, the IAP guidelines continue to recommend this owing to socio-logistic reasons. Antimicrobial prophyalxis is indicated for: • Following treatment of: (i) the first UTI in all children below 2 years of age, and (ii) complicated UTI in children below 5 years old, while awaiting imaging studies. • Children with VUR. • Patients showing renal scars following a UTI even if reflux is not demonstrated. Prophylaxis may be stopped if a radionuclide cystogram or MCU repeated 6 months later is normal. • Children with frequent febrile UTI (3 or more episodes in a year) even if the urinary tract is normal. • Prophylactic antibiotics are not recommended for pelviureteric obstruction, urolithiasis or neurogenic bladder without recurrent infection. For long-term suppressive therapy the antimicrobials recommended are: • Cotrimoxazole in the dose of 2-3 mg/kg/dose of TMP at nighttime. • Nitrofurantoin in the dose of 1-2 mg/kg/dose at nighttime. • Ampicillin/amoxycillin 10-20 mg/kg/day bid for 3-6 months in newborns and infants where cotrimoxazole and nitrofurantoin are contraindicated. • Cephalexin 10 mg/kg bed time dose. With prophylactic treatment urine may stay sterile but adequate drug levels in tissue may not be achieved and renal infection may continue without being detected. Recurrences can occur due to infections caused by bacteria that are resistant to the antibiotic used for prophylaxis, or by sensitive bacteria (due to poor compliance, inadequate or infrequent dosing). Poor bladder emptying also predisposes to breakthrough infections. Breakthrough UTI should be treated with appropriate antibiotics. Change of the medication being used for prophylaxis is not usually required. There is no role for cyclic therapy, where the antibiotic used for prophylaxis is changed every 6-8 weeks. Patients having recurrent breakthrough infections may benefit from double prophylaxis with cotrimoxazole and nitro- furantoin.12 268 Rational Antimicrobial Practice in Pediatrics

Antimicrobial prophylaxis should be continued till age 1 year in those with grade 1 and 2 VUR and reinitiated if breakthrough UTI happen after termination of prophylaxis. In those with VUR grade 3-5, prophylaxis should be continued till age 5 years. In those aged more than 5 years prophylaxis should be continued if there is bladder bowel dysfunction.

Resistant UTI Following are main causes of resistant UTI in children. • Indiscriminate and unwarranted use of antimicrobials are the main causes of drug resistant urinary tract infections. Classic example is use of ampicillin in diarrheal diseases (mostly viral in nature), which wipes the E. coli from gut flora or causes resistant strains, which colonise urinary tract leading to ampicillin resistant E. coli UTI. • Drug is used on mere suspicion of UTI, e.g. fever with few pus cells in urine. • The dose and duration of drug therapy for UTI is inadequate and short. • Underlying lesion is not treated properly, e.g. obstruction not relieved or improper management of meningomyelocele with bladder dysfunction. • Patients admitted in PICU–nosocomial infection Organisms responsible for resistant UTI are usually multi drug resistant E. coli, Klebsiella, Proteus and Pseudomonas species. Carbapenems, aminoglycosides, 4th generation cephalosporins, beta lactam-beta-lactamase inhibitor combinations, quinolones and aztreonam, may be needed for treatment of resistant UTI. To avoid development of antimicrobial resistance following measures should be taken. • Use antibiotics only when necessary • Select appropriate antibiotic preferably based on culture and drug sensitivity. • Use antibiotic for an adequate period of time, e.g. 10–14 days for acute UTI. • Drug combinations may be useful to delay development of drug resistance. • Cotrimoxazole may work out to be as effective and safe and cheaper than cephalosporin or fluoroquinolone in treatment of uncomplicated UTI. • Once started the drug must not be changed if clinical result is good (fever, toxicity, vomiting, etc. reduced) for 3-4 days. Even if the urine culture report suggests resistance to the drug, clinical response is taken as positive response to continue the treatment for 14 days; sometimes vitro studies do not correlate with in vivo response to antimicrobial therapy. • Too large or too low dosage should be avoided as it may produce either toxicity or cause bacterial resistance. This is particularly true for aminoglycosides with narrow margin of safety. If any adverse effect is observed, complete withdrawal of the drug and substitution with second choice of drug according to culture and drug sensitivity is mandatory. Antibiotics should not be used routinely in all fevers without understanding their nature simply with hope of giving quick benefits, e.g. with cold and cough without sending for urine culture in patients with vesicoureteral reflux. Antimicrobial Therapy in Urinary Tract Infections 269

• If the patient is educated and can understand the importance of being guided by urine cultures for the choice of the drug, it is better to treat recurrence of UTI by intermittent antimicrobial therapy for febrile UTI than chronic suppressive therapy. Chronic chemoprophylaxis can result in resistant strains of E. coli and may not eliminate renal parenchymal infection. • Use of probiotic such as lactobacilli in resistant UTI may help replenish gut flora with nonpathogenic strains of organisms that may prevent overgrowth and colonization with uropathogenic E. coli. • Changing pH of urine to reduce multiplication and use of cranberry juice are additional measures of reducing multiplication of resistant strains of gram-negative organisms causing UTI.11 Asymptomatic Bacteriuria No treatment is necessary if urine culture is positive, but no symptoms pertaining to urinary tract are associated. However, a close watch for symptoms pertaining to bladder, lower urinary tract or febrile episodes need to be kept to label the significant bacteriuria as “asymptomatic”.

CONCLUSIONS For suspected severe acute urinary tract infection antimicrobial therapy should be started immediately after urine culture is sent. First drug of choice for community acquired uncomplicated UTI in older infants and children can be oral cotrimoxazole or amoxyclav or cephalexin. In all neonates and young infants, upper UTI in older infants and children, in presence of vomiting or suspected non-compliance, nosocomial UTI aminoglycoside or a third generation cephalosporin is preferred. Resistant UTI can be treated with betalactam- beta lacatamase inhibitor combinations, aminoglycosides, quinolones, aztreonam, imipenem depending on the organism and antibacterial drug sensitivity. Duration of treatment for UTI in children below 5 years should be 10-14 days, for lower UTI above 5 years age can be 3-5 days. Antimicrobial treatment with oral drugs (according to culture sensitivity report) should be continued till evaluation and diagnosis of underlying urologic lesions is complete. Long-term prophylaxis should be given for patients with VUR and postoperative urologic conditions or neurogenic/non neurogenic bladder dysfunction for as long as 6 months to 5 years. Recurrent UTI without underlying lesions require long-term appropriate antimicrobial drug therapy to prevent renal scars.

 REFERENCES 1. Hansson S, Jodal U. Urinary tract infection In Pediatric Nephrology. 5th edition. Avner, Harmon, Niaudet (Eds). Lippincott,Williams and Wilkins. Philadelphia. 2004;1008-16. 2. Levtchenko E, Lahy C, Levey J. et al. Treatment of children with acute pyelonephritis a prospective randomised study. Pediatr Nephrol. 2001;16:878-84. 3. Shaw KN and Gorelick MH, Urinary Tract Infection in the pediatric patient Pediatr Clin North Am. 1999;46:1111-24. 270 Rational Antimicrobial Practice in Pediatrics

4. Karen R, Chan E. A meta-analysis of randomized controlled trials comparing short and long course antibiotic therapy for urinary tract infection. Pediatrics. 2002;109:15-22. 5. Williams G, Lee A, Craig C. Antibiotics for prevention of urinary tract infection in children–a systematic review of randomized controlled trials. J Pediatr. 2001;138:868-74. 6. Le Saux N, Moher D. Evaluating benefits of antimicrobial prophylaxis to prevent urinary tract infections in children–a systematic review. Can Med Assoc J. 2002;163:523-9. 7. Chemotherapy of Urinary Tract Infections In Pharmacology and Pharmacotherapeutics. 17th edition. Satoskar, Bhandarkar (Eds). Ainapure Popular Prakashan Mumbai. 2001;705-14. 8. Knoderer CA, Everett J, Buss WF. Clinical issues surrounding once daily aminoglycoside dosing in children. Pharmacotherapy. 2003;22:44-56. 9. Rationale for use of Fluoroquinolones in Pediatric UTI. Infect Urol. 2002;15:3-8. 10. Lee B, Bhuta T, Craig J, Simpson J. Methenamine hippurate for preventing UTI (Cochrane Review). The Cochrane Library Issue 1, 2002. 11. Jepson RG, Mihaljevic L,Craig J. Cranberries for treating Urinary tract infection. Cochrane Review. The Cochrane Library Issue 1, 2002. 12. Indian Pediatric Nephrology Group. Indian Academy of Pediatrics. Consensus statement on management of urinary tract infections. Indian Pediatr. 2001;38:1106-15. Antimicrobial Therapy in Skin and Soft Tissue Infections 271 2323 Antimicrobial Therapy in Skin and Soft Tissue Infections Tanmay Amladi, Sangeeta Amladi

 INTRODUCTION Infections of the skin in children are caused by bacterial, viral, fungal and parasitic organisms. Bacterial infections or pyodermas are the commonest infections in children. There are many commensals on the human skin, i.e. Staphylococcus epidermidis, Micrococcus, Corynebacterium, Brevibacterium species.1 Occasional overgrowth of these can cause minor infections of the skin and its appendages. However, it is usually pathogenic bacteria such as the Staphylococcus and Streptococcus species that are primary skin pathogens. A host of other bacteria, viruses, fungi and parasites cause secondary skin involvement too.2 All these are more common in tropical climates like India, where a combination of heat, humidity, multi-layered clothing on the child, ostensibly to “protect against colds”, the use of home-made skin applications daily (especially in infants who are massaged), and, of course, poor hygiene itself are contributory factors.

 BACTERIAL SKIN INFECTIONS Impetigo This is infection and inflammation of the epidermis, typically in preschool and school children. There are two types (1) impetigo contagiosum (Tilbury Fox) where initial macules become vesiculopustules and scabs and crusts with oozing with local lymphadenopathy, often with nasal carriage of the pathogens, that may be S. aureus and/or S. pyogenes and (2) bullous impetigo, caused by S. aureus that consists of fragile small and large bullae that rupture leaving annular or circinate erythematous scaly areas. Bullous impetigo is particularly common in neonates. 272 Rational Antimicrobial Practice in Pediatrics

Treatment If the lesions are few and superficial, not involving the head face or neck, and in an older child, who is afebrile, local therapy with antibacterial creams such as Fusidic Acid, Mupirocin may be adequate. In extensive lesions, lesions of the face and neck area, in a small infant, in a febrile patient, or when local therapy shows no response, systemic antibacterials should be used. Antibiotics that will work for both streptococci and staphylococci include cloxacillin, cotrimoxazole, erythromycin, azithromycin, clarithromycin, coamoxyclav or cephalexin/cefadroxil for a period of 7 to 10 days in standard doses. Macrolide resistance is increasing in S. aureus and S. pyogenes hence macrolide therapy may fail. Hence, use of cloxacillin or first generation cephalosporins may be more appropriate. Consider possibility of community acquired MRSA in toxic/nonresponding patients and send appropriate cultures. Community acquired (CA) MRSA will require therapy with alternative drugs such as cotrimoxazole, clindamycin or linezolid depending on antimicrobial sensitivity.

Ecthyma Deeper infection caused by S. aureus or Group A streptococci. There is a thick crust on small pustules on an erythematous base, difficult to detach, with an underlying ulcer and purulent discharge. It can spread by autoinoculation and heals with scarring.

Treatment Systemic antibacterials as for impetigo. Topical therapy not effective alone.

Folliculitis This refers to pyogenic infection of the hair follicles, e.g. on scalp or face in children (Bockhart’s impetigo), on the beard area (sycosis barbae) recurrent folliculitis of the legs (dermatitis cruris pustolosa et atrophicans) seen in young males in India. S. aureus is the usual etiologic agent.

Treatment Topical therapy with mupirocin, fusidic acid, nadifloxacin, , erythromycin ointment may be used for localized disease. For generalized, persistent, recurrent cases or when topical therapy fails systemic antibacterials such as cloxacillin, cephalexin, cefadroxil coamoxyclav may be used. Other measures include withdrawal of unnecessary oil application, gram flours etc on the baby’s body, and by switching to soap that keeps the skin from excessive oiliness, and maintaining hygiene. Zinc oxide cream helps in subsidence. If over the scalp, shaving the scalp by hygienic methods and subsequent application of lotion containing calamine will help.

Recurrent Pyodermas Measures recommended for preventing recurrent pyodermas include use mupirocin ointment in the nares by index case and family contacts, use of chlorhexidine or triclosan based Antimicrobial Therapy in Skin and Soft Tissue Infections 273 soap, regular bathing, regular change of bed linen and use of daily clindamycin @150 mg per day for 3 months.

Cellulitis/Erysipelas Erysipelas is a superficial cellulitis with prominent lymphatic involvement, presenting with an indurated, “peau d’orange” appearance with a raised border that is demarcated from normal skin. It is almost always due to S. pyogenes. Cellulitis is an acute, spreading pyogenic inflammation of the dermis and subcutaneous tissue. The area, usually on the leg, is tender, warm, erythematous, and swollen. It lacks sharp demarcation from uninvolved skin. The main etiologic agent of cellulitis is S. pyogenes. Other organisms include S. aureus, H. influenzae (in children), gram-negative bacilli and Pseudomonas aeruginosa (in immunocompromised). In diabetics cellulitis is polymicrobial caused by a host of gram-positive and gram-negative aerobic and anaerobic organisms. Cellulitis should be differentiated from necrotizing fasciitis, an illness of high morbidity and mortality.

Treatment For mild infections treatment can be on an outpatient basis. Antibiotic options include cephalexin, cefadroxil, cefuroxime and co amoxyclav. If community acquired MRSA is suspected then clindamycin/cotrimoxazole/erythromycin and in older children doxycycline may be used. For severe infections hospitalization and parenteral antibiotics are needed. Antibiotic options for those with no immunocompromise include cefazolin, cloxacillin, coamoxyclav, clindamycin. For suspected/confirmed MRSA IV vancomycin/linezolid are required. Therapy may be switched to oral once systemic symptoms abate and skin findings start resolving (usually 3–5 days); total duration of therapy is 7–14 days. Other measures include immobilization and elevation of the affected limb and drainage of abscesses.

Staphylococcal Scalded Skin Syndrome A condition caused by epidermolytic toxins released by staphylococci. Typically in young children, with fever, pain and tenderness of lesions that consist of superficial flaccid blisters that rupture leaving painful raw areas; it heals within 2 weeks of IV antibiotics with scaling leaving behind no sequelae—the blister fluid is culture negative.

Treatment This is a serious condition that will need hospitalization and treatment with IV antibacterials such as IV co-amoxiclav/cloxacillin/cefazolin. Other supportive measures such as fluids, management of denuded skin are needed.

Scarlet Fever This is because of release of pyrogenic exotoxin from S. pyogenes; it is uncommon in the tropics. The features include fever, constitutional symptoms, severe tonsillitis, an 274 Rational Antimicrobial Practice in Pediatrics erythematous rash on the 2nd day, which soon becomes confluent and subsides with scaling within 7–10 days. For mild cases oral Pencillin V/amoxicillin may be used. Severe cases need hospitalization and IV Penicillin G/ampicillin/amoxicillin.

Toxic Shock Syndrome (TSS) Toxic shock syndrome (TSS) is an acute, toxin-mediated illness, like endotoxic shock, and is characterized by fever, rash, hypotension, multiorgan involvement, and desquamation. TSS reflects the most severe form of the disease caused by Staphylococcus aureus and Streptococcus pyogenes. Mortality associated with streptococcal TSS is 5-10% in children, much lower than in adults (30-80%), and is 3–5% for staphylococcal TSS in children. Treatment involves supportive care and IV anti-bacterial drugs such as cloxacillin/ cefazolin/coamoxyclav. There is some evidence to suggest that clindamycin may be used as adjunctive therapy to block toxin production. IVIG may be used since toxic shock syndrome is believed to be a super antigen mediated illness.

Necrotizing Fasciitis Necrotizing fasciitis is a serious skin, soft tissue infection involving the fascia and the muscles commonly leading to septic shock and multiorgan failure. It is more common in neonates, diabetics, immunocompromised and sometimes healthy children following varicella. The causative agents include S. pyogenes (especially following varicella), S. aureus, anaerobes and sometimes gram-negative bacilli. It is often confused with cellulitis. Presence of severe pain, toxicity, hypotension, hyponatremia, profound leukocytosis, hyperglycemia and renal dysfunction are pointers for necrotizing fasciitis. Differentiation from cellulitis is important as necrotizing fasciitis needs early, radical and often repeated surgical debridement. Antibiotic options include a combination of cefotaxime/ ceftriaxone with clindamycin. Clindamycin is a good drug for MSSA, anaerobes and is also a protein synthesis inhibitor. If MRSA is suspected vancomycin or linezolid should be added.

 COMMON VIRAL INFECTIONS Herpes Virus Infections (Herpes simplex, Herpes zoster, Varicella) These consist of typical vesicular lesions–in simplex, at the mucocutaneous junctions and skin, in zoster, along dermatomes and usually unilateral, and in varicella, pleomorphic generalized rash, with or without fever and lymphadenopathy

Treatment H. simplex: Few lesions of herpes labialis may be treated with topical acyclovir (5%) or penciclovir cream every 2–3 hours for 3–7 days. For primary/recurrent herpes simplex infection oral acyclovir/valacyclovir/femciclovir may be used. Recurrences in immunocompromised individuals may be prevented by oral acyclovir/valacyclovir. For Antimicrobial Therapy in Skin and Soft Tissue Infections 275 doses see the chapter on antiviral agents. Severe disease/disseminated disease/neonatal disease will require IV acyclovir. Varicella zoster: Treatment should be initiated within 24 hours of onset and includes acyclovir (20 mg/kg/dose, max dose 800 mg qid for 5 days) or valacyclovir 1 gm tds/ famciclovir 500 mg tds (pediatric dose not available) for 5 days. In immunocompromised will need to be given IV 10-12 mg/kg 8 hourly for 7–10 days. Herpes zoster: Treatment should be initiated within 72 hours of rash. Acyclovir (20 mg/ kg/dose, max 800 mg qds) or valacyclovir 1 g tds or famciclovir 500 mg tds for 7 days. In immunocompromised or disseminated zoster IV acyclovir may be needed.

Molluscum Contagiosum This condition typically consists 2–3 mm, firm, umbilicated, pearly papules with waxy surface. Usually asymptomatic. Infrequently: Larger, coalescent lesions (giant molluscum) in immunocompromised hosts. They are spread on the host’s skin and to others by touch; generally they are more common on skin folds, genital region, the face and fingers. It is a self-limited disorder and usually no treatment is necessary. Most cases resolve in 6–9 months. Parents should be counseled. If treatment is desired: curettage, manual expression, liquid nitrogen, trichloroacetic acid, keratolytics, imiquimod, retinoids, electrodessication, tape stripping, laser or cantharidin can be used. Destructive methods should be avoided as far as possible as they increase the risk of scar formation. Imiquimod is applied at night for 12 hours, three evenings per week for 4–6 weeks, or clinical clearance.

 COMMON FUNGAL INFECTIONS Pityriasis Versicolor/ Tinea Versicolor Caused by Malassezia furfur (Pityrosporum ovale) this disease is characterized by hypopigmented and/or hyperpigmented scaly patches (nonelevated or minimally elevated) affecting mainly the trunk, neck and proximal extremities. Lesions are usually multiple, small, round or oval in shape or coalescent into large, irregularly shaped patches. They are asymptomatic or sometimes there may be mild pruritis.

Treatment Topical therapy alone is the first line regimen and is effective in most cases. Topical agents include selenium sulfide/ketoconazole/zinc pyrithione shampoo, clotrimazole/ ketoconazole/miconazole/terbinafine cream/lotion applied once daily for 1–2 weeks. Systemic therapy is indicated in those where topical therapy fails, extensive lesions, frequent recurrences, or inability to apply the lotion because of hypersensitivity. Ketoconazole 400 mg po/fluconazole 300 mg/ 3-6 mg/kg/dose single dose and repeated weekly for 4 weeks or itraconazole 200 mg once a day for 7 days may be used. 276 Rational Antimicrobial Practice in Pediatrics

Candidiasis Candidiasis of skin consists of red inflamed superficial flat lesions of irregular shape and size, involving flexures and skin folds, and perineal, genital and inguinal areas, where sweat and body secretions tend to accumulate. Local Clotrimazole/Miconazole cream will be effective in most cases. Oral Fluconazole @ 3-6 mg/kg/day would be indicated in immunocompromised hosts, extensive involvement, nonresponse to topical treatment.

Tinea Tinea or ringworm caused by dermatophytic fungi can occur on the hands (T. manis), feet (T. pedis) or trunk (T. corporis) or scalp (Tinea capitis) or nails (onychomycosis). Tinea capitis needs systemic treatment with griseofulvin (15–20 mg/kg/day, max 500 mg for 4-8 weeks) or itraconazole 5 mg/kg/day (max 100 mg) for 2–4 weeks or fluconazole 6 mg/kg/day for 3 weeks or once a week for 4-8 weeks. Ketoconazole/selenium sulfide shampoo should be used as adjunctive treatment. For T. corporis local therapy with terbenafine/clotrimazole/ketoconazole/miconazole/tolnaftate may be sufficient. For extensive lesions of tinea corporis and tinea pedis additional oral therapy with griseofulvin/itraconazole/ fluconazole for 2–4 weeks may be needed. Onychomycosis needs systemic therapy with itraconazole (5 mg/kg/day max 200 mg) for 8 weeks (fingernails) or 12 weeks (toenails) or fluconazole (6 mg/kg once a week) for 6–12 months.

 COMMON PARASITIC INFECTIONS Scabies These lesions are often unobtrusive and missed, until secondary bacterial infection sets in (infected scabies); the patient presents with intense itching; typically excoriation marks are present anywhere over the body and lesions may be seen in the web spaces and genital and buttock areas. Immunocompromised, debilitated and malnourished individuals have generalized crusted lesions.

Treatment Gamma Benzene Hexachloride (Lindane 1%) or Benzyl benzoate can be applied daily below the neck (half diluted with water for infants and small children) after bath, for three days and then a repeat application for 2–3 consecutive days after an intervening gap of about one week. These preparations are cheap and come in large family packs, if more than two or three family members need treatment. Permethrin (5%) is available as a cream and a single application is effective. Although, it is more expensive it is preferred to lindane and benzyl benzoate for children. Oral Ivermectin (200 g/kg) two doses separated by 2 weeks offers no advantage over local treatment for routine use, but has a place of use if local skin conditions do not permit use of the above or patient prefers oral therapy. Antimicrobial Therapy in Skin and Soft Tissue Infections 277

Itching may continue for a while after the application, that can be treated using antihistaminics. Secondary bacterial infection may need oral antibacterials. All family members should be treated. Clothes and bed linen should be washed at 60°C and those items that cannot be washed should be sprayed with insecticide powder.

Pediculosis Sites of infection include head, body and pubis. Head lice can be treated by permethrin (1%) shampoo. Other options include pyrethrins with piperonyl butoxide or for refractory cases malathion (0.5%).

 REFERENCES 1. Sangeeta A, Indian Journal of Practical Pediatrics. 2005;7:2. 2. Schachner Lawrence A, Hansen Ronald C. Pediatric Dermatology, 3rd edition, 2003. 3. Johns Hopkins point of care information technology (POC-IT) . ABX Guide. Available from URL: www.hopkins-abxguide.org. Accessed on September 25th, 2006. 278 Rational Antimicrobial Practice in Pediatrics 2424 Antimicrobial Therapy in Skeletal Infections Apurba Ghosh, Monjori Mitra, Mallar Mukherjee

 INTRODUCTION Osteomyelitis and septic arthritis are usually bacterial in origin and share common pathogens. Hence, antimicrobial therapy of these two illnesses is discussed together with salient differences alluded to at different places. The most common etiologic agent is S. aureus but other organisms may also be responsible as discussed later. Diagnosis is established by clinical symptomatology, complete blood count, estimation of acute phase reactants, plain X-rays, USG and MRI. Bacteriologic diagnosis should be sought for and is positive in 50% to 80% of the patients. The yield is highest when multiple specimens are cultured including blood, bone, and synovial fluid. In the preantibiotic era, the mortality rate for acute osteomyelitis was substantial. As an example, it was approximately 20 percent in those with Staphylococcus aureus osteomyelitis. With current antimicrobial regimens and surgical approaches, successful treatment (survival and complete resolution of radiographically apparent damage to bone) is now achieved in nearly all affected children. The decision to initiate antimicrobial therapy for acute osteomyelitis/septic arthritis is often made before the diagnosis is confirmed, by either imaging or culture. In this setting, epidemiologic factors such as the child’s age, underlying medical condition, and organisms prevalent in the community will suggest likely pathogens and the appropriate antimicrobial agents. Surgical therapy, which may include drainage of an abscess/joint or removal of devitalized bone, must be initiated promptly when it is indicated. Immobilization of the affected extremity may relieve pain. It also may prevent pathologic fractures when bone involvement, as detected by plain radiography or other imaging modalities, is extensive. Evaluating the need for immobilization is particularly important for patients with vertebral osteomyelitis or osteomyelitis of the proximal femur. Antimicrobial Therapy in Skeletal Infections 279

 EMPIRIC ANTIMICROBIAL THERAPY Isolation of a pathogen from bone, periosteal collection, joint fluid, or blood confirms the diagnosis in children with suspected osteomyelitis/septic arthritis and is essential for planning proper treatment. However, no organism is identified by cultures of blood and pathologic specimens in as many as one-half of children with clinical and radiologic findings consistent with osteomyelitis. Thus, treatment usually begins with the prompt initiation of empiric intravenous antibiotic therapy, which is followed by a specific antimicrobial regimen once the etiologic organism is identified. There are no studies that directly compare the empiric approach to a strategy of waiting until the diagnosis of osteomyelitis/septic arthritis is firmly established (particularly by the identification of a causative organism) to immediate administration of antimicrobial therapy. Despite this, the empiric approach is widely used in children because of the excellent cure rate (compared with historic controls) and, as mentioned, the inability to identify the causative organism in as many as 50 percent of cases. Acute bacterial hematogenous osteomyelitis/septic arthritis should be treated initially with parenteral antimicrobial agents, whether or not the organism causing the infection has been identified. Epidemiologic factors such as the child’s age, underlying medical condition, and organisms that are prevalent in the community will suggest likely pathogens and the appropriate antimicrobial agent. The ideal choice for empiric therapy would be a single intravenous agent that has an effective oral counterpart. This is because the response to intravenous therapy is an important consideration when choosing an oral agent for sequential therapy, particularly for the patient with negative cultures. The following section provides a guide to empiric therapy based principally upon the patient’s age and the antimicrobial sensitivities of the likely infecting organism.

Neonates and Young Infants For neonates and young infants from birth to three months of age, initial intravenous antimicrobial therapy should be directed against the most common bacterial isolates responsible for hematogenous osteomyelitis/septic arthritis in this age group. These include S. aureus, gram-negative bacilli, and group B Streptococcus (uncommon in India). An empiric regimen consisting of a third-generation cephalosporin, such as cefotaxime, plus an antistaphylococcal agent with nafcillin/oxacillin) is used. Neonates who have been in an intensive care unit for more than one week, are at risk of hospital–acquired infection with resistant gram-negative organisms, methicillin-resistant S. aureus (MRSA), coagulase negative staphylococci and fungi, should receive a carbapenem such as imipenem/ meropenem with vancomycin and fluconazole till cultures are available.

Older Infants and Children Initial intravenous antimicrobial therapy should primarily be directed against S. aureus. In children less than 3 years of age, S. pneumoniae and Hib should also be covered 280 Rational Antimicrobial Practice in Pediatrics especially if they have not received appropriate immunization. Therefore, suggested regime is an antistaphylococcal agent in all along with cefotaxime/ ceftriaxone in children less than 3–5 years.

Choice of Antistaphylococcal Agent Options for antistaphylococcal agent include cloxacillin, clindamycin, vancomycin, teicoplanin and linezolid. The specific choice of antistaphylococcal agent depends on the local prevalence of CA-MRSA and the susceptibility of these MRSA to clindamycin.5,6 An antistaphylococcal penicillin (nafcillin/oxacillin) or cefazolin is preferred if less than 10 percent of the community S. aureus isolates are methicillin resistant. Most experts suggest using either vancomycin or clindamycin when 10 percent or more of community S. aureus isolates are methicillin resistant.6 However, inducible resistance to clindamycin that is not apparent using most standard techniques may occur in some isolates. Therefore, the susceptibility of all CA-MRSA isolates to clindamycin must be determined using the “D test”. The following factors should be considered in choosing between vancomycin or clindamycin: • Infections caused by CA-MRSA with inducible resistance to clindamycin should be treated with vancomycin to avoid the risk of subsequent treatment failure7,8 • Vancomycin is generally recommended for empiric treatment when 15 percent of the MRSA isolates in the community also are resistant to clindamycin. • Because of the association between CA-MRSA and life-threatening infection, vancomycin should be used for empiric therapy for patients who appear seriously ill.9 For patients who are severely ill, some experts would add nafcillin or oxacillin to vancomycin to provide better coverage for methicillin-susceptible S. aureus. • Clindamycin is preferred for children with only localized signs of infection, when resistance to clindamycin is not a concern. Alternatives to vancomycin or clindamycin when MRSA is a concern include linezolid (600 mg per dose IV every 12 hours for children 12 years of age; 10 mg/kg per dose IV every 8 hours for children <12 years of age [maximum dose 600 mg]) or teicoplanin.6,10 In the current Indian scenario with limited data on incidence of CA MRSA and clindamycin resistant CA MRSA, cloxacillin is still the appropriate anti staphylococcal agent.

Coverage for K. Kingae in Children with Osteomyelitis In addition to S. aureus, K. kingae should be considered as a possible pathogen for patients younger than three years (especially those attending day care), and those with indolent osteomyelitis or a history of oral ulcers preceding the onset of musculoskeletal findings.5-7 K. kingae usually is susceptible to cephalosporins (e.g, cefazolin), but consistently resistant to vancomycin, and often resistant to clindamycin and antistaphylococcal penicillins (e.g, oxacillin, nafcillin).5,6 Initial empiric coverage for K. kingae in young children is not provided because the vast majority of cases of osteomyelitis result from S. aureus and other gram-positive pathogens, and because initial multidrug therapy may complicate Antimicrobial Therapy in Skeletal Infections 281 a transition to oral therapy when an organism is not identified in culture. In addition, K. kingae generally produces relatively mild musculoskeletal infections. For children between 3 and 36 months of age who require vancomycin or clindamycin for empiric coverage of CA-MRSA, empiric coverage for K. kingae with cefazolin may be added if the child does not improve as expected. Alternatively, cefazolin may be substituted for vancomycin or clindamycin if CA-MRSA is not identified in cultures of blood, bone, or soft tissue aspirates

Specific Predisposing Factors Other antimicrobial agents, in addition to an agent to treat S. aureus, should be administered when clinical factors suggest specific pathogens. These include the following: • Patients with sickle cell disease should receive empiric therapy with a third-generation cephalosporin because Salmonella species are the most common cause of osteomyelitis in this setting. • In patients with chronic granulomatous disease, osteomyelitis is frequently caused by unusual organisms (e.g. Aspergillus and other fungi, Serratia species, and other filamentous or gram-negative bacteria), as well as staphylococci.8,9 Surgical sampling or debridement of bone lesions is essential for accurate microbiological diagnosis, and addition of a third-generation cephalosporin is prudent as initial therapy. Debridement combined with voriconazole has proven successful in some patients with invasive bone Aspergillus.10 • Patients with recent gastrointestinal surgery or complex urinary tract anatomy are at risk for infection with enteric gram-negative organisms. An initial therapy with ampicillin and either an aminoglycoside or a third-generation cephalosporin, such as cefotaxime or ceftriaxone is suggested. • Organisms that cause infection among injecting drug users (IDU) vary markedly between different communities. Pseudomonas aeruginosa frequently has been reported among IDUs with osteomyelitis. A regimen of ceftazidime plus either nafcillin/oxacillin or vancomycin, which would cover both S. aureus and gram-negative bacilli is suggestd.

 MODIFICATION OF INITIAL EMPIRICAL THERAPY Antimicrobial therapy can be chosen with greater specificity when an organism and its antimicrobial sensitivities are identified from bone, periosteal collection, joint fluid, and/ or blood. Often, the initial empiric regimen can be continued, or coverage narrowed, based on this new information. In some situations, however, the sensitivity patterns are unusual, and the following points should be considered: • Ceftriaxone alone should be used with caution for the initial treatment of staphylococcal osteomyelitis even though invitro sensitivity is demonstrated; numerous treatment failures have been described. • If MSSA is identified cloxacillin is the drug of choice. Cefazolin may be used if cloxacillin is unavailable 282 Rational Antimicrobial Practice in Pediatrics

• For MRSA infections, vancomycin, teicoplanin orf linezolid may be used. In community acquired MRSA infections, clindamycin may be used if inducible clindamycin resistance is absent. Daptomycin should be avoided as bone levels are inadequate. • High doses of the fluoroquinolone class of antibiotics can cause articular cartilage damage in young animals, generating some concern about the long-term use of these agents in infants and children.13 However, tendinopathy and Achilles tendon rupture have been frequently and clearly described, most often in adults. In view of the potential adverse musculoskeletal effects of fluoroquinolones, quinolones are not recommended for children with typical osteomyelitis, including MRSA, regardless of in vitro susceptibility.

 MONITORING RESPONSE TO THERAPY Monitoring the response to initial therapy provides important information about the patient’s clinical course and guides treatment decisions. Most children with osteomyelitis follow a predictable and uncomplicated course, leading to full recovery. Patients who are not responding to treatment as expected require reevaluation and adjustment of therapy. Throughout the entire course of therapy, the need for possible surgical intervention, the possibility of misdiagnosis, and/or inadequate antimicrobial response should be reconsidered.

Monitoring Tools • History and physical examination—Constitutional symptoms, such as activity level and appetite, should be noted. A careful physical examination also should be performed frequently throughout the course of treatment, with particular attention to the pattern of fever, signs of local inflammation, and the development of new sites of infection. A reduction in fever and pain, as well as increased comfort.A reduction in fever and pain, as well as increased comfortwith movement, are expected within seven days and may be seen in toddlers in as little as three to five days. • ESR and/or CRP levels—The ESR and CRP levels are generally reliable laboratory markers of inflammation and response to therapy. The ESR usually increases during the first several days after diagnosis and then declines in the weeks that follow. CRP also increases early in the infection returns to normal sooner than ESR usually within 10 days. In addition, the rate at which CRP returns to normal may be a sensitive indicator of a complicated clinical course. • White blood cell (WBC) count—Elevations in peripheral WBC count in children with hematogenous osteomyelitis are variable and nonspecific. The peripheral leukocyte count, if initially elevated, usually normalizes within 7 to 10 days after starting effective antimicrobial and/or surgical therapy. • Plain radiographs—A plain radiograph of the affected area(s) should be obtained as part of the initial evaluation for all patients with suspected osteomyelitis. Subsequent studies may help to delineate the severity of disease or the development of complications. Areas of devitalized bone (sequestra) become evident within two to four weeks, although complete resolution of radiographic abnormalities may take months. Antimicrobial Therapy in Skeletal Infections 283

Uncomplicated Clinical Course Improvement usually occurs rapidly with appropriate antimicrobial therapy, within three to four days. After 7 to 10 days of antimicrobial therapy, many patients have improved sufficiently to be treated as outpatients. In these patients, the following studies are suggested: 1. ESR and/or CRP 2. WBC count 3. Plain radiographs

Complicated Clinical Course As previously mentioned, initial improvement usually occurs rapidly (often within three to four days) with appropriate antimicrobial therapy. Failure of the previously mentioned indicators to improve after seven days of treatment suggests a lack of response and/or worsening of the child’s condition. This may indicate the following: • Development of a complication, such as thrombophlebitis • The need for surgical intervention, such as drainage of abscesses or removal of sequestra • Ineffective antimicrobial therapy, as would occur with unusual pathogens, such as a fungus or Mycobacterium tuberculosis • A diagnosis other than osteomyelitis such as chronic multifocal recurring osteomyelitis or a malignancy Prompt reevaluation with ESR and/or CRP, WBC count, and plain radiographs is indicated. Further imaging, such as magnetic resonance imaging, may be necessary to identify a lesion requiring surgery.14

 OUTPATIENT THERAPY Continued treatment as an outpatient may be considered when there has been unequivocal clinical improvement. This is indicated by the following: • The patient has been afebrile for 48 to 72 hours • Local signs and symptoms of infection are reduced considerably • White blood cell (WBC) count has normalized • Erythrocyte sedimentation rate (ESR) has decreased by at least 20 percent, or there has been a 50 percent decrease in the concentration of C-reactive protein (CRP) Once all of these conditions have been met, outpatient therapy may be initiated. A percutaneously inserted central catheter (PICC) is frequently employed for a prolonged course of parenteral antibiotics and can be used for home therapy. Oral antibiotics also may be used to complete therapy in children with hematogenous osteomyelitis and avoid the well-documented risks associated with prolonged use of indwelling vascular catheters. With careful selection of appropriate patients and meticulous monitoring, outcomes are equivalent when treatment is completed with either oral or intravenous therapy. There is no minimum duration of initial intravenous therapy needed for successful treatment of osteomyelitis. Treatment with intravenous antibiotics for periods of seven days or less, followed by oral therapy, appears to be as successful as longer initial parenteral courses. 284 Rational Antimicrobial Practice in Pediatrics

Children who are being treated as outpatients with either intravenous or oral antibiotics should be seen at one- to two-week intervals and monitored for continued clinical improvement, as well as for complications related to high-dose antibiotic therapy, such as cytopenia, antibiotic-associated diarrhea, and pseudomembranous enterocolitis. An ESR, complete blood count, and biochemical profile, including liver function tests, at each visit are obtained. In addition, drug levels for those children receiving oral therapy, are also should be obtained. A radiograph should be repeated at the end of therapy.

Choice and Dose of Oral Agent The choice of oral antibiotic should be based on susceptibility testing of the organism (when a pathogen is identified), response to parenteral antibiotic therapy, bioavailability of the oral medication, and palatability of the oral preparation. Antibiotics administered orally for hematogenous osteomyelitis must be given in higher doses than those used for treatment of other infections and recommended in package inserts. Specific antibiotics and the recommended starting doses are as follows:17 • Amoxicillin (25 mg/kg per dose administered every 6 hours) • Cephalexin (37.5 mg/kg per dose administered every 6 hours) • Clindamycin (13 mg/kg per dose administered every 8 hours) • Cloxacillin (31 mg/kg per dose administered every 6 hours) • (25 mg/kg per dose administered every 6 hours) • Penicillin V (22 mg/kg per dose administered every 4 hours) • Linezolid (600 mg per dose administered every 12 hours for children 12 years of age; 10 mg/kg per dose administered every 8 hours for children <12 years of age (maximum 600 mg per dose)) Diarrhea, a frequent complication of high-dose oral beta-lactam therapy, can be mitigated by using the lower doses indicated above and adding probenecid (40 mg/kg per day in four divided doses, maximum of 2 grams per day).

Drug Monitoring Expert opinion differs regarding the routine use of drug monitoring for patients on oral therapy for osteomyelitis. Although, eschewed by some, monitoring is suggested because rare patients will have inadequate antibiotic levels in serum despite high oral antibiotic doses, and the consequences of inadequate treatment of osteomyelitis can be severe.

 DURATION AND EFFICACY OF THERAPY Treatment failure and complications from hematogenous osteomyelitis have been repeatedly linked to short duration of therapy.18 Treatment failures are sometimes seen when the total length of treatment is shorter than 20 to 21 days, whereas failures are uncommon (approximately 3 percent) when therapy is four weeks or more. However, as per recent information treatment of osteomyelitis and septic arthritis for a period of 3 weeks has been associated with excellent outcomes. Antimicrobial Therapy in Skeletal Infections 285

One should administer antibiotics until the erythrocyte sedimentation rate is within the normal range or for four weeks, whichever is longer. Once this has occurred, a plain radiograph should be performed to look for evidence of new bone lesions, even if there is no clinical evidence of treatment failure. Therapy can be safely stopped if the ESR and CRP are normal and the radiograph shows no evidence of sequestra or new lytic bone lesions. This individualized approach will lead to durations of therapy of four weeks in most cases. In patients with septic arthritis 3-4 weeks of therapy is generally considered sufficient.

 OTHER ISSUES Treatment of Culture-Negative Osteomyelitis Patients with clinical and radiologic findings consistent with osteomyelitis often do not have a pathogen isolated from microbiologic specimens. A bacteriologic diagnosis is not confirmed in 20 to 50 percent of cases but does not preclude successful treatment or the use of sequential IV and oral therapy.19 The decision to continue empiric antibiotic therapy for patients in whom cultures are negative must be carefully considered. An important factor is the initial response to such therapy: • In those who improve rapidly on a single antibiotic, empiric initial therapy should be continued. As in those with a positive culture and an uncomplicated clinical course, sequential therapy may be considered. Nevertheless, the differential diagnosis for osteomyelitis should again be reviewed and likely alternative diagnoses excluded before the child is committed to a long course of antibiotic therapy. This is particularly important for children whose imaging studies remain negative. • For patients with findings consistent with osteomyelitis whose initial cultures are negative and who do not respond to empiric antibiotic treatment as expected, an aggressive attempt must be made to isolate unusual pathogens or fastidious organisms, such as K. kingae. The yield of K. kingae is enhanced by inoculating aspirates into blood culture bottles.20 An aspirate of any involved soft tissue or bone biopsy also should be obtained for histopathologic staining and culture for bacteria. In addition, appropriate serologic testing or tuberculin skin testing should be performed when exposure to Coccidioides or Brucella species, or to M. tuberculosis, is suspected. As previously mentioned, patients with culture-negative osteomyelitis who have responded to empiric therapy with a single antibiotic and have had an uncomplicated clinical course may be treated with sequential therapy focused on likely common pathogens (S. aureus, Streptococcus pyogenes). These children also should be immunocompetent and fully immunized in most circumstances.

Management of Associated Venous Thromboembolism Patients with associated venous thromboembolism are usually managed in conjunction with a hematologist. Management typically involves anticoagulation until the thrombus has resolved on Doppler imaging 286 Rational Antimicrobial Practice in Pediatrics

Indications for Surgery • Subperiosteal and soft tissue abscesses and intramedullary purulence should be drained • Sequestra should be removed • Contiguous infectious foci should be debrided adequately and treated with effective antimicrobial therapy • The affected joint should be drained either through percutaneous route or open route These lesions are diagnosed using various imaging techniques, principally plain radiography and magnetic resonance imaging. CT scans also may reveal evidence of sequestra or involucra and are sometimes useful to plan a surgical intervention. In addition, children who are not improving on antibiotic therapy may require surgical procedures to drain persistent collections of pus or debride necrotic bone.

Chronic Osteomyelitis Chronic osteomyelitis, although uncommon, has been described most often with inadequate duration of therapy. Infection is generally considered chronic when signs and symptoms of bone inflammation have been present for at least two weeks, with radiographic evidence of devitalized bone. Treatment of chronic osteomyelitis involves removing devitalized bone and long-term administration of antibiotics. The choice of antimicrobial agents and the duration of therapy have not been carefully evaluated, largely because of the rarity of the disease and the fact that cases tend to have patient-specific etiologic and anatomic factors. Antibiotic regimens that have been successful in small studies include oral cloxacillin plus probenecid, and nafcillin plus oral rifampin. Based on these limited data, the combination of rifampin and a beta-lactam for the treatment of chronic staphylococcal osteomyelitis that is methicillin susceptible are suggested. Adjunctive measures, such as local irrigation with antimicrobial solutions with or without detergents and surgical implantation of beads impregnated with antibiotics, have not been conclusively shown to affect outcome.21 The treatment of chronic osteomyelitis often requires repeated surgical debridement, bone grafting, and very prolonged antimicrobial therapy. Associated complications include joint stiffness, limb shortening, and pathologic fractures. Therefore, fastidious treatment of acute hematogenous osteomyelitis and careful follow-up throughout treatment are

CONCLUSIONS S. aureus is the most common pathogen causing osteomyelitis and septic arthritis in children. All efforts should be made to establish a microbiologic diagnosis. Cloxacillin with or without 3rd generation cephalosporins is empirical therapy of choice. Surgical intervention should be carried out when needed. Recent data suggests that rapid switch from IV to oral therapy once clinical improvement has occurred and 3–4 weeks of total treatment is as good as the erstwhile approach of prolonged IV treatment and treatment durations lasting for 4–6 weeks in uncomplicated childhood osteomyelitis and septic arthritis. Antimicrobial Therapy in Skeletal Infections 287 essential to avoid this complication. Pitfalls in the treatment of chronic osteomyelitis include the following: • Under dosing of antimicrobial agents • Inadequate surgical debridement • Treatment for inadequate periods of time • Failures in adherence to the antimicrobial therapy

 REFERENCES 1. Goergens ED, McEvoy A, Watson M, Barrett IR. Acute osteomyelitis and septic arthritis in children. J Paediatr Child Health. 2005;41:59. 2. Martínez-Aguilar G, Avalos-Mishaan A, Hulten K, et al. Community-acquired, methicillin-resistant and methicillinsusceptible Staphylococcus aureus musculoskeletal infections in children. Pediatr Infect Dis J. 2004;23:701. 3. Gonzalez BE, Martinez-Aguilar G, Hulten KG, et al. Severe Staphylococcal sepsis in adolescents in the era of community-acquired methicillin-resistant Staphylococcus aureus. Pediatrics 2005;115:642. 4. Saigal G, Azouz EM, Abdenour G. Imaging of osteomyelitis with special reference to children. Semin Musculoskelet Radiol. 2004;8:255. 5. Kaplan SL. Osteomyelitis in children. Infect Dis Clin North Am. 2005;19:787. 6. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18. 7. Lewis JS 2nd, Jorgensen JH. Inducible clindamycin resistance in Staphylococci: should clinicians and microbiologists be concerned? Clin Infect Dis. 2005;40:280. 8. Frank AL, Marcinak JF, Mangat PD, et al. Clindamycin treatment of methicillin-resistant Staphylococcus aureus infections in children. Pediatr Infect Dis J. 2002;21:530. 9. Gonzalez BE, Martinez-Aguilar G, Hulten KG, et al. Severe Staphylococcal sepsis in adolescents in the era of community-acquired methicillin-resistant Staphylococcus aureus. Pediatrics. 2005;115:642. 10. Chen CJ, Chiu CH, Lin TY, et al. Experience with linezolid therapy in children with osteoarticular infections. Pediatr Infect Dis J. 2007;26:985. 11. Rayner CR, Baddour LM, Birmingham MC, et al. Linezolid in the treatment of osteomyelitis: results of compassionate use experience. Infection 2004;32:8. 12. Drew RH, Perfect JR, Srinath L, et al. Treatment of methicillin-resistant staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. For the Synercid Emergency- Use Study Group. J Antimicrob Chemother. 2000;46:775. 13. Bradley JS, Jackson MA, Committee on Infectious Diseases, American Academy of Pediatrics. The use of systemic and topical fluoroquinolones. Pediatrics 2011;128:e1034. 14. Courtney PM, Flynn JM, Jaramillo D, et al. Clinical indications for repeat MRI in children with acute hematogenous osteomyelitis. J Pediatr Orthop. 2010;30:883. 15. S. aureus osteomyelitis in children. South Med J 1982; 75:138. Zaoutis T, Localio AR, Leckerman K, et al. Prolonged intravenous therapy versus early transition to oral antimicrobial therapy for acute osteomyelitis in children. Pediatrics. 2009;123:636. 16. Arnold JC, Cannavino CR, Ross MK, et al. Acute Bacterial Osteoarticular Infections: Eight-Year Analysis of C-Reactive Protein for Oral Step-Down Therapy. Pediatrics. 2012. 17. Martínez-Aguilar G, Hammerman WA, Mason EO Jr, Kaplan SL. Clindamycin treatment of invasive infections caused by community-acquired, methicillin-resistant and methicillin susceptible Staphylococcus aureus in children. Pediatr Infect Dis J. 2003;22:593. 18. Peltola H, Pääkkönen M, Kallio P, et al. Short- versus long-term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture-positive cases. Pediatr Infect Dis J. 2010;29:1123. 288 Rational Antimicrobial Practice in Pediatrics

19. Bonhoeffer J, Haeberle B, Schaad UB, Heininger U. Diagnosis of acute haematogenous osteomyelitis and septic arthritis: 20 years experience at the University Children’s Hospital Basel. Swiss Med Wkly. 2001;131:575. 20. Yagupsky P. Kingella kingae: from medical rarity to an emerging paediatric pathogen. Lancet Infect Dis 2004;4:358. 21. Overturf, GD. Bacterial infections of the bone and joints. In: Infectious Diseases of the Fetus and Newborn, 7th edition, Remington, JS, Klein JO, Wilson CB, et al (Eds), Elsevier Saunders, Philadelphia 2011. p.296. Antimicrobial Therapy in CNS Infections 289 2525 Antimicrobial Therapy in CNS Infections Lalitha Iyer, VP Udani

 BACTERIAL MENINGITIS Acute bacterial meningitis remains an important cause of morbidity and mortality in developing countries. Since the routine use of Haemophilus influenzae type b vaccine and the pneumococcal vaccine in developed countries, the incidence of meningitis has fallen. This has yet to occur in countries like India. Predisposing factors for meningitis include respiratory infections, otitis media, mastoiditis, head trauma, human immunodeficiency virus (HIV) infection and other immune deficiency states. The emergence of resistant Streptococcus pneumoniae has resulted in new challenges to treat bacterial meningitis. Etiology of bacterial meningitis is unique to the age of the infant and is somewhat different in developing versus developed countries. Though, a wide range of antibiotics are available for therapy, judicious and rational use of antimicrobials needs to be ascertained. However, there is a lack of good microbiological data from developing countries as compared to developed countries. This is partly because of the lack of good microbiological laboratories especially in smaller cities and towns in India leading to a dearth of knowledge on the prevalence of common community and nosocomially acquired infections agents causing meningitis. Also there is little information on the sensitivity patterns in different regions. The next two sections reviews the usual and unusual organisms which are responsible for bacterial meningitis in neonates and in infants/children considered separately. Subsequently few paragraphs focus on the antibiotics usually employed in meningitis. Finally specific management questions are addressed.

