UTILIZATION PATTERN, SAFETY PROFILE AND COST ANALYSIS OF ANTIMICROBIALS PRESCRIBED IN AN INTENSIVE CARE UNIT OF A TEACHING HOSPITAL

Dissertation

Submitted to THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY

In partial fulfilment of the requirements for the award of the degree of

M.D PHARMACOLOGY

Branch VI

May2018 UTILIZATION PATTERN, SAFETY PROFILE AND COST ANALYSIS OF ANTIMICROBIALS PRESCRIBED IN AN INTENSIVE CARE UNIT OF A TEACHING HOSPITAL

Dissertation

Submitted to THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY

In partial fulfilment of the requirements for the award of the degree of

M.D PHARMACOLOGY

Branch VI

May 2018

ACKNOWLEDGEMENT

In the first place, I would like to express my gratitude to my professor, mentor and guide Dr. Reneega Gangadhar , for her valuable and constant guidance, supervision and support throughout the study. Her patience and understanding during times of difficulties in the study period helped me a lot under such circumstances. Her constant motivation has helped me to overcome all the challenges and difficulties that

I came across this research work. Her encouragement from the inception of this research to its culmination has always been profound. It has been an extraordinary experience working under her.

I am very much grateful to my co-guide Dr. Kaniraj Peter. J, Professor for valuable support and guidance in carrying out the study.

I extend my sincere heartfelt thanks to Dr. Velayuthan Nair , Chairman and

Dr. Rema. V. Nair , Director, for providing facilities to accomplish my dissertation work. I also thank the Principal of the Institution Dr. Padmakumar for his valuable support extended to me.

I thank my Associate professor Dr. Ganesh. V, for his help and support throughout the study period.

I am thankful to Dr. V. M. Sandeep, Assistant Professor for his help, support, valuable suggestions and encouragement throughout the study period.

I also thank my Assistant Professor Mr. Sarath Babu. K for his critical inputs at all stages of my study. His suggestions never failed to help me in times of difficulties during the study.

I express my special thanks to my colleague Dr. Suhaina. A. S for giving me constant support and encouragement as well as for her constructive criticism and valuable inputs. I also thank my senior Post Graduates Dr. Prathab Asir. A, Dr. Anandhalakshmi. A and Dr. Arjun.G.Nair, and my junior Post Graduates

Dr. Priyanga. R, Dr.Ramakrishnan. S and Dr. Charmila. V for their help and support.

Mrs. Florence Vimala. P and Mrs. Sangeetha. M deserves special mention for their technical help and support.

CONTENTS

Table of Contents Sl. No Chapter Page No 1. Introduction 1 2. Review of literature 4-65 3. Aims and objectives 66 4. Materials and Methods 67-72 5. Observations and Results 73-91 6. Discussion 92-97 7. Conclusion 98-99 8. References I-X 9. Annexure XI-XVI I IHEC certificate XI II Consent form XII III Case record form XIII IV ATC classification XIV

VI ADR Reporting Form XVI

List of tables Table Title Page No No 1. Historical landmark and the scientists who contributed 11 to AMA 2. Discovery of AMA 12 3. Antimicrobial drugs classified based on chemical 15 structure 4. Antimicrobial drugs classified based on Mechanism of 17 action 5. Antimicrobial drugs classified based on Type of 18 organisms 6. Antimicrobial drugs classified based on spectrum of 19 activity 7. Antimicrobial drugs classified based on Type of action 19 8. Antimicrobial drugs classified based on Orgin 20 9. Dosage Guide For Commonly Used Antimicrobial 50 Agents 10. Classification of the Adverse Effects of Antimicrobial 62 Drugs 11. Age Distribution of the patients 73 12. Gender wise distribution of patients 74

13. Frequency of co-morbidity found in patients 76 14. Summary of Prescribing Indicators Data 79 15. Utilization of AMAs expressed as number of DDD/1000 81 patients/day and cost/DDD 16. Utilization of Fixed Drug Combination AMAs 82 expressed as number of DDD/1000 patients/day and cost/DDD 17. Frequency of distribution of AMAs in each prescription 83 18. Most commonly used Beta-lactam antibiotics 84 19. Most commonly prescribed antibiotics injected 85 20. Percentage of prescription with single drug and 89 combination of AMAs 21. Cost of individual class of AMAs for single day and 89 during total duration of the stay 22. Frequency and percentage of encounter with ADRs 90 23. Causality Assessment of ADRs according to WHO 90