Organisms Neonatal age (< 4 weeks) Early onset (< 7 days) neonatal meningitis is mainly caused by bacteria acquired from maternal vaginal flora. In developed countries Group B streptococci (GBS), 290 Rational Antimicrobial Practice in Pediatrics

Enterobacteriaceae and Listeria monocytogenes are predominant pathogens. The microbiological profile of neonatal meningitis is poorly studied from the India. Studies available focus primarily on epidemics with unusual organisms like Salmonella worthington, etc.1 There are more studies in neonatal sepsis and it is reasonable to extrapolate the results to meningitis. The neonatal-perinatal database published in 2005 from data from multiple tertiary centers suggests that gram-negative organisms like E. coli and Klebsiella are the most common pathogens in early onset sepsis (EOS).2 Group B streptococcus is hardly ever encountered in Indian studies but may be underestimated.3 Etiology of late onset sepsis (LOS) (> 7 days) includes both perinatally acquired organisms and nosocomial pathogens. The risk of peculiar organisms increases with several practices in the NICU e.g. use of respiratory equipment in the NICU increases the risk of infection caused by Serratia marcescens, Pseudomonas aeruginosa and Proteus species. Invasive devices predispose infants to the infections caused by Staphylococcus epidermidis, Pseudomonas, Citrobacter, and Bacteroides species. In premature newborns who receive multiple antibiotics, hyperalimentation, and who undergo various surgical procedures, Staphylococcus epidermidis and Candida species also are reported in greater frequency. Here it should be mentioned that fungal infections are on the rise in all nurseries. Initially these used to be candida albicans though recently other candida species are becoming prominent. In Indian studies of LOS where data is mostly from highly specialized neonatal units, offending strains of Klebsiella, Staphylococcus (both epidermidis and aureus), Enterococci, Enterobacteria, Serratia, Pseudomonas and Citrobacter are commonly encountered .2 The gram-negative organisms show resistance routinely to third generation cephalosporins and ampicillin while Staphylococcus is often methicillin resistant.2 Also the organisms commonly encountered are fairly variable in their prevalence and their sensitivity to different antibiotics, highlighting the need for good local culture-sensitivity facilities to decide which antibiotics would be most appropriate. Data on community acquired late onset neonatal sepsis in India is lacking. Infants and older children In children older than 4 weeks, S. pneumoniae, H. influenzae b and N. meningitidis are the most common etiologic agents.4 H. influenzae type b, once the most common pathogen, essentially has disappeared in developed countries where the conjugate vaccine is routinely used. In Indian studies there is a high negative culture rate probably because of widespread antibiotic use before the CSF has been examined. A recent study suggests, however, that parenteral antibiotics (mostly ceftriaxone) does reduce the culture rates but the main effect is reduction of CSF protein and increase in CSF glucose.5 The rates of positive cultures rarely exceeds 50%. The initial impression that H. influenzae is not a common organism has been disproved in several recent studies.6 A study conducted in south India analyzed 100 episodes of acute bacterial meningitis in children 1 month to 12 years. Organisms were isolated in 35% of cases; two major pathogens were H. influenzae (17%) and S. pneumoniae (12%).7 Serotypes 1 and 5 are the most common S. pneumoniae seen in India and thankfully there is a low resistance to the penicillins though higher resistant rates are seen for other antibiotics like chloramphenicol.8,9 Antimicrobial Therapy in CNS Infections 291

Specific Classes of Antimicrobial Agents Penicillins: Ampicillin either alone or with chloramphenicol in postneonatal meningitis and with an aminoglycoside in neonatal meningitis were the usual first line empiric antibacterial agents used in the 1970s and 1980s. Presently there is a growing resistance in S. pneumoniae to the penicillins while 60% of H. influenzae isolates are resistant to ampicillin in recent Indian studies.6,8,9 Similarly gram-negative organisms in neonatal meningitis are routinely resistant to ampicillin.2 These high resistance rates preclude the use of the penicillins as empiric agents in bacterial meningitis both in the neonatal period and beyond. Chloramphenicol: This is an excellent drug for meningitis as it has very high CNS penetration. It also is absorbed very well with high CNS levels making it a useful antibiotic when long term treatment is sometimes necessary in complicated meningitis (when IV access maybe a problem). However, resistance rates have soared with H. influenzae being resistant in up to 60% of cases.6 It can now be considered only after culture reports confirm susceptibility and cannot be used as a first line empiric agent. The intramuscular formulation of chloramphenicol has however been successfully used in management of meningococcal epidemics. Aminoglycosides: CSF penetration of aminoglycosides is an issue but these have been found useful in management of neonatal meningitis where gram-negative pathogens are common. There is a growing resistance to gentamicin in most Indian neonatal units to the tune of 80% and this cannot be considered an empiric agent anymore.2 Amikacin efficacy is still fairly high against common gram-negative organisms like Klebsiella and E. coli. However, enterococci and Salmonella, which are increasingly becoming nursery offenders are routinely resistant. Cephalosporins: In clinical trials, the third-generation cephalosporins have been found to be superior to chloramphenicol and cefuroxime and are recommended for the treatment of community acquired childhood bacterial meningitis.10,11 They are usually highly effective against community-acquired agents like H. influenzae, S. pneumoniae and N. meningitidis. Emerging resistance in pneumococci to cephalosporins in developed countries have created a problem with their use as monotherapy. Cefotaxime and ceftriaxone are also quite effective in meningitis caused by aerobic gram-negative bacilli (e.g. Escherichia coli or Klebsiella species). Cure rates of 78-94% are reported as compared to high mortality rates of 40–90% for previous regimens that usually included an aminoglycoside, with or without chloramphenicol. Ceftazidime, has also shown efficacy in several studies of patients with Pseudomonas meningitis. Cefaperazone has been shown to have high cure rates. Fourth-generation cephalosporin, cefepime, has been shown to be safe and therapeutically equivalent to cefotaxime in the treatment of bacterial meningitis in infants and children.12 Cefepime also has greater in vitro activity than the third-generation cephalosporins against Enterobacter species and Pseudomonas aeruginosa and has been used successfully in some patients with meningitis caused by these bacteria.12 However, 292 Rational Antimicrobial Practice in Pediatrics given the increasing frequency of antimicrobial resistance among gram-negative bacilli, especially in the hospital setting third generation cephalosporins may be inadequate and in vitro susceptibility testing of isolates is critical to guide antimicrobial therapy in nosocomially acquired meningitis especially in neonates. Vancomycin: Vancomycin has proven useful in the therapy of bacterial meningitis caused by penicillin-resistant pneumococci. Due to poor CSF penetration, vancomycin should always be combined with a third generation cephalosporin even in patients with meningitis caused by penicillin and cephalosporin-resistant strains. Vancomycin has a role in late onset neonatal meningitis, post neurosurgery and post shunt meningitis caused by MRSA & MRSE. When used for the treatment of bacterial meningitis, vancomycin should be administered to maintain serum vancomycin trough concentrations of approximately 15- 20 g/mL. Rifampin: This drug has good CSF penetration and in vitro activity against many meningeal pathogens. However, when used alone, resistance rapidly develops, hence rifampin must be used in combination with a third-generation cephalosporin, with or without vancomycin, in patients with pneumococcal meningitis caused by highly penicillin- or cephalosporin resistant strains. Rifampin should only be added if the organism is shown to be susceptible and there is a delay in the expected clinical or bacteriologic response. Rifampin should also be combined with vancomycin in patients with CSF shunt infections caused by staphylococci, especially in cases in which the shunt cannot be removed. Carbapenems: Meropenem, which has a broad range of in vitro activity and less seizure proclivity than imipenem, has been studied in both children and adults with bacterial meningitis.13 In these studies, meropenem has been shown to have clinical and microbiologic outcomes similar to those of cefotaxime or ceftriaxone and can be recommended as an alternative to these agents for treatment of bacterial meningitis. Meropenem has also been used successfully in isolated patients with pneumococcal meningitis caused by penicillin- and cephalosporin-resistant strains and in meningitis caused by gram-negative isolates that are resistant to standard therapy a commonly encountered situation in neonatal meningitis. Fluoroquinolones: On the basis of limited published literature in children these agents should only be utilized for meningitis caused by multidrug-resistant gram-negative bacilli. This is often the case in the neonatal period when unusual multidrug resistant organisms are cultured, e.g. Salmonella Worthington.1 Fluoroquinolones are also used in treatment failures or when there are specific contraindications to using standard antimicrobial agents. In a multicenter, randomized trial in children with bacterial meningitis the newer fluroquinolone trovafloxacin was comparable to ceftriaxone in terms of clinical efficacy and CSF sterilization.14 Although trovafloxacin is no longer utilized because of concerns of liver toxicity, these data suggest the potential usefulness of the new fluoroquinolones in patients with bacterial meningitis. Antimicrobial Therapy in CNS Infections 293

Empiric Initial Treatment in Patients with Suspected Bacterial Meningitis Poor outcome is associated with greater amounts of antigen or a larger number of microorganisms in CSF samples obtained before initiation of antimicrobial therapy. Delayed CSF sterilization after 24 hours of antimicrobial therapy is a risk factor for subsequent neurologic sequelae. Antibiotics should be administered as soon as IV access is obtained. However, every attempt should be made to procure CSF for routine and culture studies prior to IV antibiotics unless the patient is in extremis. Neonates16 At the outset one should re-affirm that all antibiotic use in the newborn should be parenteral- preferably intravenous for the whole duration of treatment. As a rule oral antibiotics should be strongly discouraged at any point during the course. We have reported unrecognized ventricultis in infants where the infection was presumably acquired in the newborn period, was treated inadequately and finally led to a localized sequestered ventricular infection presenting as a hydrocephalus in early infancy.15 Secondly all neonates on antibiotics should always receive vitamin K prophylaxis preferably weekly till the antibiotic course is over. In early onset meningitis empiric therapy should necessarily cover community-acquired agents from the maternal flora like E. coli and Klebsiella. It is probably unnecessary to worry about group B streptococci in the Indian context. Listeria is also an unusual agent in our country. However, empirical choice in an individual neonatal unit must consider data regarding pathogens and their susceptibility within that unit. This is especially true in late-onset meningitis where nosocomial pathogens are the main offenders. It is of critical importance when there is an epidemic situation when the organism characteristics in the previously diagnosed patient would help decide choice in the current patient. It used to be standard practice to initiate therapy in suspected meningitis with ampicillin and an aminoglycoside (gentamicin) combination in the past. Ampicillin had good coverage against gram-positive organisms like GBS, enterococci, L. monocytogenes, etc. and also achieved adequate levels in the CSF. With the rapid increase in resistance to penicillins in most studies from India this practice may have to be abandoned unless there are local data confirming sensitivity to this drug. Among aminoglycosides, gentamicin and tobramycin were extensively used in combination with ampicillin. Despite concerns about the adequacy of their CSF levels, these agents have proven effective when used in combination. Aminoglycosides when used with penicillin and ampicillin also have synergistic action against isolates of group B streptococci and enterococci. For both early onset neonatal meningitis and for community acquired late onset meningitis in an antibiotic naïve patient where gram-negative organisms are the predominant etiology empiric therapy should include cefotaxime in combination with an aminoglycoside. This should be preferably amikacin rather than gentamicin as the resistance to gentamicin is fairly high especially for late onset meningitis. This recommendation is based on the lower MBCs (minimum bactericidal concentration) of gram-negative bacteria to cefotaxime compared to penicillins and aminoglycosides and the high CSF concentrations that can be safely achieved. Cefotaxime therapy increases the proportion of infants who will have 294 Rational Antimicrobial Practice in Pediatrics sterile CSF cultures 48–72 hours into treatment, though mortality and morbidity remain comparable to those of historical studies. There are no randomized controlled clinical trials comparing the safety and efficacy of cefotaxime to ampicillin and aminoglycoside combinations. Ceftriaxone is another third generation cephalosporin is another very useful drug with it’s wide coverage. However, it causes sludging of bile and may increase the risk of bilirubin encephalopathy in high-risk newborns by competing with bilirubin for binding with albumin. In situations of suspected listeria or enteroccocal infections one would not be able to use third generation cephalosporins without ampicillin as none of the cephalosporins have any activity against these organisms. For nosocomially acquired neonatal meningitis empiric therapy depends on local prevalence and susceptibility patterns. Choices include cefepime, meropenem with or without vancomycin/linezolid with or without aminoglycosides. Third generation cephalosporins must not be used if there is high prevalence of extended spectrum ß lactamase producing organisms. A recent Cochrane review of the use of intraventricular antibiotics in neonatal meningitis concluded that there is no place for this practice at the present time as the only randomized controlled trial showed a 3 fold increase in mortality when this procedure was adopted.17 For doses see Tables 1 and 2. The duration of antibiotic use depends on the etiologic agent as well as whether complications have developed, a situation which occurs with some regularity in our setting becasue of excessive empiric use of antibiotics for short durations, without doing a CSF. In promptly diagnosed, vigorously treated gram-positive meningitis even a 10-14 days course of parenteral antibiotics would suffice (exception S. aureus meningitis where treatment for 4 weeks is required). However, if the organism is gram, negative, a minimum of 21 days of parenteral antibiotics would be considered adequate or at least 2 weeks after the CSF has been sterilized. In complicated meningitis (ventriculitis, hydrocephalus, abscess) the parenteral antibiotics may need to continue for 6–8 weeks. Infants and children4 Since their development, penicillins and sulfonamides have been the standard, but much has changed as a result of widespread antimicrobial resistance against these drugs and the need for development of newer agents. Decisions on the choice of a specific antimicrobial agent are based on knowledge of in vitro susceptibility and relative penetration into CSF in the presence of meningeal inflammation. Clinical trials have most often compared newer agents with what has been determined to be “standard” antimicrobial therapy, even though this “standard” therapy has not always been extensively studied in patients. Initial antibiotic selection should provide coverage for all 3 common pathogens: S. pneumoniae, N. meningitidis and H. influenzae. In the recent past ampicillin and chloramphenicol were considered adequate as the first line empiric treatment for meningitis beyond 3 months of age with good coverage of all 3 common organisms as well as excellent CSF penetration. The increasing resistance to these antibiotics in India and Antimicrobial Therapy in CNS Infections 295

TABLE 1 Antibiotic dosages for neonatal bacterial meningitis to be adjusted by weight and age dosage (mg/kg/d) and intervals of administration Body Body Body Body Weight Weight Weight Weight <2000 g <2000 g >2000 g >2000 g Antibiotic Route of Age 0-7 Age >7 Age 0-7 Age >7 administration Days Days Days Days Penicillins Ampicillin IV, IM 100 divided 150 divided 150 divided 300 divided q12 h q8 h q8 h q6 h Penicillin-G IV 100,000 U 150,000 U 150,000 U 250,000 U divided q12 h divided q8 h divided q8 h divided q6 h Oxacillin IV, IM 100 divided 150 divided 150 divided 200 divided q12 h q8 h q8 h q6 h Ticarcillin IV, IM 150 divided 225 divided 225 divided 300 divided q12 h q8 h q8 h q6 h Cephalosporins Cefotaxime IV, IM 100 divided 150 divided 100 divided 150 divided q12 h q8 h q12 h q8 h Ceftriaxone IV, IM 50 once daily 75 once daily 50 once daily 75 once daily Ceftazidime IV, IM 100 divided 150 divided 100 divided 150 divided q12 h q8 h q8 h q8 h

TABLE 2 Antibiotics for neonatal bacterial meningitis that need to be dosed according to age (Newborn age is gestational age plus weeks of life) Antibiotic Desired Newborn Newborn Newborn Newborn Serum level Age<26 Age 27-34 Age 35-42 Age >43 (mcg/mL) Weeks Weeks Weeks Weeks (mg/kg/dose) (mg/kg/dose) (mg/kg/dose) (mg/kg/dose) Aminoglycosides Amikacin** 20–30 (peak), 7.5 q24 h 7.5 q18 h 10 q12 h 10 q8 h <10 (trough) Gentamicin** 5–10 (peak), 2.5 q24 h 2.5 q18 h 2.5 q12 h 2.5 q8 h <2.5 (trough) Tobramycin** 5–10 (peak), 2.5 q24 h 2.5 q12 h 2.5 q12 h 2.5 q8 h <2.5 (trough) Glycopeptide Vancomycin*,** 20–40 (peak), 15 q24 h 15 q18 h 15 q12 h 15 q8 h* <10 (trough) * Beyond 28 days (4 week) of life, dose of vancomycin is 20 mg/kg/dose q8 h. ** Serum levels must be monitored when patient has kidney disease or is receiving other nephrotoxic drugs. 296 Rational Antimicrobial Practice in Pediatrics also worldwide as well as the rare but important complication of aplastic anemia with chlopramphenicol has now relegated these drugs to the back-burner. In the 1980s several studies using third generation cephalosporins esecially ceftriaxone and cefotaxime established the clear superiority of these as empiric therapy for bacterial meningitis beyond 3 months. This was especially true of ceftriaxone, which not only covered all 3 common organisms but also had the advantage of long duration of action (twice a day initially and later once daily) but also could be given intramuscularly with adequate levels once IV access became a problem. This practice has since changed in countries with an evolving pneumococcal resistance to the third generation cephalosporins. It is now recommended by the American Academy of Pediatrics and Infectious Disease Society of America to use a combination of ceftriaxone and vancomycin in suspected serious invasive preumococcal disease like meningitis till culture results. However, early vancomycin use may increase the risk of hearing loss and hence, other antibiotics like rifampicin in combination or meropenem alone have been used. In India where culture results are often unreliable and where the incidence of reported pneumococcal resistance to the penicillin and cephalosporins is still low it does not seem prudent to use this empiric combination, which would add significant expense to the treatment. For doses see Table 3. Although even 5 days has been shown to be effective in uncomplicated meningitis.18 most authorities recommend a 10–14 day course has been

TABLE 3 Dosage of antimicrobial agents in infants and children Agent Total daily dose (dosing interval in hours) Amikacin 20–30 mg/kg (8) Ampicillin 300 mg/kg (6) Aztreonam 6–8 gm (6) Cefipime 150 mg/kg (8) Cefotaxime 225–300 mg/kg (6–8) Ceftazidime 150 mg/kg (8) Ceftriaxone 80–100 mg/kg (12-24) Chloramphenicol 75-100 mg /kg (6) Gentamicin 7.5 mg/kg (8) Meropenam 120 mg/kg (8) Naficillin 200 mg/kg (6) Oxacillin 200 mg/kg (6) Penicillin G 0.3 mU/kg (4–6) Rifampicin 10–20 mg/kg (12–24) Tobramycin 7.5 mg/kg (8) Vancomycin 60 mg/kg (6) Antimicrobial Therapy in CNS Infections 297 the recommended duration.19,20 Intravenous antimicrobial therapy is recommended for the duration of treatment to ensure that adequate CSF concentrations of specific antimicrobial agents are attained. However, many children in our scenario are diagnosed late, are partly treated or already have complications like subdural empyema necessitating much longer durations. Often this would need the duration of therapy to be individualized on the basis of the patient’s clinical response. Also in case of a significant subdural empyema surgical drainage often with large craniotomies would be necessary to ensure an optimal result.

Pathogen Specific Therapy See Table 4.

Other Therapy What s the role of adjunctive dexamethasone therapy in patients with bacterial meningitis?4 At present, there are insufficient data to make a recommendation on the use of adjunctive dexamethasone in neonates with bacterial meningitis. In a meta-analysis of clinical studies published during 1988–1996, adjunctive dexamethasone (0.15 mg/kg every 6 hour for 2- 4 days) had confirmed benefit for H. influenzae type b meningitis if commenced with or before antimicrobial therapy. However, contrary results from low-income countries made a recent Cochrane review conclude that steroids do not apparently reduce hearing loss in low-income countries.21 This was thought to be due to rampant use of antibiotics given prior to steroid administration. However, recent randomized controlled studies with lage number of patients from Latin America suggest that steroids are ineffective in reducing hearing loss and neurological sequelae/death.22-24 This hold true even for patients given steroids prior to or simultaneously administered with parenteral antibiotics.22 Steroid use should not be considered “standard of care” in meningitis in low-income countries. If they are at all used, dexamethasone should be initiated 10-20 minutes prior to, or at least concomitant with, the first antimicrobial dose, at 0.15 mg/kg every 6 hour for 48 hours. What is the role of adjuvant glycerol in childhood bacterial meningitis? This orally administered hyperosmolar agent used to reduce increased intracranial hypertension in the past has made a comeback in bacterial meningitis. It has been shown to reduce the mortality rates as well as severe neurologic sequelae in studies from the developing world.24 It however, does not reduce the risk of hearing loss.22 It is given as 1.5 g/kg (max 25 gm) 4 times daily for the 1st 48 hour and seems to work by its hyperosmolar action.

 BRAIN ABSCESS25 Brain abscesses are most common in children between 4 and 8 years. Otogenic brain abscess secondary to chronic otitis media and mastoiditis are located mostly in temporal lobe and cerebellum and are becoming less common because of the widespread use of antibiotics for ear and mastoid infections. Other causes of brain abscess include 298 Rational Antimicrobial Practice in Pediatrics

TABLE 4 Recommended therapy for specific pathogens4 Microorganism, susceptibility Standard therapy Alternative therapies Streptococcus pneumoniae Penicillin MIC <0.06 g/mL Penicillin G or ampicillin Third-generation cephalosporin >0.12 g/mL Vancomycin plus a Fluoroquinolone third-generation cephalosporin Neisseria meningitidis Penicillin MIC <0.1 g/mL Penicillin G or ampicillin Third-generation cephalosporin, chloramphenicol 0.1-1.0 g/mL Third-generation Chloramphenicol, fluoroquinolone, cephalosporin meropenem Escherichia coli and other Third-generation Aztreonam, fluoroquinolone, Enterobacteriaceae cephalosporin meropenem, trimethoprim- sulfamethoxazole, ampicillin Pseudomonas aeruginosa Cefepime or ceftazidime Aztreonam, ciprofloxacin, meropenem Haemophilus influenzae Beta-lactamase negative Ampicillin Third-generation cephalosporin, cefepime, chloramphenicol, fluoroquinolone Beta-lactamase positive Third-generation Cefepime, chloramphenicol, cephalosporin fluoroquinolone Staphylococcus aureus Methicillin susceptible Nafcillin or oxacillin Vancomycin, meropenem Methicillin resistant Vancomycin Trimethoprim-sulfamethoxazole, linezolid Staphylococcus epidermidis Vancomycin Linezolid Enterococcus species Ampicillin susceptible Ampicillin plus gentamicin Ampicillin resistant Vancomycin plus gentamicin Ampicillin and vancomycin Linezolid resistant embolization due to congenital heart disease with right-to-left shunts, meningitis (especially neonatal), soft tissue infection of face and scalp, orbital cellulitis and sinusits (mostly in frontal lobe), dental infections, penetrating head injuries, immunodeficiency states and rarely as part of shunt infections. Antimicrobial Therapy in CNS Infections 299

The etiology often determines the microbiology. In penetrating head injury it tends to be singular and caused by S. aureus, whereas those resulting from septic emboli, or congenital heart disease have several causative organisms. These include S. aureus, streptococci (viridans, pneumococci, microaerophilic) anaerobic organisms (gram-positive cocci, Bacteroides spp, Fusobacterium spp, Prevotella spp, Actinomyces spp, and Clostridium spp) and gram-negative aerobic bacilli (enteric rods, Proteus spp, Pseudomonas aeruginosa, Citrobacter diversus and Haemophilus spp). Neonatal citrobacter and Salmonella meningitis often get complicated by brain abscesses.

Treatment All efforts must be made to aspirate the abscess and obtain material for gram stain and culture. Exceptions are multiple abscesses, poor surgical risk, positive blood culture or difficult location. Empiric therapy before the causative organisms is isolated and for unknown predisposing factors or those resulting from otogenic infections involves a combination of third generation cephalosporin, cloxacillin and metronidazole so that a broad coverage is assured including against anaerobes. Monotherapy with meropenem which has good activity against gram-negative bacilli, anaerobes, staphylococci, and streptococci including virtually all antibiotic–resistant pneumococci is a reasonable alternative. If there is a history of head trauma, neurosurgery or sinusitis therapy should include vancomycin, ceftazidime/cefepime and metronidazole to take care of staphylococci and P. aeruginosa. Initial treatment of a lesion resulting from cyanotic heart disease, odontogenic infections, lung abscess is penicillin and metronidazole. In neonatal meningitis with abscess formation meropenem should be the primary drug often in combination with an aminoglycoside. In immunocompromised patients, broad-spectrum antibiotic coverage is used and often empiric amphotericin B therapy for fungi and cotrimoxazole for nocardia may need to be considered. The choice of the antibiotics is altered once results of culture and sensitivity are available. Patients with cerebritis, small abscess < 3 cm, multiple abscesses may be treated with medical therapy alone. Clearly surgical drainage by repeated aspiration or excision is an important part of management of large abscesses especially if these are chronic and thick walled or are causing life-threatening mass effect and increased ICP. Duration of therapy is 4–12 weeks if abscess is drained. If abscess not drained then longer duration may be required till radiological resolution (4 months till 1 year).

 CSF SHUNT INFECTIONS25,26 The incidence of shunt infections ranges from 1–20% with an average of 10%. The highest rates are reported in young infants. Most infections are a result of intraoperative contamination of the surgical wound by skin flora. Accordingly coagulase negative staphylococci are isolated in more than half of the cases. Staphylococcus aureus is isolated in approximately 20% and gram-negative bacilli in 15%. Four distinct clinical syndromes have been described: colonization of the shunt, infection associated with 300 Rational Antimicrobial Practice in Pediatrics wound infection, distal infection with peritonitis, and infection associated with meningitis. The most common type of infection is ‘colonization’ of the shunt with symptoms occurring few months after the surgical procedure. S. epidermidis is the most common organism in upto a third of cases in the Indian scenario. Wound infection presents with obvious infection or dehiscence along the shunt tract and most often occurs within days to weeks of the surgical procedure. S. aureus is the most common isolate. Distal infection of VP shunt with peritonitis presents with abdominal symptoms, usually without evidence of shunt malfunction. In these cases gram-negative isolates predominate and mixed infection is common. Infection associated with meningitis is caused by the usual meningeal pathogens Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type b.

Treatment Recently antibiotic impregnated shunts have substantially reduced the risk of shunt infections. These are, however, very expensive and are not in routine use in India. Till then we have to deal with a significant proportion of patients with VP shunts developing shunt infections more in young children and more in the first 4 months of the procedure. There are numerous reported methods for the treatment of CSF shunt infections, but no randomized, prospective studies have ever been performed. The principles of antimicrobial therapy for CSF shunt infections are generally the same as those for the treatment of acute bacterial meningitis. However, direct instillation of antimicrobial agents into the ventricles through either an external ventriculostomy or shunt reservoir is occasionally necessary in patients who have shunt infections that are difficult to eradicate or who cannot undergo the surgical components of therapy. No antimicrobial agent has been approved by the US Food and Drug Administration for intraventricular use, and the specific indications are not well-defined. Antimicrobial dosages have been used empirically with dosage adjustments and dosing intervals based on the ability of the agent to achieve adequate CSF concentrations. All shunt infections should be treated empirically with antibiotics covering MRSA and MRSE as these infections are mostly nosocomial. A suitable combination is a third generation cephalosporin/meropenem with vancomycin. Later changes could be made after culture– sensitivity results. When using intra shunt antibiotics monitoring of CSF levels is necessary to avoid toxicity. Rifampicin may be added if infection is with MRSA/MRSE and the shunt cannot be removed. Does the shunt need to be removed? Removal of all components of the infected shunt and some component of external drainage, in combination with appropriate antimicrobial therapy, appears to be the most effective treatment for CSF shunt infections. Success rates are lower when the shunt is treated in situ, because of the ability of many of these microorganisms to adhere to prostheses and survive antimicrobial therapy. When wound infection is diagnosed the shunt always needs to be removed. To allow for continued CSF drainage a temporary catheter or an Ommaya reservoir is often placed. Antimicrobial Therapy in CNS Infections 301

Timing of shunt reimplantation: For shunt infections caused by S. aureus, 10 days of negative culture results are recommended prior to reshunting and for gram-negative bacilli, a 10–14 day course of antimicrobial therapy should be used, although longer durations may be needed depending on the clinical response.

 REFERENCES 1. Udani R, Kabra NS, Nanavati RN, Baweja S. Outbreak of Salmonella Worthington meningitis in a neonatal intensive care unit. Indian Pediatr 1999;36:300-3. 2. National Neonatal Perinatal Database: Report 2002-2003 ICMR, New Delhi Publications. 2005;45-57. 3. Shet A, Ferrieri P. Neonatal and maternal group B streptococcal infections: a comprehensive review. Indian J Med Res. 2004;120:141-50. 4. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM et al. Practice Guidelines for the Management of Bacterial Meningitis.. Clin Infect Dis. 2004;39:1267-84. 5. Nigrovic LE, Malley R, Macias CG, et al. Effect of antibiotic pretreatment on cerebrospinal fluid profiles with bacterial meningitis. Pediatrics. 2008;122 (4):726-30. 6. Sahai S, Mahadevan S, Srinivasan S, Kanungo R. Childhood bacterial meningitis in Pondicherry, South India. Indian J Pediatr. 2001;68:839-41. 7. Are Haemophilus influenzae infections a significant problem in India? A prospective study and review. Invasive Bacterial Infections Surveillance (IBIS) Group of the International Clinical Epidemiology Network. Clin Infect Dis. 2002;34:949-57. 8. Kanungo R, Rajalakshmi B. Serotype distribution and antimicrobial resistance in Streptococcus pneumoniae causing invasive and other infections in south India. Indian J Med Res. 2001;114:127-32. 9. Prospective multicentre hospital surveillance of Streptococcus pneumoniae disease in India. Invasive Bacterial Infection Surveillance (IBIS) Group, International Clinical Epidemiology Network (INCLEN). Lancet. 1999;353:1216-21. 10. Peltola H, Anttila M, Renkonen OV. Randomised comparison of chloramphenicol, ampicillin, cefotaxime, and ceftriaxone for childhood bacterial meningitis. Finnish Study Group. Lancet. 1989;(8650):1281-7. 11. Girgis NI, Abu el-Ella AH, Farid Z, Haberberger RL, Woody JN. Ceftriaxone alone compared to ampicillin and chloramphenicol in the treatment of bacterial meningitis. Chemotherapy. 1988;34(Suppl 1): 16-20. 12. Saez-Llorens X, O’Ryan M. Cefepime in the empiric treatment of meningitis in children. Pediatr Infect Dis J. 2001;20:356-61. 13. Odio CM, Puig JR, Feris JM, Khan WN, Rodriguez WJ, McCracken GH Jr. Bradley JS. Prospective, randomized, investigator-blinded study of the efficacy and safety of meropenem vs. cefotaxime therapy in bacterial meningitis in children. Meropenem Meningitis Study Group. Pediatr Infect Dis J. 1999;18:581- 90. 14. Saez-Llorens X, McCoig C, Feris JM, Vargas SL, Klugman KP, Hussey GD, et al. Trovan menigitis Study Group.Quinolone treatment for pediatric bacterial meningitis: a comparative study of trovafloxacin and ceftriaxone with or without vancomycin. Pediatr Infect Dis J. 2002;21:14-22. 15. Udani V, Udani S, Merani R, Bavdekar M. Unrecognised ventriculitis/meningitis presenting as hydrocephalus in infancy. Indian Pediatr. 2003;40:870-3. 16. Heath PT, Nik Yusoff NK, Baker CJ. Neonatal meningitis. Arch Dis Child Fetal Neonatal Ed. 2003; 88: F173-8. 17. Shah S, Ohlsson A, Shah V. Intraventricular antibiotics for bacterial meningitis in neonates. Cochrane Database Syst Rev. 2004;(4):CD004496 18. Molyneux E, Nizami S, Saha S et al. 5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double –blinded randomized equivalence study. Lancet 2011;28:377(9780):1837-45. 19. Kavaliotis J, Manios SG, Kansouzidou A, Danielidis V. Treatment of childhood bacterial meningitis with ceftriaxone once daily: open, prospective, randomized, comparative study of short-course versus standard-length therapy. Chemotherapy. 1989;35:296-303. 302 Rational Antimicrobial Practice in Pediatrics

20. Scholz H, Hofmann T, Noack R, Edwards DJ, Stoeckel K. Prospective comparison of ceftriaxone and cefotaxime for the short-term treatment of bacterial meningitis in children. Chemotherapy. 1998; 44: 142-7. 21. Brouwer MC, Mcintyre P, de Gans J, et al. Corticosteroids for acute bacterial meningitis. Cochrane database Syst. Rev. 2010;(9):CD004405. 22. Peltola H, Roine I, Fernandez J, et al. Hearing impairment in bacterial meningitis is little relieved by dexamethasone or glycerol. Pediatrics. 2010;125(1):e1-8. 23. Mongeluzzo J, Mohamad Z, Ten Have TR, Shah SS. Corticosteroids and mortality in children with bacterial meningitis. JAMA. 2008;299(17):2048-55. 24. Peltola H, Roine I, Fernandez J, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo controlled trial. Clin Infect Dis. 2007;45(10):1277-86. 25. Johns Hopkins Point of Care Information Technology. Antibiotics Guide. Available at URL: www.hopkins- abxguide.org. Accessed on October 11, 2006. 26. Morris A, Low DE. Nosocomial bacterial meningitis, including central nervous system shunt infections. Infect Dis Clin North Am. 1999;13:735-50. Antimicrobial Therapy in Neonatal Sepsis 303 2626 Antimicrobial Therapy in Neonatal Sepsis Umesh Vaidya, Deepak Karpe, Shilpa Kalane

 INTRODUCTION Management of neonatal sepsis constitutes the major clinical workload of all neonatal units, in view of it prevalence and high mortality and morbidity. The clinician faces challenges in the diagnosis of sepsis, indications and choice of antimicrobials and duration of treatment. Considerable variations in recommendations, wide choice of drugs, nonavailability of standard bacteriology/reliable sepsis screen markers and variable local antibiotic resistance patterns lead to indiscriminate and inconsistent use of antimicrobials. The morbid ‘sepsis phobia’ in clinicians leads to anxiety and over-treatment of ‘precious’ babies. The over -anxious clinician would attribute any neonatal symptom to sepsis and antibiotics are initiated on the slightest pretext. No wonder, India is facing an enormous and growing problem of antibiotic use and abuse in newborn care.1 Experts have expressed a lot of concern regarding antibiotic abuse and increasing resistance and the need to bring in rationality in practice guidelines. The present article provides standard recommendations for rational antimicrobial use in neonatal infections.

 CURRENT SCENARIO IN INDIA2 The National Neonatal Perinatal Database (NNPD) Report 2002-2003 reveals an incidence of neonatal systemic infection of 3% in intramural and 39.7% in extramural births. Septicemia contributes to 18.6% and 39% mortality in the two groups respectively. 12.9% of intramural babies and 84.2% extramural babies receive antibiotic therapy in hospital settings. In babies diagnosed with systemic infection, only one third grew organisms in blood culture (proven sepsis), the remaining were clinical sepsis (probable sepsis). The common organisms causing neonatal septicemia are not remarkably different in the intramural and extramural babies. Figure 1 shows organisms causing sepsis in extramural neonates from 18 centers. Klebsiella (27%), S. aureus (15%), E. coli (12%) and Pseudomonas (13%) are the common 304 Rational Antimicrobial Practice in Pediatrics

Figure 1: Organism causing sepsis in extramural neonates in 18 centers (n=1410) isolated organisms. Group B Streptococcus does not figure in the list of isolates. Although, fungal infection is not common, unfortunately there appears to be rise in the incidence of fungal infections in NICUs across the country. Study from North India demonstrated 22.8% rate of invasive fungal infection in preterm babies staying for more than one week in the Neonatal Intensive Care Unit (NICU).3 In our institute, overall incidence of fungal sepsis is 9.19% and all of them have been non-albicans Candida. Table 1 shows the antibiotic sensitivity patterns of common isolates. There is increasing prevalence of extended spectrum beta lactamase and Amp C producing strains of gram- negative bacilli (E. coli, Klebsiella, Pseudomonas) across neonatal ICU’s in the country making third generation cephalosporins redundant. Most of these strains also show resistance to aminoglycosides and quinolones.

TABLE 1 Antibiotic sensitivity (percent) of common isolates (NNPD DATA 2002–2003) Klebsiella S. aureus E. coli Pseudomonas Enterobacter Penicillin 0.44 3.2 13.3 0 0 Ampicillin 1.6 10.7 2 18.7 11.1 Cloxacillin 1.3 12.8 2.6 14.2 0 Amikacin 22.7 45.3 62.7 75.3 64.5 Cefotaxime 12.6 27.5 24.3 87.9 12 Ceftriaxone 4.8 23.8 32.5 91.9 5.6 Ceftazidime 5 16.8 39.5 87.2 41.7 Vancomycin 7.4 75.5 16.7 0 50 Piperacillin 1.7 3.3 11.6 57.1 0 Ciprofloxacin 27.1 37.1 52.1 92.1 67.3 Antimicrobial Therapy in Neonatal Sepsis 305

In our institute, current sepsis surveillance (2011-2012) revealed gram-negative organisms in 67.78% of cases, with Klebsiella (35.05%), Acinetobacter baumanii (21.26%), E. coli (6.89%) being the common microbes. Staphylococcus aureus (4.02%), was the major gram- positive isolate. Most gram-negative isolates were sensitive to colistin4 and meropenem. Resistance to meropenem was predominantly seen with Acinetobacter baumanii. Unless antibiotic usage becomes more responsible and there is widespread intelligent change of practice based on bacteriological surveillance, antibiotic resistance will continue remain a huge challenge in neonatal units. At the same time it must be remembered that this is the antibiotic susceptibility pattern from tertiary care neonatal ICU’s and may not reflect susceptibility of community-acquired strains.

 DIAGNOSIS OF NEONATAL SEPSIS Use of standard definitions in reporting neonatal sepsis facilitates proper recording of data and policy making. The following definitions are acceptable and as per standard nomenclature:2 a. Culture positive/Proven sepsis In an infant having clinical picture suggestive of septicemia, pneumonia or meningitis the presence of either of the following • Isolation of pathogens from blood or CSF or urine or abscess(es) • Pathological evidence of sepsis on autopsy b. Culture negative/Probable sepsis In an infant having clinical picture suggestive of septicemia, the presence of any one of the following criteria is enough for assigning probable diagnosis of sepsis: • Existence of predisposing factors: maternal fever or foul smelling liquor or prolonged rupture of membranes (>24 hours) or gastric polymorphs (>5 per high power field) • Positive septic screen (two of the four parameters) (1) TLC <5000/mm and band to total polymorph ratio of >0.2 (both essential), (2) absolute neutrophil count less than 1800/cu mm, (3) C-reactive protein >1 mg/dL and (4) micro ESR > 10 mm 1st hour. • Radiological evidence of pneumonia. Early onset sepsis is occurrence of sepsis within first 72 hours of life, whereas late onset sepsis in occurrence beyond 72 hours of life.2

 APPROACH TO NEONATE WITH SUSPECTED SEPSIS Figure 2 shows a simple approach to a neonate with suspected sepsis.5 As the signs of sepsis in a neonate are variable and diverse, clinical experience and close observation are essential for diagnosis. Both over diagnosis and complacency can be detrimental and objective evaluation rather than ‘personal anxiety’ should be used in diagnosis. If the clinical condition of the baby is stable, one should wait for results of the sepsis screen before initiation of antibiotic therapy. Appropriate clinical stabilization may be done while awaiting results. However, if there is reasonable clinical ground for suspicion 306 Rational Antimicrobial Practice in Pediatrics

Figure 2: Approach to neonate with suspected sepsis of sepsis of rapid deterioration in general condition, early antibiotic therapy is mandatory. A lumbar puncture is recommended in all neonates with suspected sepsis prior to or along with initiation of antibiotic therapy.

Which Antibiotic to Use for Empiric Therapy Universal recommendation for empiric therapy cannot be made as considerable variations occur in bacteriological patterns across units.6 Yet, certain basic policy can be framed and implemented based on bacteriological surveillance, sensitivity patterns and brainstorming sessions of unit staff. All newer antibiotics should be periodically evaluated and use should be regulated. Although selecting antibiotics for empiric therapy, one would normally resort to broad- Antimicrobial Therapy in Neonatal Sepsis 307

TABLE 2 Antibiotic policy for neonates (KEM Hospital, Pune, 2012) Indication Antibiotics Comments FIRST LINE Risk of sepsis Co–amoxiclav + Aminoglycosides are (Premature rupture Aminoglycoside used in rotation based on of membranes, sensitivity pattern maternal fever, foul smelling liquor) SECOND LINE Nosocomial/outborn Piperacillin - Vancomycin if staph referral with no previous Tazobactum + suspected antibiotic use Amikacin THIRD LINE Nosocomial infection Meropenem or Choice may vary based with prior extreme Colistin + Amikacin on previous antibiotic antibiotic use use. Decision made by Outborn referral of consultant only neonate who is very sick and shows rapid deterioration along with extreme prior antibiotic use PS: Antifungal therapy with fluconazole or amphotericin B based on clinical setting / fungal cultures. spectrum antibiotics, so that more organisms are covered. This policy is likely to result in causing resistant organisms in NICU.1 Some antibiotics, particularly amoxicillin and cefotaxime are particularly notorious for selecting resistant organisms.7 Experts agree that the best regime is a penicillin or semi-synthetic penicillin along with an aminoglycoside.8 For hospital-acquired infections particularly in referral units, specific plan for using first line, second line and reserve antibiotic needs to be made. The antibiotic policy practiced presently in our NICU is shown in Table 2. Needless to state that certain alterations from the basic policy may be necessary in individual situations. The antibiotic policy needs to be reviewed for its suitability over a period of time.

 MANAGEMENT OF SPECIFIC INFECTIONS IN NEONATES Neonatal Meningitis Antibiotic therapy should achieve adequate drug levels to sterilize the CSF. Antibiotics, which have a good CSF penetration, should be chosen. Until a definitive diagnosis has been made, a combination of a third generation cephalosporin and an aminoglycoside should be started intravenously immediately after the cultures have been drawn. Third generation cephalosporins are recommended because of good CSF penetration and safety profile. aminoglycosides have poor CSF penetration and should not be used as sole agents for therapy of meningitis. Until recently, chloramphenicol was the antibiotic of choice in neonatal meningitis due to its superior penetration into CSF. If serum concentrations 308 Rational Antimicrobial Practice in Pediatrics are kept between 15 and 25 mg/L, toxicity from this drug is extremely rare. However, with the advent of third generation cephalosporins, chloramphenicol is now not recommended for use in neonatal meningitis. Controlled trials have failed to show any benefit of intraventricular or intrathecal therapy over systemic therapy.9 For nosocomially acquired meningitis or meningitis after extreme antibiotic use a carbapenem (meropenem) with/ without an aminoglycoside may be indicated. Once a specific pathogen has been isolated and its susceptibilities identified, the best drug or combination of drugs should be employed. Benzyl penicillin is the drug of choice for Group B Streptococcus infection. A combination of ampicillin and gentamicin, which have synergistic action, is preferred in infections with Listeria and Enterococci. A combination of an aminoglycoside with a ureidopenicillin (piperacillin) or a cephalosporin such as ceftazidime should be chosen for meningitis because to Pseudomonas aeruginosa. In most hospital acquired cases of meningitis usually carbapenems with or without colistin may be required owing to the high prevalence of resistance in gram-negative organisms. A CSF examination should be repeated 48 hours after initiation of antibiotics to document improvement. With appropriate antibiotic therapy, the CSF becomes sterile very quickly. Pleocytosis and alteration of CSF chemistry may continue for some weeks making later CSF results difficult to interpret. Anti microbial therapy should be continued for a minimum of 14 days for gram-positive organisms (4 weeks for S. aureus) and 21 days for gram- negative organisms.10

Neonatal Pneumonia Pneumonia in neonates may be acquired in utero (congenital), during birth or nosocomially. Congenital pneumonia may be caused by TORCH group of organisms, Listeria or secondary to chorioamnionitis. Pneumonia acquired during passage in through the maternal genital tract may be due to Group B Streptococcus, E. coli, Klebsiella species, Mycoplasma hominis, Ureaplasma urealyticum and Chlamydia trachomatis.11 In nosocomial pneumonia, common organisms involved are S. aureus, S. epidermidis, E. coli, Klebsiella and P. aeruginosa. For early onset pneumonia therapy should be with ampicillin/penicillin or 3rd generation cephalosporin/beta lactam-beta lactamase inhibitor combination and an aminoglycoside. The choice depends on the setting and local resistance patterns. For nosocomial pneumonia choice depends on the prevalent microbial flora in NICU and their sensitivity. Azithromycin or erythromycin is the drug of choice for suspected infections due to atypical pathogens. There is no consensus regarding duration of therapy but shorter courses may be as effective as prolonged courses.12

Urinary Tract Infection The most frequent infecting organism is E. coli, but Klebsiella species and Enterococci can also cause urinary tract infection. In very preterm LBW babies and who have received long courses of antibiotics, Candida albicans is an important etiological agent. Antimicrobial Therapy in Neonatal Sepsis 309

Empirical therapy with a broad-spectrum penicillin and gentamicin or a third generation cephalosporin may be started but antibiotics must be changed according to urine culture reports. If urine culture alone is positive in a term infant, treatment is completed with oral therapy once the infant is afebrile. Treatment duration in absence of a positive blood or CSF culture is 10 to 14 days. It is recommended that infants with UTI undergo renal ultrasound and vesicourethrocystogram imaging to identify any underlying anatomic or functional abnormalities (reflux) that may have contributed to the development of the UTI. Infants should receive UTI prophylaxis with amoxicillin (10-20 mg/kg once a day) after completing UTI treatment until imaging studies are performed.

Osteomyelitis and Septic Arthritis The commonest organism causing osteomyelitis and septic arthritis is S. aureus. Group B streptococci; Klebsiella and E. coli are also prominent. Staphylococcus epidermidis and Candida albicans are emerging as important etiological agents in extremely preterm infants. All efforts should be made to obtain material for culture and sensitivity. In patients with community acquired infection, cloxacillin and a third generation cephalosporin should be started until culture and sensitivity results are available. In patients with history of prolonged NICU stay treatment depends on local flora and should include an antifungal. Therapy should be continued for at least 6 weeks (at least 3 weeks intravenously)

Neonatal Tetanus Treatment of neonatal tetanus consists of the administration of human tetanus immunoglobulin (500 units) and crystalline penicillin (50,000 units/kg per day) for 10– 14 days as well as supportive care with mechanical ventilation, sedatives and muscle relaxants.13

TABLE 3 Duration of antibiotic therapy Condition / Diagnosis Duration Bone/Joint infection 4–6 weeks Meningitis a. Gram-positive organisms (except S. aureus) 14 days b. S. aureus 28 days c. Gram-negative organisms 21 days Pneumonia (culture negative) 7–10 days Urinary tract infection 10–14 days Culture positive sepsis (no meningitis) 14 days Clinical sepsis (Based on clinical suspicion 7–10 days and / or septic screen positivity 310 Rational Antimicrobial Practice in Pediatrics

TABLE 4 Drug doses (mg/kg) of commonly used antibiotics in neonates Drug Route Birthweight < 2000 g Birth weight >2000 g 0-7 d > 7 d 0-7 d >7 d Amikacin IV, IM 7.5q 12 h 7.5q 8 h 7.5 q 12 h 7.5q 8 h Ampicillin, IV 25 q 12 h 75q 8 h 75q 8 hr 100q 6 h doses for IV, IM 50q 12 h 50q 8 h 50q 8 h 75q 6 h meningitis Cefotaxime IM, IV 50q 12 h 50q 12 h 50q 8 h 50q 6 h Ceftazidime IM,IV 50q 12 h 50q 8 h 50q 8 h 50q 8 h Ceftriaxone IM, IV 50q 24 h 50q 24 h 50q 24 h 75q 24 h Ceftizoxime IV, IM 50q 12 h 50q 12 h 50q 12 h 50q 12h Ciprofloxacin IV 5q 12h 5q 12h 5q 12h 5q 12 h Netilmicin IV, IM 2.5q 12 h 2.5q 12 h 2.5q 12 h 2.5q 12 h Penicillin G IV, IM 25000 U 25000 U 25000 U 25000 U q 12 h q 8 h q 8 h q 6 h 75000 to 75000 to 75000 to 75000 to 100000 U 100000 U 100000 U 100000 U q 12 h q 8 h q 8 h q 6 h Piperacillin IV, IM 75 q 12 h 75q 8 h 75q 8 h 75q 6 h Tobramycin IV, IM 2.5q 18 h 2.5q 12h 2.5q 12 h 2.5q 8 h Meropenem IV, IM 20 mg q 12 h 20 mg q 12 h 20 mg q 12 h 20 mg q 8 h Vancomycin IV 15 mg q 18 h 15 mg q 12 h 15 mg q 12 h 15 mg q 8 h Aztreonam IV 60 mg q 12 h 90 mg q 8 h 90 mg q 8 h 120 mg q 6 h * All doses except Penicillin G are expressed in mg/kg

 DURATION OF ANTIBIOTIC THERAPY Standard recommendations for duration of antibiotic treatment are shown in Table 3. Recent evidence suggests that it is rational and safe to stop antibiotics after 48-72 hours if sepsis screen and blood culture are negative.14 The decision should include consideration of the clinical course as well as the risks associated with longer courses of antimicrobial agents. In a retrospective study by Cordero and Ayers, the average duration of treatment in 695 infants (<1000 g) with negative blood cultures was 5 ± 3 days.15 Cotten et al have suggested an association with prolonged administration of antimicrobial agents (>5 days) in infants with suspected early-onset sepsis (and negative blood cultures) with death and necrotizing enterocolitis.16 Two recent papers also support this association.17,18 Unwarranted prolonged use of antibiotics increases the risk of emergence of resistant strains.19 Antimicrobial Therapy in Neonatal Sepsis 311

 FUNGAL SEPSIS As discussed earlier fungi are assuming an important role in nosocomial sepsis especially in extremely low birth weight and very low birth weight infants who have prolonged NICU stay and who have received antibiotics. Receipt of TPN especially intralipids and presence of central lines and gut surgery are other important risk factors. Prophylaxis with IV fluconazole in a dose of 3–6 mg/kg twice a week in very low birth weight babies has shown to be efficacious and is now a level IA recommendation. Prophylaxis should be continued till all IV is discontinued. Empirical antifungal therapy should be initiated appropriately in babies with these risk factors and clinical features of sepsis. Blood cultures are positive only in 50% of instances. The choice of empirical therapy depends on whether the baby has received fluconazole in the past and the prevalence of azole resistant Candida in the unit. Choices include fluconazole @ 12 mg/kg/day or amphotericin B. There is limited data on use of echinocandins in neonates. The duration of therapy for systemic fungal infection is 3 weeks after blood cultures are negative. Ophthalmic

TABLE 5 Adjunctive therapy in neonatal sepsis Intervention Outcomes and conclusions Granulocyte transfusion No difference shown in mortality or sepsis: more RCTs needed G-CSF or GM-CSF No difference shown in mortality or sepsis: more RCTs needed ?GM-CSF improves survival in sepsis with neutropenia Activated protein C Not recommended Exchange transfusion ?Improves survival in gram-negative sepsis Pentoxifylline ?Improves survival in proved sepsis, more RCTs needed Reduce oxidative stress: Insufficient evidence Selenium Melatonin Insufficient evidence Glutamine No difference shown in mortality or sepsis or disability free survival: More RCTs not a high priority Lactoferrin Reduce late-onset sepsis, RCTs needed to evaluate effects on disability-free survival Probiotic Reduce all cause mortality and NEC Prebiotics Insufficient evidence Broad spectrum peripartum Broad-spectrum antenatal antibiotics increase NEC, functional antibiotics impairment and cerebral palsy at 7 years. Prolonged postnatal antibiotic therapy after sterile cultures is associated with increased risk of death and NEC RCTs needed to evaluate effect of early curtailment of antibiotics after sterile cultures on disability free survival IVIG No role Breast milk Reduces sepsis 312 Rational Antimicrobial Practice in Pediatrics examination should be done to rule out endophthalmitis. CSF should be done to rule out meningeal involvement. If CNS involvement is present, treatment is required for several weeks till all clinical, CSF and radiologic abnormalities have resolved.

 ADJUNCTIVE THERAPY IN NEONATAL SEPSIS (TABLE 5) Few immunologic interventions to treat or prevent neonatal sepsis have been reliably evaluated in RCTs, because of inadequate sample sizes. Promising or possible therapeutic interventions in severe or gram-negative sepsis include exchange transfusions, pentoxifylline, and IgM-enriched IVIG. Promising or possible prophylactic interventions include lactoferrin, with or without a probiotic; selenium; early curtailment of antibiotics after sterile cultures; and earlier initiation of breast milk (colostrum) in high-risk preterm infants. Current probiotic products are safe and effective in substantially reducing all- cause mortality and NEC, with no increase in sepsis.21

CONCLUSIONS Golden rules for rational use of antibiotics in neonates 1. Enforce strict measures to prevent nosocomial infection. Re look at handwashing practices, disinfection protocols, procedure asepsis, minimum invasion, equipment sharing, nurse patient ratio, isolation policy and training. 2. Form Neonatal Infection Review Group and monitor bacteriological patterns and sensitivity on a monthly basis. Such group should include microbiology personnel, nurse, residents along with neonatologist. 3. Improve laboratory capabilities in bacteriology and sepsis screen makers sufficiently, so that antibiotics can be stopped with confidence if sepsis work up is negative. Prolonged, unwarranted use of antibiotics does not prevent, but in fact causes antibiotic resistance. 4. Formulate Antibiotic Policy using bacteriology surveillance data. Use antibiotics with low resistance potential like amikacin, piperacillin, quinolones, cefepime. 5. Restrict use of antibiotics with high resistance potential such as ampicillin, gentamicin, ceftazidime, meropenem.12 6. Always perform sepsis screen/blood culture before starting antibiotics 7. Never treat colonization such as positive ETT culture/catheter tip culture unless strong clinical/systemic infection. 8. Do not start prophylactic antibiotics just because of central catheter, chest drain, surgery, etc. Such procedures are expected to be done in a aseptic manner. 9. Follow standard recommendations on dose and duration of antibiotic treatment in proven sepsis (Tables 4 and 5). 10. Avoid indiscriminate use of newer antibiotics in clinical practice unless appropriately studied for sensitivity pattern. Antimicrobial Therapy in Neonatal Sepsis 313

 REFERENCES 1. Isacs D. Neonatal sepsis: the antibiotic crisis. Indian Pediatr. 2005;42:9-13. 2. National Neonatal Perinatal Database: Report 2002-2003 ICMR, New Delhi Publications. 2005;45-57. 3. Singh K, Chakrabarti A, Narang A, Gopalan S. Yeast colonisation and invasive fungal infection in preterm neonates in a tertiary care centre. Indian J Med Res. 1999;110:169-73. 4. Jajoo, et al. Intravenous Colistin administration in neonates. Pediatr Infect Dis J. 2011;30(3):218-21. 5. Jeeva Sankar, et al. Sepsis in The Newborn. Indian J Pediatr. 2008;75(3):261-6. 6. Paul VK, Agarwal R. Neonatal sepsis. NNF Manual of Neonatal Care, First Edition. Prism Books Pvt Ltd. 2004;16:121-34. 7. De Man P, Verhoeven HA, et al. An antibiotic policy to prevent emergence of resistant bacilli. Lancet. 2000;355:973-8. 8. Isaacs D. Rationing antibiotic use in neonatal unit. Arch Dis Child. Fetal Neonatal Ed. 2000; 82:F1-F2. 9. McCracken GH, Nelson JD. Antimicrobial therapy for newborns. 2nd Edition, New York: Grune and Stratton; 1983. 10. Volpe JJ. Neonatal Meningitis. In: Volpe JJ (Ed). Neurology of the newborn, 3rd edition. Philadelphia: WB Saunders. 1995:730-68. 11. Wamg EE, Ohlsson A, Kelner JD. Association of Ureaplasma urealyticum colonisation with CLD of prematurity: result of a meta analysis. J Pediatr. 1995;127:640-44. 12. Escobar G, Zukin T, Usatia NI, et al. Early discontinuation of antibiotic treatment in newborns admitted to rule out sepsis, a decision rule. Pediatr Infect Dis J. 1994;13:860 -6. 13. Nelson: Pocketbook of Pediatric Antimicrobial therapy, 1995, P17 Johnson: The Harriet lane Handbook, 1993, P. 554. 14. Isaacs D, Wilkimson AR, Moxon ER. Duration of antibiotic courses for neonates. Arch Dis Childhood. 1987;62:727-44. 15. Cordero L, Ayers LW. Duration of empiric antibiotics for suspected early-onset sepsis in extremely low birth weight infants. Infect Control Hosp Epidemiol. 2003;24(9):662–6. 16. Cotten CM, Taylor S, Stoll B, et al. NICHD Neonatal Research Network. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics. 2009;123(1):58-66. 17. Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr. 2011;159:720–5. 18. Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. J Pediatr. 2011;159(3):392–7. 19. Cunha BA. Antibiotic resistance. Med Clin North Am. 2000;84:1407-29. 20. Pappas PG, Kauffman CA, Andes D, Benjamin DK, Jr, Calandra TF, Edwards JE Jr, et al. Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases. 2009;48:503-35. 21. Tarnow Mordi, et al. Adjuncive immunological interventions in neonatal sepsis. Clin Perinatol. 2010;37:481-99. 314 Rational Antimicrobial Practice in Pediatrics 2727 Antimicrobial Therapy in Septic Shock Sunit Singhi, KS Laxmi

 INTRODUCTION Shock is a clinical syndrome in which blood flow and oxygen delivery to tissues is disturbed leading to tissue hypoxia, with resultant compromise of cellular metabolic activity and organ function. Survival from shock is related to both the adequacy of the initial resuscitation and the degree of subsequent organ system dysfunction. The main goal of therapy is rapid cardiovascular resuscitation with the reestablishment of tissue perfusion using rapid volume replacement (fluid therapy) and vasoactive drugs. The definitive treatment of shock requires reversal of the underlying etiologic process, which in case of septic shock is an infection. Apart from bacterial infections the possibility of severe falciparum malaria and dengue as etiology for septic shock in the Indian scenario should be considered, investigated and appropriately managed.

Principles of Antimicrobial Therapy Initiation of Antibiotic Therapy Intravenous antibiotic therapy should be started within the first hour of recognition of severe sepsis.

Choice of Initial Antibiotic Therapy The infecting organism often is unknown when therapy is initiated. • Cultures should always be taken prior to initiating antibiotic therapy. A Gram strain of potentially infected material often permits a rapid presumptive diagnosis. • The initial empiric antibiotic therapy should include one or more drugs that have activity against the likely pathogens and that penetrate the presumed source of sepsis. Therapy should be broad enough since there is little margin for error in critically ill patients. Several studies have shown that appropriate initial antibiotic therapy has the greatest impact on reducing mortality in sepsis. Antimicrobial Therapy in Spetic Shock 315

• Local susceptibility patterns must be considered as they vary widely between community acquired and hospital acquired infection. • Based on the clinical scenario, the probable infecting organism should be covered. Enteric gram-negative bacteria commonly cause early onset sepsis in neonates especially very low birth weight infants (VLBW) infants. Haemophilus influenzae is a likely pathogen in unvaccinated healthy children less than 3 years of age with community-acquired sepsis. S. pneumoniae and Salmonella typhi/paratyphi are leading causes of community acquired sepsis in children of all ages. Conditions leading to impaired immune response (malnutrition, burns, hematologic malignancy) predispose to infections with Pseudomonas and Staphylococcus. Diabetes predisposes to infections with Staphylococcus and fungi. Asplenia, nephrotic syndrome, B cell immuno-deficiency predispose to infections with capsulated organisms. See Table 1 for choice of empirical antibiotic therapy. • Careful history should be taken and clinical examination performed to identify the possible focus, as microbial etiology depends on the clinical focus.

Dose of Antibiotics (Table 2) All patients should receive a full loading dose of each antibiotic. Patients with sepsis or septic shock often have abnormal renal or hepatic function and may have abnormal volumes of distribution due to aggressive fluid resuscitation. Appropriate subsequent dosage modifications have to be made in such cases.

Duration The antibiotic regimen should always be reassessed after 48 hours on the basis of microbiological and clinical data with the aim of using a narrow spectrum antibiotic to prevent the development of resistance, to reduce toxicity and to reduce costs. Do not add change antibiotics if patient is persistently hypotensive/febrile; look for GI bleed, pulmonary embolism, undrained abscess, adrenal insufficiency, or IV line infection. The duration should typically be 7–14 days and guided by clinical response.

Source Control Every patient presenting with severe sepsis should be evaluated for the presence of a focus of infection amenable to source control measures, e.g. drainage of an abscess, debridement of infected necrotic tissue, removal of a potentially infected device, etc.

Antibiotic Therapy of Septic Shock (Table 1) Septic Shock in Neonates Neonatal sepsis can be divided into two main subtypes depending on whether the onset is during the first 72 hours of life or later. Early onset septicemia is caused by organisms prevalent in the genital tract or in the labour room/operation theater. In our country, early onset infections are mostly caused by gram-negative bacteria such as E. coli, Klebsiella, etc. while in the West most cases are due to Group B streptococci and E. coli. About two third cases of late onset septicemia 316 Rational Antimicrobial Practice in Pediatrics

TABLE 1 Choice of empirical antibiotic in patients with septic shock with respect to clinical settings Clinical setting Usual pathogens Preferred therapy Alternate therapy Unknown source Salmonella Ceftriaxone with Piperacillin tazobactam from the typhi/paratyphi aminoglycoside OR community S. pneumoniae Newer Quinolone H. influenzae (Levo/Gatifloxacin) Enterobacteriaceae

Think of malaria and dengue Lung source S. pneumoniae Ceftriaxone/ Substitute new H. influenzae cefotaxime/amox clav fluoroquinolone Staphylococcus and azithro/clarithro (levo/gati/moxi) aureus for macrolide M. pneumoniae IV line sepsis S. epidermidis Vancomycin May substitute linezolid S. aureus (MSSA) PLUS for vancomycin Klebsiella Meropenem OR Add antifungals if fungus Enterobacter Imipenam OR suspected Serratia Cefepime OR Pip Tazo Urosepsis Entero- Ceftriaxone Aztreonam bacteriaceae OR OR Cefotaxime Ampicillin + Amikacin OR Quinolone AND aminoglycoside Meningitis S. pneumoniae Ceftriaxone Add vancomycin if drug H. influenzae OR resistant pneumococci meningococci Cefotaxime suspected Intra-abdominal Enterobacteriaceae Ceftriaxone plus Quinolone (Cipro/Levo) source B. fragilis Metronidazole plus either metronidazole enterococci OR OR Piperacillin/tazobactam Clindamycin OR Meropenem OR Imipenem are caused by gram-negative bacilli viz Klebsiella pneumoniae, E. coli, Pseudomonas aeruginosa, while the rest are contributed by gram-positive organisms including Staphylococcus aureus and coagulase negative staphylococci. The logical initial antibiotic choice would be a combination of an aminoglycoside (amikacin) and a third generation cephalosporin (cefotaxime or ceftazidime is recommended). Antimicrobial Therapy in Spetic Shock 317

TABLE 2 Doses of various antibiotics in pediatric septic shock Drug Dose Frequency Route Ampicillin 50 mg/kg/dose 6 hrly IV, IM Ampicillin + Sulbactam 50 mg/kg/dose of ampicillin 6 hrly IV or IM Amikacin 15–22.5 mg/kg OD IV or IM Amoxycillin 50 mg/kg/ dose 8 hrly, 12 hrly IV, IM (for babies <1 wk), 6 hrly (2–4 wk) 4-6 hrly (>4 wk) Amoxicillin + Dose same as amoxicillin 4:1 8 hrly IV. IM Clavulanic acid Amphotericin B 0.5–1.5 mg/kg/day Infusion with D5W IV Over 4–8 weeks Amphotericin B 2–3 mg/kg/day over 1 h Infusion with D5W IV Lipid/Liposomal Total dose 20–60 mg/kg Over 2-4 weeks Fluconazole 12 mg/kg stat, 6–12 mg/kg/dose OD IV Itraconazole 5 mg/kg/dose 12–24 hrly IV,Oral Voriconazole 6 mg/ kg/dose stat over 2 hours, 12 hrly IV, IV, oral Repeat after 12 hours, then 4 mg/kg/dose Ceftriaxone 50 mg/kg/dose 12 hrly IV or IM Cefepime 50 mg/kg/dose 8 hrly IM or IV Cefotaxime 50 mg/kg/dose 4–6 hrly, 12 hrly IV for neonates Ceftazidime 50 mg/kg/dose 6–8 hrly IV, IM Gentamicin >10 yr: 7 mg/kg on day 1, then 5 mg/ kg/ dose, 1 wk to 10 yr: 8 mg/ kg on day 1, then 6 mg/kg, Neonates: 5 mg/kg OD IV, IM Cloxacillin 50–100 mg/ kg/dose 4–6 hrly IV Vancomycin 10 mg/kg/dose 6-8 hrly IV over Neonates: 10 mg/kg/dose 1 hour Piperacillin + Piperacillin: 75-100 mg/kg / dose 6–8 hourly IV Tazobactam Ticarcillin + 50–75 mg/kg/dose 6–8 hrly IV Clavulanic acid Cefoperazone 50 mg/kg/dose of cefoperazone 8 hrly IV sulbactum Meropenem 40 mg/kg/dose 8 hrly IV Imipenem + Cilastin 25 mg/kg/dose of imipenem 6 hrly IV IV—Intravenous, IM—Intramuscular 318 Rational Antimicrobial Practice in Pediatrics

In the event of nosocomial neonatal sepsis antibiotic spectrum may have to be broadened depending on the locally prevalent flora/antibiotic sensitivities and previous antibiotic therapy in the index case.

Septic Shock without Focus in Infants and Older Children If the clinical focus is not obvious on initial history taking and examination, antibiotics should cover for S. pneumoniae, H. influenzae, Salmonella typhi/paratyphi and UTI causing gram-negative organisms such as E. coli. An appropriate choice would be ceftriaxone along with aminoglycoside. The aminoglycoside would cover a possible ESBL producing community acquired urinary tract pathogen as well.

Community Acquired Pneumonia with Shock Streptococcus pneumoniae, Haemophilus influenzae, and staphylococci are the important causes of community-acquired pneumonia in children < 5 years. Infants younger than 6 months may have gram-negative organisms. In children older than 5 years the possibility of infection with atypical organisms such as C. pneumoniae and M. pneumoniae should be also considered. In children with septic shock with pneumonia, the initial antibiotic should be an intravenous beta-lactam such as cefotaxime/ceftriaxone/coamoxiclav plus in children more than five years a cover for atypical organisms (azithromycin/clarithromycin). Young infants should receive cefotaxime/ceftriaxone and an aminoglycoside. Cloxacillin should be added if there are pneumatoceles, empyema or if staphylococcal infection is suspected. If community acquired MRSA is suspected then vancomycin or linezolid should be used instead of cloxacillin.

CNS Infection (Meningitis) with Shock Etiologic agents are S. pneumoniae, meningococci and H. influenzae. Ceftriaxone should be started without waiting for lumbar puncture result. Vancomycin should be added if resistant pneumococci are suspected.

Shock with Intra-abdominal Focus Most intra-abdominal infections involve pathogens acquired from endogenous flora and empiric therapy should cover E. coli, other enterobacteriaceae, E. faecalis and Bacteroides fragilis. Infections that result after initial surgery or antibacterial therapy involve drug resistant pathogens, e.g. gram-negative facultative bacilli, Staphylococci and Pseudomonas aeruginosa and are more difficult to treat. Empirical regimens consist of either (a) metronidazole or clindamycin with a III generation cephalosporin (ceftriaxone, cefotaxime) or (b) piperacillin–tazobactum/cefoperazone- sulbactam/ticarcillin-clavulanate/ampicillin-sulbactum or (c) carbapenem (imipenem or meropenem). Antibiotics are ineffective unless supported viscus is repaired, obstruction relieved or abscess drained. Antimicrobial Therapy in Spetic Shock 319

Shock with Urinary Tract Infections (UTI) E. coli accounts for 75-90% of all pediatric UTI’s. Others include Klebsiella, Proteus and Staphylococcus saprophyticus. Enterococcus and Pseudomonas should be considered in children with recurrent infections or abnormal urinary tracts or in hospitalized children. In presence of fever and hypotension, pyuria and urine Gram stain helps in making early diagnosis. Empiric therapy for community acquired UTI consists of a third generation cephalosporin (cefotaxime or ceftriaxone) or IV quinolone. In a child who has received antibiotics in the past or has history of a UTI due to an ESBL producing organism an aminoglycoside should be added to the cephalosporin or quinolone. In nosocomial UTI’s choice of antibiotics would depend on previous antibiotic therapy, local flora and sensitivity patterns.

Cellulitis with Septic Shock Staphylococcus aureus and Streptococcus pyogenes cause most cases of community- acquired cellulitis. In neonates, gram-negative bacilli and in children younger than 5 years Haemophilus influenzae and Streptococcus pneumoniae are also implicated. It is imperative to distinguish simple cellulitis from necrotizing fasciitis (an infection commonly associated with multiorgan failure). The primary etiologic agent of necrotizing fasciitis is Streptococcus pyogenes but other agents including staphylococci, anerobes and gram- negative bacilli may contribute. Neonates should receive cloxacillin with an aminoglycoside or cefotaxime. Children less than 5 years should receive cloxacillin with cefotaxime/ceftriaxone. Older children may be treated with cloxacillin alone. For necrotizing fasciitis a combination of ceftriaxone/ cefotaxime/crystalline penicillin with a protein synthesis inhibitor such as clindamycin/ linezolid is recommended. If community acquired MRSA is suspected, an anti-MRSA agent such as vancomycin/teicoplanin/linezolid may be given at the outset for seriously ill patients with cellulitis/necrotizing fasciitis.

Febrile Neutropenia with Shock With impaired immunity, polymicrobial infection is not unusual. The normal flora of the patient may be altered due to repeated exposure to antimicrobials and nosocomial multidrug resistant microbes. The patient may become colonized with resistant strains of organisms such as extended spectrum beta lactamase (ESBL) producing strains of gram-negative organisms and (MRSA) methicillin resistant Staphylococcus aureus vancomycin resistant enterococci (VRE) seen in the West fortunately are seen less commonly in India. In all such patients with shock initial choice should be an aminoglycoside (amikacin) + vancomycin + ceftazidime OR antipseudomonal pencillin (piperacillin-tazobactum or ticarcillin-clavulanate) OR cefipime OR Carbapenem (meropenem). Vancomycin is included in the initial regime of all febrile neutropenic patients with shock. The use of ceftazidime should be avoided if the prevalence of ESBL is high. 320 Rational Antimicrobial Practice in Pediatrics

Intravascular Access Device with Shock Gram-positive cocci (S. epidermidis, S. aureus, MRSA), gram-negative bacteria (Klebsiella, Enterobacter, Acinetobacter) and fungi (candida spp.) account for these infections. Empiric antibiotic therapy with vancomycin with a gram-negative cover is indicated. The choice of gram-negative cover depends on the prevalence of ESBL in the institution. If there is no ESBL problem (rarity in India) then cefotaxime/ceftriaxone may be used. Else the choice could be cefepime or piperacillin tazobactam or ticarcillin clavulanate or cefoperazone sulbactam or a carbapenem. The use of aminoglycosides should be preferably avoided due to additive nephrotoxicity with vancomycin. Antifungals may be needed if infection with fungi is suspected. Device removal is mandatory. Antibiotics are given for one week after removal of IV line for gram-negative bacilli and two weeks for S. aureus.

Nosocomial Infections with Shock Antibiotic therapy should comprise of a broad-spectrum cover for resistant gram-negative organisms. This could be provided by piperacillin-tazobactam/cefoperazone sulbactam/ ticarcillin clavulanate/cefepime/carbapenem with or without an aminoglycoside. The choice among these would depend on local sensitivity patterns. For serious nosocomial infections such as shock due to presumed ESBL producing organism a carbapenem is preferred to a beta-lactam–beta-lactamase inhibitor combination. In the current scenario of infection with carbapenemase producing organisms, use of colistin may be required if local sensitivity patterns so indicate.

CONCLUSIONS In conclusion, patients in septic shock must receive as soon as possible an appropriately selected empiric antibiotic therapy, usually a combination, to cover most likely pathogens for a given clinical setting. Further therapy should be based on culture reports and suitably de-escalated and is usually given for 2 weeks. Source control (removal of IV lines, devices, drainage of abscess, etc. must be attempted otherwise antibiotic therapy will be ineffective.

 RECOMMENDED READING 1. Bowlware KL, Stull T. Antibacteiral agents in pediatrics. Infect Dis Clin North Am. 2004;18:513-31,viii. 2. Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to use of beta-lactams, glycopeptides and linezolid. Infect Dis Clin North Am 2003;39:47-54. 3. Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730-51. 4. Kang CI, Kim SH, Park WB, Lee KD, Kim HB, Kim EC. et al. Bloodstream infections caused by antibiotic-resistant gram-negative bacilli’ risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. Antimicrob Agents Chemother. 2005;49:760-6. 5. Pong AL, Brodley JS. Guidelines for the selection of antibacterial therapy in children. Pediatr Clin North Am. 2005;52:869-94. 6. San Joaquin VH, Stull TL. Antibacterial agents in pediatrics. Infect Dis Clin North Am. 2000;14:341-55,viii. 7. Singhi S. Severe infections and antibiotics. In: Basic Pediatric Intensive Care. Jaypee Publishers, Delhi, 2005;159-65. Antimicrobial Therapy in Nosocomial Infections 321 2828 Antimicrobial Therapy in Nosocomial Infections Soonu Udani, Neha Gupta

 BACKGROUND Hospital-acquired infections or health care associated infections (HAI) encompass almost all clinically evident infections that do not originate from the patient’s original admitting diagnosis. Within hours after admission, a patient’s flora begins to acquire characteristics of the surrounding bacterial pool. Most infections that become clinically evident after 48 hours of hospitalization are considered hospital-acquired unless there is evidence of presence or incubation at the time of admission. Infections that occur after the patient’s discharge from the hospital can be considered to have nosocomial origin if the organisms were acquired during the hospital stay. Nosocomial infections (NI) are caused by viral, bacterial, and fungal pathogens. These pathogens should be investigated in all febrile patients who are admitted for a nonfebrile illness. Many children in hospital wards acquire viral infections. These are usually mild and pass off without much intervention. However, serious infections like respiratory syncytial virus (RSV), influenza and rota virus diarrhea can cause significant morbidity. Bacterial and fungal infections are less common. However, they are significantly associated with a higher morbidity and mortality. Most patients who are infected with nosocomial bacterial and fungal pathogens are predisposed because of invasive supportive measures such as intubation and the placement of intravascular lines and urinary catheters. Fungal infections are more likely to arise from the patient’s own flora; occasionally, they are caused by contaminated solutions (e.g. those used in parenteral nutrition). Antimicrobial therapy for NIs has become complicated due the high level of antibiotic resistance encountered.1 Changing patterns of resistance and of microbial flora in hospitals need the clinician to be highly aware of current trends in treatment. It cannot be stressed enough that no textbook recipe will apply to every hospital or clinical setting. Local patterns of resistance and of microbial flora are two key determinants of both, empiric 322 Rational Antimicrobial Practice in Pediatrics and definitive treatment. This article will look at the options for treatment of the above groups, against a background of probable evidence and best practice guidelines.

 CENTRAL-LINE ASSOCIATED BLOOD STREAM INFECTIONS (CLABSIS) Diagnosis The use of short or long-term indwelling catheters is no longer restricted to the intensive care units. Oncologists and surgeons often treat or even discharge home, children with indwelling lines or ports. Central venous catheters (CVC) related infections can occur at the exit site, in the subcutaneous tunnel or pocket, or in the bloodstream. Although local signs will characterize the first three, the last needs to be accurately diagnosed for appropriate management. Most CLABSIs among children in the western world are caused by coagulase-negative staphylococci (which account for 34% of cases), followed by S. aureus (25%). Among neonates, coagulase-negative staphylococci account for 51% of CLABSIs, followed by Candida species, enterococci, and gram-negative bacilli. These will vary with each institution. In India, enteric gram-negative bacilli are more common causes of CLABSIs.2 The most reliable diagnosis of a CLABSI is made by semiquantitative (roll plate) or quantitative catheter culture techniques (sonication methods) and have much greater specificity than qualitative broth cultures. A definitive diagnosis of CLABSI requires that the same organism to grow from at least 1 percutaneous blood sample culture plus from the catheter tip or that 2 blood samples for culture be obtained (1 from a catheter hub and 1 from a peripheral vein) that meet CLABSI criteria for quantitative blood cultures or differential time to positivity (DTP) of >2 hours. For quantitative blood cultures, a colony count of microbes grown from blood obtained through the catheter hub that is at least 3-fold greater than the colony count from blood obtained from a peripheral vein best defines CLABSI. This method is rarely used and especially in the presence of fever, the qualitative method is taken as evidence of a CLABSI.3

Initial Therapy Management of CLABSI is determined by several factors including the severity of the infection, metastatic complications, the type of catheter, whether or not local infection is present, the etiologic agent as well as the certainty of diagnosis. In adults with CLABSI, it is recommended that most nontunneled CVCs should be removed. However, this may not always be feasible in the neonatal and pediatric populations. Successful treatments of CLABSI without catheter removal have been reported3 but may depend on (a) the pathogen identified, (b) whether or not local infection is present and (c) hemodynamic stability. Such children should be closely monitored, and the device should be removed in the event of clinical deterioration or recurrence of CLABSI. In contrast, treatment of catheter-associated fungemia without removal of the catheter has a low success rate and is associated with higher mortality. Recent reports involving Antimicrobial Therapy in Nosocomial Infections 323 children with Candida CLABSI found that the addition of antifungal lock therapy led to a high cure rate without catheter removal, but there are insufficient data to recommend routine catheter salvage using this approach.3 If the patient with a suspected CLABSI is in septic shock, has local infection or metatstatic complications cultures should be sent, the catheter removed and empirical antimicrobial therapy started. Choice of antimicrobial therapy depends on severity of illness, local ICU patterns and prior antibiotic use. Empiric therapy should include antimicrobial agent with activity against gram-negative bacteria including Pseudomonas species, such as -lactam/-lactamase inhibitors (L/LI) or carbapenems (for severe illness) or colistin (in units with high rates of carbapenem resistance and in patients who have already received carbapenems) and an agent with activity against gram-positive bacteria, such as vancomycin. The empiric use of both an antipseudomonal -lactam and an aminoglycoside may be appropriate in severely ill patients or when infection with a resistant gram-negative organism is suspected. Use of empirical antifungal therapy should be considered in patients with multiple risk factors for candidemia. If the patient is stable, there is no local infection or metastatic complications then the catheter may be retained (especially a tunneled or implanted catheter) and empirical antibiotic therapy started till reports are available. Antibiotic lock therapy with or without systemic antibiotic therapy can also be used for catheter salvage.3 A percutaneous catheter may be removed since it is relatively easy to insert another (guidewire exchange must not be done). Subsequent therapy depends on the culture reports. If the diagnosis is not confirmed then search for an alternative focus should be performed.

Pathogen Specific Treatment Coagulase-negative staphylococci (Other than S. lugdunensis) This is the most common and least virulent organism, with less sepsis and rarely a poor outcome and it is usually possible to retain the catheter. For methicillin-sensitive isolates, cloxacillin is the drug of choice.5 Intravenous vancomycin/teicoplanin/daptomycin will be required for methicillin-resistant isolates. Linezolid is not approved for management of CLABSI in adults due to inferior outcome in randomized controlled trials to comparator drugs. If the catheter is removed 5–7 days therapy will suffice. If the catheter is retained, the recommended duration of therapy is 10–14 days after a negative blood culture drawn through the CVC has been obtained. However, if a neonate has 3 positive blood cultures despite appropriate antibiotic therapy, the catheter should be removed because of the increase risk of end- organ damage.6 However, relapses are more frequent (20%) when the catheter is kept in situ as compared to when it is removed (3%).7 Staphylococcus aureus This is a more virulent pathogen whether it is sensitive or resistant to methicillin. Serious systemic infection, seeding to organs and joints and even endocarditis occur. A transesophageal echocardiography (TEE) should be considered in children with prolonged BSI prior to treatment, persistent BSI while receiving appropriate antimicrobial therapy, 324 Rational Antimicrobial Practice in Pediatrics a new murmur identified on physical examination, or congenital heart disease to look for endocarditis.8 For S. aureus CLABSI, the patient is better off without the catheter. ALT for catheter salvage can be considered only in case of extenuating circumstances. If the pathogen is methicillin-resistant (MRSA) then IV Vancomycin is the usually chosen drug. The dose ranges from loading dose 30–60 mg/kg/day divided 8 hourly, adjusted for gestational age and renal clearance. Monitoring of vancomycin levels is highly desirable. Teicoplanin may be a substitute if IV therapy has to be changed to once a day or intramuscular dosing. The frequently asked question here is always about linezolid, orally administered without levels being monitored. For initial therapy, only the IV route is acceptable. Once cultures revert to negative, oral therapy may be given. In a study on neonates with varying infections, clinical cure rates at follow-up in the intent-to-treat group were higher, but not significantly different, for linezolid vs. vancomycin (78% vs 61%; P = 0.196). Fewer linezolid-treated neonates had drug-related adverse events than vancomycin-treated neonates.8 Conventional wisdom cautions against the serial use of different drugs. In practice, because of its better tissue concentration, we restrict the use of linezolid for deep soft tissue infections, empyemas, pneumonias or long-term therapy. Two weeks of appropriate antimicrobial therapy, chosen based on susceptibility test results, is recommended for uncomplicated S. aureus CLABSI. Longer duration of therapy (4–6 weeks) may be necessary for patients with prolonged BSI (>3 days), persistent fever, or complicated infection.3 Gram-negative bacilli Over the past decade, the incidence of gram-negative bacilli resistant to third- and fourth- generation cephalosporins has increased.9 In general, for uncomplicated CLABSIs, antimi- crobial therapy should be administered 10–14 days after documented first negative blood culture. Catheter removal has been shown to be beneficial in the treatment of infections with specific gram-negative bacilli with propensity for biofilms such as Pseudomonas spp., Burkholderia cepacia, Acinetobacter baumannii, and Stenotrophomonas spp.

Candida The catheter must be removed whenever clinically feasible. In India, Candida non-albicans species are more common (Candida tropicalis being the most common). Antifungal susceptibility should be performed in all cases. Fluconazole resistance has been detected among 10% of C. albicans as well as C. non-albicans species. Antifungal therapy is recommended for all cases of CLABSI due to Candida species, including cases in which clinical manifestations of infection resolve after catheter withdrawal and before initiation of antifungal therapy. Empiric therapy for candidemia in adults includes an echinocandin (Caspofungin, Anidulafungin) or fluconazole.10 Data on echinocandin use in children is limited. Choose an echinocandin/amphotericin B for moderately severe to severe illness and for patients with recent azole exposure. Treat for 14 days after first negative blood culture result and resolution of signs and symptoms associated with candidemia. However, a diligent search needs to be made in the eyes, liver, urinary tract and bones and Antimicrobial Therapy in Nosocomial Infections 325 joints (if symptoms suggest), as treatment will then be more prolonged. Dissemination occurs in 17% and mortality may be as high as 26%.11

 CSF SHUNT INFECTIONS These fall into the purview of catheter related infections except that they may be isolated to the shunt, CSF or rarely invade the blood stream. The most common causative organism is CoNS as contamination is invariably at the time of insertion. Other pathogens include S. aureus and P. acnes. Every effort at identification of the causative organism MUST be made prior to starting antimicrobials of any nature. The CSF from a lumbar tap and from the ventricles must be separately sampled and the shunt sent for culture once it is removed. The usual empiric antibiotic therapy includes a meropenem, because of high ESBL prevalence rate9 or third generation cephalosporin (cefotaxime/ceftriaxone) with vancomycin till culture reports are available. L/LI combinations have poor CSF penetration. Optimal treatment comprises of shunt removal and placement of a reservoir if the child cannot tolerate removal. Antibiotics are given for 3–4 weeks, and intravenously for at least the first 2 weeks. With this method, success is seen in 88% whereas if the shunt is kept in situ, success rates are only 33%.12

 CATHETER RELATED UTI’S11 Probably the most frequently used indwelling catheter is the urinary catheter in the bladder. Rates of infection are directly proportional to the time the catheter is in place. Protocols for catheter care are also useful in reducing infections. The patient’s own gut flora is usually responsible, but indirectly, hospital flora are encountered, as the patient’s own flora gets replaced very quickly by pathogens prevalent in the unit. For either short- or long-term catheters, the infection rate is about 5–10% per day if a closed system is used. Escherichia coli remains the most common; other enteric gram-negative bacilli, Enterococcus, and Candida spp. also are frequent. Bacteria tend to show increased resistance because of the repeated antimicrobial courses. Urinary tract infection (UTI) usually follows formation of biofilm on both the internal and external catheter surface. The biofilm protects organisms from both antimicrobials and the host immune response. Morbidity from UTI with short-term catheter use is limited if appropriate catheter care is practiced. In patients with long-term catheters, fever from a urinary source is common with a frequency varying from 1 per 100 to 1 per 1000 catheter days. Asymptomatic catheter-acquired UTI should not be treated with antimicrobials. Antimicrobial treatment does not decrease symptomatic episodes but will lead to emergence of more resistant organisms. Candida colonization is very common in patients with indwelling catheters and those who are on broad–spectrum antibiotics and should not be treated unless it is considered as a marker of disseminated sepsis or if the patient is immunocompromised. Candiduria usually resolves with removal of the catheter and discontinuation of antibiotics. Therapy for bacteriuria and infection should include removal of the catheter if possible. If the catheter remains in place, infection often persists despite 326 Rational Antimicrobial Practice in Pediatrics appropriate antimicrobial treatment or recurs immediately after cessation of therapy. For symptomatic infection (complicated pyelonephritis and BSI), systemic antimicrobial therapy is necessary. Wherever possible, antimicrobial selection should be delayed until culture results are available. Whether to administer initial treatment by an oral or parenteral route is determined by clinical presentation. If empirical therapy is required, antimicrobial selection is based on variables such as route of administration, anticipated infecting organism and susceptibility, and patient tolerance. Renal function, concomitant medications, local formulary and cost may also be considered in selection of the antimicrobial agent. The usual empiric therapy for CAUTIs includes a L+LI combinations14,15 or a carbapenem depending upon severity of illness and local antimicrobial susceptibility pattern. The duration of therapy is usually 10–14 days, but patients who respond promptly and in whom the catheter must remain in situ may be treated with a shorter 7-day course to reduce antimicrobial pressure. Relevant clinical trials are necessary to define optimal antimicrobial regimens for the management of catheter-acquired UTI.

 VENTILATOR ASSOCIATED/INTUBATION ASSOCIATED OR HOSPITAL ACQUIRED PNEUMONIAS (VAP/HAP) Normal people frequently aspirate oropharyngeal secretions during sleep but host defenses prevent lung infection and the types of organisms are less virulent. In nonhospitalized patients being treated with histamine type 2 (H2) blockers; gram-positive organisms predominate whereas in hospitalized patients aerobic gram-negative organisms are predominant. In HAP the source of microorganisms may be endogenous (aspiration) or exogenous (inhalation). Sinusitis without HAP can be a source of fever in the PICU. In children this possibility is often ignored. Nasotracheal intubation (42% vs 6% for oral)16 and prolonged nasogastric tubes in situ may contribute to poor drainage and resulting infection. According to meta-analyses of the efficacy of stress ulcer prophylaxis in ICU patients, HAPs were significantly lower in those receiving sucralfate than in those receiving agents that reduced gastric pH like the proton pump inhibitors.17 Despite advances in antimicrobial therapy, the treatment of HAP’s remains unsatisfactory, as the entire diagnostic process is fraught with inaccuracies and pitfalls. All efforts to pinpoint an accurate diagnosis are expensive, technically difficult and require time; whereas the survival of the patient may well depend on rapid and correct administration of an appropriate agent. This was shown in a study by several investigators.18,19 The mortality rates were considerably higher for those where the first choice of antibiotic proved to be incorrect. Two factors seem to render the choice of antibiotics particularly difficult in the PICU. First, HAPs are likely to result from highly resistant organisms, as most patients are treated with antibiotics. Second, multiple organisms are very often cultured from the respiratory secretions of these patients. Because of the emergence of multi–drug resistant (MDR), extended spectrum  lactamase producing (ESBL) gram-negative organisms and the increasing role played by MRSA, even a protocol combining imipenem and amikacin might not ensure adequate coverage. Finally, although appropriate antibiotics will surely Antimicrobial Therapy in Nosocomial Infections 327 improve survival of those with true HAPs, use of broad-spectrum empiric antibiotics in patients without infection or with infections caused by susceptible microorganisms, has the tremendous potential to disseminate the growth of multi-resistant colonizers and superinfectors, which will then pose an immediate and remote danger to current and future patients. This aspect and very real danger should be made clear to every physician treating patients in the neonatal and pediatric ICU. Institution of a VAP bundle for the prevention of this condition with high morbidity and mortality for all intubated patients is essential (Table 1).

TABLE 1 VAP bundle • Upright position unless contraindicated • No circuit change unless soiled • Use HME unless contraindicated in very small children

•H2 blocker instead of PPI as far as possible • Early feeding with 4 hourly residue check • Hold feed if aspirate > 10% of feed volume • Aseptic suctioning technique • Do not keep connector on or unsterile test lung • Do not use sterile glove for unsterile handling • Use in line suction whenever feasible • Daily wake up • Least paralysis possible • Chest PT and position change

Factors Contributing to the Selection of Initial Treatment 1. Putative causative organism and antibiotic susceptibility. 2. History of prior antibiotic use. 3. Data of surveillance cultures in the same patient if available. 4. Information from direct microscopic examination of secretions. Early onset pneumonias—within first 4 days of hospitalization, in patients who have not received prior antibiotics are mainly caused by susceptible Enterobacteriaceae, Haemophilus, sensitive Staphylococci or S. pneumoniae. Causes of late onset HAP include additional legionella and MDR pathogens Pseudomonas, Acinetobacter and MRSA. Even in late onset HAPs, patients who have had no prior antibiotics show better sensitivity patterns.

Monotherapy vs Combination Therapy (Table 2) A meta-analysis has evaluated all prospective randomized trials of -lactam monotherapy compared with -lactam-aminoglycoside combination regimens in patients with sepsis. In this evaluation, clinical failure was more common with combination therapy and there was no advantage in the therapy of P. aeruginosa infections, compared with monotherapy. 328 Rational Antimicrobial Practice in Pediatrics

TABLE 2 Empirical antibiotic therapy for hospital acquired pneumonia HAP/HCAP Potential pathogens Recommended antibiotic 1. Early onset HAP– Streptococcus pneumoniae, Nonpseudomonal 3rd generation no prior antibiotics Haemophilus influenzae, cephalosporin MSSA, enteric gram- (cefotaxime/ceftriaxone) negative bacilli (E. coli, Or Levofloxacin, moxifloxacin, K. pneumoniae, Enterobacter or amoxicillin-clavulanate species, Proteus species, Serratia marcescens) 2. Late onset HAP/VAP/ Additional MDR pathogens: Choice depends on ICU flora and HCAP with risk factor Pseudomonas aeruginosa or antibiotics to which a patient is for MDR pathogens Klebsiella pneumoniae (ESBL), exposed Acinetobacter species or The primary drug may vary from Legionella pneumophila, an antipseudomonal MRSA cephalosporin (ceftazidime/cefepime) to BL- BLI combinations (cefoperazone + sulbactam, piperacillin– tazobactam, cefepime tazobactam) to carbapenems (imipenem/doripenem/ meropenem) to colistin With or without a antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) or Aminoglycoside (amikacin, gentamicin, or tobramycin) With or without Linezolid or vancomycin

In addition, combination therapy did not prevent the emergence of resistance during therapy, but did lead to a significantly higher rate of nephrotoxicity. However, it is safer to use 2 drugs for sick patients especially with hypotension and gram-negative infection.

De-escalation Once microbiological data becomes available, it is also necessary to de-escalate therapy to avoid prolonged use of broader spectrum of antibiotic therapy than is justified.18 Although benefit may not be immediately obvious, it will benefit the index patient, as well as the PICU and hospital as a whole.

Duration Most experts recommend that the duration be adapted to the severity of disease, the time to clinical response and the pathogen responsible. Recent studies have demonstrated Antimicrobial Therapy in Nosocomial Infections 329 equivalent efficacy of 8 days versus 15 days therapy.20 However, 2–3 weeks therapy is definitely recommended for multilobar involvement, malnutrition, cavitation and gram- negative necrotizing pneumonia due to P. aeruginosa, and Acinetobacter.

CONCLUSIONS • Nosocomial infections lead to an increased mortality in ICU patients. • Morbidity, costs and length of stay are adversely impacted. • Strict infection control practices with handwashing contribute to controlling the incidence. • Abuse of antibiotics and overuse of third generation cephalosporins lead to colonization and super infection with resistant gram-negative pathogens. • Every effort should be made to reach a microbiological diagnosis. • While using combination broad-spectrum antibiotics may be justified in the ill patient every effort to de-escalate therapy to be narrowest spectrum should be made. • Early use of antifungal agents in the cohort considered most susceptible: preterms, long ICU stay, prolonged antibiotic use, immunocompromised (oncology, transplant), those with central lines, parenteral alimentation or those with isolation of candida from multiple nonsterile sites. • Interventions (“Bundles”) should be implemented in order to prevent the nosocomial infections

 REFERENCES 1. Deep A, Ghidival R, Kandian S, Shinkre N. Clinical and Microbiological Profile of Nosocomial Infections in the Pediatric Intensive Care Unit (PICU). Indian Pediatr. 2004;41:1238-46. 2. Gopalakrishnan R, Sureshkumar D. Changing trends in antimicrobial susceptibility and hospital acquired infections over an 8-year period in a tertiary care hospital in relation to introduction of an infection control programme. J Assoc Physicians India. 2010;58:25-31. 3. Mermel LA, Allon M, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49:1-45. 4. National Nosocomial Infections Surveillance (NNIS) System: National Nosocomial Infections Surveillance (NNIS) System report, data summary from October 1986-April 1998, issued June 1998. Am J Infect Control. 1998;26:522-33. 5. Flynn PM, Shenep JL, Stokes DC. In situ management of confirmed central venous catheter related bacteremia. Ped Infect Dis J. 1987;6:729-34. 6. Benjamin Jr DK, Miller W, Garges H. Bacteremia, central catheters and neonates: When to pull the line. Pediatrics. 2001;107:1272-76. 7. Raad I, Davs S, Khan A, et al. Impact of central venous catheter removal on recurrence of catheter related CoNS bacteremia. Infect Control Hosp Epidemiology. 1992;13:215-21. 8. Valente A, Jain R, Scheurer M, et al. Frequency of infective endocarditis among infants and children with Staphylococcus aureus bacteremia. Pediatrics. 2005;115:e15–e19. 9. Hawser SP, Samuel K. Bouchillon SK, Daryl J. Hoban DJ, et al. Emergence of High Levels of Extended- Spectrum -Lactamase-Producing Gram-Negative Bacilli in the Asia-Pacific Region: Data from the Study for Monitoring Antimicrobial Resistance Trends (SMART) Program, 2007. Antimicrob Agents Chemother. 2009;53:3280-84. 10. Pappas PG, Kauffman CA, Andes D. Clinical practice guidelines for the management of candidiasis: 2009 update by the infectious diseases society of America. Clin Infect Dis. 2009;48:503-35. 330 Rational Antimicrobial Practice in Pediatrics

11. Zaoutis TE, Greves HM, Laulenbach E. Risk factors for disseminated candidiasis in children with candidemia. Ped Infect Dis J. 2004;23:635-41. 12. Schreffer RT, Schreffer AJ, Witter RR. Treatment of CSF shunt infection: a decision analysis. Ped Infect Dis J. 2002;21:632-6. 13. Warren J. Catheter-associated bacteriuria in long-term care facilities. Infect Control Hosp Epidemiol 1994;15:557. 14. Patel V, Soman R, Rodrigues C, Singhal T, Mehta A, Dastur FD. Outcome of treating infections due to ESBL producing organisms with non-carbapenem- antimicrobials. An observational study. Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America, San Diego, California. Oct 3-7, 2007(Abstract #1100). 15. Rodríguez-Baño J, Navarro MD, Retamar P. -Lactam/-Lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum -lactamase-producing Escherichia coli: A post hoc analysis of prospective cohorts. Clin Infect Dis. 2012;48:167-74. 16. Bach A, Boehrer H, Schmidt H Nosocomial sinusitis in ventilated patients: nasotracheal vs orotracheal intubation. Anaesthesia. 1992;47:335-9. 17. Messori A, Trippoli, Vainai M. Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomized controlled trials. BMJ. 2000;321:1103-6. 18. Torres A, Fagon JY, Chastre J, et al, Incidence, risk and prognosis factors of nosocomial pneumonia in mechanically ventilated patients. Am Rev Resp Dis. 1990;142:523-8. 19. Kollef MH, Ward S. The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator associated pneumonia. Chest. 1998;113:412-20. 20. Hospital acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy and preventive strategies. A consensus statement, American Thoracic society November 1995. Am J Respir Crit Care Med. 1996;153:1711-25. 21. Hoffken G. Niederman MIS. Nosocomial pneumonia: The importance of de-escalating strategy for antibiotic treatment of pneumonia in the ICU. Chest. 2002;122:2183-96. 22. Paul M, Benuri-Silbiger I, Soares-Weiser K, Liebovici L. -Lactam monotherapy versus -lactam- aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ, doi:10.1136/bmj.38028.520995.63 (published March 2, 2004). Available at URL http://bmj.bmjjournals. 23. Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare- associated Pneumonia. American Thoracic society October 2004. Am J Respir Crit Care Med. 2005;171:388–416. Antimicrobial Therapy in Febrile Neutropenia 331 29 Antimicrobial Therapy in Febrile Neutropenia Nitin K Shah, MR Lokeshwar

INTRODUCTION The survival of childhood cancer patients has significantly improved in last two to three decades due to availability of better chemotherapeutic protocols, improved supportive care including blood components and effective antimicrobial therapy. The current treatment protocols are very intense which frequently expose the patients to episodes of severe neutropenia during which the patient is at risk of developing potentially fatal invasive infections. In fact the causation of cancer mortality has shifted from one due to bleeding in past to one due to infections currently. Though better understanding and timely management of infections have reduced mortality in cancer patients, it still is a leading cause of morbidity and mortality. Availability of colony stimulating factors, though shortening the duration of neutropenia, has not reduced the mortality rates due to infections.1 Besides malignancies, other situations where one faces a patient with febrile neutropenia include neonate with sepsis, bone marrow failure syndromes, HIV infection, organ transplant recipients, congenital neutropenia, drug-induced neutropenia, and though rare in pediatric patients, pre-leukemic conditions like myelodysplastic syndrome. Like in many other clinical challenges, there is no substitute to a systematic approach to a child who has febrile neutropenia.

 DEFINITIONS Fever is defined as a single oral temperature record of 38.3°C (101°F) or a temperature of 38°C (100.4°F) for 1 hour. Neutropenia is defined as absolute neutrophil count (ANC) <500 cells/mm3 or a count of <1000 cells/mm3 with predicted fall to <500 cells/ mm3 in next few days.1 332 Rational Antimicrobial Practice in Pediatrics  GENERAL CONSIDERATIONS Though there are many other causes of fever in a setting of neutropenia, occult or overt infections account for 50% of these episodes, 85% of which are bacterial in origin, 50% of them are bacteremic at onset, 80% of them originate from patient’s own flora and 50% of the time the patient is colonized while in hospital. The other causes of fever in a neutropenic patient include blood products, drugs, malignant process itself especially before remission is achieved, thrombophlebitis, etc. A sick looking patient with chills and hypotension is always likely to have sepsis.1-3 The incidence of infection is inversely proportional to the neutrophil count and duration of neutropenia. The chances of infection are 14% when the ANC is 500-1000 as compared to 24-60% when it is < 100 cells/mm3. Thirty percent develop fever or infection when neutropenia lasts for less than 7 days as compared to nearly 100% when it remains low for > 7 days. Neutropenia < 500 cells/mm3 and duration > 7 days are taken as the critical events while managing patients with febrile neutropenia.2 Similarly mortality is 47% in those with ANC < 100 cells/mm3 as compared to 14% in those with ANC > 1000 cells/mm3. Besides neutropenia, there are other arms of immunity which could be possibly deranged in these patients such as loss of natural barriers like IV devices or mucositis, low CD4 counts, hypogammaglobulinemia as seen in patient with CLL or HIV, macrophage function defects, malnutrition, etc.1,2

 CAUSATIVE ORGANISMS Till 1970s gram-negative organisms were the leading cause of infection in a neutropenic patient. The first EORTC trial microbiological data on the causative organisms showed that the proportion of gram-negative to gram-positive organisms for the period 1973- 1976 was 71% vs. 29% which changed to 33% vs. 67% for the period of 1988-1994.4 With the use of antibiotics to cover the gram-negative infections, gram-positive organisms have become the leading cause of infections now currently accounting for more than 60-70% of isolates. In some centers including those in India, multidrug resistant gram- negative infections have again become common, probably due to misuse of drugs like piperacillin-tazobactum and carbapenems. The common gram-positive organisms seen include coagulase negative staphylococci, S. aureus, S. viridans, S. pneumoniae, enterococci and sometimes bacillus species, Corynebcterium species etc. The common gram-negative organisms isolated include E. coli, Klebsiella, Pseudomonas species and sometimes Proteus species, Acinetobacter, etc. One can also encounter anaerobic organisms like bacteroides, fusobacterium (mainly oral mucosa) and others. Lastly fungal infection is a common secondary infection especially in the presence of use (or misuse) of antibiotics and or steroids, mucositis or indwelling catheter. C. albicans is the most common pathogen isolated followed by Aspergillus fumigatus. However with the liberal use of triazoles especially fluconazole in some centers, one can see increasing incidence of other pathogens like fluconazole resistant C. glabrata or C. krusei, non-fumigatus aspergillus and other molds like Fusarium spp., zygomycetes. etc.1,3,4 Antimicrobial Therapy in Febrile Neutropenia 333

 DRUG RESISTANCE Misuse and abuse of antibiotics has led to the global problem of common organisms developing resistance to commonly used first line antibiotics. This includes common pathogens seen in febrile neutropenic patients like penicillin resistant S. pneumoniae or S. viridans, methicillin resistant staphylococci, vancomycin resistant enterococci, beta lactamase [including extended spectrum beta lactamase (ESBL)] producing gram negative bacilli like E. coli, Pseudomonas or Klebsiella, etc. Many of these organisms are multi- drug resistant with cross-resistance to multiple antibiotics. Of late even carbapenem resistance is evolving fast in gram-negative organisms especially Pseudomonas. All this should be kept in mind while selecting the antibiotics for the initial therapy before the culture reports are available or still worst in those whom the cultures are sterile and the patient is not responding to the first line therapy.1,5,6

 EVALUATION Clinical and laboratory evaluation should be thoroughly done in every patient with febrile neutropenia.

Clinical Clinically look at the common sites of infection like oral cavity and periodontal region, GI tract, lungs, skin, IV sites, perianal and perineal region. Typical signs of inflammation may be absent in a neutropenic patient in spite of obvious infection and hence patient may have skin infection without typical cellulitis, lung infection without the typical infiltrates on X-ray, meningitis without obvious clinical signs or CSF pleocytosis and urinary tract infection without pyuria. Pain may be the only symptom of localization.1,4

Laboratory Laboratory evaluation includes estimation of complete blood counts, serum creatinine, serum transaminases, and serum electrolytes. These investigations will help define any organ dysfunction and guide therapy while using potentially nephrotoxic antimicrobials like aminoglycosides, amphotericin B, etc. Most important is to obtain blood cultures. The yield is highest with two blood culture sets taken from two separate venipunctures. Blood from one venipuncture is inoculated in one aerobic and one anaerobic bottle; hence two sets indicate 4 bottles. If the suspicion for anaerobic infections is small then a set may consist of two aerobic bottles. If there is a central venous catheter then one set should be from the catheter and one from a peripheral vein. The yield of culture depends on the volume of blood inoculated in the culture medium and at least 2-5 mL of blood should be inoculated per pediatric automated culture bottle even in children.1,2 Blood cultures should be obtained before the antibiotics are administered. Ideally blood cultures should be done using radiometric methods as they are quick and can tell the differential time taken for positivity when simultaneous cultures are obtained from peripheral site and catheter lumen in a suspected case of catheter related bloodstream 334 Rational Antimicrobial Practice in Pediatrics infections.1 High-grade bacteremia with >500 cfu/mL is associated with greater morbidity and mortality. Lastly if possible, quantitative or semi-quantitative culture of catheter tip should be done whenever the catheter is removed for suspected/established line sepsis. Routine cultures of urine or stools are not indicated as the yield is poor; however they should be done whenever local urinary or GI infection is suspected. Similarly culture from local discharge at IV site infection or local wound should be done whenever present. Routine X-ray of the chest is not indicated unless patient has chest symptoms or the patient is being treated as an outpatient.1,3

 INITIAL ANTIBIOTIC THERAPY As the course of bloodstream infections in a neutropenic patient can be rapid and fatal, empirical antibiotics are justified in febrile neutropenic patients. The choice of initial antibiotics will depend on the suspected most likely organism and its sensitivity pattern which in turn will depend on the local pattern, previous experience and exposure to antibiotics. Other factors that influence choice of initial antimicrobial therapy include presence of catheter; condition of the patient especially presence of high fever and chills, hypotension or a focus of infection which make it high risk for severe systemic infections meriting better and longer antibiotic course; risk factors in the patient like low-risk or high-risk for severe infection; and toxicities of the drugs used like nephrotoxicity of aminoglycosides used with amphotericin B.1 Even though gram-positive organisms are common isolates in febrile neutropenic patient and even though some of these gram positive organisms may be drug resistant and hence need vancomycin. Vancomycin as a rule should not be used as initial therapy for febrile neutropenia. Infections caused by most of the vancomycin needing organisms are indolent and delaying vancomycin for 2-3 days till culture reports are available does no harm. Penicillin resistant S. viridans may lead to severe infection and need vancomycin, but it is sensitive to cefipime, carbapenems which are commonly used first line antibiotics as discussed below. Use of vancomycin as the first line therapy routinely is likely to do more harm by inducing vancomycin resistance in organisms, especially enterococci. Clinical situations which require vancomycin as first line therapy are discussed later in the chapter.1,7 Hence one has to decide whether vancomycin is required upfront or no as shown in Table 1, is the patient low risk (oral antibiotic can be used) or high risk (intravenous antibiotics are required) as shown in Table 2 and whether patient can be treated on outdoor basis (low risk patients only). Outpatient therapy for low risk patients is not approved for children. There are 3 options available for initial antibiotic therapy: (a) single therapy where vancomycin is not required, (b) two drugs therapy where vancomycin is not required and (c) therapy with vancomycin plus 1 or 2 more drugs as shown in Figure 1. Antimicrobial Therapy in Febrile Neutropenia 335

TABLE 1 Indications of using vancomycin in patients with febrile neutropenia 1. Suspected serious catheter related infection 2. Unstable patient with hypotension 3. Known colonization with drug resistant gram positive organisms in past 4. Use of quinolones prophylaxis in past 5. Isolation of organisms on culture meriting vancomycin like a. Methicillin resistant staphylococci b. Penicillin resistant S. viridans c. Penicillin resistant S. pneumoniae 6. Relative indications like fever > 40°C, presence of severe mucositis

Figure 1: Initial antibiotic therapy in febrile neutropenia

Single Antibiotic Therapy without Vancomycin Most of the studies have shown no significant difference in the response to monotherapy or multi-drug therapy for empirical initial therapy of febrile neutropenic patients. The single antibiotic used should cover gram-negative infection especially pseudomonas infection. Accordingly one can use ceftazidime, cefipime, carbapenem or piperacillin- tazobactam as single drug. Of these cefipime, piperacillin tazobactam and carbapenems are better suited as single drugs as they cover beta lactamase (including some ESBL) producing gram-negative organisms as well as drug resistant S. viridans. Ceftazidime does not cover ESBL producing gram-negative organisms and resistant Pseudomonas. Hence in centers where there is a high prevalence of ESBL and other beta lactamases (most tertiary centers in India have this problem), use of ceftazidime should be avoided. If a patient with suspected ESBL gram-negative infection is seriously sick then carbapenems 336 Rational Antimicrobial Practice in Pediatrics should be used as first line empirical therapy. In any case one should monitor the clinical response and condition of the patient and change antibiotics as required as discussed below. Aminoglycosides should not be used as a single drug nor should quinolones be used alone.1,5,8

Two Drug Combination without Vancomycin Two antibiotics combination is used empirically as initial therapy in complicated cases to achieve better coverage and to reduce chances of development of drug resistance. In low risk adults therapy can be initiated with ciprofloxacin and amoxicillin-clavulanic acid (Table 2 and Figure 1). In high-risk adults, the usual second drug added to one of the single drug options discussed earlier is an aminoglycoside. However in most beta lactamase producing gram-negative organisms show increasing cross-resistance to aminoglycosides making this option redundant. Besides, aminoglycosides will add to nephrotoxicity seen with many other drugs used in this situation.1,5 With the current situation of carbapenem resistance in gram-negative organisms in India, colistin may be needed as a 2nd drug in certain situations.

TABLE 2 Factors defining patient at low risk to develop severe infection

1. Neutrophil count  100/ mm3, monocyte count 100/ mm3 2. Duration of neutropenia < 7 days and recovery expected within 10 days 3. Normal results of imaging studies including X-ray of chest 4. Normal results of organ function tests 5. No catheter-related infection suspected 6. Malignancy in remission 7. Clinically stable patient without co-morbidity (Excludes pediatric patient for initial oral antibiotic therapy)

Figure 2: Management approach in patients afebrile in first 3-5 days after initial empirical antibiotic therapy Antimicrobial Therapy in Febrile Neutropenia 337

Therapy with Vancomycin plus 1 or 2 Drugs Before knowing when to use vancomycin, one should learn when NOT to use vancomycin! Vancomycin resistant enterococci have already emerged as a problem due to misuse of vancomycin in some centers. Vancomycin is not recommended as a first line drug routinely except certain situations, which suggest high chances of infection with organisms needing vancomycin. These include catheter induced sepsis, complicated patient with high fever and hypotension, cultures showing infection with one of the drug resistant gram-positive organism, a patient known to be colonized with such an organism in past, and may be patients with mucositis, fever > 40°C, or past prophylaxis with quinolones. In all these situations vancomycin should be used in combination with drugs used in the first options under single antibiotic use with or without addition of aminoglycosides. Teicoplanin may be used in place of vancomycin and recently available linezolid is equally effective as vancomycin, besides being also effective in vancomycin resistant enterococci.1,5,8

 ANTIBIOTIC THERAPY IN THE FIRST 5-7 DAYS After starting empirical antibiotics one has to decide on the follow-up and the duration for which antibiotics need to be continued. The culture reports will be available in the first 48-72 hours. If positive, the drugs should be adjusted to the narrowest suitable antibiotic. If vancomycin is started and the organisms show sensitivity to other drugs, vancomycin should be stopped. If the patient shows deterioration one may have to add or change antibiotics even before 72 hours, otherwise it usually takes 3-5 days for response to the first line antibiotics. Low risk patients may show response as early as 2 days. Accordingly the patient may be afebrile in first 3-5 days or the patient may continue to have persistent fever in the first 3-5 days. The approach to both these situations is different as shown in Figures 2 and 3.1,5

Figure 3: Management approach in patients with persistent fever in first 3-5 days after initial empirical antibiotic therapy 338 Rational Antimicrobial Practice in Pediatrics

Patient is Afebrile in the First 3-5 Days of Initial Antibiotic Therapy If the causative organism is identified, the antibiotics are adjusted according to the sensitivity pattern. When the cultures are negative and there is no discernible focus of infection and the patient is low risk to start with, one can after 48 hours of IV antibiotics change to oral antibiotics, i.e. ciprofloxacin plus amoxicillin-clavulanic acid in adults and cefixime in children as studies have shown that the outcome is the same with both approaches.9-12 Oral antibiotics are much convenient, cheaper and acceptable to the patients.

Patient has Persistent Fever in the First 3-5 Days of Initial Antibiotic Therapy When the cultures are negative and the patient is still febrile on day 3 after the initial antibiotics, possibilities include: (i) the patient has non-bacterial infection, (ii) delayed response as some patients may take up to 5 days for the response, (iii) infection with drug resistant organisms, (iv) a break-though secondary infection, (v) super-added fungal infection, (vi) sub-optimal antibiotic levels, or (vii) presence of organ infection like abscess. The patient should be re-evaluated at 72 hours including thorough clinical examination, repeat cultures, serum creatinine, serum transaminases, imaging as deemed appropriate, checking of the catheter site. If the reassessment yields positive result, antibiotics are changed accordingly. If not and the patient is still febrile at 5 days, one has one of the 3 choices: (a) continue same antibiotics, (b) Change/add antibiotics, (c) add antifungal with or without change in antibiotics (Figure 3).1,3 a. Continue the same antibiotics: If the patient is clinically stable, there is no discernible focus and the cultures are negative on reassessment, one can continue the same antibiotics as some patients may respond only on or after 5 days.1 b. Change/add antibiotics: If the patient shows progression with new symptoms, diarrhea, abdominal pain, hypotension, new pulmonary infiltrates, IV line discharge one has to change or add antibiotics. This will depend on the initial antibiotics used. If vancomycin was not used before, one needs to add it. If vancomycin was used and the cultures are negative and the patient has not responded, it is unlikely that the patient has infection with organisms needing vancomycin and one should stop vancomycin in such cases. One can also consider using alternative antibiotics like colistin, carbapenem, piperacillin-tazobactam or cefipime depending on what was not used initially.1 c. Add antifungal: It has been proved that patients with profound neutropenia of more than 7-10 days who fail to respond to antibiotics for 5-7 days have 30% chances of fungal infections. Most physicians would start antifungals when the patient is still febrile with neutropenia in spite of adequate antibiotics at the end of 5-7 days. However, if recovery of neutropenia is expected within next few days, one can withhold antifungals. One has to investigate for fungal infection thoroughly like cultures, sinus studies, imaging, etc.1,5 In centers where fluconazole is not used for prophylaxis and chances of infection with Aspergillus fumigatus or fluconazole resistant species like C. krusei or C. glabrata are low, one can use fluconazole as it is cheap, oral and convenient. However, where there are chances of resistant Candida infection or likelihood of aspergillus (respiratory Antimicrobial Therapy in Febrile Neutropenia 339 infections or sinusitis), one should use amphotericin B. Liposomal amphotericin and amphotericin B have been tried in a comparative trial where it has been shown that though both have similar efficacy, liposomal amphotericin is safer and has less chances of break through fungal infections. Other drugs which can be used for empirical therapy for febrile neutropenia include the echinocandins (caspofungin) or voriconazole.1,3,5

 DURATION OF ANTIBIOTICS The most important determinant to decide when to stop antibiotics is neutrophil count as shown in Figure 4. When the ANC is >500 cells/mm3, the patient is afebrile for more than 2 days, the patient is clinically stable without any complications and no organism is isolated on cultures, one can stop the antibiotics. If the patient is afebrile but continues to have ANC < 500 cells/mm3, one should ideally continue antibiotics for the whole neutropenic period, however this will increase the toxicities, cost and chances of development of drug resistance. Hence, the antibiotics can be stopped after the patient is healthy and afebrile for a minimum period of 5-7 days even if the ANC is still low. The patient should be monitored and antibiotics should be restarted after evaluation if the patient develops fever again. In patients with persistent fever, or afebrile patient with unstable condition, mucositis, GI infections, unstable signs and profound neutropenia one should continue antibiotics for a longer time may be for 2 weeks or more depending on the condition. At 2 weeks if the patient is afebrile one can shift to prophylactic antibiotics.1,3,5

Figure 4: Duration of antibiotics in febrile neutropenia 340 Rational Antimicrobial Practice in Pediatrics

The decision as to when to stop antifungal therapy is more difficult to make than when to start it. If the fungus is isolated on cultures, one should continue antifungal accordingly. Candida infection should be treated with antifungal for 2 weeks after the blood culture turns negative. For aspergillosis one has to continue amphotericin B till chest signs are normal, cultures are negative and imaging shows clearance of infection, which usually will take 4-6 weeks. If the fungus has not been isolated one can stop antifungals when the patient is clinically well, ANC is >500 cells/mm3 and imaging studies are normal. If the ANC is still low one can continue antifungal for 2 weeks after the patient is clinically well with normal imaging. For patients who are febrile in spite of ANC >500 cells/mm3, one should rule out other causes of infections like viral infections, fungal infections or mycobacterial infections. One needs to do appropriate cultures, CMV viral load and imaging studies and clinical evaluation and one can stop antibiotics 5 days after the ANC is more than 500/mm3.1

 OUTCOME Outcome of the febrile neutropenic patients with bacteremia depends on many variables in spite of the best therapy. In a study of bacteremic patients with febrile neutropenia done over 2 decades showed that the percentage of patients responding ultimately to the antibiotics has gone up recently, reflecting better understanding of the disease and better management options available of late. Patients with sepsis due to Pseudomonas or Enterobacter species have less response rate (84% vs 93%) as compared to all other etiological agents put together due to more chances of complex sepsis (with organ disease) with these two agents. Sepsis caused by drug resistant organisms (e.g. MRSA or penicillin resistant streptococci) had poor response to initial therapy but responded well with the change to appropriate antibiotics. In cases with sepsis caused by gram- positive organisms the response rate was similar whether there was simple sepsis (without major organ involvement) or complex sepsis (with major organ involvement), whereas in cases with sepsis caused by gram-negative organisms the response rates were less for complex sepsis as compared to simple sepsis. Response rate was better when the neutrophil count recovered as compared to when it decreased or remained low. Those with shock at presentation fared worse than those who did not have shock. Lastly the choice of correct antibiotics led to better outcome.13

 OTHER ISSUES Antiviral Therapy Antiviral drugs are indicated only for treating definite viral infections like HSV, varicella, cytomegalovirus infection, etc. They are not indicated as empirical therapy or as prophylactic therapy. CMV viremia has emerged as not an uncommon cause of prolonged pyrexia in neutropenia resulting from cancer chemotherapy unlike earlier where it was more commonly seen in stem cell transplant patients. Diagnosis is by doing quantitative viral Antimicrobial Therapy in Febrile Neutropenia 341 load. In patients with CMV disease, IV ganciclovir should be started and continued till it returns to normal. Later patient should be put on maintainence dose of oral valganciclovir till period of intense chemotherapy is over. One should also watch for relapse in future with further chemotherapy.

Antibiotic Prophylaxis Neutropenia is a good predictor for subsequent episodes of fever and infection. Early afebrile period in a neutropenic patient thus provides an opportunity to start antibiotic prophylaxis to prevent or reduce the chances of subsequent infections. Various drugs have been used for this purpose. Most of the drugs are aimed at selective sterilization of gut, the main source of pathogens in febrile neutropenic patients. Nonabsorbable drugs like neomycin, polymixin and vancomycin have been found to be inferior to absorbable drugs like TMP-SMX or quinolones.1,14 TMP-SMX has been shown to significantly reduce the incidence of fever and infections as compared to placebo. Similarly quinolones have been shown to be better that TMP- SMX and quinolones plus penicillin have been shown to be better than quinolones alone when used prophylactically.14 Even antifungal drugs are used for this purpose and flucanazole and itraconazloe have been shown to reduce incidence of candida infections when used prophylactically in centers where there is high incidence of candida infections. However, use of antibiotics for prophylaxis leads to toxicities, marrow suppression, increased chances of fungal infection and most important emergence of drug resistant organisms and fungi (like C. krusei or C. glabrata with flucanazole use) all of which counter the benefits of reduced infections. This is an intellectual paradox in that sense. The most important problem is emergence of drug resistant organisms, a situation which is not desirable or acceptable, and hence the use of antibiotic for prophylaxis is condemned in spite of high levels of benefits. However TMP-SMZ is used as prophylaxis for PCP infection irrespective of neutropenia, especially in leukemic patients who are at high risk of developing PCP infection. This is also likely to reduce other bacterial infections.

Cost Considerations in Febrile Neutropenia Various studies have shown tremendous scope for cost reduction while treating patients with febrile neutropenia without compromise in the outcome or morbidity. Basic principles of personal hygiene and precautions taken in the hospital by caretakers including health care workers go a long way in preventing episodes of febrile episodes in cancer patients and the ultimate cost of therapy. Besides this, intelligent management of febrile neutropenia episodes can also bring down the cost of therapy. Correct choice of antibiotics (avoidance of expensive antibiotics like vancomycin and carbapenems when not indicated), correct dose, use of oral antibiotics in low-risk patients (in adults), step down with early discharge after response to initial antibiotics (possible in pediatric patients), avoiding indiscriminate use of antifungal like amphotericin B and reserving use of liposomal amphotericin B only for those who cannot tolerate regular 342 Rational Antimicrobial Practice in Pediatrics amphotericin B and avoiding unnecessarily prolonged course of therapy are some of the measures one can use to bring down the cost. Outdoor therapy and oral antibiotics are two options that bring down the cost of therapy. In pediatric patients outdoor treatment or oral antibiotics as the initial treatment is not recommended as there is very little experience with this modes of therapy in pediatric patients. However in low risk pediatric patients one can step down to oral drugs and discharge the patient early when the patient becomes afebrile after 48 hours of IV antibiotic therapy.11,12 Similarly drugs like vancomycin and carbapenems are often misused as panacea of all ‘PUO’ in sick children with febrile neutropenia (often without proper cultures), which not only increases the cost but also induces emergence of drug resistance; this is to condemned. They should be used only when indicated. One can also consider use of linezolid in place of vancomycin in a stable patient who needs vancomycin as it is less expensive being an oral agent. Similarly liposomal amphotericin B though safer has same efficacy as amphotericin B and is at least 15 times more expensive.

CONCLUSIONS In summary febrile neutropenia is often an emergency while dealing with patients who are immune compromised. This is one situation where empirical antibiotic therapy is perfectly justified and it is often to err on doing more than lose a patient. Unless treated in time the mortality is high and the time available often is in hours and not days. Proper clinical evaluation may provide some hints as to the type and the site of infection, however the classical signs of inflammation are usually missing in these patients. The main emphasis is on obtaining proper cultures and on starting appropriate antibiotics without waiting for the reports of investigations. One needs to use first line antibiotics depending on local spectrum and sensitivity and on recent local experience. One needs to modify the drugs depending on the reports of cultures. Lastly one has to be careful while dealing with catheters in these patients even when they do not have infections as essentially the catheter related infections are best avoided.

 REFERENCES 1. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis, 2002; 34: 730-50. 2. Giamarellou H, Antoniadou A. Infectious complications of febrile leucopenia. Infect Dis Clin North Am 2001; 2: 457-82. 3. Zinner SH. Changing epidemiology of infections in patients with neutropenia and cancer: Emphasis on gram-positive and resistant bacteria. Clin Infect Dis. 1999; 29: 490-94. 4. Pizzo PA. Fever in immunocompromised patients. N Engl J Med. 1999; 341: 893-900. 5. Hughes WT, Armstrong D, Bodey GP, Brown AE, Edwards E, Feld R, et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis. 1997; 25: 551-73. 6. Jones RN. Contemporary antimicrobial susceptibility patterns of bacterial pathogens associated with febrile patients with neutropenia. Clin Infect Dis. 1999; 29: 495-502. Antimicrobial Therapy in Febrile Neutropenia 343

7. Rubin M, Hathorn JW, Marshall D, Gress J, Steinberg SM, Pizzo PA. Gram-positive infections and the use of vancomycin in 550 episodes of fever and neutropenia. Ann Int Med. 1988; 108:30-35. 8. Elting LS, Rubenstein EB, Rolston K, Cantor SB, Martin CG, Kurtin D et al. Time to clinical response: An outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care. J Clin Oncol 2000;18: 3699-3706. 9. Kern WV, Cometta A, Bock RD, Langenaeken J, Paesmans M, Gaya H. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. N Engl J Med 1999; 341: 312-8. 10. Freifeld A, Marchigiani RN, Walsh T, Chanock S, Lewis L, Hiemenz J, et al. A double blind comparison of empirical oral and intravenous antibiotic therapy for low risk febrile patients with neutropenia during cancer chemotherapy. N Engl J Med 1999; 341: 305-11. 11. Klaassen RJ, Goodman TR, Pham B, Dayle JJ. “Low-risk” prediction rule for pediatric oncology patients with fever and neutropenia. J Clin Oncol 2000; 18: 1012-9. 12. Shenep JL, Flynn PM, Baker DK, Hetherington SV, Hudson MM, Hughes WT, et al. Oral cefixime is similar to continued intravenous antibiotics in the empirical treatment of febrile neutropenic children with cancer. Clin Infect Dis. 2001;32:36-43. 13. Elting LS, Rubenstein EB, Rolston KV, Bodey GP. Outcomes of bacteria in patients with cancer and neutropenia: Observation from two decades of epidemiological and clinical trials. Clin Infect Dis. 1997; 25: 247-59. 14. Kern W, Kurrle E. Ofloxacin versus trimethoprim-sulphamethoxazole for prevention of infection in patients with acute leukemia and granulocytopenia. Infection. 1991;19:73-80. 15. Jarvis WR, Edwards JE, Culver DH, Hughes JM, Horan T, Emori TJ et al. Nosocomial infection rates in adults and pediatric intensive care units in United States. Am J Med .1991;91:1855-1915. 344 Rational Antimicrobial Practice in Pediatrics 3030 Antimicrobial Prophylaxis Meenu Singh, Shreya Singh

 INTRODUCTION Antimicrobials are frequently used medications in children. Generally, prophylactic antibiotic and other antimicrobial use in children to prevent serious illness is successful only in certain specific circumstances. The ideal antimicrobial used should be effective, non- toxic with few side effects and not alter the indigenous bacterial flora or induce development of bacterial resistance. There are fears that extensive prophylactic antimicrobial use may enhance the emergence of resistant organism. Also, the benefit of prophylactic antibiotics is limited when there is a high prevalence of antibiotic-resistant organisms in the community. The basic principles of prophylactic antimicrobial therapy are: • The risk or potential severity of infection should be greater than the risk of side effects from the antimicrobial agent • The prophylactic agent should be given the shortest period necessary to prevent target infection, and • The agent should be given before the expected period of risk (e.g. surgical prophylaxis) or as soon as possible after contact with an infected individual, e.g. prophylaxis for meningococcal meningitis. Thus, clinicians must balance the benefits against the current problem of the emergence of resistance. This chapter addresses most, but not all, of the situations in which prophylactic antimicrobials are used for children. Antimicrobial prophylaxis can be given to prevent infection or disease by a specific pathogen, to prevent infection in an infection-prone body site or for the general protection of a vulnerable host. Prophylaxis directed towards a specific pathogen is usually more successful than the protection of infection-prone body sites of highly susceptible children. Problems with compliance, adverse reactions and the development of resistance can be significant with the long-term use of broad-spectrum prophylactic antibiotics.1 Antimicrobial Prophylaxis 345

 SPECIFIC PATHOGEN PROPHYLAXIS The requirements for the consideration of prophylaxis for a specific pathogen are as follows: • The organism poses a significant risk in an identifiable situation. • The antibiotic susceptibility of the organism is predictable and stable. • Eradication of the organism is possible with relatively nontoxic antibiotics. Prophylaxis may involve short-term courses of therapy for a few days (e.g. prophylaxis against Neisseria meningitidis in family contacts) or several months (e.g. anti-tuberculosis medication for infant contacts); long-term therapy for years (e.g. prophylaxis against group A Streptococcus among individuals with rheumatic heart disease); or lifelong treatment (e.g. Pneumocystis prophylaxis for symptomatic individuals infected with HIV). In some situations, both the individual at risk and his or her close contacts (who are not at risk) may need prophylaxis (e.g. the use of prophylaxis to prevent secondary causes of Haemophilus influenzae meningitis). In following section specific pathogens for which antibacterial prophylaxis is generally recommended, the situations in which prophylaxis should be used and the antibiotics and doses most commonly used are suggested. Infection with organisms resistant to the prophylactic regimen should be considered likely for children who become ill despite prophylaxis, and empirical antibiotics that will treat the infection appropriately should be chosen. The antibiotic chosen for treatment depends on the prophylactic antibiotics used and the antibiotic resistance patterns in the local community.

Group A Streptococcus Indication Prevention of first attack of acute rheumatic fever (primary prevention) Prevention of initial attack depends on identification and eradication of the group A streptococcus that produces episodes of acute pharyngitis. Appropriate antibiotic therapy instituted in time, up to approximately 1 week/ 9 days after onset of symptoms of acute group A streptococcal pharyngitis, is highly effective in preventing first attack of acute rheumatic fever from that episode. However, primary prevention is not possible in patients who develop subclinical pharyngitis and therefore do not seek medical treatment (30%). The regimen includes 10 days of orally administered penicillin V (250 mg /dose bid- tid), or a single intramuscular injection (IM inj) of benzathine penicillin (0.6-1.2 million IU). In patients allergic to penicillin, erythromycin 40 mg/kg/day in two to four doses for ten days may be substituted for penicillin. A 10-day course of narrow spectrum oral cephalosporin is an acceptable alternative for patients allergic to penicillin. Prevention of recurrent rheumatic fever (secondary prevention) Secondary prevention is directed at preventing acute group A streptococcal pharyngitis in patients at substantial risk of recurrent acute rheumatic fever. Patients with documented histories of rheumatic fever, including those with isolated chorea and those without evidence 346 Rational Antimicrobial Practice in Pediatrics of rheumatic heart disease, must receive prophylaxis. Secondary prevention requires continuous antibiotic prophylaxis, which should begin as soon as the diagnosis of acute rheumatic fever has been made and immediately after a full course of antibiotic therapy has been completed. Ideally, patients should receive prophylaxis indefinitely. However, in patients who do not have evidence of carditis and valvular involvement and are not in high-risk occupation (e.g. school teachers, physicians, nurses), antibiotic prophylaxis may be discontinued at 21-25 years or at least 5 years have elapsed since the last episode of acute rheumatic fever whichever is longer. If the patient has rheumatic valvular disease, the prophylaxis should be continued longer, possibly for life. The chance of recurrence is highest in the first 5 years after acute rheumatic fever. The decision to discontinue prophylactic antibiotics should be made only after careful consideration of potential risks and benefits and of epidemiological factors such as the risk of exposure to group A streptococcal infections. The regimen of choice for secondary prevention is a single IM inj of benzathine penicillin G every 21 days. In compliant patients, continuous oral antimicrobials prophylaxis can be used. Penicillin V given twice daily and sulfadiazine given once daily are equally effective when used in such patients. It should be remembered that sulfonamides are not effective for the prophylaxis of infective endocarditis. For the exceptional patient who is allergic to both penicillin and sulfonamides, erythromycin given twice daily may be used (Table 1).2-5

TABLE 1 Drugs for secondary prophylaxis of Group A streptococcal infections Route of Antibiotic Dose Frequency Administration Intramuscular Benzathine penicillin G 0.6 million IU for Every 3-4 weeks < 30 kg 1.2 million IU for > 30 kg Oral Penicillin V 250 mg Twice daily Oral Sulfadiazine 500-1000 mg Once daily Oral Erythromycin 250 mg Twice daily

Contact of an individual with invasive group A streptococcal disease Contact of an individual with invasive disease, including necrotizing fascitis may be advised penicillin V 10 mg/kg (max 300 mg) orally four times daily or erythromycin 10 mg/kg (max 250 mg) orally four times daily or cephalexin 12 mg/kg (maximum 250 mg) orally four times daily for 10 days. However, scarce information is available to confirm the benefit from routine prophylaxis or to recommend a specific antibiotic. The decision to offer prophylaxis is made on a case-by-case basis.6,7 Antimicrobial Prophylaxis 347

Group B Beta Hemolytic Streptococcus (GBS) Indication Neonatal GBS disease is uncommon in India and hence routine screening for GBS is not required in Indian women and the guidelines mentioned below apply to the west. Maternal prophylaxis to prevent early neonatal GBS disease is given depending on the vaginorectal GBS screening cultures, which should be performed for all pregnant women at 35-37 weeks of gestation. Any woman with a positive prenatal screening culture, GBS bacteriuria during pregnancy, or a previous infant with invasive GBS disease should receive intrapartum antibiotics. Woman whose culture status is not known (culture not done, incomplete, or results unknown) and who deliver prematurely (<37 weeks) or experience prolonged rupture of membranes (18 hours or more) or intrapartum fever (38° C or more) should also receive intrapartum chemoprophylaxis. Routine intrapartum prophylaxis is not recommended for women with GBS colonization undergoing planned cesarean delivery, who have not begun labor or had rupture of membranes.8,9

Drug, Doses and Duration Penicillin G 5 x 106 units IV every 6 hours or ampicillin 2 g IV loading dose then 1 to 2 g every 4 to 6 hours is the drug of choice as no strains demonstrating resistance to penicillin have been identified. Cefazolin should be used in most cases of intrapartum prophylaxis for penicillin intolerant women. For penicillin allergic women clindamycin or erythromycin should be used, if isolates are demonstrated to be susceptible. Vancomycin should be used if isolates are resistant to clindamycin and erythromycin or if susceptibility to these agents is unknown. Therapy is continued until delivery.8,9

Streptococcus Pneumoniae Indication The frequency and severity of pneumococcal disease is increased in patients with sickle cell disease, asplenia, deficiencies in humoral and complement mediated immunity, HIV infection and certain malignancies, e.g. leukemia, lymphoma, chronic heart, lung or renal (especially nephrotic syndrome) disease and CSF leak syndromes. Because current vaccines do not eliminate all pneumococcal invasive infections, prophylaxis is recommended for children at high risk of invasive pneumococcal disease, including children with asplenia or sickle cell disease.

Drugs Penicillin V or Amoxicillin (orally in BD doses, 125 mg for children < 3 years, 250 mg for children > 3 years) substantially decreases the incidence of pneumococcal sepsis in children with sickle cell disease. IM benzathine penicillin G (0.6-1.2 mIU every 3-4 weeks) may also provide adequate prophylaxis. For children younger than six months of age with congenital asplenia, E. coli is a concern; therefore, trimethoprim/ sulfamethoxazole (5 mg TMP/25 mg SMX/kg once a day) is the preferred agent. 348 Rational Antimicrobial Practice in Pediatrics

Erythromycin may be used in children allergic to penicillin, but efficacy is unproved. Alternative antibiotics may be necessary in communities with a high prevalence of penicillin- resistant S. pneumoniae.

Duration The duration of prophylaxis is controversial. If oral prophylaxis is used, strict compliance must be encouraged. Most experts in infectious diseases agree that continued prophylaxis is indicated in children up to five years of age. In children who become asplenic after five years of age, prophylactic antibiotics should be given for at least one year after splenectomy. Some experts in infectious diseases recommend continuing prophylaxis into adulthood and throughout childhood. Studies show the emergence of penicillin resistance in pneumococci worldwide; penicillin resistance occurs more commonly in individuals who received antibiotic prophylaxis. Because patients with asplenia who receive continuous penicillin treatment are at risk of acquiring antibiotic-resistant pneumococci, alternative approaches need to be considered. Prophylaxis in sickle cell disease may be safely discontinued at 5 years of age in children who have received all recommended pneumococcal vaccines and who had not experienced invasive pneumococcal disease. Given the rapid emergence of penicillin-resistance pneumococci, prophylaxis can not relied on to prevent disease. Despite the use of prophylactic antibiotics and/or vaccines, children with asplenia or hyposplenia be considered at high risk of serious bacterial infection and, thus, be closely monitored for febrile illness, promptly assessed for infectious causes when fever occurs, and receive aggressive antimicrobial therapy whenever an infection is suspected regardless of vaccination history or penicillin prophylaxis.10-12

Neisseria Meningitidis Indication Prophylaxis is recommended as soon as possible for household, day care, and nursery school contacts and for those who have had contact with patients oral or nasopharyngeal secretions during the 7 days before the onset of illness. Prophylaxis is not routinely indicated for medical personnel except those with intimate exposure, such as mouth- to-mouth resuscitation, intubation or suctioning before antibiotic therapy was begun. Hospitalized patients should be placed on droplet precautions for 24 hour after initiation of effective therapy.13

Antibiotic(s) Recommended • Rifampin 10 mg/kg, max dose 600 mg orally every 12 hour for four doses (5 mg/ kg for infants younger than one month of age) OR • Ceftriaxone 125 mg for children <12 years; 250 mg for > 12 years, as single IM inj. OR • Ciprofloxacin 500 mg orally as single dose may also be given for nonpregnant individuals 18 years or older. Antimicrobial Prophylaxis 349

Haemophilus Influenzae b (Hib)14 Indication Chemoprophylaxis is recommended for all household, day care, nursery and play school contacts (children and adults excepting pregnant women) of children with invasive Hib disease if there is one unvaccinated child contact less than four years of age in household (other than the index case). Risk of infection is inversely related to age (for children > 3 months).

Antibiotic(s) Recommended Rifampin orally, once daily for four consecutive days. 0-1 mo 10 mg/kg/dose; > 1 mo 20 mg/kg/dose (max 600 mg)

Bordetella Pertussis15 Indication Prophylaxis should be given promptly to all household contacts, such as those in day care, regardless of age, history of immunization, or symptoms. Antibiotic prophylaxis is not routinely recommended for exposed health care workers. Booster dose of vaccine should be considered according to immunization status. However, certain authorities now advocate against routine prophylaxis as studies have shown no impact on clinical pertussis and restrict antibiotics to those contacts at the first respiratory symptom.

Drugs, Dose and Duration Erythromycin 40-50 mg/kg/day orally divided four times daily (max 2 g/day) for 14 days. Clarithromycin (15 mg/kg/day in two doses for 7 days) and azithromycin (10 mg/kg for 5 days in children less than 6 months and 10 mg/kg on day 1 and 5 mg/kg day 2-5 in those more than 6 months) are potential newer macrolides that may be used.

Corynebacterium Diptheriae16 Indication All asymptomatic household contacts and those who have had intimate respiratory and habitual physical contact with a patient are given antimicrobial prophylaxis, irrespective of immunization status. Consider diphtheria toxoid vaccine according to immunization status. The efficacy of prophylaxis is presumed but not proved.

Drugs, Dose and Duration Erythromycin 40-50 mg/kg/day, orally in four divided doses for 7 days or Benzathine penicillin G 0.6 mIU for < 30 kg, 1.2 mIU for >30 kg as a single IM inj.

Mycobacterium Tuberculosis See chapter on chemotherapy of tuberculosis. 350 Rational Antimicrobial Practice in Pediatrics

Malaria Malaria is a peculiar problem in that there may be frequent recurrences and it does not confer any protective immunity despite the repeated infections. There is no vaccine at present. Chemoprophylaxis should be complemented by personal protection when feasible and by other methods of vector control.

Indications for Chemoprophylaxis • All travelers from a non-malarious area to a malaria endemic area as a short-term measure including soldiers, police and labor forces serving in highly endemic area. • All pregnant women in a malarious area. • Residents of a malarious area are not advised chemoprophylaxis. It should not be prescribed as a remedy to prevent re-infections in an endemic area.

Drugs and Dosage for Chemoprophylaxis in Visitors17,18 Most parts of India have a high transmission of P. vivax malaria and Chloroquine resistant P. falciparum is reported from all parts of India. For visitors to North Eastern India, mefloquine is recommended as the first choice and Chloroquine + Proguanil as the second choice. For visitors to other areas, Chloroquine + Proguanil is advised. As per directives from the CDC the prophylaxis of choice for visitors to India is Mefloquine. No prophylaxis is needed for visitors to areas with low transmission like the high altitude states of Jammu and Kashmir, Himachal Pradesh and Sikkim, which are free from malaria. See Table 2 for details of malaria prophylaxis for other countries. Malarone (atovaquone and proguanil) is the chemoprophylactic of choice for areas with resistant P. falciparum infection but is expensive and not readily available.

Herpes Simplex Acyclovir or valacyclovir administered prophylactically during periods of high risk in immunocompromised hosts and in individuals with frequently recurrent (> 6 episode in a year) genital or oral herpes viral disease markedly decreases the rate of recurrence. Chemoprophylaxis is usually given for 6-12 months and then the need is reassessed. Acyclovir administered before a known trigger factor, such as intense sunlight, usually prevents recurrences. Acyclovir 200 mg four times a day or 500 mg twice a day is used. Famcyclovir and valacyclovir are other drugs, which have been used for prophylaxis.

Varicella Acyclovir is recommended for post-exposure prophylaxis in immunocompromised patients and in neonates whose mothers have had chickenpox 5 days before and 2 days after delivery or neonates with exposed to varicella whose mothers who have no history of varicella, if varicella zoster immunoglobulin is not available or affordable. It has to be given in a dose of 10-20 mg/kg/dose 4 times a day starting 7-9 days after exposure and continued for another 7 days.19 Antimicrobial Prophylaxis 351

TABLE 2 Chemoprophylaxis for malaria Type of malaria transmission Drugs Dosage Areas with chloroquine sensitive P. falciparum Chloroquine 5 mg of base/ kg once weekly (Start one week before (up to 300 mg of base) exposure, continue during exposure and for 4 weeks thereafter Areas with chloroquine Chloroquine 5 mg/ kg of base once weekly resistant P. falciparum (Same as above) (low degree, not wide spread) + < 2 yrs: 50 mg/day; Proguanil 2-6 yrs: 100 mg/d (Start 1-2 days before, 7-9 yrs: 150 mg/day; continue during exposure >9 yrs: 200 mg/d and for 4 weeks thereafter Areas with chloroquine Mefloquine* <15 kg: 5 mg of salt/kg; resistant P. falciparum (Start 2-3 weeks before, 15-19 kg: ¼ tab/wk; (High degree, widespread) continue during exposure 20-30 kg: ½ tab/wk; and for 4 weeks thereafter) 31-45 kg: ¾ tab/wk; or >45 kg: 1 tab/wk Chloroquine plus Proguanil As above or Doxycycline** >7 years: 2 mg/kg up to (Start 1-2 days before, adult dose (100 mg) continue during exposure and for 4 weeks thereafter) * Mefloquine is contraindicated in first trimester of pregnancy, patients with epilepsy, psychosis, heart blocks, and patients receiving beta-blockers. ** Doxycycline is contraindicated for children less than 8 years of age

Influenza Influenza is particularly severe in pregnant women, children with underlying cardiopulmonary disease, including congenital and acquired valvular disease, cardiomyopathy, bronchopulmonary dysplasia, asthma, cystic fibrosis, and neuromuscular diseases affecting the accessory muscles of breathing. Virus is shed for longer periods of time in children receiving cancer chemotherapy and children with immunodeficiency. Hence, prophylaxis may be considered in these patients if they have had significant exposure to influenza irrespective of their vaccination status. However protection lasts only as long as the prophylaxis continues. Also, during an influenza outbreak risk of exposure continues for a long time. Additionally use of drugs may potentiate resistance. For these reasons, chemoprophylaxis is of limited benefit and may be substituted by early treatment (initiating antivirals after the first respiratory symptom). 352 Rational Antimicrobial Practice in Pediatrics

Controlled clinical trials have demonstrated efficacy of both amantadine and rimantadine in prophylaxis (70-90% protection) and therapy of Influenza-A infections. These drugs block penetration of Influenza-A virus in host cell and prevent its replication. These drugs shorten the duration of fever, headache, cough, sore throat, general malaise; and reduce the viral shedding. A 3-5 days course of 5 mg/kg/day of any drug in two divided doses is recommended for prophylaxis of influenza-A infections.20,21 However, since the currently circulating influenza viruses are resistant to amantadine/ rimantidine, oseltamivir is now the preferred drug for prophylaxis. Oseltamivir may be used as prophylaxis in weight adjusted doses (75 mg in those above 35 kg) once daily for 7-10 days.

Pneumocystis Jiroveci Patients at high risk of P. jiroveci pneumonia should be placed on chemoprophylaxis. High-risk group includes patients with congenital (Severe Combined Immunodeficiency Disorder) and acquired immunodeficiency disorders, malignancies, organ transplant recipients and those receiving intensive immunosuppressive therapy for cancer or other diseases are candidates for prophylaxis. Drug, dosage and schedules are covered in section “Prophylaxis in HIV patients”.22,23

Others Leprosy Studies in India have established that dapsone 1–4 mg/kg/week orally gives protection among child contacts ranging from 35-53%. Prophylaxis was given for at least 3 years or until the index case in each household became bacteriologically negative. In another study cedapsone a long-acting drug, given as single IM injection every 10 weeks was also found as effective as dapsone. General applicability of chemoprophylaxis is still to be determined.13 Plague Chemoprophylaxis is highly recommended for all plague contacts, medical, paramedical, nursing, and public health personnel exposed to the risk of infection. Tetracycline is the drug of choice but sulfonamide is cheaper alternative.13

 PROTECTION OF INFECTION-PRONE SITES The requirements for the use of antibiotic prophylaxis to prevent infection of infection- prone sites are as follows: • The vulnerability to the infection is brief. • A limited number of potential infecting organisms are present. • The antibiotic susceptibilities of the organisms are known and stable. • Antibiotics can penetrate the affected body site in effective concentrations. In following section we will discuss the circumstances under which site-specific prophylactic antibiotic therapy should be considered including the antibiotic(s) of choice and specific recommendations in some instances. In general, the continued need for Antimicrobial Prophylaxis 353 prophylactic antibiotics used for the protection of infection-prone sites, such as the middle ear and the urinary tract, should be reviewed at least every three months. Also, prophylactic antibiotics given for surgical procedures should be used to achieve maximum protection during the procedure and should not be continued for prolonged periods of time afterward. Most patients undergoing procedures are adequately protected with antibiotic therapy immediately before the procedure. In some instances, repeated antibiotic administration after the procedure is recommended, but the treatment should rarely be required more than 6 h after the procedure.

Heart: Prevention of Bacterial Endocarditis24 See Tables 3 to 6.

Urinary Tract25 See chapter on Antimicrobial Therapy of UTI.

Prophylaxis for Other Body Sites See Table 7.

 PROTECTION OF THE VULNERABLE HOST It is appropriate to protect a vulnerable host in only a few circumstances. It is impossible to eliminate all the bacteria from a human host; often, attempts to do so result in a life-threatening infection with antibiotic-resistant organisms or fungi. Many opportunistic infection in which chemoprophylaxis is recommended, we have already discussed. Detailed discussion of them is beyond the scope of this book. Here we will discuss HIV infection

TABLE 3 Cardiac conditions associated with moderate to high-risk of endocarditis: Endocarditis prophylaxis recommended High-risk category • Prosthetic cardiac valves, including bioprosthetic and homograft valves • Previous bacterial endocarditis • Complex cyanotic congenital heart diseases (e.g. single ventricle states, transposition of great arteries, tetralogy of Fallot) • Surgically constructed systemic pulmonary shunts or conduits Moderate-risk category • Most other congenital cardiac malformations except isolated secondum atrial septal defect • Acquired valvular dysfunctions (e.g. rheumatic heart disease) • Hypertrophic cardiomyopathy • Mitral valve prolapse without valvular dysfunction 354 Rational Antimicrobial Practice in Pediatrics

TABLE 4 Prophylactic regimens for dental, oral, respiratory tract, or esophageal procedures: Recommendation of American Heart Association Drug Route Doses Timing with procedure Majority of Amoxicilin Oral 50 mg/kg, max 2 gm 1 hour before procedure patients Those patients Ampicillin IM/IV 50 mg/kg, max 2 gm 30 min before procedure unable to take oral medication Patients allergic Clindamycin or Oral 20 mg/kg, max 600 mg 1 hour before procedure to penicillin Cephalexin* or Oral 50 mg/kg, max 2 gm 1 hour before procedure Cefadroxil* or Azithromycin or Oral 15 mg/kg, max 500 mg 1 hour before procedure Clarithromycin Allergic to Cefazolin* IV/IM 25 mg/kg, max 1 gm 30 min before procedure penicillin and or unable to take Clindamycin IV 20 mg/kg, max 600 mg 30 min before procedure oral medications *Cephalosporins should not be used in individuals with immediate-type hypersensivity reaction (urticaria, angioedema or anaphylaxis) to penicillins.

TABLE 5 Prophylactic regimens for genitourinary, gastrointestinal (excluding esophageal) procedures: Recommendation of American Heart Association Situation Agents Regimens High-risk patients Ampicillin IM/IV ampicillin 50 mg/kg max 2.0 gm, gentamicin + Gentamicin 1.5 mg/kg within 30 min of starting the procedures; 6 h later, ampicillin 25 mg/kg IM/IV or amoxicillin 25 mg/kg orally High-risk patients Vancomycin + IV vancomycin 20 mg/kg over 1-2 h + gentamicin allergic to ampicillin/ Gentamicin 1.5 mg/kg; complete injection infusion within 30 min amoxacillin of starting the procedure Moderate-risk Amoxicillin Oral amoxicillin 50 mg/kg 1 h before procedure, or patients or ampicillin IV/IM ampicillin 50 mg/kg within 30 min of starting the procedure Moderate-risk Vancomycin IV vancomycin 20 mg/kg over 1-2 h; complete the patients allergic injection infusion within 30 min of starting the to ampicillin or procedure amoxicillin Antimicrobial Prophylaxis 355

TABLE 6 Procedures and endocarditis prophylaxis Endocarditis prophylaxis recommended Endocarditis prophylaxis not recommended Dental Dental extractions Restorative dentistry (operative or prosthodontic) with or Periodontal procedures including surgery, without retraction cord scaling and root planing, probing, and recall Local anesthetic injections maintenance Intracranial endodontic treatment; post-placement and Dental implant placement and reimplantation of build-up avulsed teeth Placemat of rubber dams, removable prosthodontic or Root canal instrumentation or surgery only orthodontic appliances beyond the apex Postoperative suture removal Initial placement of orthodontic bands Taking oral impressions, radiographs Intraligamentary local anesthetic injections Fluoride treatments Prophylactic cleaning of teeth or implants Orthodontic appliance adjustment where bleeding is anticipated Shedding of primary teeth

Respiratory Tract Tonsillectomy and/or adenoidectomy Endotracheal intubation Surgical operations that involve respiratory Bronchoscopy with a flexible bronchoscope, mucosa with or without biopsy Bronchoscopy with rigid bronchoscope Tympanostomy tube insertion Gastrointestinal Tract Sclerotherapy for esophageal varices Transesophageal echocardiography Esophageal stricture dilatation Endoscopy with or without intestinal biopsy Endoscopic retrograde cholangiography with biliary obstruction Biliary tract surgery Surgical operations that involve intestinal mucosa Genitourinary Tract Cystoscopy Vaginal delivery Cesarean section In uninfected tissue Urethral catheterization Uterine dilation and curettage Therapeutic abortion Sterilization procedures Insertion or removal of intrauterine devices Others Cardiac catheterization including balloon angioplasty Implanted cardiac pacemakers, implanted defrillators and coronary stents Incision biopsy of surgically scrubbed skin Circumcision 356 Rational Antimicrobial Practice in Pediatrics

TABLE 7 Prophylaxis for specific body sites Body site Disease(s) Antibiotic(s) prevented recommended Comments Conjunctivae26,27 Neonatal Ophthalmic drops of Single application at birth will not prevent ophthalmia due to erythromycin 0.5% chlamydial pneumonia; if not given, Neisseria or silver nitrate 1% ensure adequate follow-up of the infant gonorrhoeae* ophthalmic solution and/or Chlamydia or trachomatis Povidone-iodine 2% Treatment may fail due to inadequate administration of the ointment or solution Surgical Postoperative Antibiotics chosen Effectiveness varies depending upon the wound28 wound infection depend upon procedure procedure and background rate of but for most situations postoperative infections cefazolin/cefuroxime are adequate Given no more than Prolonged use of antibiotics following the 1 h before the start procedure generally has no benefit and of the procedure may result in super-infection with multiply Repeat dose needed antibiotic-resistant bacteria or fungi if surgery lasts for more than 4 hours Stopped within 24 hours of the procedure Middle ear29,30 Recurrent otitis Amoxicillin 20 mg/kg/day It is uncertain whether prophylactic media (3-4 episode orally once daily antibiotics should be recommended in 6 months or Sulphisoxazole for the prevention of recurrent otitis 6 episode in a 50 mg/kg day media; use should be limited to children year) who are extremely otitis prone, very symptomatic and episodes are frequent and close together. Reassess need every three months

TMP/SMX is not appropriate for prophylactic use * An infant born to a woman who has untreated gonococcal infection should receive a single dose of ceftriaxone 50 mg/kg, max 125 mg IV/IM in detail as it is rapidly growing problem in our country and knowledge among most of the pediatricians is scarce.

Postexposure Prophylaxis (PEP) Following Occupational Exposure to HIV30 All categories of health care personnel are at potential risk of acquiring HIV during care of an HIV infected patient, however, the risk is usually low (average risk is 0.3%). “Health care personnel” are defined as persons (i.e. employees, students, clinicians, public safety workers, or volunteers) whose activities involve contact with patients or with blood or other body fluids from patients in a health care or laboratory setting. Antimicrobial Prophylaxis 357

Indications Significant exposure (as defined below) to an HIV positive patient. Both risk of infection and possible side effects of drugs should be carefully considered when deciding whether to give PEP or not. Significant exposure is defined as: • A percutaneous injury (i.e. needle-stick or cut with a sharp instrument) • Contact of mucus membrane or non-intact skin (especially when the exposed skin is chapped, abraded, or afflicted with dermatitis), • Body fluids that are potentially infectious include blood, semen, vaginal secretions, cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids especially if contaminated with visible blood. • Exposure to tears, sweat, urine, faeces, saliva of an HIV-infected person is normally not considered as an exposure unless these secretions contain visible blood. If HIV status of the source is unknown then samples must be sent and PEP started and discontinued if results are negative.

Prophylactic Regime This depends on the severity of exposure and the nature of disease of the host and either the basic or expanded regime may be recommended (Tables 8 and 9). If there is a possibility of drug resistance then expert consultation is advised. The treatment should be started promptly, preferably within 1-2 hours after the exposure. However, ARV should be offered even when the patient presents late after exposure for any possible

TABLE 8 Prophylaxis following occupational exposure to HIV Exposure type HIV status of source patient HIV positive class 11 HIV positive class 22 HIV status unknown3 Percutanoeus injury Less severe4 Basic PEP Expanded PEP Generally no PEP 6 More severe5 Expanded PEP Expanded PEP Generally no PEP 6 Mucous membrane/non intact skin exposure Small volume7 Consider basic PEP Basic PEP Generally no PEP6 Large volume8 Basic PEP Expanded PEP Generally no PEP6 1. Asymptomatic HIV infection or known low viral load (e.g. <1,500 RNA copies/mL 2. Symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load 3. Needle from a sharps disposal container, deceased HIV with no samples for testing 4. Solid needle, superficial injury 5. Large-bore hollow needle, deep puncture, visible blood on device, or needle used in patient’s artery or vein) 6. Consider basic PEP where exposure to infected HIV person/device likely 7. Few drops 8. Major splash 358 Rational Antimicrobial Practice in Pediatrics

TABLE 9 Regimens following occupational exposure to HIV Basic regimen Zidovudine (AZT/ZDV)—300 mg twice a day and lamivudine 150 mg twice a day for 4 weeks Expanded regimen Basic regimen (ZDV+ 3TC) + Indinavir—800 mg/thrice a day for 4 weeks. Instead of indinavir, lopinavir- ritonavir, efavirenz, abacavir or nelfinavir may be used benefit. The need for compliance and possible side effects should be explained and the patient should be counseled for refraining from activities that result in transmission of HIV to a susceptible person.

Prophylaxis for Prevention of HIV Transmission from HIV Infected Pregnant Mother31 Apart from other strategies to prevent HIV transmission from a pregnant mother to child, a course of antiretroviral drugs is given to both mother and child. There are multiple regimes used but three of them are commonly used in NACO program for chemoprophylaxis and have been proven to reduce the risk of transmission (Table 10). The most effective regime for preventing perinatal transmission is PI based HAART to mother during pregnancy and labour and 6 weeks zidovudine to the baby (reduces risk of transmission to 1–2%).

Prophylaxis for Prevention Against Opportunistic Infections in an HIV Infected Child The section detailed below discusses prophylaxis in HIV infected children. In adults, there has been revision of guidelines to stop prophylaxis in adults and adolescents when they have sustained rise in CD4 counts over a period of 3-6 months. Recent

TABLE 10 Regimes for prevention of mother-to-child transmission of HIV31 Trial Breast Regimen Intrapartum Postpartum Postpartum Relative Comments feeding antipartum (Mother) (Child) efficacy PACTG No From 14-34 IV ZDV None Oral ZDV 68% Costly, 076 1994 weeks, 2 mg/kg over 2 mg/kg At 18 Requires oral Oral ZDV* 1 h, followed every 6 hrly months & IV, must be 100 mg × 5 by 1 mg/kg/h for 6 weeks started early Thailand No From Oral ZDV None None 50% Shorter 1998 36 weeks, 300 mg At 18 duration Oral ZDV every 3 h months 300 mg × 2 HIVNET Yes None at NP 200 mg None NP 2 mg/kg 47 % at Highly cost- 012 onset at onset of within 14-16 effective, NACO’s labor 72 hours weeks technically national of birth feasible program * ZDV—Zidovudine, ** NP—Nevirapine Antimicrobial Prophylaxis 359 data indicates that prophylaxis in children can also be discontinued once there is sustained rise in the CD4 counts above the age specific targets over a period of 3-6 months.32,33

PCP Prophylaxis22,23,32 PCP prophylaxis should be given to: • All HIV infected children from the age of 4 weeks to 12 months. • All children with indeterminate status should receive prophylaxis from the age of 4 weeks till 12 months. It can be stopped at 4 months of age if HIV infection has been excluded • HIV infected children 12 months and above should receive prophylaxis if CD4 counts are < 15% or absolute CD4 counts are <500 in 1-5 years and < 200 in 6-12 years age group. • All children who have been treated for Pneumocystis carinii pneumonia. See Table 11 for drugs and doses for PCP prophylaxis. TABLE 11 Drugs and doses for prophylaxis against PCP Drug Dose TMP-SMX 150 mg/m2/day PO of TMP in two divided doses 3 consecutive days/ Drug of choice alternative days a week/daily or as single dose three consecutive days a week Dapsone 2 mg/kg/day PO (max. dose 100 mg) daily or 4 mg/kg (max dose 200 mg) weekly, screen for G-6-PD deficiency Pentamidine Inhaled—300 mg pentatamidine isoethionate inhaler every 28 days for > 5 years

Prophylaxis for Mycobacterium Tuberculosis in HIV/AIDS Patients15 One of the most common HIV-related opportunistic infection (OI) is tuberculosis in high prevalence areas. Prophylaxis with isoniazid 10 mg/kg/day for 12 months is advocated in the following circumstances: • All tuberculin positive children with Mantoux > 5 mm, who had previously not received treatment for tuberculosis. • Children with recent contact with an infectious tuberculosis patient (sputum smear positive), regardless of the results of tuberculin skin test or history of previous treatment. • Children with a history of prior untreated or inadequately treated past tubercular infection that healed, regardless of the result of tuberculin skin test. In all above settings active tuberculosis should be ruled be ruled out by history, clinical examination, chest radiograph and other tests.

Mycobacterium Avium Complex (MAC) Infections Defective cell mediated immunity as reflected by low CD4 counts is an important risk factor for the development of these infections. Disseminated infection with MAC rarely 360 Rational Antimicrobial Practice in Pediatrics

TABLE 12 Indication for initiating prophylaxis against Mycobacterium avium complex (MAC) Age CD4 count: cells/uL <12 months < 750 1-2 years < 500 2-6 years < 75 > 6 years < 50

TABLE 13 Drugs and doses for preventing Mycobacterium avium complex (MAC) Drug Dose and schedule Clarithromycin 15 mg/kg/day PO in 2 doses, max 1000 mg/day Azithromycin 10 mg/kg/day PO single daily dose, max. 500 mg/day or 20 mg/kg weekly (max dose 1200 mg). Weekly dose only for primary prophylaxis not for secondary prophylaxis Rifabutin 5-10 mg/kg/day PO single dose, max 300 mg/dose, dose needs to be adjusted with some antiretroviral drugs are administered concurrently Ethambutol 15 mg/kg/day (max 900 mg) occurs during the first year of life. The incidence of these infections is very less in India. Primary prophylaxis is given before the development of disease in patients with low CD4 counts as in Table 12. Either azithromycin/clarithromycin/rifabutin may be used. For doses see Table 13. Secondary life long prophylaxis is indicated in patients who have suffered from MAC. Regimes include clarithromycin/azithromycin with ethambutol with or without rifabutin. For doses see Table 13.

Recurrent Bacterial Infections Children with recurrent bacterial infections should receive daily prophylaxis with TMP- SMX 150 mg/m2 in two divided doses for preventing for preventing recurrent bacterial infections including Salmonella infections.

Prophylaxis for Viral Infections33 Herpes simplex 1 and 2 infections: Oral acyclovir 80 mg/kg/day in 3-4 divided doses is given for prophylaxis in HIV patients with frequent or severe relapses or if they have severe and slowly healing lesion. Herpes zoster: Daily acyclovir is recommended if patients have recurrent episodes of zoster. Cytomegalovirus: Life-long prophylaxis with ganciclovir 5 mg/kg/day IV daily is initiated after an episode of end organ disease.33 Antimicrobial Prophylaxis 361

Toxoplasmosis Children with severe immunosuppression (CD4 count < 15%) should be screened for IgG antibodies against Toxoplasma and prophylaxis should be given to those with positive IgG antibodies against Toxoplasma gondii. Children who receive TMP-SMX for PCP (on a daily basis) are also protected against Toxoplasma gonadii infections. Other drugs for those that cannot tolerate cotrimoxazole an alternative is dapsone (children more than 1 month) 2 mg/kg or 15 mg/m2 (max 25 mg) PO daily with pyrimethamine 1 mg/ kg PO daily plus leukovorin 5 mg PO every three days. Following an episode of CNS toxoplasmosis, life-long suppressive therapy is given with sulphadiazine 100 mg/kg/day in 2-4 divided doses plus pyrimethamine 1 mg/kg or 15 mg/m2 (max 25 mg) daily plus leukovorin 5 mg PO every three days.

Prophylaxis for Fungal Infections Cryptococcal Infections Primary prophylaxis not usually recommended. Secondary prophylaxis is recommended with fluconazole 3-6 mg/kg/day PO max 200 mg/day; alternatively Itraconazole 2-5 mg/ kg/day PO single dose max 400 mg/day or amphotericin B 1 mg/kg weekly IV may be used.

Candida Children with recurrent oropharyngeal or esophageal disease should be given daily prophylaxis with oral fluconazole 3-6 mg/kg/day.

Prophylactic Antimicrobials for Prevention of Nosocomial Infections Nosocomial infections are a significant problem in pediatric intensive care units, reported incidence being 6-8%. With proper preventive strategies, the nosocomial infection rates can be reduced up to 50%. Handwashing; judicious use of interventions, and proper asepsis during procedures remain the most important practices. Selective decontamination of the gut using antimicrobials such as tobramycin, gentamicin, polymyxin and nystatin for prevention of nosocomial pneumonia, is controversial and is not recommended. More than 90% of all nosocomial bloodstream infections are in children with central venous lines. Mupirocin ointment may reduce the risk of bacterial colonization of catheters but may increase colonization rate of fungi and is only recommended for hemodialysis catheters. Antibiotic prophylaxis reduces the risk of nosocomial UTI but is not universally recommended as it selects multidrug resistant strains when the infection occurs.34,35 Prophylaxis with fluconazole or ketoconazole in critically ill children in the pediatric intensive care unit reduces invasive fungal infections by one half and total mortality by one quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated in Cochrane based systematic review, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections in units where there is high incidence of fungal sepsis, antifungal prophylaxis 362 Rational Antimicrobial Practice in Pediatrics with fluconazole should be considered but there are no consensus guidelines.36 However, twice weekly intravenous fluconazole prophylaxis is recommended in extremely low birth weight babies to prevent against invasive Candida infections (for details refer to chapter on antifungal Therapy).

 ABBREVIATIONS IM Intramuscular inj Injection IV Intravenous PO Orally mIU Million international units max Maximum GBS Group B beta hemolytic streptococcus HIV Human immunodeficiency virus PEP Post-exposure prophylaxis TMP-SMX Trimethoprim-sulfamethoxazole (cotrimoxazole) UTI Urinary tract infection MCU Micturating cystourethrogram

 REFERENCES 1. Uhari M, Nuutinen M, Turtinen J. Adverse reactions in children during long-term antimicrobial therapy. Pediatr Infect Dis J. 1996;15:404-8. 2. Dajani A, Taubert K, Ferrieri P, et al. Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever:A statement for health professional. Pediatrics 1995;96:758-64. 3. Stollerman GH. Rheumatic Fever. Lancet 1997;349:935-42. 4. Park MK, Troxier RG. Acute rheumatic fever in Pediatric Cardiology for Practitioners, 4th edition, Harcourt India Private Limited, 2002;304-10. 5. Michael A. Gerber. Rheumatic fever. In:Nelson Textbook of Pediatrics, 17th edition, 2004:874. 6. The Working Group on Prevention of Invasive Group A Streptococcal Infections. Prevention of invasive Group A streptococcal disease among household contacts of case-patients:is prophylaxis warranted? JAMA. 1998;279:1206-10. 7. American Academy of Pediatrics. Committee on Infectious Diseases. Severe invasive group A streptococcal infections:A subject review. Pediatrics 1998;101:136-40. 8. Bromberger P, Lawrence JM, Braun D, et al. The influence of intrpartum chemoprophylaxis on the clinical spectrum of early onset group B streptococcal infection in term infants. Pediatrics. 2000;106:244- 50. 9. Centers for disease control and prevention:Prevention of Perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Morb Mort Wkly Rep 2002;51 (RR-11):1-22. 10. American Academy of Pediatrics. Committee on Infectious Diseases. Policy statement:Recommendation for prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine, pneumococcal polysaccharide vaccine and antibiotic prophylaxis. Pediatrics 2000;106:362-75. 11. Buchanan GR, Smith SJ. Pneumococcal septicemia despite pneumococcal vaccine and prescription of penicillin prophylaxis in children with sickle cell anemia. Am J Dis Child 1986;140:428-32. 12. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease (Cochrane Review) The Cochrane Library, Issue 1, 2006. 13. American Academy of Pediatrics, Committee on Infectious Diseases:Meningococcal disease prevention and control strategies for practice based physician. Pediatrics 2000;106:1500-6. Antimicrobial Prophylaxis 363

14. Dickinson GM, Bisno AL. Antimicrobial prophylaxis of infection. Infect Dis Clin North Am. 1995;9:783- 804. 15. Tiwari T, Murphy TV, Moran J. National Immunization Program, CDC. Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC Guidelines. MMWR Recomm Rep. 2005;54 (RR-14):1-16. 16. Farizo KM, Strebel PM, Chen RT, Kimbler A, Cleary TJ, Cochi SL. Fatal respiratory disease due to Corynebacterium diphtheriae: case report and review of guidelines for management, investigation, and control. Clin Infect Dis. 1993;16:59-68. 17. Malaria. In CDC Yellow Book. Health Information for international travel, 2005-2006. Available from:http:/ /www2.ncid.cdc.gov/travel/yb/utils/ybBrowseC.asp. Accessed on June 23, 2006. 18. WHO. Travel advice for malaria. Available at http://www.who.int/ith/ Accessed on June 23, 2006. 19. Waugh SML, Pillay D, Carringoton D, Carmon WF. Antiviral prophylaxis and treatment. J Clin Virol 2002;25:241-66. 20. Couch RB. Prevention and treatment of influenza. N Engl J Med 2000;343:1778-87. 21. Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of neuraminidase inhibitor Zanamivir in the treatment of influenza A and B virus infections J Infect Dis 1999;180:254-261. 22. Hughes WT. Pneumocystis carinii pneumonia. Semin Pediatr Infect Dis 2001;12:309-14. 23. Harris RE, McCallister JA, Allen SA, Barton AS, Baehner RL. Prevention of pneumocystis pneumonia. Use of continuous sulfamethoxazole-trimethoprim therapy. Am J Dis Child 1980;134:35-8. 24. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA. 1997;277:1794-1801. 25. Bagga A, Babu K, Kanitkar M, Srivastava RN. Indian Pediatric Nephrology Group. Indian Academy of Pediatrics Consensus statement on management of urinary tract infections. Indian Pediatr. 2001;38: 1106-15. 26. O’ Hara MA. Ophthalmia Neonatorum. Pediatr Clin North Am. 1993;40:715-25. 27. Isenberg SJ, Apt L, Wood M:A controlled trial of povidone- iodine as prophylaxis against ophthalmia neonatorum. N Engl J Med 1995;332:562. 28. Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther 1997;39:97-101. 29. Mandel EM, Casselbrandt ML, Rockette HE, Bluestone CD, Kurs-Lasky M. Efficacy of antimicrobial prophylaxis for recurrent middle ear infection. Pediatr Infect Dis J 1996;15:1074-82. 30. Centers for Disease Control and Prevention. Updated U.S. Public Health Service. Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis. MMWR 2001;50 (No. RR-11). 31. Fowler MG, Simonds RJ, Roongpisuthipong A. Update on Perinatal HIV transmission. Pediatr Clin North Am. 2000;47:21-38. 32. Grubman S, Simonds RJ. Preventing Pneumocystis carinii pneumonia in human immunodeficiency virus-infected children:new guidelines for prophylaxis. CDC, US Public Health Service and the Infectious Disease Society of America. Pediatr Infect Dis J 1996;15:165-8. 33. Recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. Guidelines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children. MMWR 2009;58:1-166. 34. Centers for Disease Control and Prevention. Guidelines for prevention nosocomial pneumonia. MMWR 1997;46:1-79 35. Lodha R, Uma C, Mouli N, Mrinal N, Kabra SK. Nosocomial Infections in Pediatric Intensive Care Units. Indian J Pediatr 2001;68:1063-1070. 36. Playford EG, Webster AC, Sorrell TC, Craig JC. Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients. The Cochrane Database of Systematic Reviews 2006;(1): CD004920. 364 Rational Antimicrobial Practice in Pediatrics 3131 Antimalarial Therapy Tanu Singhal, Ashok Kapse

 INTRODUCTION Malaria is an important public health problem with a reported 300–500 million cases per year and 1 million deaths. Around 90% of the deaths occur in children of Sub-Saharan Africa. The exact malaria burden in India is unknown but considerable. The increasing resistance in malaria vectors to insecticides, failure of the National Malaria Control Program, rising cases of malaria due to Plasmodium falciparum and increasing resistance in P. falciparum to antimalarials in India is a matter of serious concern. This article discusses the pharmacology of antimalarial drugs and choice of antimalarial therapy in detail.

 ANTIMALARIAL DRUGS Chloroquine Chloroquine belongs to group of 4-aminoquinolines; the other antimalarial in this group is amodiaquine.

Antimalarial Activity Chloroquine is active against all stages of schizonts of P. malariae, P. ovale and against chloroquine-sensitive strains of P. falciparum and P. vivax. It also has gametocytocidal activity against P. vivax, P. malariae, P. ovale as well as immature gametocytes (stages 1–3) of P. falciparum. Drug is inactive against hypnozoites and hence, needs to be combined with primaquine to achieve radical cure of P. vivax. and P. ovale.

Mechanism of Action Malarial parasite utilizes hemoglobin for its amino acid requirements. Hemoglobin digestion releases large quantities of heme; free heme is toxic to malarial parasites. To protect them parasite convert toxic heme into an innocuous crystal called as hemozoin. Chloroquine binds heme and thereby prevents it from being incorporated into the hemozoin crystal.1 Antimalarial Therapy 365

Pharmacokinetics Chloroquine has excellent oral bioavailability; a single dose of 10 mg/kg achieves therapeutic level for P. vivax and chloroquine-sensitive P. falciparum parasites within 30 minutes. Parenterally, the drug achieves dangerously high levels; therefore it should always be used with great caution particularly in pediatrics. Drug is preferentially concentrated in erythrocytes and this concentration is enhanced in parasitized erythrocytes. The drug has a high capacity for binding to the melanin-containing tissues of the skin and eye. Chloroquine is eliminated slowly and has an elimination half-life of around 10 days; however, it may be detected in blood for up to 56 days.

Resistance Status P. falciparum: Barring certain parts of globe (Central America, and the Caribbean) falciparum has acquired a significant resistance to chloroquine. P. vivax: Although there are isolated reports of emerging resistance in P. vivax from certain quarters (Papua New Guinea, India) the species in general is sensitive to chloroquine.2-4

Therapeutic Uses Chloroquine is first line treatment for P. vivax infection; there are few reports suggesting emergence of resistance in this species too, yet in most cases resistance is sporadic and inconsistent, and hence, does not warrant change in treatment policies.1,3,4 Due to widespread resistance, chloroquine is no more recommended as first line treatment for P. falciparum malaria. However, in areas where resistance level is low; it may still be an effective drug for P. falciparum malaria; provided used in combination with other antimalarials. Even in areas of low resistance it might be safer to use a more effective drug for severe/complicated malaria and in vulnerable populations like small children and pregnant women. Owing to prolonged duration of action chloroquine used to be a favorite drug for malarial chemoprophylaxis; however with advent of extensive resistance, drug has fallen out of favor for prophylactic purpose.1

Use in Pregnancy No abortifacient or teratogenic effects have been reported with chloroquine; therefore, it is the safest antimalarial for treatment or chemoprophylaxis of malaria during pregnancy.5

Dosages Oral: Orally chloroquine should be prescribed in doses of 25 mg per kg as base, to be given over a period of three days. Drug could be used in one of the following two regimens: 1. First regimen consists of 10 mg of base per kg as first dose, followed by 5 mg/kg 6–8 hours later and 5 mg/kg on each of the following 2 days. 366 Rational Antimicrobial Practice in Pediatrics

2. A more practical regimen is 10 mg/kg of base on the first and second days and 5 mg/kg on the third. Though this regimen is pharmacokinetically bit inferior, clinical results are similar. Increasing the dose beyond 25 mg/kg of base does not aid to clinical cure rate, conversely repeated administration of such high doses may produce adverse reactions.6 Parenteral: In a situation where child is unable to take or retain oral medication chloroquine could be used intramuscularly, however, dose should not exceed than 2.5 mg/kg. Dose could be repeated at 6 hours interval if needed. Intravenous bolus injection of chloroquine should never be given.

Side Effects Serious adverse reactions to chloroquine are rare at the usual antimalarial dosages; transient headaches, nausea, and vomiting, gastrointestinal symptoms and “blurred vision” may occur following chloroquine administration, this could be avoided by administering the dose after a meal. Dark skinned people could suffer from intolerable pruritus, and as it may compromise compliance; it is advisable to use an alternative effective drug in the event of re-infection. Antihistamines are futile for chloroquine induced pruritus however, calamine lotion may alleviate it. Chloroquine may precipitate attacks of acute porphyria and psoriasis in susceptible individuals. Irreversible visual impairment resulting from accumulation of chloroquine in the retina was a rare but recognizable complication of long-term chloroquine prophylaxis. Cumulative total doses of 1 g of base per kg body weight or 50–100 g of base have been associated with retinal damage.

Over Dosage Chloroquine has a low safety margin, as little as twice the therapeutic dose ingestion may culminate into acute toxicity. Poisoning may result into cardiovascular failure with hypotension and cardiac arrhythmias rapidly progressing to cardiovascular collapse, convulsions, cardiorespiratory arrest, and death. Diazepam, adrenaline and mechanical ventilation constitute modern management of chloroquine toxicity. Diazepam competes with chloroquine for benzodiazepine receptors in cardiac myocytes while adrenaline counteracts the chloroquine effects on myocardium and vasculature.1

Contraindications Chloroquine is contraindicated in persons: with known hypersensitivity, with a history of epilepsy, and suffering from psoriasis.

Availability This is a very cheap drug and readily available. Drug is available in all suitable forms like tablets, syrup, drops and injections. Tablets containing 150 mg or 300 mg of chloroquine base as phosphate or sulfate, syrup containing 10 mg base per mL and drops containing Antimalarial Therapy 367

50 mg base per mL are available. Chloroquine injections are dispensed as 5 mL ampule, each mL containing 40 mg of chloroquine.

Amodiaquine Amodiaquine is a 4-aminoquinoline antimalarial drug similar in structure and activity to chloroquine. After oral administration, amodiaquine is rapidly and extensively metabolized to a pharmacologically active metabolite, desethylamodiaquine, metabolite is concentrated in erythrocytes and is slowly eliminated with a terminal elimination half-life of up to 18 days. In chloroquine sensitive strains the drug has slightly better antimalarial activity than chloroquine, however, there is significant cross-resistance among chloroquine resistant strains.7,8 Orally amodiaquine is prescribed in doses of 10 mg/kg of base per day for 3 days (total dose 30 mg/kg). Adverse reactions to amodiaquine are generally similar to those to chloroquine, the most common being nausea, vomiting, abdominal pain, diarrhea and itching; there is some evidence that itching may be less common with amodiaquine than with chloroquine. In the mid, 1980s, fatal adverse drug reactions (hepatitis and agranulocytosis) were reported in travelers using amodiaquine for malaria chemo- prophylaxis.9,10 As a consequence, WHO recommended that the drug should not be used for chemoprophylaxis or even as an alternative treatment for chloroquine failure.1,7 Following this recommendation amodiaquine used declined globally till recently when it is again being used in treatment of falciparum malaria as a combination with artemisinin derivatives.

Quinine Extracts of cinchona bark; quinine and its congener quinidine are effective antimalarial drugs.

Antimalarial Activity Quinine is a potent blood schizonticidal activity against all malarial species including chloroquine and antifolate resistant strains. It is active against gametocytes of all species excluding P. falciparum. Drug is devoid of hypnozoitocidal activity.

Mechanism of Action Like chloroquine, quinine also interferes with parasitic metabolism of heme; quinine opposes polymerization of hemin into hemozoin.

Pharmacokinetics Quinine has excellent oral bioavailability and peak plasma concentrations that are reached within 1-3 h. It readily crosses the placental barrier and is found in cerebrospinal fluid. Quinine is extensively metabolized in the liver, has an elimination half-life of 10–12 h in healthy individuals and is subsequently excreted in the urine. 368 Rational Antimicrobial Practice in Pediatrics

Some of the pharmacokinetic characteristics are affected by age of the patient, and also by malaria. The volume of distribution is less in young children than in adults. In patients with acute malaria, the volume of distribution is reduced and systemic clearance is slower than in healthy subjects, these changes are proportional to the severity of the disease.7,12

Resistance Status Though significant resistance to quinine has not yet occurred some decrease in sensitivity to quinine has been detected in areas of South-East Asia where it has been extensively used for malaria therapy. Poor compliance and incomplete treatment are responsible for this decreased sensitivity. There is some cross-resistance between quinine and mefloquine, suggesting that the wide use of quinine in Thailand might have influenced the development of resistance to mefloquine in that country.

Indications Quinine till some time ago was the drug of choice for severe falciparum malaria in most countries.10 It has now been supplanted by the artemisinin derivatives. For uncomplicated falciparum malaria in chloroquine resistant areas quinine is often used but there are problems with compliance due to troublesome side effects. Quinine should always be used in combination with other antimalarial drugs such as tetracycline, clindamycin and pyrimethamine-sulfadoxine. Quinine is inferior to chloroquine, mefloquine and artemisinin derivatives in the treatment of vivax malaria and is best avoided for P. vivax infections.

Use in Pregnancy Quinine is safe in pregnancy. Studies have shown that therapeutic doses of quinine do not induce labor and that the stimulation of contractions and evidence of fetal distress associated with the use of quinine are in fact due to fever and other effects of malarial disease. The risk of quinine-induced hypoglycemia is, however, greater than in non- pregnant women, particularly in severe disease.

Dosage Quinine can be given by the oral, intravenous or intramuscular routes. Quinine should not be given alone for the treatment of malaria as short courses, e.g. 3 days, owing to the possibility of recrudescence and resistance. Parenteral: If parenteral therapy is indicated as in severe malaria quinine should be given intravenously as 10 mg/kg of salt by slow infusion in isotonic fluid or 5% dextrose saline slowly over 4 h every 8-hourly. A loading dose of 20 mg per kg is recommended for severe and complicated malaria.12 The loading dose should be avoided if there is reliable evidence that the patient has received quinine/halofantrine/mefloquine in the past 24 hours (both halofantrine and mefloqune produce additive cardiac toxicity). If facilities for intravenous infusion are not available quinine can be given intramuscularly in the Antimalarial Therapy 369 same dosage with the same therapeutic results. In this case the drug should be diluted to a concentration of 60 mg/mL and divided into two halves, one half being delivered into each anterior thigh.1,10 Whenever parenteral quinine is used, oral treatment should be resumed as soon as the patient is able to take it, and continued for the completion of the course. In situations where infusion need is beyond 48 hours or in renal failure, the dose should be reduced to half. Total duration of therapy is seven days. A second drug such as doxycycline, clindamycin, SP should be added once oral intake is possible. Oral: Quinine, 10 mg of salt per kg three times daily for 7 days. As discussed earlier quinine should be combined with single dose pyrimethamine-sulfadoxine (1 mg/kg of pyrimethamine) or tetracycline (5 mg/kg 6 hourly for 7 days) or doxycycline (2 mg/kg twice a day for 7 days) or clindamycin (20–40 mg/kg divided in 3 daily doses for 5 days). Tetracyclines cannot be used in children aged less than 8 years. A single gametocidal dose of primaquine (0.75 mg/kg) should be given at end of therapy to interrupt transmission as quinine is not effective against gametocytes of P. falciparum.

Side Effects Cinchonism, a symptom complex characterized by tinnitus, hearing impairment, and sometimes vertigo or dizziness, occurs in a high proportion of treated patients. Symptoms appear even at the lower limit of the therapeutic range of the drug. These symptoms are usually reversible and rarely constitute a reason for withdrawing the drug but do reduce compliance with 7 days therapy. Serious side effects with parenteral quinine are rare, if it is administered properly. Severe hypotension may develop if the drug is injected too rapidly. Quinine produces prolongation of the QTc interval in the ECG but significant conduction or repolarization abnormalities are rare and iatrogenic dysrhythmias are extremely uncommon in normal hearts. Routine ECG monitoring during quinine infusion is not required if there is no evidence of pre-existing heart disease. Quinine is known to produce hypoglycemia through stimulatory action on the pancreatic ß cells. Hypoglycemia is particularly common in children and pregnant women. Frequent blood glucose monitoring is a must. Care should be taken to monitor and treat for hypoglycemia in children administered IM quinine as they may not have an IV access for IV fluids. Quinine produces hemolysis in G6PD deficiency; it also produces hemolysis in non- G6PD deficient patients by a still not well-elucidated immune mechanism. Hemolysis and hemoglobinuria at presentation is not a contraindication to quinine if the patient is not known to G6PD deficient. If hemolysis develops during quinine therapy, it may be advisable to shift to artemisinin derivatives.

Toxicity A single dose of quinine of > 3 g is capable of causing serious and potentially fatal intoxication. Intoxication has three main elements; (1) central nervous system depression and seizures, (2) dysrhythmias, hypotension and cardiac arrest and (3) blindness 370 Rational Antimicrobial Practice in Pediatrics

Contraindications Quinine is contraindicated in persons: with known hypersensitivity, with underlying cardiac disorders, on cardio-suppressant drugs and with G6PD deficiency. Thrombocytopenia, jaundice, renal failure, hypotension are not contraindications for quinine administration. Administration of mefloquine prior to quinine administration is not a contraindication to use of quinine but ECG monitoring is desirable and the loading dose should be avoided.

Formulations Tablets of quinine hydrochloride, quinine dihydrochloride or quinine sulfate containing 100 mg and 300 mg quinine salt is available. Injectable solutions of quinine hydrochloride, quinine dihydrochloride or quinine sulfate containing 82%, 82% and 82.6% quinine base respectively.

Quinidine Quinidine is an isomer of quinine, with similar antimalarial properties. It is slightly more effective than quinine but has a greater cardio-suppressant effect; drug interactions of quinidine are similar to those of quinine. Quinidine is used in areas where quinine is unavailable such as the United States.1

Pyrimethamine—Sulfadoxine/Sulfalene (SP) Synergistic combinations that act against the parasite-specific enzymes, dihydropteroate synthetase (DHPS) and dihydrofolate reductase (DHFR) constitute effective antimalarial drugs. Because trimethoprim has a much lower affinity than pyrimethamine for the parasite dihydrofolate reductase enzyme, cotrimoxazole the combination of sulfamethoxazole and trimethoprim has weak antimalarial properties, and therefore, should not be used for the treatment of malaria.

Antimalarial Activity Pyrimethamine: Sulfadoxine is schizontocidal for P. falciparum; it is devoid of hypnozoitocidal activity and gametocytocidal activity. They, however, have been shown to be sporontocidal in animal models.7 Antifolates have inherently weak blood schizonticidal effects against P. vivax.1

Mechanism of Action Folate metabolism is the target of several antimalarials as well as drugs used against other pathogens. Due to its high rate of replication the malaria parasite has a high demand for nucleotides as precursors for DNA synthesis and thus is particularly sensitive to antifolates. The malaria parasite synthesizes folates de novo and is unable to utilize exogenous folates. In contrast, human beings must obtain preformed folates and cannot synthesize folate. The inability of the parasite to utilize exogenous folates makes folate biosynthesis, a good drug target. Folate is synthesized from 3 basic building blocks, Antimalarial Therapy 371

GTP, p-aminobenzoic acid (PABA), and glutamate, in a pathway involving 5 enzymes. One of these enzymes, dihydropteroate synthese (DHPS), is inhibited by sulfa-based drugs. DHFR is a ubiquitous enzyme that participates in the recycling of folates by reducing dihydrofolate to tetrahydrofolate. The tetrahydrofolate is then oxidized back to dihydrofolate as it participates in biosynthetic reactions (e.g. thymidylate synthase). Inhibiting DHFR will prevent the formation of thymidylate and lead to an arrest in DNA synthesis and subsequent parasite death. Pyrimethamine and proguanil are the two most common DHFR inhibitors used as antimalarials. These drugs inhibit DHFR from the parasite to a greater degree than the host enzyme, and thus, show a selective toxicity towards the parasite.

Pharmacokinetics Sulfadoxine, sulfalene and pyrimethamine are highly bound to protein with relatively long mean elimination half-lives of around 180 h, 65 h and 95 h, respectively. All three drugs cross the placental barrier and are also detected in breast milk.

Resistance Status P. falciparum: The long half-life of sulfa drug-pyrimethamine combinations provides a potent selective pressure for parasite resistance in areas of high transmission, therefore, where ever drug has been in extensive use, significant resistance evolved within short time.13,16,17 There is no cross-resistance with the 4-aminoquinolines, mefloquine, quinine, halofantrine or the artemisinin derivatives. P. vivax: Combination is inherently less effective against P. vivax.1

Indications Chemotherapy: Sulfa drug-pyrimethamine combinations are effective against P. falciparum and have been successfully used in uncomplicated falciparum malaria in areas with resistance to chloroquine. However, with use resistance to these agents rapidly appears and they soon lose their utility. These drugs should be used in combination therapy with artemisinin derivatives only in areas where there is no significant resistance to these drugs. Sulfadoxine-pyrimethamine is the most widely used formulation; sulfalene- pyrimethamine has been largely used in the Indian subcontinent. Although comparative data is lacking; it is generally assumed that these two formulations are equipotent. Folic acid, even in physiological doses, can antagonize the action of sulfadoxine, hence, it has been suggested that folic acid supplements should be delayed for one week after sulfa drug-pyrimethamine treatment to avoid an inhibitory effect on antimalarial efficacy. Pyrimethamine-sulfadoxine should not be used for management of vivax malaria or for mixed infection. Chemoprophylaxis: Sulfa drug-pyrimethamine combinations are no longer recommended for chemoprophylaxis because of the risk of severe adverse reactions.18 372 Rational Antimicrobial Practice in Pediatrics

Use in Pregnancy Studies in Kenya and Malawi have shown that administration of a full adult treatment dose of sulfadoxine-pyrimethamine at the first attendance at an antenatal clinic during the second trimester of pregnancy and repeated once at the beginning of the third trimester is effective in clearing or preventing placental infection and peripheral parasitemia with P. falciparum and reducing the risk of low birth weight. Following these reports several national malaria control programs have adopted this intermittent regimen for the prevention of malaria during pregnancy.14,15,18 No teratogenic effects were ever noted with use of sulfa drug-pyrimethamine combinations for malaria treatment in pregnant women; while there is a theoretical risk of jaundice among premature babies born to mothers given sulfa drugs late in the third trimester; increased incidence of kernicterus has not been observed.1

Use in Lactating Women Both pyrimethamine and sulfadoxine are excreted in small amounts in breast milk. Diarrhea and rash have been reported in nursing infants exposed to sulfonamides through breast milk; however, these reports are rare, and more serious adverse reactions have not been documented. Thus, sulfonamide excretion in breast milk does not appear to pose a significant risk for most infants. Pyrimethamine is considered safe during breastfeeding.

Dosage Sulfadoxine-pyrimethamine and sulfalene-pyrimethamine are recommended as single dose therapy calculated as 1.25 mg/kg of pyrimethamine.

Side Effects Sulfa drug-pyrimethamine combinations are generally well tolerated when used at the recommended doses for malaria therapy; however, in a person allergic to sulfa drugs, serious hypersensitivity reactions involving skin could occur. Serious events usually occur following multiple doses, it is rare when drug is used in a single dose. Life-threatening events, like erythema multiforme (Stevens-Johnson syndrome) and toxic epidermal necrolysis, have been reported in 1 in 5000 to 1 in 8000 people taking the drug for weekly chemo- prophylaxis.19 The combination is, therefore, no longer recommended for prophylactic use.

Contraindications The use of sulfadoxine- or sulfalene-pyrimethamine combinations are contraindicated in persons with known hypersensitivity to sulfa drugs or pyrimethamine, in persons with severe hepatic dysfunction and in infants less than two months of life.

Formulations Formulations available are as follows: 1. Tablets containing 500 mg of sulfadoxine and 25 mg of pyrimethamine. Antimalarial Therapy 373

2. Syrup containing 250 mg of sulfadoxine and 12.5 mg of pyrimethamine. 3. Ampules containing 500 mg of sulfadoxine and 25 mg of pyrimethamine in 2.5 mL of injectable solution (Not available in our country).

Mefloquine Mefloquine is a 4-quinoline methanol chemically related to quinine.

Antimalarial Activity Mefloquine is a potent long-acting blood schizonticide active against P. falciparum resistant to 4-aminoquinolines and sulfa drug-pyrimethamine combinations. It is also highly active against P. vivax and, P. malariae and most probably P. ovale. It does not have gametocytocidal activity and is ineffective against the hepatic stages of malaria parasites.

Mechanism of Action Mechanism of action is same as that of chloroquine. Mefloquine binds hemin and there by foils parasite attempt to form hemozoin crystal.

Pharmacokinetics Mefloquine has a long elimination half-life, varying between 10 and 40 days in adults. Elimination half-life tends to be shorter in children and pregnant women. The pharmacokinetic parameters of mefloquine are changed in acute falciparum malaria; the drug reaches a higher serum levels, probably due to a contraction of the apparent volume of distribution.20

Resistance Status P. falciparum: Owing to its long elimination half-life and consequent prolonged sub therapeutic concentrations in the blood, the development of resistance is a likely occurrence especially in areas of high transmission. Since the late 1980s, resistance of P. falciparum to mefloquine has developed in South-East Asia. More than 50% of patients have recrudescences of parasitemia within 28 days after a dose of 15 mg/kg. The sensitivity of P. falciparum populations recrudescing after treatment with mefloquine is substantially reduced compared with the original population. P. falciparum resistance to mefloquine is also accompanied by cross-resistance to halofantrine and reduced sensitivity to quinine.21 Resistance to mefloquine is also being reported in India from various places including around Mumbai.

Indications Chemotherapy: Drug should be reserved for known or suspected uncomplicated chloroquine resistant falciparum malaria, sensitive to mefloquine and only as a companion drug with the artemisinin derivatives. In Thailand, introduction of combination therapy of mefloquine and artesunate significantly decreased mefloquine resistance that had been observed when mefloquine was used alone. 374 Rational Antimicrobial Practice in Pediatrics

Chemoprophylaxis: Mefloquine is drug of choice as chemoprophylactic agent for travelers to areas with significant risk of chloroquine-resistant falciparum malaria.

Dosages Treatment: 15 mg to 25 mg of mefloquine base per kg. For many years, the standard dose of mefloquine for treatment of uncomplicated malaria has been 15 mg/kg, however development of resistance forced to increase the dose to 25 mg/kg. The bioavailability of mefloquine considerably improves, if it is taken after food, drinking of water before drug administration also improves oral bioavailability.20 The higher dosage of mefloquine (25 mg/kg) is associated with greater drug intolerance, especially vomiting in young children. If vomiting occurs within one hour of drug intake, a full dose needs to be repeated. Vomiting after one hour does not require repeat therapy. Tolerability could substantially be improved by administrating drug as divided doses of 15 mg/kg and 10 mg/kg 8 hours apart.20 Chemoprophylaxis: 5 mg of mefloquine base per kg weekly, maximum 250 mg of base per week. To achieve an optimal efficacy chemoprophylaxis should at least be started 2–3 weeks before departure and continued for 4 weeks after return. Use in pregnancy: While mefloquine may be given with confidence for both chemoprophylaxis and treatment during the second and third trimesters of pregnancy, it should be avoided during the first trimester. Lactating women: Mefloquine is excreted in breast milk in small amounts; however, circumstantial evidence suggests that no adverse effects occur in breastfed infants whose mothers are taking mefloquine.

Side Effects Mefloquine has higher potential for adverse effects. Side effects comprises of: gastro- intestinal, neuropsychiatric, and cardiac problems. Gastrointestinal problems: Vomiting, diarrhea and abdominal pain may occur in some of the patients. Vomiting is three times more common with higher doses (25 mg/kg body weight), splitting the dose significantly reduces vomiting. Neuropsychiatric problems: These include affective disorders, anxiety disorders, hallucinations, sleep disturbances including nightmares and, in a few people, overt psychosis, toxic encephalopathy, convulsions and acute brain syndrome.22 Neuropsychiatric problems are higher in Caucasians and Africans compared to Asians.23 The frequency of neuropsychiatric adverse reactions is reported to be more common following mefloquine treatment than prophylactic use, and is proportional to the dose taken with a usual incidence of 1 in 15000.23 Cardiovascular effects: Bradycardia and sinus arrhythmia have been reported in certain patients treated with mefloquine. Antimalarial Therapy 375

Drug Interactions Concomitant administration of mefloquine with other related compounds such as quinine, quinidine and chloroquine may produce ECG abnormalities and increase the risk of convulsions. In general, mefloquine should not be administered within 12 hours of the last dose of quinine. The use of halofantrine after mefloquine causes significant lengthening of the QTc interval and has been linked with cardiac arrests in patients treated with both drugs. Halofantrine should, therefore, not be used in persons who have recently received mefloquine. Concerns were raised that coadministration of mefloquine, with drugs which are used to treat cardiovascular disease such as antiarrhythmic drugs, beta-adrenergic blocking agents and calcium channel blockers as well as antihistamines, tricyclic antidepressants and phenothiazines might contribute to the prolongation of the QTc interval. However, no evidence of such drug interaction has been reported to date and co-medication with such drugs is no longer contraindicated.

Contraindications The use of mefloquine is contraindicated in persons: with a history of allergy to mefloquine, with a history of severe neuropsychiatric disease, and receiving halofantrine treatment.

Formulations, Cost Considerations and Comparisons Tablets containing 274 mg of mefloquine hydrochloride, equivalent to 250 mg of mefloquine base are available. Because of its high cost, increasing prevalence of resistance and potentially serious side effects mefloquine is not a favored antimalarial drug as a single agent, its main use these days is as an add on drug with artemisinin compounds. It is however, the preferred drug for chemoprophylaxis for travelers visiting chloroquine resistant P. falciparum endemic areas.

Halofantrine Antimalarial Activity and Pharmacokinetics Halofantrine, a phenanthrene methanol has blood schizonticidal activity against all falciparum species, however, it is inactive against gametocytes or the hepatic stages of malaria parasites. Systemic absorption of halofantrine is erratic and unpredictable, however, it increases up to six-fold in the presence of fatty foods.24

Indications Therapy: It is active against P. falciparum infections that are resistant to chloroquine and to sulfa drug-pyrimethamine combinations. Early studies indicated that halofantrine was also active against some but not all isolates with reduced susceptibility to mefloquine. However, recent work indicates cross-resistance between mefloquine and halofantrine.25 Chemoprophylaxis: There are no data to support the use of halofantrine for malaria prophylaxis. 376 Rational Antimicrobial Practice in Pediatrics

Use in pregnancy: Preclinical studies in rodents have demonstrated toxicity in terms of increased frequency of postimplantation embryonic death and reduced fetal body weight; halofantrine should therefore be avoided during pregnancy.

Dosages Oral: 8 mg of halofantrine base per kg in three doses at 6-h intervals.

Side Effects Halofantrine has lot of side effects. Adverse effects include nausea, abdominal pain, diarrhea, pruritus and skin rashes. A serious problem with halofantrine use is prolongation of the QTc interval, patient may develop potentially fatal ventricular dysrhythmias.26,27 Complication is likely to occur if drug is taken in higher than recommended doses and in those who have also received mefloquine, or who were known to have pre-existing prolongation of the QTc interval.

Contraindications The use of halofantrine is contraindicated in: persons with a history of allergy to the drug, persons with pre-existing cardiac disease, persons with a family history of sudden death or of congenital prolongation of the QTc interval, persons who have received treatment with mefloquine in the previous 3 weeks, pregnant women, breastfeeding mothers and children under one year.

Formulations Halofantrine is available as tablets containing 250 mg of halofantrine hydrochloride equivalent to 233 mg of halofantrine base. Pediatric suspension containing 20 mg per mL is also available. Drug is unavailable in our country.

Cost Considerations and Comparisons In the present form halofantrine has no place in malarial treatment. Its high cost, variable bioavailability, cross-resistance to mefloquine and the fact that fatal cardiotoxicity has been reported in certain risk groups following standard therapy, precludes its uses as regular antimalarial.1 It may be used on an individual basis in patients known to be free from heart disease in areas where multiple drug resistance is prevalent and no other effective antimalarial is available.

Artemisinin Compounds Artemisinin (qinghaosu) is the antimalarial principle isolated from Chinese herb artemisia annua L. It is a sesquiterpene lactone with a peroxide bridge linkage. Artemisinin is poorly soluble in oil or water but the parent compound has yielded many derivatives like dihydroartemisinin, artemether, arteether, and artesunate, which have circumvented solubility problem.1 Antimalarial Therapy 377

Antimalarial Activity Artemisinin derivatives are very potent and most rapidly acting blood schizonticidal drugs. They act on all stages of the parasites of all species including trophozoites, schizonts and mature schizonts. Compounds are devoid of hypnozoitocidal action, but have considerable gametocytocidal activity against all Plasmodium species.

Mechanism of Action Chemical structure of Artemisinin compound contains a labile peroxide bridge. Hemozoin catalyzes the decomposition of this labile bridge. The process of decomposition generates free oxygen radicals, which are toxic to parasite membrane.1

Disposition All derivatives are metabolized to a common bioactive metabolite, dihydroartemisinin.

Resistance Status So far there is no confirmed in vivo evidence of resistance of P. falciparum to artemisinin and its derivatives however, in vitro, susceptibility of P. falciparum strains from the China- Laos People’s Democratic Republic and China-Myanmar border areas have indicated declining susceptibility of P. falciparum to artemisinin derivatives.28

Indications The antimalarial activity of artemisinin and its derivatives is extremely rapid and most patients show clinical improvement within 1–3 days of treatment, therefore, these drugs are recommended for both uncomplicated as well severe falciparum malaria.29-31 Though these compounds have excellent antimalarial activity, they are beset with problem of high recrudescence rate. Recrudescence rate is related to length of treatment and is unacceptably high when duration of therapy is lesser than 5 days particularly if drugs are used as monotherapy. Monotherapy with these drugs is therefore not recommended.29 Artemisinin compounds have been successfully used in combination with mefloquine, sulfadoxine-pyrimethamine and lumefantrine. As other effective antimalarial drugs are available these compounds are not recommended for treatment of malaria due to P. vivax, P. malariae or P. ovale but are especially indicated for mixed infection with P. falciparum and P. vivax. Chemoprophylaxis: There is no rationale at present for using artemisinin compounds for chemoprophylaxis. Use in pregnancy: Preclinical studies have consistently shown that artemisinin and its derivatives do not exhibit mutagenic or teratogenic activity, therefore, these compounds are drugs of choice for severe malaria and can be used for treatment of uncomplicated malaria during the second and third trimester of pregnancy in areas of multiple drug resistance. However, owing to lack of data, their use in the first trimester is yet not recommended. 378 Rational Antimicrobial Practice in Pediatrics

Side Effects Experience indicates that artemisinin and its derivatives are the least toxic of the antimalarial drugs, few significant adverse effects being associated with their use. Animal studies have demonstrated severe neurotoxicity following parenteral administration of very high doses of artemether or arteether.32 Such effects have not been observed with oral administration of any artemisinin derivative or with intravenous artesunate in extensive clinical trials in China, Myanmar, Thailand and Vietnam. In prospective studies involving more than 10,000 patients or in the more than two millions of persons who have received these drugs, till date there is no clinical evidence of serious neurotoxicity. Minor adverse effects may include headache, nausea, vomiting, abdominal pain, itching, drug fever and dark urine.

Contraindications There are no absolute contraindications to these drugs, however, due to lack of enough safety data, drugs should preferably be avoided during first trimester of pregnancy.

Formulations and Dosage Three artemisinin compounds: artesunate, artemether, and arteether are available in the Indian market.

Artesunate Formulations: Artesunate is available for use as oral tablet, intravenous injection and rectal suppository. Tablets contain 50 mg of sodium artesunate, while ampules for intramuscular or intravenous injection have 60 mg of sodium artesunate in 1 mL of injectable solution. Rectal capsules containing 100 mg or 400 mg of sodium artesunate are available in China but not in India. Dosage (Uncomplicated malaria): 4 mg/kg once a day for 3 days, plus mefloquine (15 mg or 25 mg of base per kg) as a single dose or split dose on the second and/or third day. Recent studies in Africa have demonstrated that combinations of artesunate (oral administration of 4 mg/kg daily for 3 days) plus a single dose of sulfadoxine- pyrimethamine on the first day are highly efficacious, although efficacy appears to be reduced in areas with pre-existing moderate levels of sulfadoxine-pyrimethamine resistance.32,33 Dosage (Severe malaria): 2.4 mg/kg by the intramuscular/intravenous route followed by 2.4 mg/kg at 12 and 24 h, then 2.4 mg/kg daily. Once the patient can swallow, the daily dose can be given orally as 4 mg/kg/day. If the second drug is clindamycin/ doxycycline treatment duration is 7 days. If the combination drug is SP/mefloquine 3 days treatment is adequate. Treatment from parenteral artesunate can also be shifted to oral artemether and lumefantrine combination. Antimalarial Therapy 379

Artemether Formulations: Artemether is an oil-soluble methyl ether derivative of dihydroartemisinin and available as ampules of injectable solution for intramuscular injection containing 80 mg in 1 mL. It is also available as an oral combination with lumefantrine. Dosage (Uncomplicated malaria): Given as artemether lumefantrine (1:6, 20 mg of artemether and 120 mg of lumefantrine) with artemether as 1.7 mg/kg/dose twice daily for 3 days. Dosage (Severe malaria): 3.2 mg/kg by the intramuscular route as a loading dose on the first day, followed by 3.2 mg/kg daily. It may then be shifted to oral combination of 3 days of artemether lumefantrine as discussed earlier.

Arteether

Formulation: Arteether is the oil-soluble ethyl derivative of dihydroartemisinin and is available as ampules containing 150 mg of arteether in 2 mL of injectable solution in our country.34 Dosage: 3 mg/kg per day by the intramuscular route for 3 days.

Primaquine36-41 Antimalarial Activity Primaquine is an 8-aminoquinoline compound. Drug is highly active against hypnozoites of the relapsing malarial parasites, P. vivax and P. ovale and gametocytes of all malaria species.

Mechanism of Action Primaquine is supposed to damage parasite mitochondria. Drug is believed to compete with dihydro-orotate dehydrogenase enzyme, which is involved in pyrimidine synthesis.1

Pharmacokinetics Primaquine is readily absorbed when taken, peak plasma concentrations occur within 1–3 hours. Primaquine is rapidly metabolized in the liver and only a small amount is excreted unchanged in the urine, suggesting extensive intrahepatic recycling.

Resistance Status P. vivax: There are geographical variations in the sensitivity of hypnozoites of P. vivax to primaquine. The parasites from the southern regions of South-East Asia and Oceania are the least susceptible while P. vivax from India seems to be the most sensitive.36 Chesson strain of P. vivax is relatively resistant to primaquine and requires longer treatment courses.41 The antirelapse effect of primaquine is related to the total dose rather than the duration of treatment. 380 Rational Antimicrobial Practice in Pediatrics

Indications Antirelapse treatment in P. vivax and P. ovale infections: Primaquine may be given concurrently with an active blood schizonticide, such as chloroquine, from the first day of treatment for the prevention of relapse. 0.3 mg/kg body weight for 14 days is mandatory for this purpose; previously recommended 5-day treatment with primaquine was derived largely on the basis of empirical views, and exerts little or no antirelapse activity.37,38 In areas with primaquine resistance higher daily doses of 0.5 or 0.75 mg/kg/day for 2 weeks may be used. When possible, G6PD deficiency should be excluded before standard therapeutic doses of primaquine are given as antirelapse therapy. Patients should be instructed to stop treatment and seek medical advice if they have abdominal pain, become weak or pale, or notice darkening of the urine. Adherence to these antirelapse regimens is generally poor. Gametocytocide: Gametocytocidal treatment is given with an objective to eliminate residual gametocytes after effective blood schizonticidal treatment; it is given in falciparum malaria when quinine/artemisinin derivatives are used for therapy. A single dose of 0.75 mg/kg is sufficient for this purpose. Primaquine may be given concurrently with the schizonticidal drug but should not be administered until the condition of the patient stabilizes. Chemoprophylaxis: Primaquine also has a causal chemoprophylactic activity but, until recently this property had not been evaluated due to the prevailing view that primaquine was too toxic for routine chemoprophylaxis. Recent studies in Iran, Java and Kenya have now shown that daily doses of 0.5 mg/kg can be effective in protecting both adults and children against falciparum and vivax infections.39-41 Use in pregnancy: Fetus is relatively deficient in G6PD hence primaquine is contraindicated during pregnancy.

Side Effects GI disturbances: May cause anorexia, nausea, vomiting, abdominal pain and cramps. These symptoms are dose related and are relatively rare at therapeutic doses. Gastric intolerance can be minimized by administering the drug with food. Hematological disturbances: Primaquine is known to cause methemoglobinemia, leukopenia and suppression of myeloid series. In higher doses primaquine causes severe suppression of bone marrow. Primaquine does not normally cause granulocytopenia at the doses recommended for malaria therapy. Primaquine can induce severe hemolysis in G6PD deficient person. It is usually self-limiting but blood transfusions may be necessary in severe cases. Over dosage: Gastrointestinal symptoms, weakness, methemoglobinemia, cyanosis, hemolytic anemia, jaundice and bone marrow depression may occur with overdosage. There is no specific antidote and treatment is symptomatic. Antimalarial Therapy 381

Contraindications Primaquine is contraindicated in pregnancy, lactating mothers and in infants below 1 year and in individuals with G 6PD deficiency. The drug is also contraindicated in conditions predisposing to granulocytopenia, including active rheumatoid arthritis and lupus erythematosus.

Drug Interactions Primaquine should not be administered with any other drug that may induce hematological disorders, like sulfadoxine and pyrimethamine, chloramphenicol.

Formulations Drug is available only in tablet formulation containing 2.5 mg, 7.5 mg and 15 mg of drug.

Tafenoquine Tafenoquine is a 5-phenoxy derivative of primaquine. It has a very long elimination half-life (14 days as compared to 6 hours of primaquine). The drug is a vast improvement over parent compound: it is seven times more active as hypnozoitocide, 14 times more effective as causal prophylactic, and 100 times more potent as blood schizontocide. Drug is better tolerated than primaquine but like parent compound does cause hemolysis in a G6PD deficient person. Tafenoquine has a great potential as antimalarial drug.

Tetracycline Antimalarial Activity Tetracycline is a broad-spectrum antimicrobial drug that has potent but slow action against the asexual blood stages of all Plasmodium species. It is also effective against the primary intrahepatic stages of P. falciparum.

Pharmacokinetics Absorption of tetracycline from the gut is poor; it is further decreased, by milk and milk products, as well as aluminum, calcium, magnesium and iron salts.

Indications Tetracycline can be used in combination with quinine in the treatment of falciparum malaria to reduce the risk of recrudescence and development of resistance; however, because of its slow action it should not be used alone for therapy. It is not used for chemoprophylaxis. Tetracycline is contraindicated in pregnancy, lactating mothers and children less than 8 years old as it impairs skeletal calcification in the fetus and can result in abnormal osteogenesis and hypoplasia of dental enamel. 382 Rational Antimicrobial Practice in Pediatrics

Dosages Quinine 10 mg of salt per kg three times daily for 7 days plus tetracycline 250 mg four times daily for 7 days (not in children under 8 years of age and not in pregnancy).

Side effects Gastrointestinal: Side effects include epigastric distress, abdominal discomfort, nausea, vomiting and diarrhea. These are dose-related and can be alleviated by giving smaller doses more often. Esophageal ulceration can be prevented by taking drug with food and by consuming copious amount of water. Bone and teeth: Ossification disorders, transient depression of bone growth, discoloration of teeth and enamel dysplasia, may occur in children. Besides, drug could also cause candidiasis, phototoxicity, angioedema, and aggravation of renal insufficiency.

Formulations Drug is available as capsules and tablets containing 250 mg of tetracycline hydrochloride, equivalent to 231 mg of tetracycline base.

Doxycycline Doxycycline is derived from oxytetracycline, and has an identical spectrum of activity. Doxycycline is readily and almost completely absorbed from the gastrointestinal tract and absorption is not significantly affected by the presence of food in the stomach or duodenum. Milk and milk products decrease drug absorption. Doxycycline, like tetracyclines, is used as an add-on drug with quinine or chloroquine. In contrast to tetracycline, doxycycline can also be used for chemoprophylaxis.42 Adverse effects include gastrointestinal irritation, phototoxic reactions (increased vulnerability to sunburn), transient depression of bone growth and discoloration of teeth and permanent enamel hypoplasia. As with tetracycline, esophageal ulceration can be prevented if the oral dose is washed down with copious amounts of water. Other gastrointestinal symptoms can be reduced if doxycycline is taken with a meal. Milk products must be avoided since they reduce absorption. Doxycycline is contraindicated in pregnancy and in nursing mothers. The dose is Quinine 10 mg salt per kg three times daily for 7 days plus doxycycline 3.5 mg/kg body weight for 7 days (not in children under 8 years of age). The dose for prophylaxis is 100 mg per day for adults and 1.5 mg/kg/day for children to be started 1 week before departure and continued for 4 weeks after return.

Clindamycin Antimalarial Activity Clindamycin is a semi-synthetic antibiotic derived from lincomycin. Like tetracycline, it is an efficient but slow acting blood schizonticide. Clindamycin has excellent oral bioavailability. Antimalarial Therapy 383

Indications Along with tetracycline and doxycycline, clindamycin provides another option as an add-on drug with an advantage that it could be used in children and pregnant women.43,44 It should not be used alone for the treatment of malaria because of its slow action.

Dosage Quinine 10 mg of salt per kg three times daily for 7 days plus clindamycin 20 mg/ kg/day (1200 mg/day) twice daily for 7 days. Clindamycin should be administered with food and copious amounts of water.

Side Effects Nausea, vomiting, abdominal pain or cramps and diarrhea may occur with clindamycin uses. Pseudomembranous colitis, a potentially fatal condition caused by Clostridium difficile toxin, may develop in some cases.

Contraindications Clindamycin is contraindicated in patients with hypersensitivity to clindamycin or lincomycin, in those with a history of gastrointestinal disease, particularly colitis and those with severe hepatic or renal impairment.

Formulations Clindamycin is available as capsules containing 75 mg, 150 mg or 300 mg of clindamycin base as hydrochloride.

Malarone (Atovaquone and Proguanil) Antimalarial Activity Atovaquone has a weak antimalarial activity against blood stages of P. falciparum parasite (trophozoite, gametocytes). Used alone, the drug has very high recrudescence rate. However, it has a synergistic effect with proguanil and this combination is highly efficacious against P. falciparum including strains that are resistant to chloroquine and mefloquine.47,49 Drug has no effect against hypnozoites.

Mechanism of Action Atovaquone inhibits mitochondrial respiration.1

Pharmacokinetics Atovaquone is absorbed slowly from the gastrointestinal tract and is subject to wide individual variability. Absorption is greatly increased if the drug is taken with a fatty meal. 384 Rational Antimicrobial Practice in Pediatrics

Indications Atovaquone is used for the treatment of uncomplicated multi-drug resistant falciparum malaria only in combination with proguanil (Malarone).1,49,50 Dose for adults is 1 g of atovaquone plus 400 mg of proguanil (4 tablets) daily for 3 days. Atovaquone reduced fetal body weight in rabbits; hence, it should not be given in pregnancy.1 Atovaquone and proguanil is also used for chemoprophylaxis of malaria in areas with multi-drug resistant P. falciparum such as the Thai-Myanmar border. It can also be used as an alternative for mefloquine and doxycycline in case these drugs are not tolerated. Prophylaxis should be started 1 day prior to departure and continued for 7 days after return. For adults the dose is 250 mg of atovaquone plus 100 mg of proguanil (one tablet) daily.

Side Effects Adverse effects include abdominal pain, nausea, vomiting, diarrhea, headache, anorexia coughing and maculopapular rash.

Drug Interactions Coadministered atovaquone increases rifampicin levels while its own concentration decreases. It also increases concentration of zidovudine and didanosine.

Formulations and Availability Film-coated tablets containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride (adult strength). Pediatric tablets contain 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride. Drug is unavailable in our country.

 CHOICE OF ANTIMALARIAL THERAPY (TABLE 1) Uncomplicated Malaria Treatment Objective53 The objective of treatment in uncomplicated malaria is to cure infection and hence, prevent morbidity and progression to severe disease. The public health goal is to reduce transmission of infection to others and reduce the infectious reservoir. An equally important secondary goal is to prevent emergence of resistance to antimalarials. Speed of response, adverse effect profile and tolerability of medications are also important issues.

Empirical therapy for uncomplicated malaria The National Malaria Eradication Program recommends presumptive diagnosis of malaria in any case of fever, collection of blood smears and administration of initial dose of chloroquine (4 tablets in adults and 10 mg/kg in children) to all patients pending reports of blood smears.54 Therapy is completed if smears are positive. In high-risk areas full dose, i.e. 25 mg/kg of chloroquine or 10 tablets are offered as presumptive therapy. There are considerable drawbacks in this approach. It is interesting to note that in the Antimalarial Therapy 385

TABLE 1 Therapy of malaria Situation Treatment Uncomplicated P. vivax malaria Chloroquine (10 mg/kg of base loading, 5 mg/kg 6 hours later and then 5 mg/kg for next two days, total dose 25 mg/ kg, max total dose is 1500 mg of base) with primaquine (0.3 mg/kg/day for 14 days) Uncomplicated P. falciparum Chloroquine as above with single gametocidal dose of malaria in areas where parasite primaquine (0.75 mg/kg) is sensitive to chloroquine Uncomplicated P. falciparum Artesunate (4 mg/kg/day, max daily dose 200 mg) for three malaria in areas of chloroquine days with SP (1.25 mg/kg of pyrimethamine, maximum dose is resistance or where resistance 75 mg of pyrimethamine) on day 1 status is unknown Uncomplicated P. falciparum Option 1: Artesunate (4 mg/kg/day) for three days with malaria in areas with resistance mefloquine 25 mg/kg of base on last day (split into two doses to chloroquine and SP 15 mg/kg (max dose is 1000 mg) and 10 mg/kg (max dose is 500 mg) 8 hours apart OR artemether lumefantrine with dose of artemether as 1.7 mg/kg/dose twice daily for 3 days OR Option 2: Quinine (10 mg/kg of salt three times a day, max daily dose is 1800 mg) for 7 days AND SP (1.25 mg/kg of pyrimethamine) OR doxycycline (3.5 mg/kg/day for 7 days, not in children below 8 years) OR tetracycline (4 mg/kg/dose, max 250 mg 4 times daily, for 7 days, not in children below 3 years) OR clindamycin (10 mg/kg twice a day, max daily dose 1200 mg for 7 days)

Primaquine single dose 0.75 mg/kg should be added to either regime for gametocidal effects Severe falciparum malaria Option 1: IV artesunate 2.4 mg/kg loading dose and then 2.4 mg/kg 12 hours later and then once oral intake is possible a) 4 mg/kg daily for total 7 days with doxycycline/ clindamycin for 7 days OR b) Switch to artesunate combination therapy as for uncomplicated malaria. (4 mg/kg of artesunate for 3 days) with SP/mefloquine/lumefantrine. Avoid mefloquine if had CNS symptoms in the beginning.

Option 2: IV quinine 20 mg/kg of salt loading and then 10 mg/kg 8 hourly. Switch to oral once possible to complete 7 days therapy. Add second drug doxycyline/ clindamycin/ SP 386 Rational Antimicrobial Practice in Pediatrics first half of 2006, out of 27.35 million blood smear examination throughout the country the slide positivity rate (SPR) was found to be only 1.3%.54 Extrapolating from these data it is evident that the use of presumptive treatment of malaria has the potential for facilitating resistance by greatly increasing the number of patients who are treated unnecessarily. Further complete and successful antimalarial therapy is possible only when the parasite species are known. Hence, all efforts should be made to establish a diagnosis of malaria by microscopic or rapid antigen detection methods prior to starting therapy. Even if the first smear is negative, a second smear/rapid antigen tests should be requested for 6–12 hours later and all other causes of fever should be excluded. In situations where facilities for smear examination are not available, bedside rapid tests may be used or atleast a clinical algorithmic approach for diagnosis of malaria should be followed.55

Therapy of uncomplicated vivax malaria55 For uncomplicated vivax malaria recommended therapy is oral chloroquine in regimes detailed earlier. Chloroquine should not be given empty stomach and fever should be brought down before administration of chloroquine. If vomiting occurs within 45 minutes of chloroquine administration the dose should be repeated after giving domperidone/ other antiemetics. This should be followed by primaquine 0.3 mg/kg/day for 14 days for radical cure. In areas with resistance to primaquine or where relapses have occurred despite standard doses, higher doses of 0.5–0.75 mg/kg should be given. Screening for G6PD deficiency is advisable prior to starting primaquine and close supervision is needed to detect any complication. In case of borderline G6PD deficiency primaquine can be given as a weekly dose of 0.6–0.8 mg/kg for 6 weeks. Primaquine should not be given to pregnant women, lactating women and infants.

Therapy of uncomplicated falciparum malaria53-55 Therapy has been complicated by widespread resistance in P. falciparum. Chloroquine resistance in India is widespread. High treatment failure (both early and late treatment failure) to chloroquine has been demonstrated in 241 PHC’s in 51 districts of 19 states in the country. Resistance to SP is slowly emerging and has been demonstrated in 12 PHC’s from districts of 7 states. There are pockets of mefloquine resistance as well. Resistance is more florid in the North Eastern States of India across the international border. The WHO now advocates combination therapy for treatment of uncomplicated falciparum malaria. Antimalarial combination therapy (ACT) is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and thus unrelated biochemical targets in the parasite. Drug combinations such as sulfadoxine- pyrimethamine, sulfalene-pyrimethamine, proguanil-dapsone, chlorproguanil-dapsone and atovaquone-proguanil have linked drug targets and not considered as ACT. The rationale for combining antimalarials with different modes of action is two-fold: (1) the combination is often more effective; and (2) in the event that a mutant parasite that is resistant to one of the drugs arises de novo during the course of the infection, the parasite will Antimalarial Therapy 387 be killed by the other drug. This mutual protection is thought to prevent or delay the emergence of resistance. To realize the two advantages, the partner drugs in a combination must be independently effective. The possible disadvantages of combination treatments are the potential for increased risk of adverse effects and the increased cost. Artemisinin and its derivatives are preferred as combination therapy agents as they produce rapid clearance of parasitemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10,000 in each asexual cycle, which is more than other current antimalarials (which reduce parasite numbers 100- to 1000- fold per cycle). Artemisinin and its derivatives are eliminated rapidly. When given in combination with rapidly eliminated compounds (tetracyclines, clindamycin), a 7-day course of treatment with an artemisinin compound is required; but when given in combination with slowly eliminated antimalarials, shorter courses of treatment (3 days) are effective. In 3-day ACT regimens, the artemisinin component is present in the body during only two asexual parasite lifecycles (each lasting 2 days, except for P. malariae infections). This exposure to 3 days of artemisinin treatment reduces the number of parasites in the body by a factor of approximately one hundred million (104 × 104 = 108). However, complete clearance of parasites is dependent on the partner medicine being effective and persisting at parasiticidal concentrations until all the infecting parasites have been killed. Thus, the partner compounds need to be relatively slowly eliminated. As a result of this, the artemisinin component is “protected “ from resistance by the partner medicine provided it is efficacious and the partner medicine is partly protected by the artemisinin derivative. It has been shown in numerous RCT’s that artemisinin based combination therapy significantly reduces treatment failure, recrudescence and gametoctye carriage as compared to monotherapy with amodiaquine, mefloquine and SP. Courses of ACTs of 1–2 days are not recommended; they are less efficacious, and provide less protection of the slowly eliminated partner antimalarial. Non-artemisinin based combination therapies (chloroquine and SP, amodiaquine and SP) are inferior to artemisinin based combination therapies and not recommended. Various options for artemisinin based combination therapy include artemether- lumefantrine, artesunate-mefloquine, artesunate-amodiaquine and artesunate-SP. The choice depends on the prevalence of resistance to the partner drug. Therapy is likely to succeed only if the 28-day cure rate to monotherapy with the partner drug exceeds 80%. As per the national program chloroquine is recommended as the first line therapy for falciparum malaria in areas where the parasite is chloroquine sensitive. Where resistance to chloroquine has been documented artesunate (4 mg/kg for 3 days) with SP (1.25 mg/kg of pyrimethamine on day 1) is recommended. Though the options for areas with SP resistance have not been addressed by the program a combination of artesunate- mefloquine (25 mg/kg split into two doses 15 mg/kg and 10 mg/kg on the last day) or artemether lumefantrine is reasonable in these areas. The other option for areas of SP resistance is oral quinine for 7 days with SP/tetracycline/clindamycin but compliance rates are poor due to side effects. 388 Rational Antimicrobial Practice in Pediatrics

It must be remembered that efficacy of the partner drug of artemisinin is vital for ACT to succeed. If partner drugs of artemisinin compounds continue to be available and used as monotherapy as they are today, there will compromise the effectiveness of ACT due to increase in resistance to partner drug.

Therapy of uncomplicated mixed malaria Therapy should be as for uncomplicated falciparum malaria with artesunate-mefloquine or artemether lumefantrine. These regimes may be associated with high recrudescence rates for vivax malaria. Dihydroartemisinin piperaquine is another antimalarial drug combination with excellent activity against P. vivax and is awaited. Quinine and SP containing regimes should be avoided as it is inherently less active against P. vivax. Radical therapy with primaquine for 14 days must be given.

Complicated or Severe Malaria Treatment Objectives53 The main objective is to prevent the patient from dying, secondary objectives are prevention of recrudescence, transmission or emergence of resistance and prevention of disabilities.

Empirical Therapy35 The outcome of severe malaria depends on rapidity with which treatment is instituted. Hence, if clinically suspected, the first dose of antimalarial should be given pending laboratory reports. However, all efforts should be made to confirm the diagnosis by repeated blood smear examinations and or rapid antigen detection tests.

Specific Antimalarial Therapy53,55,56 Two options are available: parenteral quinine or artemisinin derivatives. Parenteral chloroquine is not recommended. Artemisinin derivatives are easier to adminster as compared to quinine and equivalent in cost. Several randomized controlled trials have compared efficacy of quinine with artemisinin derivatives. A cochrane meta-analysis of these trials showed that artemisinin derivatives were overall only marginally more effective than quinine in reducing mortality from severe malaria. Side effects were similar with both agents. However, in areas where quinine resistance was widespread such as South-East Asia, the artemisinin derivatives were distinctly better. In areas with no quinine resistance such as Africa, both agents performed equally well. It has been recently proposed that the cochrane review probably failed to show a significant benefit with artemisinins as artemether was the main derivative tested and not artesunate. Recent trials have shown both IV and IM artesunate to be superior to IM artemether in terms of pharmacokinetics and clinical outcome. The SEAQUAMAT study that enrolled 1461 patients including 202 children from India, Bangladesh, Myanmar and Indonesia demonstrated significantly lower mortality with artesunate (15%) as compared Antimalarial Therapy 389 to quinine (22%). Based on these studies, the WHO recommends artesunate as the drug of choice for severe malaria in adults. However in children especially from high transmission areas, as per the WHO either artesunate/artemether/quinine may be used given the lack of evidence of benefit of one over the other therapy. Extrapolating this data to the Indian setting either quinine or artesunate may be used in the management of severe malaria in children. The regimens have been detailed earlier. This recommendation may change in future if more evidence in favor of artesunate becomes available. The use of artesunate derivatives over quinine should definitely be considered when facilities for controlled IV administration of quinine are not available, when there are contraindications to quinine use or when there is suboptimal parasitological response to quinine. Combination therapy of artesunate and quinine is of no added benefit and should be avoided.

Supportive Therapy Supportive therapy and management of complications are important components of management of severe malaria but are not in scope of this chapter.

CONCLUSIONS Management of malaria is a dynamic topic with changing resistance patterns, changing policies and availability of new drugs. All efforts should be made towards establishing a definitive diagnosis, refraining from unnecessary empiric therapy and judiciously using drugs as per recommendations to prevent development of drug resistance.

 REFERENCES 1. Warrell DA, Giles HM. Treatment and Prevention of Malaria. Essential Malariology, 4th edition. London: Edward Arnold. 2000:268–312. 2. Murphy GS, et al. Vivax malaria resistant to treatment and prophylaxis with chloroquine. Lancet. 1993;341:96–100. 3. Schuurkamp GJ, et al. Chloroquine-resistant Plasmodium vivax in Papua New Guinea. Trans R Soc Trop Med Hyg. 1992;86:121–2. 4. Rieckmann KH, Davis DR, Hutton DC. Plasmodium vivax resistance to chloroquine? Lancet. 1989;2:1183–4. 5. Cot M, et al. Increase in birth weight following chloroquine chemoprophylaxis during the first pregnancy: results of a randomized trial in Cameroon. Am J Trop Med Hyg. 1995;53:581–5. 6. Sexton JD, et al. Parasitologic and clinical efficacy of 25 and 50 mg/kg of chloroquine for treatment of Plasmodium falciparum malaria in Rwandan children. Am J Trop Med Hyg. 1988;38:237–43. 7. Bruce-Chwatt LJ, et al. Chemotherapy of malaria, revised 2nd edition. World Health Organization, Geneva, 1987. 8. Nevill CG, et al. A comparison of amodiaquine and chloroquine in the treatment therapy of falciparum malaria in Kenya. East Afr Med J. 1994;71:167–70. 9. Olliaro P, et al. Systematic review of amodiaquine treatment in uncomplicated malaria [See Comments]. Lancet. 1996;348:1196–201. 10. Neftel KA, et al. Amodiaquine induced agranulocytosis and liver damage. Br Med J (Clinical research edition). 1986;292:721–3. 390 Rational Antimicrobial Practice in Pediatrics

11. Phillips-Howard PA, Wood D. The safety of antimalarial drugs in pregnancy. Drug Safety. 1996;14:131– 45. 12. Practical chemotherapy of malaria. Report of a WHO Scientific Group. Geneva, World Health Organization, 1990 (WHO Technical Report Series, No. 805). 13. Watkins WM, Mosobo M. Treatment of Plasmodium falciparum malaria with pyrimethamine- sulphadoxine: selective pressure is a function of long elimination half-life. Trans R Soc Trop Med Hyg. 1993;87:75–8. 14. Parise ME, et al. Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. Am J Trop Med Hyg. 1998;59:813–22. 15. Verhoeff FH, et al. An evaluation of the effects of intermittent sulfadoxine-pyrimethamine treatment in pregnancy on parasite clearance and risk of low birthweight in rural Malawi. Ann Trop Med Parasitol. 1998;92:141–50. 16. Ronn AM, et al. High level of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine in children in Tanzania. Trans R Soc Trop Med Hyg. 1996;90:179–81. 17. Onyiorah E, et al. Early clinical failures after pyrimethamine-sulfadoxine treatment of uncomplicated malaria. Trans R Soc Trop Med Hyg. 1996;90:307–8. 18. Schultz LJ, et al. The efficacy of antimalarial regimens containing sulfadoxine-pyrimethamine and/or chloroquine in preventing peripheral and placental Plasmodium falciparum infection among pregnant women in Malawi. Am J Trop Med Hyg. 1994;51:515–22. 19. Miller KD, et al. Severe cutaneous reactions among American travelers using pyrimethamine-sulfa- doxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg. 1986;35:451–8. 20. Karbwang J, White NJ. Clinical pharmacokinetics of mefloquine. Clin Pharmacokinet. 1990;19:264– 79. 21. Fontanet AL, et al. High prevalence of mefloquine-resistant falciparum malaria in eastern Thailand. Bull World Health Organ. 1993;71:377–83. 22. Havaldar PV, Mogale KD. Mefloquine induced psychosis. Pediatr Infect Dis J. 2000;19:166–7. 23. Weinke T, et al. Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg. 1991;45:86–91. 24. Milton KA, et al. Pharmacokinetics of halofantrine in man: effects of food and dose size. Br J Clin Pharmacol. 1989;28:71–7. 25. Nateghpour M, et al. Development of halofantrine resistance and determination of cross-resistance patterns in Plasmodium falciparum. Antimicrob Agents Chemother. 1993;37:2337–43. 26. Nosten F, et al. Cardiac effects of antimalarial treatment with halofantrine. Lancet. 1993;341:1054–6. 27. Monlun E, et al. Cardiac complications of halofantrine: a prospective study of 20 patients. Trans R Soc Trop Med Hyg. 1995;89:430–3. 28. McIntosh HM, Olliaro P. Artemisinin derivatives for treating uncomplicated malaria. Cochrane Database System Review. 2000;CD000256(2). 29. McGready R, et al. Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg. 1998;92:430–3. 30. Bich NN, et al. Efficacy and tolerance of artemisinin in short combination regimens for the treatment of uncomplicated falciparum malaria. Am J Trop Med Hyg. 1996;55:438–43. 31. De Vries PJ, Dien TK. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs. 1996;52:818–36. 32. Ha V, et al. Severe and complicated malaria treated with artemisinin, artesunate or artemether in viet nam. Trans R Soc Trop Med Hyg. 1997;91:465–7. 33. Nosten F. Artemisinin: large community studies. Trans R Soc Trop Med Hyg. 1991;88(Suppl. 1):45–9. 34. Asthana OP, et al. Current status of the artemisinin derivatives in the treatment of malaria with a focus on arteether. Journal of Parasitic Diseases. 1997;21:112. 35. World Health Organization. Severe falciparum malaria. Trans R Soc Trop Med Hyg. 2000;94 (Suppl. 1): S1–90. 36. Singh J, et al. Antirelapse treatment with primaquine. Indian J Malariol. 1954;8:127–36. 37. Gogtay NJ, et al. Efficacies of 5-and 14-day primaquine regimens in the prevention of relapses in Plasmodium vivax infections. Ann Trop Med Parasitol. 1999;93:809–12. Antimalarial Therapy 391

38. Rowland M, Durrani N. Randomized controlled trials of 5- and 14-days primaquine therapy against relapses of vivax malaria in an Afghan refugee settlement in Pakistan. Trans R Soc Trop Med Hyg. 1999;93:641–3. 39. Fryauff DJ, et al. Randomized placebo-controlled trial of primaquine for prophylaxis of falciparum and vivax malaria. Lancet. 1995;346:1190–3. 40. Weiss WR, et al. Daily primaquine is effective for prophylaxis against falciparum malaria in Kenya: comparison with mefloquine, doxycycline, and chloroquine plus proguanil [see comments]. J Infect Dis. 1995;171:1569–75. 41. Wilairatana P, et al. Efficacy of primaquine regimens for primaquine-resistant Plasmodium vivax in Thailand. Am J Trop Med Hyg. 1999;61:973–7. 42. Anderson SL, et al. Successful double-blinded, randomised, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya. Clin Infect Dis. 1998;26:146–50. 43. Vaillant M, et al. Therapeutic efficacy of clindamycin in combination with quinine for treating uncomplicated malaria in a village dispensary in Gabon. Trop Med Int Health. 1997;2:917–9. 44. Pukrittayakamee S, et al. Therapeutic responses to quinine and clindamycin in multidrug resistant falciparum malaria. Antimicrob Agents Chemother. 2000;44: 2395–8. 45. De Vries PI, et al. Short course of azithromycin/artesunate against falciparum malaria: no full protection against recrudescence. Trop Med Int Health. 1999;4:407–8. 46. Taylor WR, et al. Malaria prophylaxis using azithromycin: a double-blind, placebo controlled trial in Irian Jaya, Indonesia. Clin Infect Dis. 1999;28:74–81. 47. Looareesuwan S, et al. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg. 1996;54:62–6. 48. Baird K, et al. Randomised, double-blind, placebo controlled evaluation of Malarone for prophylaxis of P. vivax and P. falciparum in non-immune transmigrants to Irian Jaya. ASTM Standardization News, Houston, TX, 2000. 49. Radloff PD, et al. Atovaquone and proguanil for Plasmodium falciparum malaria. Lancet. 1996;347:1511–4. 50. Sukwa TY, et al. A randomised, double-blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. Am J Trop Med Hyg. 1999;60:521–5. 51. White NJ, van Vugt M, Ezzet F. Clinical pharmacokinetics and pharmacodynamics of artemetherlumefantrine. Clin Pharmacokinet. 1999;37:105–25. 52. Van Vugt M, et al. Randomized comparison of artemether-benflumetol and artesunate-mefloquine in treatment of multidrug-resistant falciparum malaria. Antimicrob Agents Chemother. 1998;42:135–9. 53. World Health Organization. WHO guidelines for treatment of malaria. Available from URL: http:// www.who.int/malaria/docs/TreatmentGuidelines2010.pdf. Accessed on October, 2011. 54. National Vector Borne Disease Control Program. Malaria. Accessed from URL: www.namp.gov.in. Accessed on Oct 4, 2006. 55. Diagnosis and management of malaria in children. Indian Pediatr 2005; 42:1101–4. 56. McIntosh HM, Olliaro P. Artemisinin derivatives for treating severe malaria (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. 392 Rational Antimicrobial Practice in Pediatrics 3232 Antimicrobial Therapy in Visceral Leishmaniasis (Kala-azar) Nigam Prakash Narain

 INTRODUCTION Kala-azar (visceral leishmaniasis—VL) is a disease of the reticuloendothelial system seen in tropical countries caused by members of the Leishmania donovani complex (a protozoan parasite) and transmitted by the bite of a tiny 2 to 3 millimeter-long insect vector, the phlebotomine sand-fly. The disease is characterized by irregular bouts of fever, substantial weight loss, hepatosplenomegaly, and anemia (occasionally serious). If left untreated, the fatality rate can be as high as 100% within 2 years. The disease remains a significant problem in the developing world. In India, most of the cases of kala-azar are reported from Bihar, Jharkhand, UP and West Bengal. Widespread resistance to standard therapy with antimony compounds has made the treatment of kala-azar extremely complex. However, many new advances holding great promise have been made in the treatment of kala-azar in the recent years.

 ANTILEISHMANIAL DRUGS Antimony Compounds For more than 60 years, pentavalent antimony compounds meglumine antimoniate and sodium stibogluconate had been the cornerstone of treatment for kala-azar worldwide. Sodium Stibogluconate (antimony 100 mg/mL) had been used widely in children with Kala-azar in a dose of 20 mg/kg daily for 30 days with initial response rates > 90–95%.1 This drugs is given IM once daily. Most children improved and become afebrile within less than a week, whereas hematological restoration and significant subsidence of splenomegaly usually occurred within 2 weeks.2 Antimicrobial Therapy in Visceral Leishmaniasis (Kala-azar) 393

There were certain disadvantages to this drug, namely parenteral administration, long duration of therapy and frequent adverse effects. The main adverse effects are ECG changes, increased transaminases, chemical pancreatitis, and pneumonitis.3, 4 ECG changes are related to the total daily dose and the total duration of therapy. The most common changes are flattening/ inversion of T-wave and prolongation of the Q-T interval. ECG monitoring should be done before the start of therapy and at frequent intervals during the course of therapy. If significant prolongation of QTc interval occurs (QTc > 0.50 sec), sodium stibogluconate should be discontinued. ECG changes, notably alterations in T wave amplitude may be expected in the majority of patients given sodium stibogluconate; these appear to be reversible on cessation of therapy and are not of serious significance. Systemic toxicity normally relates to the total dose administered and is usually reversible. Severe adverse effects remain rare. In order to decrease the adverse effects observed with this drug, efforts are on to develop lipid formulations of antimonials. A novel liposome based meglumine antimonial formulation appears to be a promising product for the treatment of kala-azar.5 However, in India and particularly in Bihar, parasite resistance to antimony compounds has emerged as a major problem. The reported prevalence of drug resistance to antimony compounds in Bihar is over 65%.6

Pentamidine A diamidine derivative, pentamidine isoethionate has been used in the treatment of antimonial resistant kala-azar. It is given in a dose of 4 mg/kg, thrice weekly IV/IM (intravenous/intramuscular) for 6 weeks. However the drug has many significant and some irreversible adverse effects including nephrotoxicity, bone marrow suppression, hypoglycemia, diabetes mellitus, pancreatitis and arrhythmia related sudden death. The drug achieves poor response rates, approximately 75% when used as a second line drug in antimonial resistant cases; this has been a major factor in its limited use in the treatment of kala-azar.

Amphotericin B It is the current treatment of choice of kala-azar. With this drug, 98% long-term cure rates have obtained in both antimonial-unresponsive and previously untreated patients.7 It intercalates with the parasite ergosterol, and leads to damage to the cell membrane of the parasites.8 The drug is administered as 1 mg/kg on an alternate day schedule over a 30-day period. Daily therapy with 1 mg/kg/day for 2 weeks is also effective and well-tolerated. Standard protocols for hydration, premedication and monitoring should be followed. The disadvantages of the drug include expense; infusion related side effects, nephrotoxicity and need for prolonged hospitalization for IV administration and renal function monitoring.9 In an effort to limit the toxicity associated with this drug and to shorten the duration of treatment, 3 new lipid associated formulations (amphotericin B colloidal dispersion, amphotericin B lipid complex and liposomal amphotericin B) have been developed. These 394 Rational Antimicrobial Practice in Pediatrics have proved to be highly effective and better tolerated than conventional amphotericin- B. In India, long term cure rates > 90–95% have been achieved with these formulations.10 However, respiratory distress has been observed in children under 6 years.6 These lipid formulations allow administration of considerably higher daily doses and simultaneously appear to target infected tissue macrophages via enhanced phagocyte uptake. Two regimens are commonly employed: A 5–day regimen of daily infusion at 3 mg/kg or a 10-day regimen with infusions on day 1–5 and on day 10.11 In 1997, USFDA approved liposomal amphotericin B in the dose of 3 mg/kg on days 1–5, 14 and 21 for the treatment of visceral leishmaniasis in immunocompetent children.12 However in developing countries where the need is greatest, the use of these lipid formulations is prohibitively expensive. To reduce the cost, the simple mixing of amphotericin B with a commercially available fat emulsion has been proposed (at 2 mg/kg on alternate days for a total duration of 10 days). It has proved to be more affordable and equally effective.13 Recently, a single dose regimen of AmBisome (at 5 and 15 mg/kg) has been assessed in patients in India, with cure rates approaching 100%.14 A short course regimen with amphotericin B fat emulsion (5 alternate day infusions of 2 mg/kg) has been evaluated in an uncontrolled study in India, with cure rates reported in 93% of antimonial unresponsive patients.15 It is feared, however that short courses may contribute to emergence of drug resistance.

Miltefosine It is the latest addition and the first orally effective drug against kala-azar. It is hexa- decylphosphocholine (an alkylphospholipid). It is a phosphorylcholine ester of hexadecanol, a membrane active phospholipid. It was originally developed as an oral anti-neoplastic agent. The drug has a long half-life, in the range of 150–200 h. The anti-leishmanial activity of miltefosine is related to a direct cytotoxic effect on the parasite and to the activation of cellular immunity against the parasitic infection. Leishmania have high levels of ether-lipids on the surface and miltefosine acts on key enzymes involved in the later steps of metabolism of ether lipids.16 In vitro studies demonstrate that miltefosine stimulates T cells and macrophages to secrete activating cytokines, including interferon (IFN)-gamma and enhances macrophage production of microcidal reactive nitrogen and oxygen intermediates.17 The dose recommended for miltefosine is 2.5 mg/kg/day for a period of 28 days. The dose of miltefosine must be adjusted based on weight of the patient so that the total dose of 4 g/kg is not exceeded. The most important adverse effect of miltefosine is vomiting and diarrhea, which may be seen 20–40% of patients. There may be a rise in serum levels of AST, ALT, creatinine and BUN. Grade III hepatotoxicity and renal damage has also been reported.19 These adverse effects usually occur in the first two weeks of therapy and are reversible in the face of continued treatment or after discontinuation of treatment. Overall, miltefosine is well tolerated with considerably fewer adverse effects as compared to antimonials and amphotericin B.20 Antimicrobial Therapy in Visceral Leishmaniasis (Kala-azar) 395

Treatment with miltefosine at 2.5 mg/kg/day for 28 days has been almost 100% effective and well-tolerated in Phase I/II studies conducted in India among antimonial resistant and untreated kala-azar patients.18,21 It is now approved for use in all cases of kala- azar in patients more than 2 years of age.22 It is contraindicated in women of childbearing age because of its teratogenic effects in animal studies. Miltefosine is available in India by the trade name of Impavido (Zentaris) as 10, 50 and 100 mg capsules.

 AGENTS UNDER EVALUATION Sitamaquine Sitamaquine (WR6026), an 8 amino-quinoline, first reported in 1994, may be a promising oral drug. Sitamaquine (1 mg/kg/day for 4 weeks) when administrated to 8 patients provided a 50% cure rate. More recently, a phase 2 dose-escalating trial was performed in Brazil. Cure rates for patients treated for 28 days were 0% and 67% at 1 mg/kg/ day and 2 mg/kg/day, respectively. Further studies are needed to determine the efficacy and toxicity profile of this agent.23

Interferon Gamma Interferon gamma is a potent macrophage activator with synergistic activity with antimonials in mice. Interferon gamma alone has limited efficacy in human VL. Adjunctive interferon gamma therapy may accelerate or improve the response to antimonial therapy in some difficult cases. In recent trials, daily interferon-gamma injections combined with pentavalent antimonial agents were shown to accelerate the clinical response and achieve a long-term cure in approximately two-thirds of cases unresponsive to treatment with antimonial compounds alone. However, in a randomized, controlled study conducted in India, where resistance to pentavalent antimonial agents is high, the same combination given for 28 days failed to show such adjunctive activity in terms of long-term cure.24 The high cost of interferon gamma precludes its widespread use in the developing world.

Aminosidine Aminosidine is an amino glycoside antibiotic identical to paromomycin sulfate and is administered once daily, usually by the intramuscular route. Combined with antimonials, aminosidine (12–18 mg/kg for 21 days) allows a reduction in the duration of the therapy and may be more efficient than antimonials alone in areas with high levels of antimonial resistance. Aminosidine also appears to be active when used alone in some Indian studies. However, its potential for causing ototoxicity and nephrotoxicity, if of concern.25

Allopurinol At the beginning of the 1980s, non-randomized trials showed that a combination of antimonials and allopurinol (15 mg/kg/day) was efficacious in treating VL. Recently, a randomized trial in patients with antimonial-unresponsive VL, suggested that combined 396 Rational Antimicrobial Practice in Pediatrics therapy with allopurinol plus pentamidine provided higher cure rate than with pentamidine alone. Allopurinol is not recommended as monotherapy.26

Others Numerous oral agents have been tested as stand-alone agents or as combination therapy for treatment of VL. Most of them including ketoconazole, itraconazole, fluconazole, terbinafine and metronidazole have been discarded.27

 CURRENT TREATMENT OPTIONS IN KALA-AZAR Sodium stibogluconate is still recommended as the first line therapy in untreated patients of kala-azar, except in Bihar, where high degree of resistance has been found.28 The term apparent cure at the end of treatment on day 30 requires the absence of fever, general clinical improvement, a decrease in spleen size, and a parasite-free splenic or bone marrow aspirate smear. Definitive cure, measured 6 months after treatment, requires that the patient be healthy with no symptoms or signs of relapse. Relapse is defined as reappearance of signs and symptoms with positive parasite in bone marrow/splenic aspirates after initial cure with WHO recommended dosage of SSG, usually within 6 months. Primary unresponsiveness is no clinical or parasitological improvement during or after the first course of treatment with SSG. Secondary unresponsiveness occurs during relapse after one or more courses of apparently successful treatment. Evaluation of effectiveness of therapy of kala-azar is very important. Response to therapy can be assessed clinically and by repeat bone marrow/splenic examination. The role of rK39 test in predicting response to therapy is also being evaluated. Although it is an excellent test for making a diagnosis of kala-azar, the test cannot be used in predicting response to therapy or relapses, as IgG antibodies persist in blood for long time after successful treatment of infection. A new test, based on the detection of antigen in urine of the patients with VL, has been recently described. This latex agglutination test (KATEX) has a specificity of ~100% but a sensitivity of 47.7–100%. The test becomes negative after successful therapy. PCR can be used to make a definitive diagnosis of kala-azar, and in 85% patients it turns negative at the end of treatment and in 97% at 3 months.29 Patients in areas of high resistance such as Bihar, those with primary treatment failures or patients who experience relapse should be offered alternative therapy, either amphotericin B or miltefosine. If facilities for admission and close monitoring of patient during therapy were available, then amphotericin B would be the optimum treatment; else oral miltefosine may be advised for such patients, as it does not need close supervision and monitoring.

 REFERENCES 1. Reed SG. Leishmaniasis vaccination: Targeting the source of infection. J Exp Med. 2001;194:F7-9. 2. Peacock CS, Collins A, Shaw MA, Silveira F, Costa J, Coste CH, et al. Genetic epidemiology of visceral Leishmaniasis in northeastern Brazil. Genet Epidemiol. 2001;20:383-96. Antimicrobial Therapy in Visceral Leishmaniasis (Kala-azar) 397

3. Herwaldt BL. Leishmaniasis. Lancet. 1999;354:1191-9. 4. Maltezou HC, Siafas C, Mavrikou M, Spyridis P, Stavrinadis C, Karpathios Th, et al. Visceral Leishmaniasis during childhood in southern Greece. Clin Infect Dis. 2000;31:1139-43. 5. Frezard F, Michalick MS, Soares CF, Demicheli C. Novel methods for the encapsulation of meglumine antimoniate into liposomes. Braz J Med Biol Res. 2000;33:841-6. 6. Shyam Sundar, et al. MSF-DND working group-drugs for the treatment of v.leishmaniasis, current status, needs and a proposed R&D agenda, September 2001. 7. Mishra M, Biswas UK, Jha DN, Khan AB. Amphotericin versus pentamidine in antimony-unresponsive kala-azar. Lancet. 1992;340:1256-7. 8. Mishra M, Biswas UK, Jha DN, Khan AB. Amphotericin versus Pentamidine in antimony-unresponsive kalaazar. Lancet. 1992; 340:1256-7. 9. Thakur CP, Singh RK, Hassan SM, Kumar R, Narain S, Kumar A. Amphotericin B deoxycholate treatment of visceral Leishmaniasis with newer modes of administration and precautions: a study of 938 cases. Trans R Soc Trop Med Hyg. 1999;93:319-23. 10. Davidson RN, Croft SL, Scott A, Maini M, Moody AH, Bryceson ADM. Liposomal Amphotericin B in drug-resistant visceral Leishmaniasis. Lancet. 1991;337:1061-2. 11. Sundar S, Murray HW. Cure of antimony-unresponsive Indian visceral Leishmaniasis with Amphotericin B lipid complex (ABLC). J Infect Dis. 1996;173:762-6. 12. Gaeta GB, Maisto A, Di Caprio D, Scalone A, Pasquale G, Felaco FM, et al. Efficacy of Amphotericin- B colloidal dispersion in the treatment of Mediterranean visceral Leishmaniasis in immunocompetent patients. Scand J Infect Dis. 2000;32:675-7. 13. Sundar S, Agrawal G, Rai M, Makharia MK, Murray HW. Treatment of Indian visceral Leishmaniasis with single or daily infusions of low dose Liposomal Amphotericin-B: randomized trial. BMJ. 2001;323:419-22. 14. Sundar S, Agrawall G, Rai M, Makharia MK, Murray HW. Treatment of Indian visceral Leishmaniasis with single or daily infusions of low dose Liposomal Amphotericin B randomized trial. BMJ. 2001;323:419- 22. 15. Sundar S, Gupta LB, Rastogi V, Agrawall G, Murray HW. Short course, cost-effective treatment with Amphotericin B-fat emulsion cures visceral Leishmaniasis. Trans R Soc Trop Med Hyg. 2000;94:200- 4. 16. Lux H, Heise N, Klenner T, Hart D. Opperdoes FR. Ether-lipid (alkyl- phospholipid) metabolism and the mechanism of action of ether–lipid analogues in visceral leishmania. Mol Biochem Parasitol. 2000;111:1-14. 17. Murray HW, Delph- Etienne S. Visceral leishmanicidal activity of hexadecylphosphocholine (miltefosine) in mice deficient in T cells and activated macrophage microcidal mechanisms. J Inf Dis. 2000;181:795- 9. 18. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, et al. Oral Miltefosine for Indian Leishmaniasis. N Engl J Med. 2002;347:1739-46. 19. Smorenburg CH, Seynaevec, Bontenbal M, Planting AS, Sindermann H, Verweij J. Phase II study of Miltefosine 6% solution as topical treatment of skin metastases in breast cancer patients. Anticancer Drugs. 2000;11(10):825-8. 20. Sundar S, Gupta B, Makharia MK, Singh MK, Voss A, Rosenkiamer F, Engel J, Murray HW. Oral treatment of visceral Leishmaniasis with Miltefosine. Ann Trop Med Parasitol 1999:93;589-97. 21. Sundar S, Gupta B, Makharia MK, Singh MK, Voss A, Rosenkiamer F, Engel J, Murray HW. Oral treatment of visceral Leishmaniasis with Miltefosine. Ann Trop Med Parasitol. 1999:93;589-97. 22. Thakur CP, Sinha PK, Singh KR, Hassan SM, and Narain S. Miltefosine in a case of visceral Leishmaniasis: and rising incidence of this disease in India. Trans R Soc Trop Med Hyg. 2000;94:696- 7. 23. Dietze R, Carvalho SF, Valli LC, et al. Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral Leishmaniasis caused by Leishmania chagasi. Am J Trop Med Hyg. 2001;65:685-9. 24. Sundar S, Murray HW. Effect of treatment with interferon-gamma alone in visceral Leishmaniasis. J Infect Dis. 1995;172:1627-9. 398 Rational Antimicrobial Practice in Pediatrics

25. Thakur CP, Kanyok TP, Pandey AK, Sinha GP, Messick C, Olliaro P. Treatment of visceral Leishmaniasis with injectable Paromomycin (Aminosidine). An open-label randomized phase-II clinical study. Trans R Soc Trop Med Hyg. 2000;94:432-3. 26. Jha TK. Evaluation of Allopurinol in the treatment of kalaazar occurring in North Bihar, India. Trans R Soc Trop Med Hyg. 1983;77:204-7. 27. Murray HW. Treatment of visceral Leishmaniasis (kalaazar): a decade of progress and future approaches. Int J Infect Dis. 2000;4:158-77. 28. Sundar S, More D, Singh M, Singh V, Sharma S, Makharia A, et al. Failure of Pentavalent Antimony in Visceral Leishmaniasis in India: Report from the Center of the Indian Epidemic; Clin Infect Dis. 2000;31:1104-7. 29. Sundar S, Agrawal S, Pai K, Chance M, Hommel M. Detection of leishmanial antigen in the urine of patients with visceral leishmaniasis by a latex agglutination test: Am. J. Trop. Med. Hyg. 2005;73(2): 269-71. Antiretroviral Therapy 399 3333 Antiretroviral Therapy Archana Kher

 INTRODUCTION The treatment of HIV infected patients has changed remarkably since early 1996. With the rapid scale up of antiretroviral therapy, there is a dramatic decline in HIV related morbidity and mortality in both developed and developing countries. Many safe drugs and monitoring assays are developed recently. As a result the treatment guidelines for the management of HIV disease continue to change. The policies address the following issues—antiretroviral therapy initiation, which drugs to start with, when to change the initial regimen and which drugs need to change. Presently more than 20 Antiretroviral [ARV] agents have been approved by the US Food and Drug Administration (FDA) for use in HIV-infected adults and adolescents older than 16 to 18 years in the United States, but 17 are approved for children and adolescents younger than 16 to 18 years, only 15 have pediatric formulations available (see www.aidsinfo.nih.gov/other/ cbrochure/english/13en.pdf for a complete listing of HIV medications available in oral [liquid, capsule, and tablet] and intravenous formulations). Most children with perinatally acquired HIV infection in resource-rich countries are treated early with highly active ARV therapy (ART). Such ART, consisting of a combination of 3 or more potent ARV drugs, has been shown to dramatically modify the course of HIV infection in children, reducing mortality by fivefold or more and resulting in high survival rates (> 90%) into adulthood.1 Combination therapy with at least three drugs, i.e., highly active antiretroviral therapy (HAART) can suppress viral replication, improve immunologic status, lessen opportunistic infections and delay the onset of drug resistance. The Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children has updated the guidelines in August 2011.2 The working group concluded that ART was indicated for any child: • With definitive diagnosis of HIV infection • Substantial evidence for immunodeficiency (as per age related threshold values for CD4, T cell count). • Symptoms associated with HIV infection. 400 Rational Antimicrobial Practice in Pediatrics

 HIV INFECTION AND THERAPY IN CHILDREN—BASICS It is essential to review the biology of the virus for a thorough understanding of the pharmacotherapy of HIV infection. The HIV virus is an enveloped single stranded RNA virus that contains the gag, env, pol genes for the core nucleocapsid polypeptides, surface coated proteins and viral enzymes reverse transcriptase and protease respectively. The virus gains entry in the host cell by an interactive process between the envelope glycoproteins, host CD4 molecules and chemokine receptors. After entry into the T cell, the viral reverse transcriptase enzyme transcribes the single stranded viral RNA into double stranded DNA. The viral DNA enters the host cell nucleus, integrates with the host DNA, transcribes and new virions are generated. The immature virions cleave the gag and env gene products with protease enzymes during their maturation process that are then capable of infecting other host cells. Higher number of CD4 T cells in infants and young children provide a larger target population for the virus thus accounting for a higher viral load in children. On an average 10 billion virions are produced daily, the half-life being 6 hours. The viral pool has a high capacity for mutation and recombination in response to host immunity and pharmacotherapy. Mutations in the viral genome are known to occur during replication. The polymerase reverse transcriptase has 10,000 nucleotides and almost one error or mutation occurs for every 10,000 nucleotides. A large pool of defective viral variants is present during the initial stage of the disease and these variants largely contribute to drug resistance.3 Immune reconstitution Inflammatory syndrome (IRIS) is associated with inflammatory response to clinical or subclinical pathogens or nonpathogenic antigens. Management of HIV infection in infants and children is rapidly evolving and getting increasingly complex. The therapy should be initiated and continued in centers where there is adequate skill and expertise in diagnosing, investigating opportunistic infections as well as monitoring ART. A multidisciplinary team approach that includes physicians, nurses, dentists, social workers, psychologists, nutritionists, outreach workers, pharmacists is required. It is also essential to address the following issues whenever ART is being planned:4–9 a. In children infection is mostly perinatally acquired. b. Many perinatally infected children have in utero, intrapartum, postpartum or neonatal exposure to zidovudine. c. Certain virologic tests are required to diagnose perinatal HIV infection in infants below 15 to 18 months old. d. There are age specific differences in immunological markers like CD4 and T cell count. e. Pharmacokinetic parameters like drug metabolism and clearance vary with age. f. Clinical and virologic manifestations are different in growing and immunologically immature persons. g. Compliance and adherence to the ART is rather difficult in infants, children and adolescents. Antiretroviral Therapy 401

h. Adolescent females develop more fat whereas males develop more muscle mass. This could alter the drug pharmacokinetics. i. Doses in adolescents should be prescribed based on the Tanner’s stages. Those with Tanner’s stage I and II are given pediatric doses. Females with stage III and males with stage IV are prescribed adult doses. j. Availability and palatability of pediatric formulations of the ART drugs k. Physical growth and neurodevelopment needs close monitoring. l. Nutritional support is an important aspect as it influences immune function. m. Parents are usually affected and their capability to take care of the children is impaired.

 ANTIRETROVIRAL AGENTS The last few years have witnessed advent of several new ART drugs. Approval for pediatric use is based on efficacy data from clinical trials in adults with supporting pharmacokinetic and safety data from phase I and II trials in children. There are few randomized phase III trials of HAART in children. These drugs also have an important role in prevention of mother to child transmission (PMTCT) and postexposure prophylaxis (PEP).9–11 The ART drugs essentially act by inhibiting the activity of two major viral enzymes reverse transcriptase and protease. There are three classes of drugs, and combination with three drugs is used as there is better virologic and immune response, slower disease progression and improved survival 11–13.

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs) NRTIs are the first class of ART drugs that became available. The drugs in this class require intracellular phosphorylation to form active triphosphate metabolites. The drugs have no effect on chronically infected cells in which proviral DNA is already integrated into cellular chromosomes. Nucleotide RTIs [NtRTIs] have a phosphate molecule and bypass the rate limiting phosphorylation step. DNA polymerase present in mitochondria is also inhibited by NRTIs/NtRTIs. Drugs inhibit HIV replication by the following mechanisms:4–7 • The metabolites compete with the natural nucleosides for incorporation into HIV DNA during reverse transcription process. • Subsequently there is a termination in the DNA chain as it lacks 3’ hydroxyl group for 5’ to 3’ phosphodiesterase linkages that are necessary for elongation of DNA. They have short half-lives in plasma but their intracellular half-life is longer and therefore frequent doses are not necessary. The drugs in this group are Zidovudine (ZDV), Didanosine (ddI), Lamivudine (3TC), Stavudine (d4T), Zalcitabine (ddC), Abacavir (ABC), Emtricitabine (FTC) and Tenofovir (TDF). ZDV was the first ART drug to be approved for use in children. Dual NRTIs form the backbone of HAART regimens; commonly used dual NRTIs 402 Rational Antimicrobial Practice in Pediatrics are ZDV and ddI, ZDV and 3TC, d4T and ddI, d4T and 3TC, ZDV and ddC, ABC and ZDV/3TC/d4T/ddI. ZDV and d4T are not used together as their pharmacological interactions cause viral antagonism. Combination of ddC with ddI/d4T/3TC is not advocated, as experience in pediatric patients is limited. ddI is not used along with d4T and ddC, as there is greater risk of pancreatitis and peripheral neuropathy. Long-term side effects of NRTIs have been associated with damage to the mitochondria. This damage may cause low red and white cell counts, muscle pain, wasting.6,7,9,11 Zidovudine ZDV/AZT: ZDV has been a mainstay in HIV therapy in the mother and baby to prevent perinatal transmission of the virus. It is an analogue of thymidine base and has good CNS penetration. It is metabolized in the liver by the process of glucuronidation and then excreted in urine. Side effects are bone marrow suppression, anemia, liver toxicity, myopathy and mitochondrial dysfunction. Dosage in neonates and infants < 6 weeks is IV 1.5 mg/kg every 6 hours or oral 2 mg/kg every 6 hours, 6 weeks to < 18 years is 180 to 240 mg/m2 every 12 hours or 169 mg/m2 every 8 hours. Didanosine ddI: It is an analogue of adenosine, and is rapidly degraded in acidic environment, therefore should be taken on an empty stomach at least 1 hour before or 2 hours after food. Toxic effects are pancreatitis and peripheral neuropathy. The potential use of enteric-coated tablets is being explored. The dose in neonates 2 weeks to 3 months is 50 mg/m2 every 12 hours, 3 months to 8 months age is 100 mg/m2 every 12 hours, > 8 months to 3 years—90 to 150 mg/m2 every 12 hours, 3 years to 21 years—240 mg/m2 od. Lamivudine 3TC: It is a cytidine analogue and is a fairly well tolerated drug. It is used with caution in those with deranged renal function. Exacerbation of hepatitis is known in those with coexistent hepatitis B infection. Neonates (< 4 weeks age) are given 2 mg/kg od, babies > 4 weeks age—4 mg/kg, max 150 mg twice daily. Stavudine d4T: It is thymidine analogue and toxic effects include pancreatitis, peripheral neuropathy, mitochondrial toxicity, lactic acidosis, lipodystrophy, hepatomegaly, hyperlipidemia, steatosis, insulin resistance. Dosage as follows, neonates [0–13 days]— 0.5 mg/kg twice daily, 14 days to 30 kg—1 mg/kg twice daily, > 30 kg to 60 kg— 30 mg bd. Zalcitabine: It is a cytidine analogue and not used frequently in children. Abacavir ABC: This drug is an analogue of guanine and is not used in infants below 3 months of age. It can cause a severe hypersensitivity reaction and rash within 6 weeks of treatment. The drug has to be withdrawn. Rechallenge is not recommended even if symptoms have resolved, as the hypersensitivity reactions can be fatal in 5% cases. Dose is 8 mg/kg twice daily. Emtricitabine FTC: It is the long acting analogue of lamivudine. It can be given without regard to food, causes hyperpigmentation of palms and soles, renal excretion is 86%. Dose in neonates is 3 mg/kg od, > 3 months to 17 years—6 mg/kg, max 200 mg od. Antiretroviral Therapy 403

Tenofovir TDV: It is not approved in children below 12 years, adolescents above 35 kg can be given 300 mg od. Investigational doses 175 to 300 mg/m2 have been tried od.

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) These drugs act by binding directly to the HIV reverse transcriptase enzyme, thereby causing noncompetitive inhibition of the viral enzyme. The NNRTIs are metabolized by cytochrome P450 system and they interact with numerous drugs like rifampicin, rifabutin, digoxin, phenytoin, and theophylline. Serious adverse effects are known. The drugs are all potent but a single codon mutation in the HIV virus leads to resistance to all drugs in this class. They have better action on HIV-1 virus.9,11–13 Nevirapine (NVP): NVP is the first NNRTI approved for use in children. It is used in combination regimens; also a single dose of NVP (200 mg) to the mother and 2 mg/kg orally to the baby is used to reduce perinatal transmission. Untoward effects in the form of skin rash and Steven Johnson syndrome and hepatitis are reported. The drug needs to be discontinued with the development of progressive rash. NVP induces hepatic enzymes therefore it is started as a once daily dose for 2 weeks and then increased to twice daily dose as it induces CYP 450 metabolizing enzymes which increase the drug metabolism. Dosage below 8 years age is 200 mg/m2 twice daily, > 8 years– 120 mg/m2 to 150 mg/m2, max 200 mg twice daily. Efavirenz (EFV): It is used in children above the age of 3 years and its long half- life permits once a day dosage. The drug is as potent as protease inhibitors (PIs). Induction of cytochrome p450 enzymes reduces the plasma concentration of PIs when used in combination. Dose above 3 years is 200 mg to 400 mg od as per weight. It is given on empty stomach and is known to cause CNS complications. Delaviridine (DLV), Etravirine (ETR), Rilpivirine (TMC278) are not approved in pediatric patients.

Protease Inhibitors (PIs) The HIV virus copies its own genetic code into the host cell DNA and new virus copies are created. Once the viral DNA is inside a T cell DNA, the cell produces a long strand of genetic material that must be cut and put together correctly to form new copies. The protease enzyme cleaves the viral polypeptide products of the gag and gag–pol genes to form viral structural proteins and other essential enzymes. The PIs inhibit the protease enzyme and thereby block the maturation process of the virus. The PIs came after 1996. They are metabolized by the cytochrome P450 system and they cause significant reactions with the other drugs. Adverse effects include gastrointestinal disturbances, elevation of liver enzymes. Long-term side effects of PIs include changes in blood sugar levels, development of diabetes, elevations in blood fat levels, lipodystrophy. There could be fat deposits in the abdomen, back of shoulders as well as loss of fat in the arms, legs and face. Perianal abscesses are also known to occur. They are more resistant to development of drug resistance as compared to the NNRTIs.6,7,9,11 404 Rational Antimicrobial Practice in Pediatrics

Indinavir (IDV): It is not approved in neonates and infants and is available only in the capsule form. Dose of 234 to 500 mg/m2 boosted with low dose RTV studied in children. Plenty of fluid intake is recommended to minimize the risk of nephrolithisiasis. Exacerbation of chronic liver disease is known. Saquinavir (SQV): It is available as a hard gel and a soft gel capsule; the bioavailability of the soft gel capsule is better. It is not used in neonates, infants and children < 2 years. Dose in patients above 2 years of age is 50 mg/kg + RTV 3 mg/kg bd. Above 7 years of age, it is used with LPV/r. SQV has to be taken 2 hours after a full meal and is known to cause cardiac conduction defects, prolonged QT interval, ventricular tachycardia. Nelfinavir (NFV): It is available in the form of tablets and oral powder. The powder does not dissolve well and so has to be mixed with milk or ice cream. It is not used in neonates and small children below 2 years of age. Dosage in the age group 2 to 13 years is 45 to 55 mg /kg twice daily. Fosamprenavir (FPV): It is well tolerated, though a large volume/pill burden is required. It is not used in neonates and infants. In children 30 mg/kg twice daily is used, or 18 mg/kg with RTV 3 mg/kg both twice daily. It can cause hyperlipidemia, fat maldistribution, nephrolithiasis, skin rash and Stevens-Johnson syndrome, hence it is avoided in those with sulfonamide allergy. Ritonavir (RTV): This drug is not used in neonates. RTV is used as a pharmacokinetic enhancer to raise the plasma level of other PIs. The addition of ritonavir increases the concentration of lopinavir and the higher concentration inhibits the replication of many PI resistant HIV strains. Ritonavir liquid is not easily palatable, it is administered with food to increase absorption and reduce GI side effects. Lopinavir/Ritonavir (LPV/r): Oral solution 80 mg/20 mg, tablets 100 mg/25 mg and 200 mg/50 mg are available. It is used in neonates beyond 14 days or 42 days postconception in doses 300 mg/75 mg/m2 or 16 mg/4 mg/kg twice daily. From 1 year to 18 years age, a dose of 230 mg/57.5 mg/m2 twice daily used with food. Darunavir (DRV): It is not used in neonates infants and children < 6 years. Dose 375 to 600 mg with RTV boosting twice daily used, once daily higher doses used above 18 years and treatment naïve children. It can cause hepatotoxicity, Stevens-Johnson syndrome. Atazanavir (ATV): It is not used in neonates as it causes hyperbilirubinemia, hepatotoxicity and there is insufficient data below 6 years of age. A dose of 150 to 300 mg with 100 mg RTV once daily used. Cardiac conduction defects are known adverse effects. Tipranavir (TPV): It is a non-peptide PI with a sulfa moiety available as oral solution (100 mg) with 116 IU vitamin E. It is being tried in children 2 to 18 years of age as 375 mg/m2 TPV along with 150 mg/m2 of RTV twice daily. It has a potential for multiple drug interactions. In children the usual PIs used are Lopinavir/Ritonavir, Nelfinavir, and Ritonavir. Antiretroviral Therapy 405

Fusion Inhibitors Enfuvirtide (ENF, Fuzeon, T20): It is a synthetic peptide that binds to a region of the HIV envelope glycoprotein, gp41. This binding prevents fusion of the virus envelope with the membrane of the CD4 host cell. 108 mg of lyophilized powder is reconstituted with 1.1 mL sterile water to make 90 mg/mL. It is given subcutaneously and is not used in children below 6 years of age. The dose is 60 mg/m2/dose or 2 mg/kg or 90 mg twice daily. Adverse reactions include local reactions, myalgia, insomnia, depression, and peripheral neuropathy. Maraviroc is available as tablets but not approved below 16 years.2,3

Integrase Inhibitors Raltegravir is available as tablets for use above 16 years.

 WHEN TO INITIATE THERAPY? 2, 4,12,13 Many factors are taken into consideration before initiating therapy: • Severity of HIV disease and risk of progression, CD4, RNA levels • Availability of appropriate formulations and their pharmacokinetic information, drug interactions, adherence • Potency of the drugs, complexity, dosing, diet, fluid requirement, adverse effects • Comorbidity due to hepatitis B and C, liver, renal disease. Early treatment during the asymptomatic stage lowers the viral replication and fewer mutant strains emerge. The disease process is slowed down and there is better preservation of the immune function. Early ART has demonstrated better quality of life, survival, less immune activation and lower risk of immune reconstitution inflammatory syndrome (IRIS). However starting treatment late may be beneficial in some ways; there is better adherence, few adverse effects, and less drug resistant virus strains. Adherence is improved with combination drugs and once daily regimens. The goal of HAART is to achieve maximum and durable viral suppression (viral load < 50 copies/mL).

HIV Infected Infants below the Age of 12 Months Ideally ART should be initiated regardless of clinical stage, CD4 counts, viral load. The disease progression is inversely proportional to age, amongst the children who have acquired the infection perinatally, 15% deaths occur by 1 year of age and 50% develop moderate immune suppression. The median HIV RNA level during the first 2 months of life is 299,000 copies/mL and it declines to 185,000 copies/mL by one year of age.2 The drug information in infants below the age of 3 to 6 months is inadequate. The hepatic and renal functions are immature. Toxicity in the form of abnormal blood sugar levels, lipodystrophy, dyslipidemia, osteopenia are common. Resistance develops frequently due to inadequate doses, poor absorption and poor adherence, therefore testing is advised before starting ART. Opportunistic infections (OIs) may occur with normal CD4 counts. 406 Rational Antimicrobial Practice in Pediatrics

ART is ideally recommended for all infants younger than 12 months regardless of clinical, virological or immunological signs and symptoms.4

HIV Infected Children above the Age of 12 Months Following guidelines have been developed. • The CD4 threshold for recommending ART in children ages  5 years with minimal or no clinical symptoms has been increased from < 350 cells/mm to < 500 cells/mm. • ART strongly recommended for children with CD4 counts < 350 cells/mm • For children with CD4 counts 350 to 500 cells/mm, the recommendation is based on observational data in adults; hence the evidence base is not as strong • Treatment is also recommended for children with minimal or no clinical symptoms and normal immune status (CD4 percentage >25% if age 1 to < 5 years, or CD4 count >500 cells/mm if age  5 years) if plasma HIV RNA is >100,000 copies/mL. • Treatment may be considered for children age  1 year with normal immune status (CD4 percentage >25% if age 1 to < 5 years, or CD4 count > 500 cells/mm if age  5 years) and plasma HIV RNA < 100,000 copies/mL • Because of slower disease progression among older children without symptoms of advanced disease, it is important to take time to educate both the caregiver and child about the need for adherence to the regimen and to resolve potential adherence problems before initiation of therapy. This is particularly true for children age  5 years given their lower risk of disease progression and the higher CD4 count threshold now recommended for initiating therapy.4 • Adherence to therapy is essential. The chances of drug resistance are higher in patients who have been exposed to maternal ART.

 CHOICE OF A REGIMEN Two options based on the drug class are available namely 2 NRTI + 1PI, 2 NRTI + 1 NNRTI. The PI based regimen is potent but high pill burden, expense, drug interactions and poor palatability of drugs poses difficulties for adherence. NNRTI based regimens are potent, cheaper, have low pill burden and fewer interactions but resistance and also cross-resistance among the class of drugs is known to occur. Triple NRTI drugs are less potent and no longer recommended for initial therapy. Mono or dual therapy or 3 NRTI are not used. The following issues are considered when the physician plans the HAART regimen: • Taste, volume of syrup, number of pills • Dose, schedule of administering, adverse effects of the drugs • Storage and food requirements. Recommendations for initiating ART in treatment—naive children using one of the following agents plus a dual-nucleoside reverse transcriptase inhibitor (NRTI) backbone combination:4,13,14 • For children  42 weeks of postmenstrual age and postnatal  14 days of age: lopinavir/ ritonavir Antiretroviral Therapy 407

• For children age  3 years: efavirenz • For children age  6 years: atazanavir/ritonavir. The following are the preferred dual-NRTI backbone combinations: • Abacavir + (lamivudine or emtricitabine) • HLA-B*5701 genetic testing should be performed before initiating abacavir-based therapy, and abacavir should not be given to a child who tests positive for HLA- B*5701 • Zidovudine + (lamivudine or emtricitabine) • For adolescents  12 years of age and Tanner Stage 4 or 5: tenofovir + (lamivudine or emtricitabine).

 WHEN TO CHANGE THE ART TREATMENT It is important to evaluate certain issues before adopting the decision of changing the ART treatment. Monitor the clinical response, virologic and immunologic parameters, adherence, toxicities and intolerance. At times direct observed treatment is necessary to differentiate between poor adherence and treatment failure.

Monitoring The age of the child must be considered when interpreting the risk of disease progression based on CD4 percentage or count and plasma HIV RNA level. For any given CD4 percentage or count, younger children, especially those in the first year of life, face higher risk of progression than do older children. In children younger than 5 years of age, CD4 percentage is preferred for monitoring immune status because of age-related changes in absolute CD4 count in this age group. CD4 percentage or count should be measured at the time of diagnosis of HIV infection and at least every 3 to 4 months thereafter. Plasma HIV RNA should be measured to assess viral load at the time of diagnosis of HIV infection and at least every 3 to 4 months thereafter. More frequent CD4 cell and plasma HIV RNA monitoring should be considered in children with suspected clinical, immunologic, or virologic deterioration or to confirm an abnormal value. Routine monitoring of parameters like complete blood counts, biochemistry and urine analysis are dictated by the drugs used and clinical symptoms. Temporary viral load elevations between level of detection and 1000 copies/mL should not be considered as treatment failure. Many Indian studies highlight the benefits of starting ART, the results are encouraging. The limitations and other pertinent issues addressed appropriately.14-19

ART Drug Resistance Testing The final goal of ART is to reduce the HIV RNA to < 50 copies/mL. Resistance can be genotypic and phenotypic. Genotypic assays can detect mutations with > 1000 copies/ mL of HIV RNA. Genotyping resistance testing helps to identify the mutations associated 408 Rational Antimicrobial Practice in Pediatrics

TABLE 1 WHO Immunological Classification4 <11 months 12 to 35 months 35 to 59 months >5 years, [%] CD4+ [%]CD4+ [%]CD4+ absolute no. / mm 3 or CD4 None or not significant 35 30 25 >500 immune suppression Mild suppression 30–35 25–30 20–25 350–499 Moderate suppression 25–29 20–24 15–19 200–349 Severe suppression < 25 < 20 <15 < 200, < 15%

TABLE 2 Regimen Recommended by NACO for Pediatric Patients 20 Regimen P I Zidovudine + Lamivudine + Nevirapine Preferred pediatric regimen for new initiation Regimen P Ia Stavudine + Lamivudine + Nevirapine For children with Hb 9 g/dL

Regimen P II Zidovudine + Lamivudine + Efavirenz Preferred for children on anti-tuberculosis treatment; Hb >9 g/dL and weight > 10 kg Regimen P II a Stavudine + Lamivudine + Efavirenz For children on anti-tuberculosis treatment; Hb 9 g/dL and weight > 10 kg Regimen P III Abacavir + Lamivudine + Nevirapine For patients not tolerating AZT or d4Ton a NVP-based regimen Regimen P III a Abacavir + Lamivudine + Efavirenz For patients not tolerating AZT or d4T on a EFV-based regimen Regimen P IV Zidovudine + Lamivudine + For patients not tolerating both NVP Lopinavir/Ritonavir and EFV, and Hb >9 g/dL Regimen P IV a Stavudine + Lamivudine + For patients not tolerating both NVP Lopinavir/Ritonavir and EFV, and Hb >9 g/dL From NACO: www.nacoonline.org asccessed on 09/09/2012

with CXCR4 or D/M tropic virus, and can optimize the choice of drugs to be used in second line regimen. Phenotypic assays measure the ability of the virus isolates to grow in the presence of a drug and measure 50% to 90% inhibitory concentration of a drug against the virus in vitro. The result is expressed as a fold change in susceptibility above a particular cut off level. Presently in India there are limited facilities for genotypic testing. Antiretroviral Therapy 409

TABLE 3 ARV regimens recommended for initial therapy in children2 Preferred Regimens Infants > 14 days and < 42 days Two NRTIs plus LPV/r Children > 3 years Two NRTIs plus EFV2 Two NRTIs plus LPV/r Children > 6 years Two NRTIs plus ATV plus low-dose RTV Two NRTIs plus EFV2 Two NRTIs plus LPV/r Alternative Regimens Children of any age Two NRTIs plus NVP3 Children > 6 years Two NRTIs plus DRV plus low-dose RTV Two NRTIs plus FPV plus low-dose RTV Regimen used in special circumstances Two NRTIs plus ATV unboosted Two NRTIs plus FPV unboosted (children age (for treatment-naive adolescents age  2 years) Two NRTIs plus NFV (children age > 13 years and body weight >39 kg)  2 years) Zidovudine plus 3TC plus ABC 2-NRTI Backbone Options for Use in Combination with Additional Drugs (in alphabetical order) Preferred ABC plus (3TC or FTC) (children age  3 months) TDF plus (3TC or FTC) (adolescents age  12 years and Tanner Stage 4 or 5 only) ZDV plus (3TC or FTC) Alternative ddI plus (3TC or FTC) TDF plus (3TC or FTC) (adolescents age  12 years and Tanner Stage 3) ZDV plus ABC ZDV plus ddI Use in special circumstances d4T plus (3TC or FTC) TDF plus (3TC or FTC) (adolescents age  12 years and Tanner Stage 2)

 NATIONAL AIDS CONTROL ORGANIZATION, NACO The care, support and treatment of PLHIV is an important component of National AIDS Control Program, Phase-III (NACP-III) and aims to provide comprehensive care to PLHIV with respect to prevention and treatment of opportunistic Infections, antiretroviral therapy (ART), psychosocial support, home based care, positive prevention and impact mitigation. The free ART services were introduced on 1st April 2004 in eight government hospitals located in six high prevalence states. Since then, the services have been scaled-up to 272 centers providing ART to more than 3,22,000 patients across the country. In order to facilitate the delivery of ART services nearer to the beneficiaries, 410 Rational Antimicrobial Practice in Pediatrics

TABLE 4 ARV Regimens not Recommended 2 Not Recommended or Insufficient Data to Recommend for Initial Therapy ETR-containing regimens EFV-containing regimens for children age <3 years TPV-containing regimens SQV-containing regimens IDV-containing regimens Dual (full-dose) PI regimens full-dose RTV or use of RTV as the sole PI Unboosted ATV-containing regimens in children age <13 years and/or body weight < 39 kg NFV-containing regimens for children age < 2 years Unboosted DRV-containing regimens Once-daily dosing of LPV/r, boosted DRV, or boosted or unboosted FPV Triple- NRTI regimens other than ABC + ZDV + 3TC Triple-class regimens, including NRTI plus NNRTI plus PI Regimens with dual-NRTI backbones of ABC + ddI, ABC + TDF, ddI + TDF, and ddI + d4T TDF-containing regimens in children age <12 years or children age 12 years and Tanner Stage 1 MVC-containing regimens Rilpivirine-containing regimens RAL containing regimen, T 29 containing regimens LPV/r should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days. EFV is currently available only in capsule form and should be used only in children age 3 years who weigh 10 kg. Unless adequate contraception can be ensured, EFV-based therapy is not recommended for adolescent females who are sexually active and may become pregnant. NVP should not be used in postpubertal girls with CD4 count >250 cells/mm3, unless the benefit clearly outweighs the risk. concept of Link ART Centre (LAC) was conceived and presently 369 LAC have been established. The second line ART is being provided since 2008 at 10 centers of excellence and 5 upgraded ART centers in the country. National Pediatric HIV AIDS initiative was launched on 30 November 2006. Currently there are 7 Pediatric ART centers where comprehensive care is being provided to pediatric patients, 19500 children are receiving ART.20 Antiretroviral Therapy 411

TABLE 5 WHO staging system for HIV infection and disease in children CLINICAL STAGE I • Asymptomatic • Generalized lymphadenopathy CLINICAL STAGE II • Unexplained chronic diarrhea • Severe persistent or recurrent candidiasis outside the neonatal period • Weight loss or failure to thrive • Persistent fever • Recurrent severe bacterial infections CLINICAL STAGE III • AIDS-defining opportunistic infections (OIs) • Severe failure to thrive (wasting in the absence of known etiology)* • Progressive encephalopathy • Malignancy • Recurrent septicemia or meningitis *Persistent weight loss of >10% of baseline or <5th percentile on weight-for-height chart on 2 consecutive measurements >1 month apart in the absence of another etiology or concurrent illness.

TABLE 6 1994 CDC Revised Human Immunodeficiency Virus Pediatric Classification System: Clinical Categories CATEGORY N: NOT SYMPTOMATIC Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in Category A. CATEGORY A: MILDLY SYMPTOMATIC Children with 2 or more of the following conditions but none of the conditions listed in Categories B and C: • Lymphadenopathy (> 0.5 cm at > 2 sites; bilateral = 1 site) • Hepatomegaly • Splenomegaly • Dermatitis • Parotitis • Recurrent or persistent upper respiratory infection, sinusitis, or otitis media CATEGORY B: MODERATELY SYMPTOMATIC Children who have symptomatic conditions, other than those listed for Category A or Category C, which are attributed to HIV infection. Examples of conditions in clinical Category B include, but are not limited to, the following: • Anemia (< 8 gm/dL), neutropenia (<1,000/mm3), or thrombocytopenia (<100,000/mm3) persisting >30 days Contd... 412 Rational Antimicrobial Practice in Pediatrics

TABLE 6 Contd... • Bacterial meningitis, pneumonia, or sepsis (single episode) • Candidiasis, oropharyngeal (e.g. thrush) persisting for >2 months in children age >6 months • Cardiomyopathy • Cytomegalovirus(CMV) infection with onset before age 1 month • Diarrhea, recurrent or chronic • Hepatitis • Herpes simplex virus (HSV) stomatitis, recurrent (e.g. >2 episodes within 1 year) • HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 month • Herpes zoster (e.g. shingles) involving at least 2 distinct episodes or more than 1 dermatome • Leiomyosarcoma • Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex • Nephropathy • Nocardiosis • Fever lasting >1 month • Toxoplasmosis with onset before age 1 month • Varicella, disseminated (e.g. complicated chickenpox) CATEGORY C: SEVERELY SYMPTOMATIC • Serious bacterial infections, multiple or recurrent (e.g. any combination of at least 2 culture- confirmed infections within a 2-year period), of the following types: septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitis media, superficial skin or mucosal abscesses, and indwelling catheter-related infections) • Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs) • Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar lymph nodes) • Cryptococcosis, extrapulmonary • Cryptosporidiosis or isosporiasis with diarrhea persisting >1 month • CMV disease with onset of symptoms at age >1 month (at a site other than liver, spleen, or lymph nodes) • Encephalopathy (at least 1 of the following progressive findings present for at least 2 months in the absence of a concurrent illness other than HIV infection that could explain the findings): (a) failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychological tests; (b) impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy demonstrated by CT or MRI (serial imaging is required for children age <2 years); (c) acquired symmetric motor deficit manifested by 2 or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbance; (d) HSV infection causing a mucocutaneous ulcer that persists for >1 month; or (e) bronchitis, pneumonitis, or esophagitis for any duration affecting a child age >1 month • Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes) • Kaposi’s sarcoma (KS) • Lymphoma, primary, in brain • Lymphoma, small, noncleaved cell (Burkitt’s), or immunoblastic or large cell lymphoma of B- cell or unknown immunologic phenotype

Contd... Antiretroviral Therapy 413

TABLE 6 Contd...

• Mycobacterium tuberculosis, disseminated or extrapulmonary Mycobacterium, other species or unidentified species, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes) • Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site other than or in addition to lungs, skin, or cervical or hilar lymph nodes) • Pneumocystis carinii pneumonia (PCP) • Progressive multifocal leukoencephalopathy (PML) • Salmonella (nontyphoid) septicemia, recurrent • Toxoplasmosis of the brain with onset at age >1 month • Wasting syndrome in the absence of a concurrent illness other than HIV infection that could explain the following findings: (a) persistent weight loss >10% of baseline; OR (b) downward crossing of at least 2 of the following percentile lines on the weight-for-age chart (e.g. 95th, 75th, 50th, 25th, 5th) in a child age >1 year; OR (c) <5th percentile on weight-for-height chart on 2 consecutive measurements, >30 days apart PLUS (a) chronic diarrhea (e.g. at least 2 loose stools/day for >30 days); OR (b) documented fever (for >30 days, intermittent or constant)

CONCLUSIONS Management of infants and children affected with HIV infection should be initiated at centers where a trained team of all medical, laboratory and nursing staff is available. Facilities for treatment, investigations of OIs and management of complications should be available. Common complications during treatment include pain, nutrition failure, lactic acidosis, hepatic toxicity, and hyperlipidemia hyperglycemia, osteopenia, and hypersensitivity and skin rashes. As pharmacotherapy of HIV infection is rather complicated, preventing the infection will always remain an important strategy for control. Palliative care must feature as an important component of care.

 REFERENCES 1. Increasing Antiretroviral Drug Access for Children With HIV Infection Committee on Pediatric AIDS, Section on International Child Health www.pediatrics.org/cgi/doi/10.1542/peds.2007-0273 doi:10.1542/ peds.2007–0273. 2. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection prepared by The Working Group on ART and Medical Management of HIV Infected Children convened by National Pediatric and Family HIV Resource Center (NHPRC), Health Resources and Services Administration (HRSA), and National Institute of Health (NIH) http://aidsinfo.nih.gov/ContentFiles/lvguidelines/Pediatric Guidelines.pdf. 11 August 2011. Accessed Sept 2012. 3. Lala MM, Merchant RH (eds). Principles of Perinatal and Pediatric HIV/AIDS. Published by Jaypee Brothers 2012. 4. WHO guidelines in resource limited settings. http://www.who.int/hiv/pub/arv/en accessed Sept 2012 5. Rongkavillit C, Asmar B I. Antiretroviral drugs in Pediatrics. Ind J Pediatr. 2001;68:641–8. 6. Tashima KT, Flanigan TP. Antiretroviral therapy in the year 2000. Infect Dis Clin N America. 2000;14:827–47. 414 Rational Antimicrobial Practice in Pediatrics

7. Palumbo PE. Antiretroviral therapy of HIV infection in children. Ped Clin of N America. 2000;47:155– 69. 8. Kaul DA, Patel JA. Management of Pediatric HIV infection. Ind J Pediatr. 2001;68:623–32. 9. Ritchie DJ. Antiretroviral agents. In Manual of HIV Therapeutics, chapter 5, 2nd edition. Editor Powderly W G. Published by Williams and Wilkins. 2001:33–47. 10. Singh S. Human immunodeficiency virus infection. Ind Pediatr. 2000;37:1328–40. 11. Powderly WG. Antiretroviral therapy. In Manual of HIV Therapeutics, 2nd edition. Editor Powderly W G. Published by Williams and Wilkins. 2001:48–60. 12. Gupta S B, Pujari S N, Joshi S R, Patel A K. API consensus guidelines for use of antiretroviral therapy in adults [API–ART Guidelines]. JAPI. 2006;34:37–73. 13. Kumaraswamy, N, Patel A, Pujari S. ART in Indian setting: When and what to start with, when and what to switch to. Ind J of Med Research. 2011;134:787–800. 14. Mothi SN, Karpagam S, Swamy VHT, Lala Mamta, Sarvode SM. Pediatric trends and challenges. Ind J of Med Research. 2011;134:912–9. 15. Natu SA, Daga SR. Antiretroviral therapy in children, Indian experience. Ind Pediatrics. 2007;44:339– 43. 16. Pensi T. Fixed dose combinations of lamivudine, stavudine, nevirapine in treatment of pediatric HIV, A Preliminary report. Ind Pediatrics. 2007;44:519–21. 17. Parakh A, Dubey A P, Kumar A, Maheshwari A, Saxena R. Efficacy of first line WHO recommended generic HAART regimens in Indian children. Katmandu Univ Med J. 2009;7[3]:220–5. 18. Lodha R, Upadhyay A, Kabra S K. Antiretroviral therapy in HIV infected children. Ind Pediatrics. 2005;42:789–96. 19. Shah I. Management of Pediatric HIV, 2nd edn. 2012. 20. Care, support and treatment. National AIDS control program Phase III India. www.nacoonline.org accessed Sept 2012. Anthelmintic Therapy 415 3434 Anthelmintic Therapy S Balasubramanian, Sumanth Amperayani

 INTRODUCTION Parasitic infections of the gastrointestinal (GI) tract occur in all geographic regions of the world and produce a substantial morbidity in children. Prevalence is highest in the economically deprived regions of the world, notably in the tropics. There has been controversy regarding the clinical relevance of many of these common intestinal parasitic infections, which often appear to coexist with their hosts without causing significant clinical problems. However, recent studies confirm the importance of many of these infections, particularly in immunocompromised children with severe under-nutrition or human immunodeficiency virus (HIV) infection. In this chapter, we shall discuss the pharmacology of the commonly used anthelmintic drugs followed by brief discussion on the treatment of commonly occurring helmintic infections in India.

 ANTHELMINTIC DRUGS Benzimidazoles The benzimidazoles, albendazole and mebendazole, have broad-spectrum activity against roundworm, whipworm, hookworm, pinworm and wireworm species. They act on the parasite by binding to tubulin, inhibit microtubule assembly, decrease glucose absorption and inhibit fumarate reductase.

Albendazole Pharmacokinetics It is poorly soluble in water, but well absorbed with a fatty meal. It is rapidly metabolized in the liver to the active form, Albendazole sulfoxide, which has a serum half-life of 8–9 h, and is excreted by the kidneys. It is usually very well tolerated as a single dose or daily for 3 days. Dose 15 mg/kg/day PO, duration depends on the type of helminthic infection. 416 Rational Antimicrobial Practice in Pediatrics

Indications It is the drug of choice for ascaris, hookworm, pinworm, trichuris, trichinosis, filariasis (along with diethylcarbamazine), cysticercosis and hydatid disease. It can also be used as an alternative drug for cutaneous and visceral larva migrans and strongyloides. Adverse effects Usually well tolerated. Rarely dizziness. Worm migration is uncommon with albendazole treatment, but prolonged therapy may cause alopecia, reversible marrow suppression or hepatocellular damage. Drug interactions Phenytoin, phenobarbitone and carbamazepine decrease levels. Precautions Use with caution in patients with renal and hepatic disease. Contraindicated in pregnancy.

Mebendazole Dose 100 mg Q 12 h for 3 days. For enterobiasis 100 mg once, may be repeated after 2–4 weeks. Indications Can be used as an alternative drug to albendazole for roundworm, pinworm infections. Less effective than albendazole for hookworm and whip worm infections. Adverse effects Diarrhea, nausea, abdominal pain. Allergic reactions, hair loss and granulocytopenia occur with high doses. Drug interactions Serum concentrations increased by cimetidine and decreased by barbiturates, carbamazepine, Phenytoin, rifampicin, rifapentine, rifabutin. Precautions Used with caution in patients with liver disease.

Pyrantel Pamoate Pyrantel is a depolarizing neuromuscular blocking agent which paralyzes worms until they are expelled in feces. Pyrantel pamoate is active against Ascaris and Enterobius, only partially effective against hookworm and ineffective against Trichuris and Strongyloides.

Dose Dose is 11 mg/kg (maximum dose is 1 gm), and can be repeated after 2 weeks for pinworm infections. Anthelmintic Therapy 417

Indications It can be used as an alternative drug to albendazole/mebendazole for roundworm or pinworm infections.

Adverse Effects Headache, dizziness, abdominal pain, insomnia, skin rash.

Drug Interactions Piperazine antagonizes pyrantel.

Levamisole Levamisole is an immune stimulant, which is effective against ascaris and hookworm, and may be more effective for intestinal obstruction from roundworms, since it acts by paralyzing the myoneural junction of the worm.

Dose For roundworm in children from 1 month–18 years 2.5–3 mg/kg (maximum 150 mg) as a single dose. For hookworm in children form 1 month to 18 years 2.5 mg/kg (maximum 150 mg) as a single dose repeated after 7 days if severe.

Indications Hookworm, roundworm.

Adverse Effects Headache, dizziness, abdominal pain, vomiting.

Drug Interactions No information.

Precautions Used with caution in patients with liver disease, epilepsy; juvenile idiopathic arthritis; Sjögren’s syndrome.

Ivermectin Ivermectin has broad-spectrum activity against helminthes and filariasis, but is the drug of choice against strongyloidiasis. Ivermectin is well-absorbed orally, accumulating in adipose tissue, metabolized in the liver, highly protein bound with a serum half-life of 12 h and excreted in stool. It is generally well tolerated, with occasional abdominal distension, chest tightness or wheezing. 418 Rational Antimicrobial Practice in Pediatrics

Dose 0.15–0.4 mg/kg/dose oral single dose. For severe crusted scabies in immunodeficient patients: 2 doses of 0.2 mg/kg separated by 2 weeks.

Indications It is the drug of choice for strongyloides stercoralis and onchocerciasis, cutaneous larva migrans and along with albendazole for bancroftian and brugian filariasis. It can also be used as alternative therapy for roundworm and trichuris. It can also be used for scabies and pediculosis.

Adverse Effects Mild pruritus, giddiness, abdominal pain, transient ECG changes, reactions due to degeneration products of microfilariae, arthralgia, skin rash, Stevens Johnson syndrome.

Drug Interaction Increases the effect of warfarin (increased INR).

Precautions Watch for reactions due to degeneration products of microfilariae. Used with caution in liver disorder and Loiasis. Not recommended for children weighing < 15 kg or < 5 years.

Nitazoxanide Nitazoxanide is a new broad-spectrum antimicrobial agent with activity against nematodes, trematodes, anaerobic bacteria and protozoal parasites such as Cryptosporidium. It is metabolized in blood to tizoxanide, which inhibits the key enzyme pyruvate ferredoxin oxidoreductase of target organisms, and is excreted in urine and feces. Adverse effects tend to affect the gastrointestinal tract, but appear to be mild and transient. In view of this wide spectrum of action, single-dose therapy in combination with other drugs is under investigation for community treatment programs.

Dose 12–47 months 100 mg, 4–11 years 200 mg, > 11 years 500 mg Q 12 h for 3 days oral.

Indications It is the drug of choice for cryptosporidiosis. It is also an alternative choice in giardiasis, and fasciola hepatica infections. In clinical trials for hepatitis C in combination with peginterferon alfa-2a.

Adverse Effects Abdominal pain and hyperhidrosis are most frequent. Vomiting, headache, nausea, diarrhea may also occur. Anthelmintic Therapy 419

Drug Interactions Decreases the effect of warfarin.

Precautions Taken with food to reduce gastrointestinal effects. Used with caution in patients with diabetes mellitus, liver and renal diseases.

Praziquantel This anthelmintic drug has predominant activity against the cestodes and trematodes.

Dose 20 mg/kg once oral (tapeworm), Q 4 h x 3 doses (schistosomiasis), Q 8h x 6 doses (other flukes), Q 8 h x 14 days (cysticercosis).

Indications It is the drug of choice for T. saginata, T. solium and also an alternative drug for neurocysticercosis.

Adverse Effects Bitter taste, nausea, abdominal pian, headache, dizziness, sedations, rashes. Fever and body aches can occur as a reaction to dead parasites.

Drug Interactions Phenytoin, carbamazepine and dexamethasone induce metabolism and reduce its bioavailability.

Precautions Patients with neurocysticercosis are often receiving antiepileptics and are at the risk of therapeutic failure of Praziquantel.

Niclosamide This drug is mainly effective against the cestodes.

Dose 50 mg/kg once oral (tapeworm) above 18 years.

Indications It is indicated for H. nana, T. saginata, T. solium.

Adverse Effects Occasional gastrointestinal upset, light-headedness, and pruritus. 420 Rational Antimicrobial Practice in Pediatrics

Drug Interactions Not available.

Precautions Not effective against larval worms. Fears of developing cysticercosis in Taenia solium infections have proved unfounded. All the same, an antiemetic can be given before treatment and a laxative can be given 2 hours after niclosamide.

 DRUG TREATMENT FOR INDIVIDUAL HELMINTIC INFECTIONS See Tables 1 and 2.

TABLE 1 Treatment of intestinal nematode infections Helminths Primary Alternative Comment Ascaris Single dose Mebendazole, albendazole pyrantel pamoate, ivermectin, nitazoxanide Hookworm Albendazole Mebendazole, Albendazole most pyrantel pamoate effective, ivermectin ineffective Enterobius Single dose Single dose pyrantel or Repeat in 2 weeks albendazole mebendazole Trichuris Albendazole Mebendazole/ivermectin Treatment not very for 3 days for 3 days effective Strongyloides Ivermectin for Albendazole twice daily for For hyperinfection repeat 2 days 7 days( not very effective) after 15 days Cutaneous Ivermectin for Albendazole twice daily larva migrans 1-2 days for 3 days Visceral larva Antihistaminics and steroids Anthelmintics migrans Albendazole/mebendazole twice daily for 5 days controversial H. nana Praziquental Niclosamide T. saginata and Praziquental Niclosamide T. solium Cysticercosis Albendazole Praziquental Echinococcus Albendazole Percutaneous aspiration injection reaspiration (PAIR) Anthelmintic Therapy 421

TABLE 2 Drugs for treatment of various helmintic infections Drug Formulation Therapeutic activity Pediatric dosage Albendazole Tab 400 mg Ascariasis +++ 400 mg stat dose Suspension Trichuriasis ++ 200 mg if < 10 kg 200 mg/5 mL Hookworm +++ Strongyloidiasis ++ Ivermectin Tab 6 mg Ascariasis +++ 200 g/kg stat dose Trichuriasis + Strongyloidiasis ++ Levamisole Tab 150 mg Ascariasis +++ 2.5 mg/kg stat dose Trichuriasis + Repeat after 7 days Hookworm ++ Mebendazole Tab 100 mg Ascariasis +++ 500 mg stat dose Syrup 100 mg/5 mL Trichuriasis ++ 100 mg twice for 3 days Hookworm ++ (or 500 mg stat dose) Pyrantel Tab 250 mg Ascariasis +++ 10 mg/kg stat dose Suspension Hookworm ++ (Repeat daily for 4 days) 250 mg/5 mL Praziquantel Tab 600 mg Schistosomiasis +++ 40–60 mg/kg stat dose (All species) or in divided doses

 MASS COMMUNITY ANTHELMINTIC TREATMENT UNICEF, the World Bank and WHO promote routine mass anthelmintic treatment programs as a cost-effective intervention and school-based programs are also popular. Albendazole and praziquantel have broad-spectrum anthelmintic activity against ascariasis, trichuriasis, enterobiasis, hookworm, giardiasis, strongyloidiasis and schistosomiasis at relatively low cost and with low rates of resistance. Mass treatment protocols may reduce the risk of drug resistance by only repeating treatment at intervals greater than the nematode generation time. Old school of thought that deworming should not be done in children under 2 years of age (as well as in pregnancy and lactation) stays invalid now as a WHO Informal Consultation states that children over 12 months of age should be included in deworming campaigns using praziquantel and albendazole/ mebendazole on the basis of improved safety data and risk-benefit analysis. Invasive parasites, which are known to cause malabsorption, weight loss or prolonged diarrhea, such as Giardia, Cryptosporidium and Strongyloides, are the most likely to affect growth, so specific studies have examined this in community settings. Giardia is the most prevalent intestinal protozoan parasite, and certainly can cause persistent diarrhea with malabsorption, weight loss and mucosal damage, but the key public health question is whether the high rates of infection without overt clinical symptoms contribute to poor growth of preschool children in the developing world. Finally, whatever said and done, control of intestinal parasites is more than a question of mass chemotherapy, and is influenced by social 422 Rational Antimicrobial Practice in Pediatrics and cultural factors that affect human behavior, such as treatment seeking and promiscuous defecation.

 RECOMMENDED READING 1. Allen HE, Crompton DW, de Silva N, et al. New policies for using antihelmintics in high risk groups. Trends Parasitol. 2002;18:381-2. 2. American Academy of Pediatrics -AAP Redbook – 2011. 3. British National Formulatory (BNF) for Children- 2012. BMJ Publications Group.RCPCH. 4. Nelson Textbook of Pediatrics , 19th edition 2012. 5. Nelson’s Pediatric Antimicrobial Therapy – 19th edition 2012-2013- American Acdemy of Pediatrics. 6. Rousham EK. Perceptions and treatment of intestinal worms in rural Bangladesh: local differences in knowledge and behaviour. Soc Sci Med. 1994;39:1063-8 7. World Health Organization. Guidelines for the Evaluation of Soil-transmitted Helminthiasis and Schistosomiasis at Community Level: a Guide for Managers of Control Programmes. Geneva: WHO, 1998. Section 3: Case ScenariosAntimicrobial in Antimicrobial Therapy: Illustrative Therapy Cases 423 3535 Antimicrobial Therapy: Illustrative Cases Tanu Singhal

 INTRODUCTION We have till this point deliberated a great deal on individual antimicrobials and antimicrobial therapy of common childhood illnesses. However, it is not often easy to make a choice in the practical setting. The objective of this chapter is to critically assess the choice of antimicrobials in various common case scenarios and suggest what might be the right choice in that setting.

 CASE 1 A 1-year-old child, with normal weight for age, presents with loose stools of 1-day duration. Stools are watery and 15–20 times per day. There is mucus but no blood. The child has fever upto 101°F, is vomiting and not accepting orally. She is brought to hospital and found to have some dehydration. She is admitted and treatment with intravenous fluids, intravenous amikacin and intravenous metronidazole is started. Stool routine examination showed 5–6 WBC and 2–3 RBC per high power field and cysts of Entamoeba histolytica.

Is antimicrobial therapy needed and is the choice appropriate? The possible etiologies of acute watery diarrhea of the above description in an infant are predominantly viruses and E coli. Antibiotics are not of any value in therapy of diarrhea caused by these organisms. Few fecal WBC and RBC can be present in any infective diarrhea and do not indicate invasive diarrhea meriting antibiotic therapy. The presence of cysts of E. histolytica is not indicative of amebic dysentery as these might represent non-pathogenic E. histolytica dispar. For diagnosis of amebic dysentery, it is essential to demonstrate the trophozoite form in a fresh stool sample. E. histolytica is responsible for less than 3% of diarrhea in children from developing countries. 424 Rational Antimicrobial Practice in Pediatrics

Antibiotics are definitely indicated in the management of diarrhea caused by Shigella, which usually presents as bloody dysentery. But even for shigella, aminoglycosides are inappropriate agents and do not work in vivo despite in vitro susceptibility. Antibiotics in case of diarrhea are indicated for bloody diarrhea and a child with severe malnutrition (as there may be associated systemic sepsis). Recommended therapeutic agents are quinolones, azithromycin or oral third generation cephalosporins. Oral colistin is often used for diarrhea but is not of any therapeutic benefit. To conclude this case and most cases of diarrhea with the exception of bloody diarrhea/ cholera/proven amebic dysentery do not merit any antibiotic therapy. Use of antibiotics only increases cost of therapy, adverse effects and contributes to antibiotic resistance.

Recommended Reading 1. The treatment of diarrhea. A manual for physicians and other senior health workers. 2005 WHO/CDD/ SER/80.2

 CASE 2 A 4-year-old child presents with fever, coryza, cough and difficulty in swallowing. His younger sib had a similar sickness few days back. On examination, he has enlarged congested tonsils and small cervical nodes. A throat swab culture is sent and he is started on oral amoxicillin. Two days later, he is slightly better and throat swab culture shows beta hemolytic streptococcus resistant to penicillin. Antibiotics are changed to coamoxiclav, which is then continued for the next 5 days.

What is the likely etiology for his sore throat? This clinical presentation is typical of a viral upper respiratory tract infection because of associated cough and coryza, presence of a similarly sick contact in the family and absence of features typical of a bacterial sore throat such as pus points on the tonsils/ flushing of the tonsillar anterior pillar.

Is sending a throat swab culture and starting antibiotics justified? Fifteen percent of the normal population carries beta hemolytic streptococcus in its throat as a normal commensal. A throat swab should be restricted to patients who present with a presumptive diagnosis of bacterial sore throat else it may pick up those cases where beta hemolytic streptococcus is only a commensal and hence lead to unjustified antibiotic therapy. This is what has happened in the index case.

Comment on the antibiotic sensitivity report of the isolate Group A beta hemolytic streptococcus is universally sensitive to penicillin with no resistance reported till date. Hence the laboratory should be asked to re-check the sensitivity report. Antibiotic therapy was not justified in this case right from the beginning and changing to coamoxiclav is even worse! Antimicrobial Therapy: Illustrative Cases 425

Recommended Reading 1. Biso AL, Gerber MA, Gwaltney JM Jr, Kaplan EL, Schwartz RH, Practice guidelines for the diagnosis and management of Group A Streptococcal pharyngitis. Infectious Diseases Society of America. Clin Infect Dis. 2002; 35: 113-25.

 CASE 3 A 6-year-old child presents with progressively increasing fever and cough of 5 days duration. There is no associated coryza. He has been taking antipyretics and cough suppressants with no improvement. On examination, he has mild tachypnea and few scattered crepitations. The complete blood count shows a Hb of 10 g/dL, a TLC of 14,000 with 60% polymorphs. CXR shows a few scattered infiltrates. He is put on tablet cefixime in a dose of 10 mg/kg/day. Two days later, he is not better.

What is the diagnosis and what are the likely organisms? This is a case of community-acquired pneumonia (CAP). The most common causes of CAP in children above the age of 5 years are S. pneumoniae, M. pneumoniae and respiratory viruses. The white cell count is not a reliable indicator of etiology in this setting.

Comment on choice of antibiotics and what would be a rational choice? In the absence of definitive etiologic diagnosis, antibiotics in CAP are prescribed on the basis of epidemiologic information and the clinical presentation. This usually means cover for pneumococcus and/or M. pneumoniae. In the index case, the initial antibiotic should at least cover pneumococcus. Cefixime a third generation cephalosporin has poor activity against S. pneumoniae. An acceptable drug would be amoxycillin. In the event of non-response in 48–72 hours or deterioration, antibiotic therapy may be switched to an antibiotic effective against M. pneumoniae such as azithromycin/ clarithromycin. An alternative reason for non-response could be drug resistant S. pneumoniae. However, since the prevalence of DRSP in India is at present low, this less likely. Using one of the macrolide as initial therapy covers both pneumococcus/ atypical pathogens but the caveat is 30% resistance in S. pneumoniae to macrolides (unpublished data, Hinduja Hospital). If the index case would be sick and require inpatient care then using a dual cover for both pathogens right at onset is desirable. In this scenario intravenous (IV) ceftriaxone/high dose amoxycillin with IV azithromycin/ clarithromycin is justified.

Recommended Reading 1. McIntosh K. Community-acquired pneumonia in children. N Engl J Med. 2002; 346: 429-37. 2. Prospective multicentre hospital surveillance of Streptococcus pneumoniae disease in India. Invasive Bacterial Infection Surveillance (IBIS) Group, International Clinical Epidemiology Network (INCLEN). Lancet. 1999; 353: 1216-21. 426 Rational Antimicrobial Practice in Pediatrics

 CASE 4 A 10-year-old child from Mumbai presents with high-grade fever of 6 days duration. He has poor appetite and has a toxic look. Physical examination is unremarkable. CBC shows a Hb of 10 g%, TLC of 5400 with 60% polymorphs, no eosinophils and normal platelets. Malarial parasites are not seen on peripheral smear. A presumptive diagnosis of enteric fever is made, blood culture is sent and ciprofloxacin started in a dose of 15 mg/kg/day. Culture is positive at 72 hours for salmonella typhi sensitive to all antibiotics including ciprofloxacin. Ciprofloxacin is continued but at day 7 the child is still spiking.

Comment on ciprofloxacin as choice for empirical antibiotic therapy The quinolones have been extensively used in Mumbai for enteric fever since the early 1990’s. There is increasing resistance to quinolones in Mumbai, a pattern seen in most places in India as well. The prevalence of nalidixic acid resistance in S. typhi in most laboratories (which is a surrogate indicator of quinolone resistance) is to the tune of 8090%. This resistance can sometimes but not always be overcome by giving high doses of quinolones (30 mg/kg/day) but raises safety concerns in pediatric age group. In this scenario use of ciprofloxacin as empirical therapy for enteric fever is inappropriate. With increasing quinolone resistance, there is also seen a return of sensitivity to other drugs such as amoxicillin, cotrimoxazole and chloramphenicol (90% sensitivity in Mumbai). Hence acceptable choice for empirical therapy would be oral cefixime (20 mg/kg/day), azithromycin (10-20 mg/kg/day), cotrimoxazole or amoxicillin.

What is the reason for continued fever despite in vitro sensitivity to ciprofloxacin? Paradoxically, despite clinical resistance to quinolones the lab continues to report strains as sensitive. This is because the current MIC’s/ disc diffusion diameters are still below the NCCLS susceptibility breakpoints. It has also been shown that resistance to nalidixic acid on routine disc diffusion methods is a surrogate marker for high ciprofloxacin MIC’s and predicts clinical failure to quinolones. In the index case, nalidixic acid sensitivity was not done by the laboratory. Therefore, it is possible that the isolate was really quinolone resistant and hence the clinical non-response.

Nalidixic acid sensitivity was asked for and reported as resistant. What should be the alternative therapy? It depends on the clinical condition. As an inpatient, IV ceftriaxone followed by a switch to oral cefixime on defervescence is an option. The total duration of therapy should be 14 days to prevent relapses. For outpatient therapy oral cefixime/oral cotrimoxazole for 14 days or oral azithromycin for 7 days may be considered. Antimicrobial Therapy: Illustrative Cases 427

Recommended Reading 1. Crump JA, Barrett TJ, Nelson JT, Angulo FJ. Reevaluating fluoroquinolone breakpoints for Salmonella enterica serotype Typhi and for non-Typhi salmonellae. Clin Infect Dis. 2003; 37:75-81. 2. Kapil A, Renuka, Das B. Nalidixic acid susceptibility test to screen ciprofloxacin resistance in Salmonella typhi. Indian J Med Res. 2002; 115: 49-54. 3. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid Fever. N Eng J Med 2002; 347: 1770-82. 4. Rodrigues C, Shenai S, Mehta A. Enteric fever in Mumbai, India: the good news and the bad news. Clin Infect Dis. 2003; 36: 535.

 CASE 5 A 5-year-old child presents to the outpatient department with fever of 3 days duration. He has pallor and spleen tip is palpable. Peripheral smear shows P. vivax and occasional ring forms of P. falciparum (Parasite index 0.1%). He is stable having no complicating features. He is given single dose pyrimethamine/ sulfadoxine (SP). Two days later fever is still present, and peripheral smear still shows both P. vivax and P. falciparum.

Is the initial choice of antimalarial appropriate? We are dealing with a case of uncomplicated mixed malaria. We need to give an antimalarial effective against both species especially falciparum. There is high prevalence of resistance in P. falciparum against SP (as also against chloroquine and to some extent mefloquine) in many areas. Additionally SP has the least efficacy of all antimalarials against P. vivax. Therapy of P. vivax with SP has been associated with delayed and incomplete parasite clearance and high relapse and recrudescence rates. It is dangerous to withhold correct medicine in a case of suspected case of falciparum malaria.

Which antimalarial should be used for treating uncomplicated mixed infection? For P. falciparum chloroquine and SP are inappropriate due to high prevalence of resistance. For P. vivax both SP and quinine are associated with delayed defervescence, high relapse and recrudescence rates. Hence mixed malaria should be treated as falciparum malaria with artemisinin combination therapy (artemether lumefantrine for 3 days). It must be remembered that use of ACT may be associated with higher rates of recrudescence in vivax malaria and better ACT for vivax malaria such as combinations of dihydroartemisinin with piperaquine are awaited. None of these drugs lead to radical cure of vivax malaria hence treatment needs to be followed up with two weeks of primaquine.

Recommended Reading 1. Pukrittayakamee S, Chantra A, Simpson JA, Vanijanonta S, Clemens R, Looareesuwan S, White NJ. Therapeutic responses to different antimalarial drugs in vivax malaria. Antimicrob Agents Chemother. 2000; 44:1680-5. 2. WHO. Guidelines for treatment of malaria. 2nd edition, 2010. Available at www.who.int/malaria/docs/ TreatmentGuidelines2010.pdf 428 Rational Antimicrobial Practice in Pediatrics

 CASE 6 A 10-year-old child presents with large number of pustules on face and legs. He is non-toxic. He is started on oral ciprofloxacin. There is only 50% reduction in severity after 5 days therapy.

Comment on the choice of initial antibiotic? S. aureus is the likely etiologic agent. Though S. aureus shows frequent in vitro susceptibility to the quinolones, they should not be used routinely in the management of S. aureus infections. They are not very effective in vivo and there is rapid emergence of drug resistance with quinolone monotherapy.

What should be the initial choice for therapy? For few lesions/local disease, topical therapy with mupirocin/sodium fusidate usually suffices. For generalized lesions, available choices include cloxacillin/coamoxiclav/1st generation cephalosporins such as cephalexin and cefadroxil. Cloxacillin is the most specific, narrowest spectrum and cheapest option. Potential disadvantages are variable oral bioavailability and non-availability as a syrup formulation. Coamoxiclav is effective but broad spectrum but very expensive. The 1st generation cephalosporins are intermediate between cloxacillin and coamoxyclav in cost and spectrum of activity. Cefadroxil may be preferred owing to its twice daily dosing viz that of cephalexin which needs to be given 3-4 times a day.

Therapy is changed to cloxacillin with no significant improvement. What are the possibilities now? There could be issues of dosing and compliance, which need to be sorted out. However, there are increasing numbers of cases of community acquired MRSA being reported. Studies from South India have reported a prevalence of 10-20% in patients presenting with pyoderma. Hence for non-response, cultures from the pustules should be sent to determine methicillin sensitivity. Community acquired MRSA strains unlike hospital MRSA are usually sensitive to other drugs like erythromycin and clindamycin. Antibiotics can then be changed as per results of sensitivity.

Recommended Reading 1. Cruciani M, Bassetti D. The fluoroquinolones as treatment for infections caused by gram-positive bacteria. J Antimicrob Chemother. 1994; 33: 403-17. 2. Nagaraju U, Bhat G, Kuruvila M, Pai GS, Jayalakshmi, Babu RP. Methicillin-resistant Staphylococcus aureus in community-acquired pyoderma. Int J Dermatol. 2004; 43: 412-4.

 CASE 7 A primigravida undergoes an emergency LSCS at 38 weeks of gestation for fetal distress. The duration of membrane rupture is 1 hour. The baby is 2.2 kg with no birth asphyxia. He is kept in the NICU of a tertiary hospital for routine monitoring of blood sugars and also given IV cefotaxime for 3 days prophylactically and discharged on day 5. Antimicrobial Therapy: Illustrative Cases 429

Comment on choice of antibiotic for prophylaxis of neonatal sepsis Prophylactic antibiotics are often administered to neonates in the presence of maternal fever or signs of chorioamnionitis or prolonged rupture of membranes till neonatal sepsis has been excluded by relevant tests. In the index case as none of these factors are present, there is no indication for antibiotic therapy and so the issue of choice of antibiotic becomes irrelevant. In fact such practice can prove dangerous at times (see further).

This child is readmitted on day 7 with fever, irritability and excessive crying. The fontanelle is bulging and the skin is mottled. Septic screen is positive and CSF is suggestive of pyogenic meningitis. CSF and Blood cultures have been sent and child started on IV ceftazidime and amikacin.

Is the choice of antibiotic appropriate? This baby has sepsis, meningitis and early septic shock. The likely etiologic agents are E. coli and Klebsiella of possible nosocomial origin. Additionally, the organism could be an extended spectrum beta lactamase producer since the child may have acquired infection in the NICU of a tertiary care hospital and there is history of exposure to 3rd generation cephalosporins. Hence we need an antibiotic that will provide a good cover for ESBL producing E. coli and Klebsiella and cross the CNS. Also the infection is very serious with a high risk of immediate mortality and long-term morbidity. Therefore it is important to get the antibiotic right the first time, as there is no room for upgradation in case of non-response or after receiving culture reports. Ceftazidime is inappropriate in this respect that it does not cover for ESBL.

What should be the appropriate antibiotic in this scenario? Available options for treating ESBL infections include cefepime, beta lactam-beta lactamase inhibitor combinations and carbapenems. Cefepime a fourth generation cephalosporin has some stability against ESBL but is susceptible to an inoculum effect. If the organism burden is high the MIC rises; it is therefore not recommended for serious ESBL infections with high organism burden as in this scenario. The beta lactam-beta lactamase inhibitor combinations also exhibit the inoculum effect; there is not enough evidence for their efficacy in serious ESBL infections and finally the betalactamase inhibitor does not cross the CNS. Hence they too are inappropriate in this scenario. The carbapenems are the drugs of choice for serious ESBL infections cross the CNS. Imipenem cilastatin should not be used for treating meningitis due to risk of seizures. Therefore the choice is meropenem in maximum permissible doses (40 mg/kg 8 hourly) for a period of 3 weeks. Once culture reports are available, antibiotics can be suitably de-escalated.

Should meropenem be given as monotherapy or as combination therapy? Meropenem is a very broad-spectrum drug and can be safely given as monotherapy. There is no need to add an aminoglycoside to the regimen as it will probably only add to toxicity with no increase in efficacy. Meropenem does not cover MRSA and 430 Rational Antimicrobial Practice in Pediatrics hence if MRSA is of concern vancomycin/linezolid may be added to broaden the empirical spectrum. However, the scenario described above is in all likelihood the consequence of a gram-negative infection so empirical MRSA cover is probably not justified.

Recommended Reading 1. Gerdes JS. Diagnosis and management of bacterial infections in the neonate. Pediatr Clin North Am. 2004; 51: 939-59. 2. Martin SI, Kaye KM. Beta-lactam antibiotics: Newer formulations and newer agents. Infect Dis Clin North Am. 2004; 18: 603-19. 3. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: A clinical update. Clin Microbiol Rev. 2005; 18: 657-86.

 CASE 8 A 7-year-old child presented to the hospital with severe abdominal pain of 3 days duration associated with fever and vomiting. On examination, he has tachycardia, tachypnea, fever and hypotension. The abdomen shows board like rigidity with absent bowel sounds. A diagnosis of acute appendicitis with perforation, secondary bacterial peritonitis with septic shock and acute respiratory distress syndrome is made and the child resuscitated with fluids, antibiotics (cefotaxime and metronidazole), ventilated and taken for urgent surgical exploration. Postoperatively, he is on the ventilator, having a jugular central venous line and urinary catheter. He steadily improves and by day 7 inotropes have been stopped and there is no fever. However, weaning from the ventilator is still not possible. Tracheal cultures are sent, there is no leukocytosis or new infiltrates on the CXR. Tracheal cultures show P. aeruginosa, colony count 105/mL sensitive to meropenem and colistin and resistant to all other antibiotics. Antibiotics are changed to meropenem and metronidazole.

Is this change of antibiotics appropriate? There is no evidence of ventilator-associated pneumonia as there is no fever/leucocytosis/ purulent secretions or new CXR infiltrates. There is an alternative cause for inability to wean the patient from the ventilator. Sending tracheal secretions for culture was not indicated and the Pseudomonas is a colonizer. Hence change of antibiotics is not justified.

Five days later this child is still on the ventilator and starts running fever. Tracheal secretions increase in quantity and are purulent. CBC shows a count of 16,000 with 80% polymorphs and CXR shows right lower zone consolidation. Tracheal secretions again grow P. aeruginosa 105/mL but now resistant to meropenem and only sensitive to colistin.

How should this infection be treated? This child now definitely has a ventilator-associated pneumonia. Unfortunately due to inappropriate antibiotic therapy earlier a valuable treatment option is lost. Carbapenem resistance in pseudomonas occurs readily following drug pressure due to induction of carbapenemases or activation of the drug efflux pump that pumps the meropenem out Antimicrobial Therapy: Illustrative Cases 431 of the bacterial cell. Treatment options now are confined to colistin. The microbiology laboratory should also be asked to check for sensitivity to imipenem if not already done as sometimes there may be discordance in sensitivity to different carbapenems due to different mechanisms of resistance. This case shows us clearly why not to mess with antibiotics in a desperate situation and land up in to a situation where nothing will work!

Recommended Reading 1. Fagon JY. Hospital-acquired pneumonia: diagnostic strategies: Lessons from clinical trials. Infect Dis Clin North Am. 2003; 17: 717-26. 2. Falagas ME, Kasiakou SK. Colistin: The revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005; 40: 1333-41. 3. Martin SI, Kaye KM. Beta-lactam antibiotics: Newer formulations and newer agents. Infect Dis Clin North Am. 2004; 18: 603-19.

 CASE 9 A 7-year-old child is admitted to the ICU with dengue hemorrhagic fever with shock. He is resuscitated with fluids and inotropes and intensively monitored. He has an indwelling central line, an arterial line and an indwelling urinary catheter but is not on the ventilator. He is also on cefotaxime and amikacin, which had been started empirically on admission and have still been continued. Patient improves gradually but by day 7 starts running fever again after a 3-day intervening afebrile period. Clinically, he is non-toxic. Nosocomial infection is thought of and complete blood count, paired cultures (central line and peripheral blood), urine routine and urine cultures, CXR and CBC sent. CBC, CXR and urine routine are normal, central line culture shows coagulase negative staphylococcus (CONS) and urine culture shows candida albicans 1000 colonies/mL. Peripheral blood culture is sterile. He is put on IV Vancomycin and IV fluconazole but fever persists even 48 hours later.

Comment on line of management and choice of antimicrobials? This child should not have received cefotaxime and amikacin in the first instance. If they were started before establishing a diagnosis of DHF, they should have been stopped once a diagnosis was made. Administration of these antibiotics will lead to selection of resistant organisms in the child and consequent risk of infection with more resistant organisms. Later, a positive central line culture alone is poorly predictive of a catheter related bloodstream infection especially if the pathogen is CONS and more likely to represent colonization of the catheter. Similarly colonization of the urinary tract with Candida is fairly common in a catheterized patient on broad-spectrum antibiotics. In the absence of local symptoms and normal urine routine as in the index case the Candida is also a colonizer.

What should be the line of management in this scenario? The index case is non-toxic, stable and has no leucocytosis. He also probably does not need the central line and indwelling catheter at this juncture. It will therefore be 432 Rational Antimicrobial Practice in Pediatrics appropriate to remove both the catheters, stop the broad-spectrum antibiotics and observe. This is sufficient to get rid of both the colonizers (CONS and Candida). If fever persists a fresh search for etiology can be made. However, if the same index case had accompanying toxicity and organ dysfunction with fever, nosocomial infection is high on the cards. The child, then, should be started empirically on broad-spectrum antibiotics based on the local experience with the ICU flora and sensitivity including a gram negative cover, gram-positive and fungal cover (since the Candida isolation from a non-sterile site may be a marker of invasive candidiasis). Here the antifungal would be given to cover for possible candidemia and not for a UTI.

Recommended Reading 1. Lundstrom T, Sobel J. Nosocomial candiduria: A review. Clin Infect Dis. 2001;32:1602-7. 2. Mermel LA, Farr BM, Sheretz RJ, Raad I, O’Grady N, Harris JS, Craven DE. Guidelines for the management of intravascular catheter- related infections. Clinical Infectious Diseases. 2001;32:1249- 72. Section 4: Ready ReckonerAntimicrobial for Dosage Formulary of 433 Antimicrobial Drugs 36 Antimicrobial Formulary Suhas Prabhu

 ABBREVIATIONS Tab = Tablet (amount per tablet) DT = Dispersible tablet (amount per tablet) Cap = Capsule (amount per capsule) Syp = Syrup/Suspension (amount per 5 mL) Drp = Drops (amount per mL) Inj = Injection (amount per vial or per mL as stated) Cre = Cream (amount % w/w) Oint = Ointment/Cream (amount % w/w) Lot = Lotion (amount % w/w) N = Newborn P = Premature baby M = Maximum (Ceiling) dose (per day) Dosage is in mg/kg/dose unless otherwise stated od = Once in a day bd = Twice a day tds = Thrice in a day qds = Four times a day d = Day(s) * Safe for use in breastfeeding mother, ! Contraindicated in breastfeeding mother ? Not enough data on use in breastfeeding mother 434 Rational Antimicrobial Practice in Pediatrics

 ANTIBACTERIAL AGENTS Name Formulations Dosage & Adverse Drug Interactions Interval Effects PENICILLINS A. Penicillinase susceptible Amoxicillin * Inj: 250, 500 mg. Oral: N; 10–20 Anaphylactic, Probenecid Cap/Tab/DT: 125, mg/kg bd. > 1 allergic reactions, increases 250, 500 mg. wk 10–15 mg/kg drug fever, rash, amoxicillin levels Syp: 125, 250 tds If penicillin (esp. with inf. mg/5 mL Drp: resistance mononucleosis), 100 mg/mL suspected 20–30 urticaria, perioral mg/kg tds Inj: edema, nausea, 30-50 mg/kg tds epigastric distress, diarrhea less common Ampicillin * Inj: Vial 250, 500, IV (or IM) N: Nausea, Chloroquine 1000 mg.Cap/ 50 mg/kg bd. epigastric reduces ampicillin Tab/DT: 125, 250, 1–4 wks 37.5–50 distress, absorption. 500 mg. Syr: 125, mg/kg qds. Upto diarrhea, Probenecid 250 mg/5 mL. 100 mg/kg qds in anaphylactic and increases Drp: 100 mg/mL Gr. B Strep. allergic reactions, ampicillin levels. Infection or men- drug fever, rash Prolongation of ingitis. > 4 wks (esp. with inf. prothrombin time 50–100 mg/kg qds. mononucleosis), with Warfarin. Oral: 12.5–25 urticaria. With allopurinol mg/kg qds. increased (Up to 100 mg/kg frequency of qds in serious skin rashes. infections) M=12000 Penicillin G * Inj. 500,000 units/ Inj IV: N: 25 mg/kg Anaphylactic and Guar gum reduces vial (300 mg)Tab. bd.1–4 wks 25 allergic reactions, absorption, 200,000, 400,000, mg/kg tds. > 4 wks drug fever, rash, Probenecid 800,000 units 25 mg/kg qds. urticaria, joint (20 mg/kg bd 600 mg = Serious infections: pains, serum M=1000 mg) 1,000,000 N: 50 mg/kg bd. sickness, Jarisch- delays excretion units (1 megaU) 1–4 wks 50 mg/ Herxheimer or 1 unit = kg tds. > 4 wks reaction, 1666 mg 45–75 mg/kg qds. neutropenia, encephalopathy, convulsions after high doses Phenoxymethyl Tab: 125 mg Oral: < 1 yr old As above Guar gum, penicillin * 250 mg 62.5 mg qds Neomycin, reduce 1–5 yrs 125 mg absorption. qds, 6–12 yrs Probenecid (20 250 mg qds, mg/kg bd M= 12–18 yrs old 1000 mg) delays 500 mg qds. 750 excretion mg qds for severe infections

Contd... Antimicrobial Formulary 435

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects Procaine Inj: Procaine Pen. 60 mg/kg od As above. Probenecid (20 Penicillin 300,000 units + IM M=2400 mg Additionally mg/kg bd M= (usually in Penicillin G procaine 1000 mg) delays combination 100,000 units. sensitivity excretion with Penicillin G)* Procaine Pen. possible 600,000 units + Penicillin G 400,000 units. Procaine Pen. 800,000 units + Penicillin G Benzathine Inj: 600,000 units, < 2 yrs 60,000 As for Penicillin G Penicillin * 12,000,000 units units/kg, 2–9 and 24,000,000 yrs (< 30 kg) units 600,000 units, > 30 kg 1,200,000 units single dose deep im Piperacillin * Inj 1000, 2000, I.V (by infusion or Anaphylactic and Probenecid 4000 mg slow inj.) P: < 2 allergic reactions, delays excretion, kg < 7 d 75 mg/kg drug fever, Inactivates bd, N: 100 mg/kg rash, leukopenia, aminoglycosides tds; > 28 d old: convulsions with Warfarin incr. INR 50–75 mg/kg tds high doses or qds M = 16000 B. Penicillinase Resistant Cloxacillin * Inj. 250, 500 mg. Oral or IV: Anaphylactic and Loss of potency Cap: 250, 500 mg. 12.5–50 mg/kg allergic reactions, when mixed with Syr: 125 mg/5 mL qds (4 hrly in drug fever, rash, aminoglycosides meningitis and urticaria, joint erythromycin, endocarditis) pains, serum Polymixin B, M = 12000 sickness, GI Vitamin C. upsets Sulpha, aspirin inhibit protein binding, increasing free Cloxacillin level C. Penicillins with Beta lactamase inhibitors Amoxicillin- clavulanate * Inj: (Amoxy. + Dosed on the Anaphylactic and Probenecid Clavulanate) amoxicillin allergic reactions, increases 1000 + 200, 500 + component Oral: drug fever, rash, amoxicillin levels 100, 250 + 50 N; 10–15 mg/kg urticaria, perioral Tab: 500 + 125, bd. > 1 wk 10–15 edema. Nausea, 400 + 57, 250 + mg/kg tds Inj: epigastric distress,

Contd... 436 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects

125, 200 + 28.5, 30 mg–50/kg tds diarrhea more Syr: 400 + 57, common 200 + 28.5, 125 + 31.25 Ampicillin – Inj. Ampicillin Calculated on Gastritis, Probenecid Sulbactam * 1000, 500 + ampicillin IV N: diarrhea, increases Sulbactam 500, 50 mg/kg bd. anaphylactic and ampicillin levels. 250. Tab: 1–4 wks 37.5–50 anaphylactic and Prolongation of Ampicillin 220 + mg/kg qds. > allergic reactions, prothrombin time Sulbactam 147 4 wks 50–100 drug fever, rash, with Warfarin. mg/kg qds. Oral: urticaria 15 mg/kg qds. M=12000 mg Piperacillin - Vials 2000 mg Dosed on Anaphylactic and Probenecid tazobactam * piperacillin + 250 piperacillin allergic reactions, delays excretion, mg tazobactam; component rug fever, Inactivates 4000 mg By IV infusion rash, leukopenia, aminoglycosides piperacillin + N: 90 mg/kg tds. convulsions with Warfarin incr. INR 500 mg Child: 50–100 high doses tazobactam mg/kg tds. M = 16000 Ticarcillin- Ticarcillin 3000 < 2 kg: 0-7 days Sodium clavulanate mg+ clavulanate 75 mg/kg bd, overload, 100 mg 8–28 days 75 diarrhea, mg/kg tds> 2 kg: cholestatic 0–7 days 75 mg/ hepatitis kg tds, 8-28 days 75 mg/kg qds Children: 50 mg/ kg qds M= 18000 CEPHALO- SPORINS 1st Generation Cephalexin * Cap/Tab/DT: 10–25 mg/kg qds Diarrhea, Probenecid 125, 250, 500 M=4000 mg dyspepsia, increases levels mg.Syp: 125, rarely nausea, 250 mg/5mL vomiting. Allergic Drp: 100 mg/mL reactions (rash,urticaria and angioed- ema) uncommon. Rarely heada- che, dizziness and fatigue. Cefadroxil * Cap/Tab/DT: 125, 10–20 mg/kg bd Rash, pruritis, Probenecid 250, 500 1000 M = 2000 mg urticaria, increases blood mg. Syp: 125, angiedema levels which may 250 mg/5mL rare. Rarely cause Drp: 100 mg/mL diarrhea, nephrotoxicity

Contd... Antimicrobial Formulary 437

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects

dyspepsia, nausea, vomiting, fatigue, headache, dizziness. Reversible neutropenia, mild elevation in transaminases and Stevens- Johnson Syndrome. Cefazolin * Vials: 125, 250, 12.5–25 mg/kg qds Skin rash, Probenecid 500, 1000 M=12000 mg eosinophilia, increases levels convulsions, bone of Cefazolin. marrow Prolongation of suppression prothrombin time with Warfarin. Nephrotoxicity with aminoglycosides CEPHALOSP- ORINS 2nd Generation Cefaclor * Tab/DT/Cap 250, 7–15 mg/kg tds. Diarrhea, Probenecid 375, 500 Syp 125, M = 1000 vomiting, skin increases levels. 187.5, 250 mg/ rash, urticaria, Prolongation of 5 mL. Drp 50 mg/ pruritus, prothrombin time mL eosinophilia, with Warfarin. May cause Nephrotoxicity serum sickness with like reactions. aminoglycosides Cefuroxime * Inj: Vials 500, Inj. IV N: 30 Hypersensitivity Increased 750, 1500 mg mg/kg bd reactions chances of Tab: 125, 250, 1–4 wks. 30 mg/kg including nephrotoxicity 500, 750 mg tds. (up to 50 mg/ rashes and when using high Syr: 125 mg/5 mL kg in severe inf.) fever. doses along > 4 wks 25–75 Gastrointestinal frusemide and/or mg/kg bd or tds disturbances like aminoglycosides. (50–100 mg/kg nausea, diarrhea in severe inf.) and vomiting. M=6000 mg. Rarely transient Oral: 10–20 mg/ rises in liver kg bd or tds function tests. CEPHALOS- PORINS 3rd Generation Cefotaxime * Inj vial 125, 250, P: < 2 Kg < 7 d Nausea, vomiting, Probenecid 500, 1000, 1500 50 - 100 mg/kg skin rash, drug delays excretion,

Contd... 438 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects bd, > 7 d tds. fever, anaphy- incr. risk of Child: 12.5–50 laxis, leukopenia, bleeding with mg/kg qds thrombocytopenia, Warfarin M=12000 local pain Ceftriaxone * Inj: Vial 100, IM or IV 50–100 Pain at inj. site. Increased 125, 200, 250, mg/kg od or 25–50 Hypersensitivity: chances of 500, 750, 1000, mg/kg bd. skin rashes, drug nephrotoxicity 2000 M = 4000 mg fever and very with concomitant rarely anaphyl- use of Frusemide, axis. Transient Aminoglycosides. rise in liver Antagonism of enzymes, biliary bacterial killing by sludge Chloramphenicol formation. Diarrhea and pseudomemb- ranous colitis rarely. Nephro- toxicity with high doses, neutropenia, thrombocytope- nia, hemolytic anemia may occur. Ceftizoxime * Vials 200, 1000 Child 30-50 mg/ Pain at inj. site, Probenecid slows kg tds rash, excretion, incr. M=12000 neutropenia, risk of bleeding thrombocytop- with Warfarin, Incr. enia, eosinophilia chances of with nephrotoxicity aminoglycosides. Ceftazidime * Vials 250, 500, IV, IM N: < 7 Pain at inj. site, Possible 1000 days and > 7 days rash, antagonism of < 1200 gm 30–50 neutropenia, effect with mg/kg bd > 7 thrombocytope- chloramphenic- days > 1200 gm nia,eosinophilia, olIncr. risk with 30–50 mg/kg tds positive Coomb’s other nephrotoxic Child: 25-50 mg/ test drugs. Chemical kg tds M = 6000 inactivation if mixed with aminoglycosides Cefoperazone * Vials: 250, 500, 50-100 mg/kg bd Skin rash, Probenecid 1000, 2000 M=4000 urticaria, Incr. increases levels. liver enzymes, Incr. chances reversible of nephrotoxicity neutropenia, with frusemide, GI upset, aminoglycosides. hypoprothrom- Antagonism of binemia bacterial killing by Chloramphenicol

Contd... Antimicrobial Formulary 439

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects

Cefixime * Tab / DT 100, 4 mg/kg bd Mild changes in False positive 200, 400. Syp. or 8 mg/kg od liver and renal reaction with 50 mg/5 mL, 10 mg/kg bd for function tests. Benedicts test in 100 mg/5 mL enteric fever Diarrhea, urine M=1200 abdominal pain, nausea, vomiting, rash and headache. Thrombocytop- enia, leukopenia, eosinophilia, pseudomembra- nous colitis (rare) and hypersensi- tivity reactions. Cefpodoxime * Tab/DT: 50, 100, Oral: 4.5 mg/kg Diarrhea, Absorption 200 mg Syr: 50, bd or 9 mg/kg od nausea, decreased by 100 mg/5 mL M = 400 mg vomiting, antacids or abdominal pain. histamine H2 Occasionally antagonists. headache, allergic rections. Cefdinir * Cap/Tab 300 Syp 7 mg/kg bd or Abd. pain, Therapeutic iron 125 mg/ 5 ml. 14 mg/kg od diarrhea, and antacids M = 600 mg nausea, reduce vomiting, absorption. constipation. Frusemide incr. Headache, nephrotoxicity. dizziness, Probenecid insomnia, delays excretion. somnolence, confusion, rash, pruritus. Hypotension, palpitation, anaphylaxis, angiedema. CEPHALOS- PORINS 4th Generation Cefepime ? Inj 250, 500, I.v. 50 mg/kg bd Pain, inflammation Probencid delays 1000, 2000 or tds (for severe at inj. Site, rash, excretion. Incr. infections) pruritus, fever, nephrotoxicity M =6000 G-I upset, CNS with frusemide, symptoms, aminoglycosides hemolytic anemia

Contd... 440 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects

Cefpirome ? Inj. 250, 500, IV or IM 50 Alteration of taste, Incompatible with 1000 mg/kg bd nausea, NaHCO3. M = 4000 abdominal pain, Probenecid constipation, delays excretion. diarrhea, Incr. pseudo- nephrotoxicity membranous with frusemide, colitis, aminoglycosides hypersensitivity reactions, neutropenia, eosinophilia, hemolytic anemia, transient mild changes in liver and renal function tests CEPHALOSPO- RINS WITH BETALACTAM INHIBITORS Cefoperazone – Cefoperazone 25-50 mg/kg As for As for Sulbactam * 500+ Sulbactam bd of Cefoperazone Cefoperazone 500; cefoperazone, Cefoperazone M = 6000 mg 1000 + Sulbactam 1000 Cefepime- Cefepime 1000 + 50 mg/kg bd As for cefepime As for cefepime Tazobactam tazobactam M= 4000 mg of 125 mg cefepime MONOBACTAMS Aztreonam ! Vial 250, 500, IV 30 mg/kg P: Local reaction at Incompatible in 1000, 2000 < 7d < 2 Kg bd, injection site, solutions with > 7d < 2 Kg & < & altered taste, metronidazole or < 7d > 2 Kg tds, jaundice, rash. vancomycin. Incr. > 7 d > 2 Kg qds Thrombocytop- effect of Warfarin M=8000 enia, neutropenia may occur GLYCOPEPTI- Vials 500, 1000 By IV infusion, Flushing soon Additive effect DES, 15 mg/kg od in after infusion, with other drugs LIPOPEPTIDES P < 28 wks gest.; drug fever, causing Vancomycin ! 18 hrly in P > 28 neutropenia, nephrotoxicity or wks gest. and nephrotoxicity, ototoxicity. age < 7 d; bd in P ototoxicity, Increased > 7 d and N < 7 d; anaphylactic neuromuscular tds in term N > 7 d. reactions should blockade with Infants & child: be given as other 10 mg/kg qds For infusion over 1–2 depolarizing

Contd... Antimicrobial Formulary 441

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects meningitis 15 mg/ hrs to avoid agents kg qds For redman reaction critically sick Maintain trough patients loading levels > 15–20 dose of 25–30 ìg/mL mg/kg For C. difficile colitis PO 125 mg qds Teicoplanin Vials 200, 400 6-12 mg/kg IV or Local reactions, Chances of (Teichomycin A) ! im od. For severe fever, allergic auditory and infections higher reactions, vestibular dose and bd for anaphylaxis, changes with 1st 3 days nausea, concomitant other diarrhea, ototoxic drugs thrombocytop- enia, elevated SGPT, SGOT, Alk. PO4ase, urea, amylase. Daptomycin Vials 350 mg Adequate data in Increase in CPK Coadministration children not levels of statins available should increases be used only as myotoxicity salvage drug For skin and soft tissue 4 mg/kg IV od For endocarditis and bacteremia 6–8 mg/kg (up to 12 mg/kg) SULPHONAM- IDES Cotrimoxazole ! Tab: (Trimethoprim Dosed on Headache, sore Potentiates the content) 20 mg, trimethoprim 2–4 tongue, rash (incl. anticoagulant 40 mg, 80 mg, wks: 3mg/kg SJ syndrome), activity of 160 mg. Syr: loading, 2 mg/kg nausea, vomiting, warfarin. 40 mg/5 mL (With bd.> 4 wks: 4–6 diarrhea, Prolongs half-life Sulphamethox- mg/kg bd M = leukopenia, of phenytoin. azole in ratio 320 mg For PCP thrombocytope- Increased toxicity of 1:5) pneumonia nia, megaloblastic of concomitant Treatment 5 mg/ anemia, jaundice, use of other anti- kg qdsFor PCP hemolysis in folate drugs prophylaxis 5 G6PD deficiency, mg/kg/day od or pseudomembr- bd anous colitis Silver Skin cream 1%, Apply tds or qds. Hypersensitivity Decr. metabolism Sulphadiazine ? Eye drops 1% Instil eye drops reactions, local of phenytoin, 4 hourly itching, burning tolbutamide

Contd... 442 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects

QUINOLONES Nalidixic Acid ! Tab/DT 125, 250, 15–18 mg/kg tds Diarrhea, Incr. bleeding with 500, 1000. nausea, warfarin, Syr. 300 mg/5 mL vomiting, rash, probenecid photosensitivity increases plasma headache, incr. conc. of nalidixic ICT, dizziness, acid. Antagonizes vertigo, seizures effect of psychosis, joint nitrofurantoin pains, diplopia, Alcohol incr. cholestasis, sedative effect metabolic acidosis, hemolysis in G6PD deficiency Norfloxacin ! Tab/ DT 100, 6–10 mg/kg bd Gastritis, Incr. levels of 200, 400, 800 mg. M = 800 anorexia, theophylline and Syr 100 mg/5 mL skin rash, S-J cyclosporine. Drp 10 mg/mL syndrome, sleep Antacids interfere Eye drops 0.3% disturbances, with absorption. irritability, Probenecid depression, delays excretion. tinnitus, Incr. bleeding with transient rise warfarin in liver enzymes, hemolysis in G6PD deficiency Ciprofloxacin ! Tab 200, 250, Oral 10–15 mg/kg Nausea, vomiting, Antacids, milk 400, 500, 750 mg. bd M = 1500 IV diarrhea, and oral iron decr. Inj. 2 mg/mL 7.5–12.5 mg/kg anorexia, skin absorption. 100 mL bottle bd or tds(cystic rash, S-J Probenecid Eye drops 0.3% fibrosis 30–40 syndrome, delays excretion. mg/kg/day) insomnia, Incr. bleeding with M = 1200 hallucinations, warfarin. Inreased depression, levels of seizures, tinnitus, theophylline, deafness, increased risk of transient rise in seizures with liver enzymes, NSAIDs Increased arthropathy, risk of QT hemolysis in prolongation with G6PD deficiency antiarrhythmics, antimicrobials (azoles, macrolides), psychoactive drugs Contd... Antimicrobial Formulary 443

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects

Ofloxacin ! Tab/ DT 50, 100, Oral 7.5 mg/kg As for As for 200, 400. Syr bd M = 800. IV Ciprofloxacin. Ciprofloxacin 50 mg/5 mL Inj. 5 mg/kg bd Also leukopenia 2 mg/mL 100 mL M = 600 eosinophilia bottle. Eye drops 0.3% Pefloxacin ! Tab 200, 400 mg. Oral 4 - 6 mg/kg Gastritis, skin As for Inj. 4 mg/mL bd. I.v. 2.5–5 rash, photo- Ciprofloxacin. 100 mL bottle mg/kg bd sensitivity, Rifampicin Eye drops 0.3% arthralgia, reduces blood insomnia, levels. myalgia, throm- bocytopenia Levofloxacin ! Tab 250, 500, Pediatric dose Nausea, vomiting, As for 750 mg. Inj 5 mg/ not established diarrhea, Ciprofloxacin mL 100 mL bottles 10 mg/kg has anorexia, skin been used rash, S-J M=750 syndrome, insomnia, hallucinations, depression, seizures, tinnitus, deafness, arthropathy, hemolysis in G6PD deficiency Sparfloxacin ! Tab 20, 100, Pediatric dose not Nausea, vomiting, As for Ciprofloxacin. 200 mg. established abd. pain, Digoxin, Eye drops 0.3% diarrhea, vancomycin, anorexia, skin ceftazidime, rash, tobramycin, photosensitivity imipenem insomnia, increase levels of hallucinations, sparfloxacin. depression, Increased Q-T convulsions, interval effect of paresthesiae, other drugs arthropathy, hypoglycemia. Gatifloxacin ! Tab 200, 400 mg. Pediatric dose not Confusion, Digoxin, Inj 2 mg/mL established agitation, insomnia, probenecid, (bottles 200 ml) hallucinations, warfarin, NSAIDs and 10 mg/mL seizures, abnormal increase levels of (40 mL bottle) vision and taste, sparfloxacin and Eye drops 0.3% tinnitus, skin rash, chances of photosensisitivity seizures nausea, vomiting, arthropathy

Contd... 444 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects Moxifloxacin ! Tab 200, 400 mg. Pediatric dose G-I disturbances, As for Inj. 2 mg/mL not established CNS effects (as Ciprofloxacin. 200 mL bottle Adults 400 mg od above), reversible Increased Q-T Eye drp 0.5% arthralgia, interval effect of hepatitis, other drugs tachycardia, pain at inj. site. Nadifloxacin ! Skin cream 0.1% Apply bd Pruritus, redness, None on local flushes, contact application dermatitis AMINOGLYC- OSIDES Streptomycin * 750, 1000 mg IM 20 mg/kg Ototoxicity Incr. nephrotoxity vials od M=1000 (vestibular and with NSAIDs, auditory), cyclosporine, nephrotoxicity, Vancomycine, neuromuscular Amphtericin B, blockade, pain cephalosporins. at inj. site Incr. ototoxicity with frusemide. Incr. n-m. blockade, apnea with muscle relaxants Kanamycin * 500, 1000 mg IM 15 mg/kg od Nephrotoxicity, As above vials M=1000 ototoxicity, neuro- muscular block Gentamicin * Inj: Vials 40 mg/ 5–7.5 mg/kg/day Nephrotoxicity Increased mL and 10 mg/mL; IM or IV infusion with haematuria, nephrotoxity with Amp: 20, 40, 60, od, bd, tds renal failure; NSAIDs, 80 mg Eye M=240 ototoxicity with cyclosporin, drops 0.3% tinnitus, hearing Vancomycin, loss; vestibular Amphotericin B, toxicity with cephalosporins. nausea, vomiting, Increased dizziness, vertigo; ototoxicity with hypomagnesemia frusemide. Incr. neuromuscular blockade, apnea with muscle relaxants Netilmycin * Amp. 50 mg/ml; 5–7.5 mg/kg/day Nephrotoxicity, As above 100 mg/mL 2, 3 mL IM or IV od, ototoxicity ampoules bd, tds Amikacin * Inj. 50 mg/ml, 15–22.5 mg/kg/ As above; skin As for Gentamicin 125 mg/ml, day im or IV rash, tremors 250 mg/mL infusion od, bd, tds M = 1000

Contd... Antimicrobial Formulary 445

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects

Neomycin * Cap 350 mg. Oral 50 mg/kg qds. Nephrotoxicity As for Gentamicin. Oint 2% Local apply. tds and ototoxicity Decr. absorption (even with oral use) of digoxin, bile acids Tobramycin ? Vials 2 mL each; IV/IM 6–7.5 Nephrotoxicity, As above 10, 30, 40 mg/ml, mg/kg/day od, ototoxicity Eye oint 0.3%, bd or tds Drp 0.3% Sisomycin * Inj 40 mg. Inj. IM/IV 1–2 Tinnitus, vertigo, As for gentamicin. Eye drops 1% mg/kg tds. Eye deafness, CNS None on local drp instil 1–2 drp disturbances, application 4 hourly nephrotoxicity. Transient eye irritation, hypersensitivity Framycetin * Eye drops 1%, Instil 1–2 drops Irritation, None on local ointment 5% tds or qds hypersensitivity application MACROLIDES Erythromycin * Cap/Tab/DT: 125, Oral: N: 10 mg/kg Gastritis, vomiting, Increased digoxin, 250, 333, 500 mg. bd < 7 d; tds if abdominal pain, theophylline, Syp: 100, 125, > 7 d but < 2 Kg; rash, false warfarin, carbame- 250 mg/5 mL 15 mg/kg tds increase in SGOT zepine levels. Drp 100 mg/mL if > 2 Kg, > 7 d levels. Reversible Increased cardiac Eye oint 0.1% Child: 7.5– hearing loss with toxicity with Oint, lotion, gel, 12.5 mg/kg qds. high doses. Cisapride, terfenan- 2%, 3%, 4% M=2000 Local dine and astemizole application bd Roxithromycin ? Tab/ DT 50, 75, 3–4 mg/kg bd Nausea, vomiting, Digoxin, 150, 300 Syr. 50, diarrhea, skin rash, terbinafin incr. 100 mg/5 mL transient incr. in roxithromycin liver enzymes absorption Clarithromycin ! Tab: 125, 250, 7.5 mg/kg bd Nausea, vomiting, Increased 500 mg Syr: M = 1000 mg diarrhea, digoxin, 125 mg/5 mL abdominal pain, theophylline, blood dyscrasias, warfarin, stomatitis, carbamazepine cholestatic levels. Cardiac jaundice, pseudo- arrhythmias with membranous terfenadine, colitis cisapride astemizole, Azithromycin ? Inj: Vials: 30 mL 10 mg/kg od or Nausea, Antacids reduce (20 mg/mL)Tab: 10 mg/kg on day vomiting, absorption. 1000, 500, 250, 1 and then 5 mg/ diarrhea, Increases 100 mg Syr: 200, kg od > 6 mths flatulence, absorption of 100 mg/5mL M = 200 mg <7 yrs, vertigo, headache, Digoxin and M = 300 mg urticaria rash, Cyclosporin 8–11 yrs, M = 400 cholestatic >12-M = 500 jaundice Enteric M=1000 mg

Contd... 446 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects Spiramycin * Tab 1.5 million < 1 yr 0.375 MU, Nausea, vomiting, Increases units (MU), 1–2 yrs .75 MU, diarrhea, skin theophylline and Syr 0.375 MU/ 3–5 yrs 1.125 MU, rash carbamazepine 5 mL 6–9 yrs 1.5 MU, levels if given 10-12 yrs 2.25 MU, concomitantly. > 12 yrs 3 MU. All doses bd LINCOSAMIDES Lincomycin ? Inj. 300 mg/mL Inj 10 mg/kg od Diarrhea, Potentiates action Cap 250, 500 mg. or bd. Oral: severe of neuro- Inj. 300, 600. 10–20 mg/kg bd pseudomemb- muscular Syr 125 mg/5 mL ranous entero- blocking agents colitis Clindamycin ! Cap 150 mg, Oral 10 mg/kg Nausea, vomiting Erythromycin Gel/Oint. 5% tds or qds diarrhea, clindamycin M=1800 mg pseudomembr- antagonism. Incr. anous neuromuscular enterocolitis, blocking with jaundice, similar drugs eosinophilia, urticaria, rashes CHLORAMPH- Inj: Vial 1000 mg Oral, IV N: 12.5– Rash itching, Levels increased ENICOL ! Tab/Cap: 250, 25 mg/kg od. peripheral and/or by phenytoin and 500 mg. Syr: 1–4 wks < 2 Kg: optic neuritis, phenobarbitone 125 mg /5 mL 12.5–25 mg/kg sore throat, Antagonizes Lotion 100 mg/mL od. 1-4 wks > 2 Kg fever, weakness, bactericidal effect Eye drops 0.5%, 12.5–25 mg/kg bd. bone marrow of penicillins 1% Ear drp 1%, > 4 wks 12.5– depression, gray 5% 25 mg/kg qds baby syndrome M = 2000 mg OXAZOLIDI- NONES Linezolid ! Tab 600, Inj. 10 mg/kg tds Headache, Reversible 2 mg/mL 100 mL M=1800 nausea, inhibitor of MAO. and 300 mL constipation, Incr. BP with insomnia, liver dopamine, dysfunction, epinephrine, thrombocytop- pseudoephedrine enia, bone phenylpropanol- marrow amine, and with suppression diet high in tyramine. TETRACYCLINES Tetracycline ! Cap/Tab 250, > 8 years age Gastritis, Iron, antacids 500 mg 5–10 mg/kg qds diarrhea, decrease M = 2000 pancreatitis, absorption, benign incr. in antagonistic to intracranial penicillins, decr. tension, teeth serum level with Contd... Antimicrobial Formulary 447

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects discolouration, antiepileptics, enamel warfarin effect hypoplasia potentiated Oxytetracycline ! Inj. 50 mg/mL, Age > 8 yrs Inj Pain at inj. As for tetracycline Cap 250, 500 mg. IM/ oral 10– site, skin rash, Eye oint 10 mg/gm 20 mg/kg tds nausea, gastritis, M = 2000 teeth discolora- Eye oint: 5–10 mm tion, enamel ribbon bd or tds hypoplasia Demeclocycline ! Tab/Cap 150, Age > 8 yrs As for As for tetracycline 300 mg 3–6 mg/kg bd Oxytetracycline M = 450 Doxycycline ! Cap/Tab/DT 50, 2.5 mg/kg bd or Skin rash, itching, As for tetracycline 100, 200 Syr 5 mg/kg od nausea, vomiting, 5 mg/ml, 10 mg/mL M = 200 diarrhea Minocycline Tab 100 mg 2.5 mg/kg bd Vestibular As for tetracycline M=200 symptoms, reversible hypersensitivity pneumonitis Tigeycycline Injection 50 mg 1.5 mg/kg loading Nausea, and then 1 mg/kg bd vomiting, hepatic M=100 mg dysfunction CARBAPENEMS Impenem- Inj 500 mg N: 20 mg/kg < Hypersensitivity, Increased risk of Cilastatin ! 7d bd, 7-21 d tds, GI intolerance, CNS side effects 21 d - 3 mths qds. hepatic with ganciclovir 3 mnths - 12 yr impairment, and cyclosporin. 15–25 mg/kg qds, convulsions. Delayed excretion > 12 yr 500 mg Positive Coomb’s with probenecid qds. May be given test as 1 gm tds M = 3000 Meropenem !, Inj 500 mg N: 20-40 mg/kg bd Allergy, GI Probenecid < 7 d; tds > 7 d intolerance, bone delays excretion Children: 10–20 marrow suppres- mg/kg tds (max sion, elevated 500-1000 mg / liver enzymes dose) Severe and rarely, infections/ seizures meningitis 40 mg/ kg tds M=6000 Ertapenem Injection 1 gm 15 mg/kg bd As other M=1000 carbapenems- seizures Doripenem Injection 500 mg pediatric dose not established, adult 500 mg tds

Contd... 448 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects

MISCELLAN- Injection 1 million 10 mg/kg of salt Nephrotoxicity, Increased EOUS units/ 80 mg loading and then neurotoxicity nephrotoxicity Colistimethate* of salt) 5 mg/kg bd with amino Polymyxin B ! Vial 5,00,000 U/ 7500–12500 Pain, flushing, Synergistic with 50 mg (1 mg = units/kg bd paresthesia, cephalosporins. 10000 units) nephrotoxicity, Incr. nephro- ototoxicity and toxicity with neurological aminoglycosides disturbances Furazolidone ! Tab 100 mg, 1.25 mg/kg qds Nausea, Hypertensive Syr 35 mg/5 mL headache, crises with MAO dizziness, inhibiters and hemolysis in nasal G6PD deficiency degcongestants, Incr. orthostatic hypotension with sedatives, narcotics Nitrofurantoin ! Tab 50, 100 mg 1.25 – 1.75 mg/kg Rash, tingling of Probenecid qds face, vomiting, delays excretion. loss of appetite, Antagonizes drug fever, effect of nalidixic jaundice, acid, incr. peripheral bactericidal neuropathy, activity by agents hemolysis in acidifying urine G6PDD, benign incr. ICT Nitrofurazone * Oint, Cream, Apply as per Local irritation, None on local Powder 2% requirement sensitivity application reactions Fusidic Acid ! Oint 2% Apply bd or tds Hypersensitivity Increases risk of reactions (rare) jaundice with rifampicin Mupirocin ! Oint, Cre 2% Apply tds Stinging and Mixing with other dryness at appl. agents may site reduce bactericidal effect Antimicrobial Formulary 449

 ANTIMYCOBACTERIAL AGENTS

Name Formulations Dosage & Adverse Drug Interactions route Effects Isoniazid ! Tab 100, 300 10 mg/kg od Peripheral Rifampicin, M=300 neuropathy, liver Ethionamide (incr. dysfunction, fever, liver injury), Al salts CNS (decr. INH absorption), CBZ, phenytoin (incr. interacting drug levels), warfarin (incr. INR), itraconazole (decr. itraconazole levels) Ethambutol ? Tab 200, 400, 15-25 mg/kg Ocular toxicity Al salts, (EMB) 600,800 od (hs) M = 1600 (scotoma, decr. didanosine (decr. visual acuity, EMB and colour blindness), interacting drug drug fever, rash, absorption) mental confusion Pyrazinamide ! Tab 250, 300, 20–35 mg/kg od Vomiting, liver INH, RMP (incr. (PZA) 500, 750, 1000 M = 2000 toxicity, rash, risk of Susp. 250 arthralgia, gout hepatotoxicity) Cycloserine ! Tab/Cap 250 15 mg/kg/day od Peripheral EMB, Ethionamide or bd neuropathy, (incr. drowsiness), M = 1000 seizures, delirium, Phenytion (incr. psychosis phenytoin levels) Ethionamide ! Tab 250 15 mg/kg/day od Hepatic Cycloserine (incr. or bd dysfunction, eurotoxicity),INH, M=1000 headache, nausea, PZA, Rifampicin vomiting, (incr. tremor, alopecia, hepatotoxicity), gynecomastia INH (incr. peripheral neuritis) Para-amino- Granules 150-200 mg/ Hepatitis, fever, salicylic acid ! kg/day given bd rash, goitrous (PAS) or tdsM=12000 hypothyroidism, leukopenia, hypokalemia Rifampicin ! Tab 100, 150, 10 mg/kg od Hepatitis, fever, Indinavir, (RMP), 200, 300, 450, M = 600 flu-like symptoms nelfinavir, TMP-SMX, 600 Syp 100 clarithromycin, fluconazole, ketoconazole (incr. RMP levels), beta-blockers, cyclosporin, warfarin, corticosteroids, phenytoin, theophylline, digoxin, nifedepine

Contd... 450 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage & Adverse Drug Interactions route Effects

(decreased interacting drug effect), nevirapine (decreased nevirapine levels), INH and PZA (increased hepatotoxicity) Dapsone ? Tab 100 mg 1–2 mg/kg od Fever, rash, Rifampicin, M = 100 nausea, anorexia, didanosine (decr. jaundice, dapsone levels), headache, pyrimethamine, hemolysis azathioprine (incr. (G6PDD), methHB marrow suppression) Clofazimine ? Cap 50, 100 mg 1–2 mg/kg od Anorexia, nausea, Increased M = 200 (In diarrhea, ototoxicity and leprosy, 6 mg/kg photosensitivity nephrotoxicity with once a month) with darkening of other drugs with skin, itching, similar toxicity

 ANTIFUNGAL AGENTS

Name Spectrum Formulations Dosage route Adverse Drug and & interval Effects Interactions Indications

POLYENE MACROL- Most Candida Vials: 50 mg. 1–1.5 mg/kg Acute infusion Incr. renal IDES spp., od; Lipoidal, reactions: pain toxicity with Amphoter- Aspergillus, liposomal and at site, fever, other icin B ? Blastomyces, colloidal chills, nausea, nephrotoxic Liposomal Coccidioides, preparations vomiting, drugs. Steroids amphoteri- Cryptococcus up to 3–5 headache, may worsen cin B neoformans, mg/kg od dyspnea, hypokalemia. Histoplasma muscle and Amphotericin- Capsulatum, joint pains, esp. induced Mucor with initial hypokalemia doses. Renal causes incr. toxicity very toxicity of common. digitalis and Hypoklemia, skeletal muscle hypomagnes- relaxants. emia, Flucytosine azotemia, toxicity may be renal enhanced. tubular AZT: effects on acidosis, bone marrow nephrocalcin- and renal osis. Less function may be

Contd... Antimicrobial Formulary 451

Contd...

Name Spectrum Formulations Dosage route Adverse Drug and & interval Effects Interactions Indications

common enhanced. Incr. anuria, cyclosporin hematuria, levels. acute renal failure. Abnormal LFT, convulsions, diplopia, peripheral neuropathy Nystatin ? Candida Tab 5 lakh N: 1 lakh U Rash, None known albicans units (To be qds, Infants 2 diarrhea, chewed or lakh U qds, vomiting, rarely applied after Child 4–6 lakh Steven Johnson crushing for U qds Syndrome oral thrush) PYRIMIDINE ANALOG 5-Fluoro cytosine ! Only in N < 7 d 25 Nausea, Cytarabine may combination mg/kg qds; vomiting, reduce plasma for Candida, > 7 d 25–50. diarrhea, skin concentrations Cryptococcus Child: 37.5–50 rash of 5 fluoro- neoformans mg/kg qds Myelosuppre- cytosine. ssion, hypo- Antacids delay calcemia, absorption hypoklemia, muscle weakness, cardiac arrest. Rarely, convulsions, headache AZOLES Miconazole ! Active against Inj. 2 mg/mL IV N: 5–7.5 Pruritus, skin Amphotericin B Cryptococcus, Cream 2%, mg/kg bd. rash, flushing, antagonizes and skin fungi eye drops 1% Child 7–14 fever, chills, Miconazole, like Candida, mg/kg tds. drowsiness, Oral Trichophyton, Topical cream: anaphylaxis, anticoagulants Microsporum bd GI upsets, increase action. Epidermop- drowsiness, Incr. serum level hyton. Also hematological and toxicity of Coccidioides disturbances phenytoin Fluconazole ! Most Candida Tab / DT 50, 12 mg/kg od Nausea, Cycloserine, spp., 100, 150. Eye M=800 on day vomiting, abd. warfarin, Blastomyces, drp 0.3% 1 and then 400 pain, phenytoin

Contd... 452 Rational Antimicrobial Practice in Pediatrics

Contd...

Name Spectrum Formulations Dosage route Adverse Drug and & interval Effects Interactions Indications

Coccidioides, diarrhea, levels are Cryptococcus skin rash, increased neoformans, elevated liver Histoplasma enzymes capsulatum Clotrimazole? Candida, Cream 1%, 2%. Topical and Side effects None Pityriasis Mouth paint 1% mouth minimal. Skin versicolor. Dusting application tds irritation Also active powder 1% or qds against Ear drp 1% Cryptococci, Aspergillus

Ketoconazole ! Candida. Also Tab 200 mg, 5–10 mg/kg Jaundice, Antacids, H2 dermatophytes, Lotion 2%, od. Local itching, rash, blockers, Actinomyces Shampoo 2% application headache, rifampicin, and some twice daily gynecomastia, cycloserine phycomycetes GI upset, skin reduces drug discoloration levels Itraconazole? Candida, Cap 100 mg 2.5–5 mg/kg bd Nausea and Food increases Aspergillus, M = 400 vomiting bioavailablility. Blastomyces, common, Carbamezap- Histoplasma headache, ine, phenytoin capsulatum, hypertension, phenobarbital Coccidioides rash, hepatitis INH, rifampicin, cyclosporine, antacids, H2 blockers decrease bioavailability Voriconazole ! Candida (incl. 7 mg/kg bd Nausea, As for C. glabrata & M = 400 headache itraconazole. C. krusei), hepatic Increases Aspergillus, dysfunction, levels of Fusarium, reversible sirolimus 2- to Blastomyces. dose-dependent 10-fold H. capsulatum, visual Malassezia disturbances Posacona- Candida, all Syrup 40 For children Nausea, as for other zole ! filamentous mg/mL aged 18 yrs vomiting, azoles fungi or older For diarrhea, fever treatment 400 and increased mg bd and bilirubin prophylaxis 200 mg tds

Contd... Antimicrobial Formulary 453

Contd...

Name Spectrum Formulations Dosage route Adverse Drug and & interval Effects Interactions Indications

MISCELLA- NEOUS Terbinafine ! Candida Tab 250 mg, > 12 Kg < 20 Kg Oral: Mild GI Cimetidine, albicans, Cream 1% 62.5, > 20 disturbances, rifampicin Pityriasis alba, < 40 Kg 125, malaise, decrease Epidermoph- > 40 Kg lethargy, rash. metabolism yton, 250 mg od Local: Trichophyton, Erythema, Microsporum irritation, dryness Griseofulvin? Effective Tab 125, 250, 2.5-5 mg/ Rash, nausea, Decreases against Epide- 375, 500 mg kg qds vomiting, effect of oral rmophyton, dizziness, anticoagulants, Trichophyton drowsiness, Barbiturates and headache, decrease effect Microsporum photosensitivity of griseofulvin Tolnaftate ! Effective Cream 10 mg/ Apply locally Stinging None on local against mL, Lotion od or bd sensation application Epidermophyton, 10 mg/mL Trichophyton, Microsporum None against Candida ECHINOCA- Effective Injection 70 mg Neonatal Liver function Cyclosporine NDINS against all and 50 mg 25 mg/m2 abnormalities increases Caspofungin? Candida and or 2 mg/kg Fever, infusion caspofungin Aspergillus but od Pediatric reactions levels not dose 50 mg/m2 Rifampicin, Zygomycetes od Adult dose dexa, phenytoin, 70 mg nevirapine and loading and efavirenz reduce then 50 mg caspofungin od levels Caspofungin reduces tac levels Micafungin ? Same as Injection 2-4 mg/kg od Liver tumors in Micafungin caspofungin 100 mg Adults 100 mg rats increases od M = 100 cyclosporin and nifedepine levels Anidulafu- Same as Injection Not approved Same as Cyclosporine ngin ? caspofungin 200 mg and for children In echinocandins increases 100 mg adults loading anidulafungin dose of levels 200 mg and then 100 mg od 454 Rational Antimicrobial Practice in Pediatrics

 ANTIRETROVIRAL AGENTS

Name Formulations Dosage & Adverse Drug Interactions Interval Effects NRTIAZT (Zidovudine) ! Cap/Tab 100, 300, P < 14 d: 2 mg/ Leukopenia, Incr. toxicity of 400 Syr 50mg/ kg bd, > 14 d tds. anemia, co-trimoxazole, 5 mL N < 90 d: 2 mg/kg headache, ganciclovir, qds. > 90 d: 160 myopathy, acyclovir, (90-180) mg/m2 insomnia, hepat- interferon-alpha. tds M= 600 otoxicity. Lactic AZT levels incr. acidosis and by probenecid, hepatomegaly cimetidine, with steatosis valproate, (rare) fluconazole and decreased by rifampicin. Clarithromycin decr. absorption of AZT. Antagonistic to D4T D4T (Stavudine)? Cap 30, 40 mg < 30 Kg 1 mg/kg Headache, Poor retroviral bd. >30 < 60 Kg gastrointestinal effect when 30 mg bd. > 60 Kg disturbances, combined with 40 mg bd rash, peripheral AZT. neuropathy, pancreatitis, lactic acidosis, hepatomegaly with steatosis DDI Cap/Tab 100, N < 3 mths Nausea, vomiting, Iron, quinolones (Didanosine) ! 250, 400 mg 50 mg/m2 bd > 3 diarrhea, abd. and tetracycline mths: 90–150 pain, pancreatitis, decrease mg/m2 BSA bd peripheral absorption. DDI neuropathy, optic decreases neuritis, lactic absorption of acidosis and dapsone, severe ketoconazole hepatomegaly itraconazole, with steatosis indinavir and increases absorption of tenofovir Lamivudine ? Tab 100, 150, N: 2 mg/ Kg bd. As for didanosine. Drug levels and 300 Syr 50 mg/ Infant, child: 4 Also skin rashes, effectively incr. by 5 mL mg/kg bd, Adol: arthralgia and AZT, Co-trimox- 2 mg/kg bd cough azole increases M = 300 blood levels of lamivudine Abacavir ? Tab 300 mg > 3 mths 8 mg/kg Nausea, vomiting, No interaction with bd M= 600 diarrhea, rash, other anti- headache, retrovirals. Ethanol anorexia, increases blood hypersensitivity levels of abacavir

Contd... Antimicrobial Formulary 455

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects reaction with fatigue, dyspnea, lymphadenopathy (potentially fatal), lactic acidosis, massive hepatomegaly Emtricitabine Available as FDC N 3 mg/Kg OD, Headache, No significant with tenofovir > 3 mths–17 yrs insomnia, interactions 6 mg/kg M = 200 diarrhea, Should not be nausea, rash, given lamivudine and skin discoloration Tenofovir Tab 300 mg 175–300 Nausea, vomiting, Reduces mg/m2 M = 300 diarrhea, atazanavir and reduced bone DDL levels mineral density, renal tubular dysfunction NNRTI Nevirapine ! Tab 50, 200. 5 mg/kg or Skin rash, incl. Levels incr. by Syr 50 mg/5 mL 120 mg/m2 od SJ syndrome, rifampicin. for 14 d, incr. to TEN, fever, Reduces levels of 120–200 mg/m2 nausea, ketoconazole and bd M = 400 headache, indinavir and abnormal LFT saquinavir Rarely fatal hepatic necrosis, neutropenia, other hypersensitivity reactions Delavirdine ! Tab 100, 300 Pediatric dose Headache, Incr. levels of not established fatigue, GI astemizole, complaints, rash terfenadine, alprazolam, midazolam, nifedepine, cisapride and warfarin. Delavirdine levels reduced by rifampicin, phenytoin, carbamazepine, phenobarbital, antacids, H2 blockers and increased by ketoconazole and clarithromycin Contd... 456 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects

Efavirenz ? Tab/Cap 50, 100, Wt. 10–15 Kg Skin rash, Incr. levels of 200, 600 200, 15–20 Kg somnolence, astemizole, 250, 20–25 Kg insomnia, altered terfenadine, 300, 25–32.5 Kg mood, confusion, midazolam, and 350, 32.5–40 Kg amnesia, warfarin. Efavirenz 400, > 40 Kg hallucinations, levels reduced by 600 mg. All incr. liver rifampicin, doses od enzymes phenytoin, carbamazepine and phenobarbital. Decreases levels of clarithromycin and PI agents like saquinavir and indinavir. PI (protease inhibitors) Saquinavir ? Tab 200 mg 50 mg/kg tds Nausea, anorexia, Incr. levels of alone or 33 vomiting, astemizole, mg/kg tds (in diarrhea, chest terfenadine, combination with and abd. pain, alprazolam, ritonavir) headache, ataxia, midazolam, M = 3600 parasthesiae, nifedepine, incr. liver quinidine, enzymes, clindamycin lipodystrophy, dapsone, diabetes, cisapride and ketoacidosis, warfarin. spontaneous Saquinavir levels bleeding in reduced by hemophiliacs rifampicin, phenytoin, carbamazepine, phenobarbital, dexamethasone, and increased by ketoconazole and nelfinavir Ritonavir ? Cap/Tab 100, 250 Start at 250 mg/m2 As for Saquinavir. Incr. levels of bd increase to Also cardiovas- saquinavir 400 mg /m2 bd. cular toxicity, nelfinavir, M = 1200 In ulcerative colitis, astemizole, combination with adrenocortical terfenadine, Lopinavir (in ratio insufficiency alprazolam, of 1:4) 75 mg/m2 midazolam, (of ritonavir) bd nifedepine, M = 250 quinidine, warfarin, rifampicin and clarithromycin.

Contd... Antimicrobial Formulary 457

Contd... Name Formulations Dosage & Adverse Drug Interactions Interval Effects

Levels of theophylline are decreased. Digoxin levels may be increased or decreased. Indinavir ! Cap 200, 400 mg 300–500 mg/m2 Nausea, abd. Incr. levels of tds M = 2400 pain, headache, astemizole, metallic taste, terfenadine, dizziness, midazolam, and jaundice, warfarin. Levels of nephrolithiasis, indinavir reduced diabetes, by rifampicin, bleeding in nevirapine, hemophiliacs, efavirenz and hemolytic increased by anemia, ketoconazole and lipodystrophy itraconazole. Coadministration of nelfinavir increases levels of both drugs, with saquinavir incr. levels of latter Nelfinavir ! Tab 250 mg 20-30 mg/kg tds Diarrhea, Incr. levels of or 50-55 mg/kg asthenia, abd. astemizole, bd M= 2500 pain, rash, terfenadine, hepatitis, alprazolam, lipodystrophy midazolam, nifedepine, quinidine, cisapride and warfarin. Nelfinavir levels reduced by rifampicin. Coadministration with nelfinavir increases nelfinavir levels and with saquinavir increases levels of the latter 458 Rational Antimicrobial Practice in Pediatrics Contd... significant metidine: incr. Probenecid incr. seizures. toxicity. Other drugs: increased renal damage. bone Dapsone, inj. site lethargy. Headache, None taste, renal toxicity, increase bone mental chan- marrow toxicity. ges, cramps With imipenem rash, nausea, vomiting, diarrhea, fatigue Reversibleneurological Probenecid and ci oses qds Interval Adverse Drug divided at 5–6 times (for ganciclovir ganciclovir Local mg/kg/ dose marrow flucytosine, AZT, route Effects5 mg/kg/ dose 12 hrly Interactions G-I upsets, orally depression, co-trimoxazole Oral 60–80 prophylaxis application5–10 mmribbon reactions. nephrotoxic simplex zoster paresthesiae clinically simplex 10 mg/kg tds retinitis in bd mised 5 CMV infection,Immunocompro- IV (induction) x 21, then 24 hrly change of delays excretion. AIDS Prophylaxisand treatment) Switch over from od for IV ganciclovir Pediatric dose 7 × BSA creat clearance keratitis 5% Chickenpox, mg/kg/day d mg Ocular and Neuro- 400 simplex Formulations Indications Dosage & Cap 250, 500 mg Oint 2% Eyeoint 0.5% Herpes zoster lA Herpes (HSV type 1& 2 HZV) Herpes HHV5 (CMV)HHV5 Pow. inj. 500 Same asganciclovir Tab 450 mg Management of Adults 900 mgHHV 1,2,3, CMV Tab 250, 500 mg Herpes Same as Same as HHV 1,2,3,(HSV type 1 Tab 200,400, 600 mgSyp Herpes 10 mg/kg IV Tds 4 to 5 Local phlebitis ZDV: Extreme & 2 HZV) mg/5 mL Cre Name Spectrum Ganciclovir ! valganci- clovir Famciclovir? Acyclovir ? Antimicrobial Formulary 459 Contd... blood of clinical ctively incr. theophylline. lamivudine Increases analgesics and Burning None sensation significance effects, leukopenia, hemolytic anemia didanosine. effe rashes,arthralgiaand cough Co-trimoxazole increases of levels symptoms(80%). Bone of marrowsuppression, of thyroid sedative effects disorder,depression, alopecia, antihistaminics, narcotic decompen- sation of liver antipsychotics disease then Interval Adverse Drug qid tds Hypertension, None 2 drp 1–2 hrly till route Effects Interactions 3–4 mg/kg odfor As Drug levels and combination) M= 300 RSV, HCV, 3 mg/kg Chronic hepatitis B Influenza respiratory mg/5 mL Formulations Indications Dosage & eye oint. 0.5% healed, Tab 100, 150, 300 Syr 50 mg/ (in 5 mL5 Also skin by AZT, Units SC or IM (Also HHV 1.2.3HHV Eye drops 0.1%, Herpetic keratitisHCVHBV, 1 Measles Vials 0.45, 3 and 5 million Chronic hepatitis 3 to 6 millionC B, od Fever, flu-like units/m effects Enhances HCV Hanta Cap 100, 200 mg HBV virus RSVParamyxo- 50 Syr viruses Name Spectrum alfa ? Idoxuridine? Interferon Ribavirin ? Lamivudine? Heptovir, HIV see Lambda, Ladiwin,Lamidac, above) section Lamivir, Lamsyn, Retrolam, Virolans Contd... 460 Rational Antimicrobial Practice in Pediatrics Contd... of Incr. effects with other agents. Incr. drug triamterene and hydrochloro- thiazide of gout, anticholinergic Acute episo- anorexia, nausea,dysuria, agitation, atropine like levels dizziness, blurred vision Interval Adverse Drug nausea, Neurologic side effects like drowsiness prophylaxis 15–24 kg: treatment od route Effects Interactions 34 kg: 60 mg GI side and kg 35 75more mg For severe effects like infections vomiting and double dose diarrhea treatment forInfluenza A Most currently circulating M=150virus is resistant influenza des Treatment and 2 inhalationsinfluenzafor Bd for od Formulations Indications Dosage & Syrup 30 mg/ Inhalation solution 5 mg prophylaxis foreach)mg (5 treatment and 5mL 45 mg 25– for prophylaxis Influenza A Cap 100 mg Prophylaxis and 5–9 mg/kg od Influenza A, B Tab 75 mg Treatment of <15 kg: 30 mg Bd for Influenza A Name Spectrum Amantadine? Oseltamivir * Zanamivir Antiviral Contd... Antimicrobial Formulary 461 ntamidine. renal drugs esp. amphotericin B damage with diarrhea,anorexia, IV pe Incr. hypokalemia, dizziness, anemia, paresthesia, genital irritation and ulceration disturbances, Interval Adverse Drug route Effects Interactions over 1-1/2–2 hrs vomiting, toxicity with seizures,nephrotoxic other slow infusionover 1-1/2–2 hrs Rash, (33%) like hypokalemia mood and renal Acyclovir resistant 40 mg/kg byHSV bd or tds slow infusion Formulations Indications Dosage & HHV 1,2,3,5 Inj. 24 mg/ mL CMV retinitis 90 mg/kg by bd Renal toxicity Additive toxicity Name Spectrum Foscarnet sodium! Contd... 462 Rational Antimicrobial Practice in Pediatrics

 ANTIPARASITIC AGENTS

Name Formulations Dosage, interval Adverse Drug Interactions and route Effects ANTIMALARIALS Amount of Chloroquine * Chloroquine base Dosed on the base Nausea, vomiting, Antacids, kaolin Inj 40 mg/mL 10 mg/kg loading abd. pain, rash, decr. Absorption Tab 150, 300 mg M = 600, then blurred vision, of chloroquine. Syr 50 mg/5 mL 5 mg/kg after 6 hrs rarely neuro- Incr. blood (M=300) and then psychiatric digoxin levels. 5 mg/kg daily for disturbances Other 2 days antimalarials decr. antimalarial effect. Amodiaquine * Tab 200 mg, As for chloroquine Skin rash, Other Syr 150 mg/ 5 mL pigmentation of antimalarials decr. skin and nails on efficacy of prolonged use, amodiaquine nausea, vomiting, Antacids and diarrhea, kaolin inhibit agranulocytosis, absorption, visual disturbances, Cimetidine peripheral increases blood neuropathy, levels of hepatitis amodiaquine Mefloquine ! Tab 250 mg 15 mg/kg loading, Nausea, vomiting, With chloroquine, then 10 mg/kg somnolence, incr. risk of 12 hrs later dizziness, rash, convulsions. M=1500 neuropsychiatric Ketoconazole, disturbances ampicillin, incl. hallucinations tetracycline and disorientation, metoclopramide neuropathy and incr. levels of convulsions mefloquine. Incr. cardiotoxicity with quinine, quinidine, digitalis, calcium channel blockers. Decreases blood levels of valproate and efficacy of typhoid vaccine Quinine ? Inj 300 mg/mL, Dosed on salt IV Disturbed vision, Antacids and Tab 100, 300 mg, 20 mg/kg loading tinnitus, hearing cimetidine reduce Syr 100, 150 mg/ over 4 hrs, then loss, rash, absorption of 5 mL 10 mg/kg tds. gastritis, quinine. Reduces Oral 10 mg/kg headache. serum levels of tds M=1800 Hypoglycemia digoxin and hypotension with IV use. Hemolysis in G6PD def.

Contd... Antimicrobial Formulary 463

Contd... Name Formulations Dosage, interval Adverse Drug Interactions and route Effects

Artesunate? Inj Vial 60, 150 IV (or IM) 2.4 Mild G-I Antagonistic effect mg/mL Tab 50 mg mg/kg loading disturbances, seen with and then 2.4 mg/kg rarely hemolysis. pyrimethamine- 12 hours later and Ist degree heart sulpha. Drug then on day 1, block levels incr. by later 2.4 od Oral tetracycline, 4 mg/kg od chloroquine, mefloquine and primaquine Artemether? Inj 80 mg/mL IM 3.2 on day 1, Ist degree heart Incr. cardiac Tab 40 mg later 3.2 od; block, leukopenia, toxicity with Oral 4 mg/kg od raised liver terfenadine, enzymes, nausea, astemizole, vomiting, quinidine, abdominal procainamide, cramps, erythromycin, and neurotoxicity tricyclic anti- depressants. Tetracycline, mefloquine and pyrimethamine interfere with action of drug Arteether ? Inj 75 mg/mL Inj. IM only. Nausea, As for artemether 1 mL and 2 mL 3 mg/kg od dizziness, vomiting, ampoules eosinophilia Pyrimethamine- Tab: pyrimetha- 1.25 mg/kg of the Unusual bleeding, Antimetabolites, Sulphadoxine ? mine 25 mg, pyrimethamine rash bruising, antirheumatics, Sulpha 500 mg. component sore throat, co-trimoxazole Syr. Pyrimetha- M=75 of fever, leukopenia, increase bone mine 12.5 mg, pyrimethamine thrombocytopenia, marrow toxicity 25 mg with sulpha megaloblastic 250, 500 mg/5 mL anemia respectively Pyrimethamine Pyrimethamine Congenital PYM : bone (PYM) 25 mg toxoplasmosis marrow sulfadiazine Sulfadiazine Neonates: PYM suppression (SDZ) 500 mg 1 mg/kg od and SDZ: rash, SJS, SDZ 50 mg/kg bd leukopenia, Children: PYM crystalluria 1 mg/kg bd for 3 days and then 1 mg/kg od (M = 25 mg) and SDZ 30–50 mg/kg qds Folinic acid 10–20 mg thrice weekly

Contd... 464 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage, interval Adverse Drug Interactions and route Effects

Primaquine ! Tab 2.5, 7.5, Dosed on the Nausea, vomiting, May inhibit 15 mg of the base base 0.25–0.75 weakness, chloroquine mg/kg od leukopenia, metabolism. With M=45 methemo- other bone marrow globinemia depressants, incr. toxicity OTHER ANTI- PARASITIC AGENTS Metronidazole ? Inj. 5 mg/ml, Inj: 10–15 mg/kg Nausea, tingling, Increases levels 100 mL bottles tds numbness, and toxicity of Tab 200, 400 mg, Oral: amebiasis metallic taste, warfarin, Syr. 100, 200 mg/ 10 mg/kg tds dark urine, phenytoin, lithium. 5 ml Giardiasis 5 mg/ headache, Cimetidine, Oral gel 0.5% kg tds M = 2400 drowsiness, rifampicin, blood dyscrasias, phenobarbitone gynecomastia increase metronidazole metabolism Tinidazole ? Inj. 2 mg/mL 3–5 mg/kg tds, Nausea, tingling, Synergy with Tab 300, 500, 50 mg/kg stat for numbness, ampicillin, 600, 1000. giardiasis metallic taste, doxycycline and Syr. 75, 150 neuropathy, co-trimoxazole. mg/5 mL leukopenia, seizures Secnidazole ! Tab 500, 1000, 15 mg/kg bd Nausea, vomiting, Increases levels 2000. Syr. 500 M = 2000 glossitis, metallic and toxicity of mg/5 mL taste, skin warfarin, rash, leukopenia, phenytoin, lithium. headache Cimetidine incr. secnidazole metabolism Ornidazole ? Inj. 5 mg/ mL 40 mg/kg od As for secnidazole Increases levels Tab 500 mg and toxicity of warfarin, increases clearance of 5 fluorouracil Hydroxyquinol- Tab 250 10–15 mg/kg tds Nausea, With alcohol, ones (Quiniodoc- Oint 3% M = 2000 headache, antabuse like hlor, Diiodo- dermatitis, effect hydroxyquinoline, diarrhea, broxyquinoline) ! goiter Diloxanide Tab 500 mg 6–7 mg/kg tds Nausea, Synergistic effect Furoate ? M =1500 flatulence, itching, with metronidazole urticaria and tinidazole

Contd... Antimicrobial Formulary 465

Contd... Name Formulations Dosage, interval Adverse Drug Interactions and route Effects

Nitazoxanide ? Tab 200, 500 mg. > 1 < 5 yr 100 mg Nausea, vomiting, No interactions Syr 100 mg/ 5 mL bd, > 5 < 10 yr Diarrhea, reported 200-250 mg bd, weakness, myalgia, > 11 yr 500 mg bd hypotension Dehydroemetine? Inj. 30 mg/mL 1 mg/kg tds Pain at inj. site, None reported vials 1, 2 ml. deep IM vomiting, nausea, myalgia, hypotension, cardiac arrhythmias Piperazine Tab 500 mg 50–75 mg/kg od Diarrhea, rash, Incr. risk of citrate ? incoordination, abnormal drowsiness, movements with confusion, phenothiazine vomiting antipsychotics.

Albendazole ! Tab 200, 400, For intestinal Gastritis, H2 antagonists Syr 200 mg/ 5mL worms: < 2 yrs dizziness, incr. blood levels 200 mg, > 2 yrs dry mouth, of albendazole. 400 mg stat. pruritus. Incr. action of oral For tissue worms Agranulocytosis antidiabetic and giardiasis: or leukopenia agents 7.5–10 mg/kg (rare) bd M = 800 Mebendazole ? Tab 100 mg. Enterobiasis G-I upset, skin As for Syr 100 mg/ 5 mL 100 mg stat; rash, hair loss, albendazole Other nematodes agranulocytosis, 100 mg bd. hypospermia Cestodes:200 mg bd Pyrantel Tab 250 mg, 11 mg/kg Nausea, vomiting, Antagonizes pamoate ? Syr. 250 mg/ 5mL od headache, piperazine M=1000 tenesmus, skin rash, headache, incr. in SGOT Niclosamide ! Tab 500 mg > 2 yrs 40 mg/kg Gastritis, No drug od diarrhea, skin interactions rash, itching, reported dizziness, headache Tetramisole ! Tab 150 mg 3 mg/kg od Gastritis, None clinically insomnia, significant. dizziness, Alcohol may agranulocytosis cause flushing Levamisole ! Tab 50, 150 mg 3–5 mg/kg od As for tetramisole Incr. blood conc. Syr 50 mg/5 mL of phenytoin and warfarin. Antabuse like reaction with alcohol

Contd... 466 Rational Antimicrobial Practice in Pediatrics

Contd... Name Formulations Dosage, interval Adverse Drug Interactions and route Effects

Sodium Cap 250 mg Dosed on the Joint pains, abd. With other Antimony Antimony 20 mg/kg pain, nausea, nephrotoxic gluconate ! IM/IV od anaphylaxis, drugs, incr. renal renal failure, toxicity hemolysis with G6PD deficiency Praziquantel ! Tab 600 mg Intestinal cestodes: Nausea, abd. Cimetidine incr. 10–15 mg/kg od. pain, fever, and Neuro-cysticercosis dizziness, carbamazepine 15 mg/kg tds sedation, and phenytoin sweating, reduce blood eosinophilia levels of praziquantel Pentamidine ! Inj. 300 mg 2–4 mg/kg od Fatigue, metallic Incr. chances of IM/IV taste, hypoten- bleeding with M = 300 sion, itching, anticoagulants, vomiting, incr. marrow hypoglycemia, suppression with leukopenia, other bone thrombocytopenia marrow toxicant drugs Diethyl Tab 50, 100 mg. 1–2 mg/kg Nausea, anorexia, No known carbamazine ? Syr 50, 120 mg/ tds skin rash, interactions 5mL M=300 urticaria, fatigue, headache, dizziness Ivermectin ! Tab 3, 6 mg 0.15–0.2 mg/kg Nausea, vomiting, None known single dose constipation, M = 12 abdominal pain, fatigue Benzyl Emulsion 25% Apply over once Irritation of eyes None reported benzoate * daily after bath and mucous membrane, hypersensitivity Permethrin * Lotion 1%, 5% Approx 30 gm Transient burning None reported applied to scalp. and stinging For scabies apply sensation, all over body pruritus, tingling, mild erythema Crotamiton * Lotion, Massage Skin irritation None reported Cream 10% thoroughly allergic reactions Antimicrobial Formulary 467

 RECOMMENDED READING 1. Davies EG, et al. Manual of Childhood Infections, 2nd Edition. Royal College of Pediatrics and Child Health. 2002. 2. Drug Index. Passi Publication Pvt. Ltd. July - Sept 2006. 3. Guidelines for Use of Antiretroviral Agents in Pediatric HIV Infection. Available at URL: http:// AIDSinfo.nih.gov. Accessed on September 10, 2006. 4. IAP Drug Formulary 2004, 1st Edition, Editor-in-chief Dr Jeeson C Unni. IAP, 2004. 5. Pediatric Index. Ed. Dr Arun Kumar Vol 5, No. 4, Jan - Feb 2006. 6. Troy D Moon, Richard A Oberhelman. Antiparasitic Therapy in Children. Ped Clin N Am. 2005;52: 917-48. Index

A Amoebic dysentery 195 therapy of infections 183 Amoxycillin clavulanic acid 264 Antimony compounds 392 Abdominal cramps 84, 192, Amphotericin B 149, 393 Antipseudomonal penicillins, 196 Amphotericin, concomitant therapeutic Abdominal pain 84 use of 73 indications of 32 Abdominal sepsis 46 Ampicillin-sulbactam 36 Antiretroviral agents 401 Acute diarrhea, treatment of Anthelmintic drugs 415 Antistaphylococcal agent, 189, 191 Antibacterial choice of 280 Acute otitis media 207 agents 24, 434 Antiviral therapy 340 Acute renal failure 221 spectrum 28, 33, 34, 36, 38 Apnea 216, 221 Acute respiratory distress Antibiotic Arcanobacterium syndrome 234 dose of 315 haemolyticum 204 Acyclovir 173 efflux 4 Arteether 379 Adefovir dipivoxil 181 in neonates, drug doses of Artemisinin compounds 376 Adenovirus 204 commonly used 310 Artesunate 378 Agar dilution susceptibility test in pneumonia 219 Articular side effects in 15 prophylaxis 341 children 94 AIDS therapy of septic shock 315 ARV regimens recommended defining opportunistic for initial therapy in infections 411 Antidiarrheal agents 197 children 409 National AIDS Control Antifungal agents at a glance Aseptic suctioning technique Program 409 169 326 patients 359 Antifungal drugs, classes of Asymptomatic bacteriuria 269 primary prevention of 149 Automated instrument cryptococcosis and Antileishmanial drugs 392 methods 19 histoplasmosis 157 Antimalarial Azithromycin 255 Albendazole 415 activity 364, 375 Azoles 154, 451 Algorithm for treatment of drugs 364 Aztreonam 38, 254 bloody diarrhea 194 therapy, choice of 384 Antimicrobial Allopurinol 395 B Amantadine and rimantadine agents in infants and 170 children, dosage of Bacampicillin 31 Amikacin 71 297 Bacilli sub-population Aminoglycosides 70, 264 choice of 193 (mitchison Aminoglycosides drugs 190 hypothesis) 229 common clinical uses of 66 for treatment of bloody Bacteria 204 dosing of once-daily 68 diarrhea 193 Bacterial cell membrane 3 Aminopenicillins not effective against Bacterial amoxicillin 31, 33 shigella 195 infection ampicillin 31, 253 resistance, mechanisms of acute 183 bacampicillin 31 2 chronic 184 therapeutic indications for susceptibility testing meningitis 289 31 methods 14, 19 resistance 28 Aminosidine 395 therapy in bloody diarrhea skin infections 271 Amodiaquine 367 192 Benzimidazoles 415 470 Rational Antimicrobial Practice in Pediatrics

Beta lactam antibiotics 32 Clavulanic acid 33 CMV 178 Blood stream infections 134 Clindamycin 382 congenital heart 173, Bone or joint infection 309 Clostridium difficile colitis 196 221, 298, 299, 324 Bone or soft tissue infection 66 Cloxacillin 30 cyanotic heart 299 Bordetella pertussis 349 CNS infection with shock 318 cysticercosis 416 Bowel bladder dysfunction 267 Colistin use in children 135 esophageal 368 Breakpoint susceptibility tests Combination antibiotic extrapulmonary 242 16 therapy 186 gastroesophageal reflux 84 Combinations of third genital ulcer 83 C generation graft versus host 161 cephalosporins with group B beta hemolytic Carbapenemases 10 probiotics 47 streptococcus 347 Carbenicillin 32 Common HIV 399 Carboxypenicillins and parasitic infections 276 HSV 174 ureidopenicillins 32 viral infections 274 hydatid 416 Catheter related UTI’s 325 Community acquired infectious 348 Caveats of AST 20 pneumonia invasive CMV 177 Cefaclor 44 with shock 318 kala-azar 392 Cefepime 47 without risk factors 217 kidney 295 Cefepime tazobactam 35, 36 Congenital tuberculosis 242 liver 86, 181 Cefixime 253 Conventional amphotericin B, Lyme’s 29, 84, 122 Cefoperazone sulbactam 35, dosage of 152 malarial 368 36 Coronavirus 204 meningococcal 185 Cefpirome 48 Corynbacterium diphheriae oral herpes viral 350 Cefpodoxime 253 204 pelvic inflammatory 122 Cefprozil 44 Cotrimoxazole 195, 253, 263, peptic ulcer 83, 87 Ceftriaxone 251 254 pneumococcal 347, 348 Cefuroxime axetil 44 Coxasackievirus 204 primary pulmonary 238 Cellulitis with septic shock 319 Cryptococcosis, renal and hepatic 416 Cephalosporin (cepham) extrapulmonary 412 rheumatic heart 345, 346, nucleus 40 Cryptosporidium 196 353 Cephalosporin CSF shunt infections 325 rheumatic valvular 346 dosage of third and fourth Culture-negative rickettsial 119 generation 48 osteomyelitis, severe neuropsychiatric general cephalosporins 45 treatment of 285 375 oral first generation 43 Cyanosis 221 Chemoprophylaxis severe pelvic drugs and dosage for inflammatory 66 350 D sexually transmitted 83, 87 for malaria 350 Daptomycin 109 sickle cell 281, 347 indications for 350 De-escalation 328 tuberculosis 228, 244 Chest PT and position change Dermatitis 411 typical cat-scratch 84 326 Determination of MIC 17 underlying cardio- Childhood tuberculosis, Diarrhea, drugs for 197 pulmonary 345 chemotherapy of Diseases Doxycycline 382 232 adenovirus 173 Drug toxicity monitoring and Chloramphenicol 117, 195, 254 chronic granulomatous management 239 Chloroquine 364 281 Drugs and doses for preventing Cholera 191 chronic lung 173 Mycobacterium avium Chronic osteomyelitis 286 chronic pulmonary complex (MAC) 361 Cidofovir 180 inflammatory 81 Dyspnea 216 Index 471

E Fourth generation Hypertrophic cardiomyopathy cephalosporins 47 353 E test (AB Biodisk, Solna, Fungal infections Hypotension 221 Sweden) 19 adverse reactions of drugs Hypoxemia 221 EBV 204, 205 158 Echinocandins 162 classes of antifungal I Ecthyma 272 drugs 149 Effective circulating volume IDV-containing regimens dual dosage of drugs 157 depletion 73 (full-dose) 410 drug interactions of Emerging cephalosporins 48 Immunocompromised status triazoles 160 Empiric antimicrobial therapy 221 treatment of 169 185, 226, 279 Impetigo 271 Fungal sepsis 311 Empiric initial treatment in Inactivating enzymes 2 Fusion inhibitors 405 patients with Inadequate observation or suspected bacterial supervision by family meningitis 293 G 221 Empirical antibiotic therapy for Ganciclovir 177 Indications for use of dilution hospital acquired Gastrointestinal procedures methods 17 pneumonia 329 354 Indications for using lipid Empirical therapy for enteric Genitourinary tract 355 formulations 151 fever, choice of Gentamicin 71 Indications of using drugs 257 Giardiasis 195 vancomycin in Empirical therapy for Gradient diffusion method 19 patients 334 uncomplicated Gram-positive organisms 309 Indigenous BL-BLI malaria 384 Gray baby syndrome 119 combinations 37 Endocarditis 66 Group A streptococcus 345 Infection with unusual Enteric fever, treatment of 255 Grunting 216, 221 pathogens 196 Establishing a microbiologic Infections in an HIV infected diagnosis of H child 358 tuberculosis 235 Influenza 204 Etiological agents for acute H2 blocker instead of PPI as Initial antibiotic therapy in lower respiratory far as possible 326 febrile neutropenia infection in children Haemophilus influenzae 9 335 214 Halofantrine 375 Insertion or removal of intra- Etiology of acute diarrhea 191 Helicobacter pylori infections uterine devices 355 ETR-containing regimens 410 83 Interferon gamma 395 Extended spectrum B Hepatomegaly 411 Intermittent regimens for lactamase (ESBL) 10 Herpes virus infections 274 tuberculosis 233 Extrapulmonary tuberculosis Herpes zoster 274 Intestinal nematode 242 High level or absolute infections, treatment resistance 2 of 420 F HIV infected children above Intravascular access device the age of 12 months with shock 320 Famciclovir 176 406 Intravenous antibiotic therapy, Febrile neutropenia 334 HIV infected infants below the indications for 217 Febrile neutropenia with age of 12 months 405 Isolation of organisms on shock 319 HIV infected pregnant mother culture meriting Flaring of the nostrils 221 358 vancomycin 334 Flucytosine 164 HIV infection and therapy in Itraconazole and fluconazole Folliculitis 272 children 400 155 Foscarnet 179 HSV 204 Ivermectin 417 472 Rational Antimicrobial Practice in Pediatrics

J Methenamine mandelate or Nephropathy 412 mandelamine 266 Nephrotoxicity 135 Jaundice Methicillin 30 Netilmycin 71 cholestatic 33, 95 Methicillin resistant staphylo- Neuraminidase inhibitors 171 increase risk of rifampicin coccal infections 7, 448 Neurotoxicity 135 107, 334 Juvenile Niclosamide 419 Metronidazole 123 idiopathic arthritis 417 Nitazoxanide 418 Microdilution broth rheumatoid arthritis 114 Nitrofurans 195 susceptibility test 16 treated with ciprofloxacin Nitrofurantoin 126, 265 Miltefosine 394 94 Nocardiosis 412 Mitral valve prolapse without Non-nucleoside reverse trans- valvular dysfunction criptase inhibitors K 353 (NNRTIs) 403 Kala-azar, current treatment Molecular genetics of anti- Nonsevere pneumonia 220 options in 396 biotic resistance 4 Nontuberculous mycobacteria Kanamycin 71 Molluscum contagiosum 275 83 Kaposi’s sarcoma (KS) 412 Monitoring for response to Nosocomial infections with therapy 237 shock 320 Monitoring of patient on Nucleoside and nucleotide L treatment 237 reverse transcriptase Monitoring response to Lamivudine 180 inhibitors (NRTIs) 401 therapy 282 Leiomyosarcoma 412 Nutritional status 216 Monobactams 38 Lincosamides 125, 446 Monotherapy vs combination Lipid formulations, dosage of O therapy 327 152 Mycobacterial infection 66 Ocular infections 66 Lower respiratory tract Mycobacterium avium Oseltamivir and zanamavir 171 infections 82 complex 359, 413 Osteomyelitis and septic Lymphadenopathy 411 Mycobacterium tuberculosis arthritis 309 Lymphoid interstitial 349, 413 Otitis externa (topical) 66 pneumonia (LIP) 412 Oxazolidinones, linezolid 106 Lymphoma, primary, in brain Oxygen saturation 221 412 N Nafcillin 30 P M Nalidixic acid 195 Nasal flaring 216 Panton-Valentine leukocidin 7 Macrodilution broth Necrotizing fasciitis 274 Parainfluenza 204 susceptibility test 15 Need for empirical antiviral Parental Malaria 350 drug oseltamivir 222 first generation Malarone (atovaquone and Neisseria meningitidis 298,348 cephalosporins 43 proguanil) 383 Neonatal meningitis 307 third generation Management of associated Neonatal pneumonia 308 cephalosporins 45 venous thrombo- Neonatal sepsis 66 Parotitis 411 embolism 285 Neonatal sepsis adjunctive Pediatric Managing patients with therapy 310, 312 respiratory infections 31 interruptions in Neonatal sepsis diagnosis of septic shock treatment 241 305 doses of various Mebendazole 416 Neonatal tetanus 309 antibiotics 316 Mechanical ventilation 221 Neonate with suspected urinary tract infections 31 Mefloquine 373 sepsis approach to Pediculosis 277 Meningitis 196, 309 305, 306 Penciclovir 176 Index 473

Penicillin resistant Infected pregnant mother Respiratory distress in S. pneumoniae 334 358 children with Penicillinase resistant infection in HIV infected pneumonia 216 penicillins, child 358 Respiratory infections in therapeutic indication Mycobacterium tuber- cystic fibrosis 133 of 30 culosis in HIV 359 Respiratory tract infection Penicillin-G (benzyl penicillin) specific body sites 357 355 28 viral infections 33 360 Rhinosinusitis 203 Pentamidine 393 Protease inhibitors (PIs) 403 Rhinovirus 204 Persistent acute otitis media Protection of Ribaviri 172 208 infection-prone sites 352 Role of corticosteroids as Persistent fever 411 vulnerable host 353 adjunctive therapy in Pertussis 82 Pseudoresistance 2 TB 234 Pharyngitis 204 Pulmonary lymphoid hyper- Pharyngitis, causes of 204 plasia complex 412 Phenoxymethylpenicillin Pyrantel pamoate 416 S (penicillin V) 30 Pyridium 266 Scarlet fever 273 Piperacilli 32 Pyrimethamine—sulfadoxine or Secondary prophylaxis of Piperacillin-tazobactam 34 sulfalene (SP) 370 group A strepto- Pityriasis versicolor or tinea Pyrimidine 451 coccal infections, versicolor 275 drugs for 346 PK-PD parameters 24 Q Semisynthetic penicillins 29 Pneumocystis carinii pneu- Sensitivity of pathogen 213 monia (PCP) 413 Quality control (QC) in dilution methods 17 Septic shock Pneumocystis jiroveci 352 in neonates 315 Pneumonia disk diffusion tests 18 Quinidine 370 without focus in infants and antibiotics in 219 older children 318 treatment of 217 Quinine 367 Quinolones Severe pelvic inflammatory Polyenes 149 disease 66 Posaconazole 160 adverse drug effects of commonly used 95 Sexually transmitted diseases Postantibiotic effect 8, 67 83 Potentially alterable factors 73 classification of 91 prophylaxis, use of 334 Shock with Praziquantel 419 intra-abdominal focus 318 Primaquine 379 urinary tract infections Principles of antimicrobial R (UTI) 319 therapy 314 Radiographic contrast Short course chemotherapy Principles of chemotherapy exposure 73 (SCC) 232 for tuberculosis 229 Rationale for antimicrobial Signs and symptoms of Probiotics 197 therapy 192 acute infection 207 Progressive multifocal Ready reckoner for dosages associated with leukoencephalopathy of antimicrobial candidemia 324 (PML) 413 therapy 433 bone inflammation 286 Prophylactic Recurrent pharyngitis 205 antibiotic therapy 185 acute otitis media 208 positive parasite in bone antimicrobial therapy 267 bacterial infections 360 marrow 396 regimens for genitourinary pyodermas 272 respiratory distress 216 354 severe bacterial infections virological or Prophylaxis for 411 immunological 406 body sites 353 Renal insufficiency 73 Single antibiotic therapy without following occupational Resistance in Staphylococcus vancomycin 335 exposure to HIV 356 aureus 7 Sitamaquine 395 474 Rational Antimicrobial Practice in Pediatrics

Skin and soft tissue infections Therapeutic options for U 82 enteric fever 251 Unalterable factors 73 Spectrum of activity 90, 104, Therapeutic options for Unboosted DRV-containing 106 GABHS pharyngitis regimens 410 Splenomegaly 411 206 Uncomplicated malaria 384 Sporins 436 Therapeutic uses of Underlying disease 215 SQV-containing regimens 410 piperacillin Unexplained chronic diarrhea Staphylococcal scalded skin tazobactam 36 411 syndrome 273 Ticarcillin clavulanate 34, 36 Unstable patient with Status of various antibiotics for Tigecycline hypotension 334 treatment of UTI 263 clinical applications of 142 Upper respiratory tract Sterilization procedures 355 dosing schedule of 141 infections 81 Streptococcus pneumoniae Tinea 276 Urinary tract infection 196, 308 5, 107, 298, 347 Toxic shock syndrome (TSS) Uterine dilation and curettage Sulfonamides 113 274 355 Surgery, indications for 286 Toxoplasmosis 83 Syndromes TPV-containing regimens 410 acute brain 374 Trimethoprim–sulfametho- V acute pneumonitis 127 xazole 115 Valacyclovir 176, 178 acute respiratory distress Tuberculosis Vancomycin resistant 234, 430 cases of tuberculosis 228 enterococcal acute retinal necrosis 175 chemotherapy of infections 6, 107 Fanconi 122 childhood 228 Vancomycin-resistant gray baby 119, 446 CNS tuberculosis 233 Staphylococcus hemolytic uremic congenital tuberculosis 242 aureus (VRSA) 8 syndrome 95 control and management Varicella 274, 350 hemorrhagic fever renal of 233 Voriconazole 158 173 extrapulmonary 232, 242 immune reconstitution intensive phase of 66 W inflammatory 400, intermittent regimens for Weight loss or failure to thrive 405 233 411 myelodysplastic 161 management of drug Widespread mucocutaneous nephrotic 215 resistant 66, 111 disease 175 red-man 102, 105 managing patients with serotonin 108 interruptions in Sjögren’s 417 treatment 240 X Staphylococcal scalded microbiologic diagnosis of X-ray skin 273 235 chest 336 Stevens-Johnson 115, multidrug resistant tuber- routine 334 126, 239, 240, 254, culosis 71, 96, 241 XDR tuberculosis 241 372, 403, 404, 418, principles of chemo- 437, 442, 455 toxic shock 107, 274 therapy for 229 Y viral sepsis 177 spinal tuberculosis 233 Yersinia enterocolitica 80, Wasting 413 steps in starting appro- 204 priate treatment 235 Yersinia pestis 121 treating XDR 108 T treatment categories and Teicoplani 104 regimens for Z Tetracycline 120, 195, 381, childhood 236 Zinc in the treatment of 446 treatment of MDR-T 243 diarrhea 190