List of figures Figure Title Page No No 1. Age wise distribution of the patients 73 2. Age wise distribution of male and female patients 74 3. Most common causes of infection on system based 75 4. Frequency of co-morbidity found in patients 76 5. Number of prescriptions containing Particular 83 Antimicrobial group 6. Number of prescriptions containing one AMA prescribed 86 7. Number of prescription containing 2 AMAs Prescribed 87 8. Number of prescription which contain 3 AMAs 88 prescribed 9. Percentage of encounters with ADRs as per WHO 91

Abbreviation

ABBREVIATIONS

ADR Adverse Drug Reaction

AE Adverse Event

AIDS Acquired Immunodeficiency Syndrome

ALI Acute Lung Injury

AMAs Antimicrobial Agents

AMR Antimicrobial Resistance

ARDS Acute Respiratory Distress Syndrome

ARF Acute Renal Failure

ASHP American Society Of Health-System Pharmacists

AST Antibiotic Susceptibility Testing

ATC Anatomical Therapeutic Chemical

BMI Body Mass Index

BSI Blood Stream Infection

CAP Community Acquired Pneumonia

CNS Central Nervous System

DDD Defined Daily Dose

DDS Dapsone

Abbreviation

DNA Deoxyribonucleic Acid

DUS Drug Utilization Study

EDL Essential Drug List

ESBLs Extended Spectrum Beta-Lactamases

FDC Fixed Drug Combination

G6PD Glucose-6-Phosphate Dehydrogenase Deficiency

GIT Gastrointestinal Tract

ICP Intracranial Pressure

ICU Intensive Care Unit

IHEC Institutional Human Ethics Committee

ICM Intensive Care Management

IM Intramuscular

IMCU Intensive Medical Care Unit

IV Intravenous

LRT Lower Respiratory Tract

MAC Mycobacterium Avium Complex

MDR Multi Drug Resistance

MIC Minimum Inhibitory Concentration

Abbreviation

MICU Medical Intensive Care Unit

MODS Multi Organ Dysfunction Syndrome

MRSA Methicillin Resistant Staphylococcus Aureus

NDM-1 New Delhi Metallo-Lactamase

NI Nosocomial Infection

NTS Non Typhoidal Salmonella

OPD Out Patients Department

PAS Paraaminosalicylic Acid

PDD Prescribed Daily Dose

PSURs Periodic Safety Updates Regulators

RNTCP Revised National Tuberculosis Control Program

SSI Surgical Site Infection

ToRs Terms Of Reference

UTI Urinary Tract Infection

VAP Ventilator-Associated Pneumonia

WHO World Health Organization

Introduction Introduction

Introduction

Infectious diseases were the major cause of morbidity and mortality before the discovery of antimicrobial agents (AMAs).1 Antimicrobial agentsare the frequently utilized drugs in an intensive care unit (ICU) setting. 2 In ICU a large number of drugs are administered to patients, most of the patients are critically ill and suffering from multiple complications. 3 These patients have frequent infection and are more prone for developing new infections. 4 ICU is a place where there is frequent use of antibiotics, poor adherence with evidence- based guidelines and broad-spectrum antibiotic overuse.5

The total AMA consumption in ICU is approximately ten times higher than the general hospital wards. 4 Bacterial resistance is increased due to inappropriate use of antibiotics. Antimicrobial agents are also used empirically in ICU without culture sensitivity test. 6 Antibiotic resistance due to hospital acquired infections is a worldwide problem and it is one of the reason for increased morbidity, mortality, length of hospital stay, and healthcare expenditures. Overuse or misuse of antibiotics increases burden of antibiotic resistance, adverse effects of these drugs along with treatment costs. 7

Drug utilization study is an essential part of pharmaco-epidemiology. 7

Drug utilization research was defined by World Health Organization (WHO) in

1977 as “the marketing distribution and use of drugs in a society, with special emphasis on the resulting medical, social and economic consequences”. This type of research provides an overview about the pattern, quality, determinations and outcome of use. The aim of drug utilization research is to motivate the 111 | P a g e

Introduction rational use of medications by the clinicians while delivering health care. 8 It is an important tool to study the clinical use of drugs in populations and its impact on the health care system. 3 Drug utilization studies are useful for information about drug use patterns and for identifying high cost drugs. Such analysis not only improves the standards of medical treatment, but also helps in the identification of problems related to drug use such as poly pharmacy, drug interaction and adverse drug reaction. 9

The defined daily dose (DDD) concept was developed to overcome objections against traditional units of measurement of drug consumption. The

DDD is defined as the assumed average maintenance dose per day for a drug used for its main indication in adults. 3

World Health Organization has defined adverse drug reaction (ADR) as

“a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the modification of physiological function”.9 ADRs is one of the major causes of iatrogenic disease. ADRs may result in hospital admission or prolonged hospitalization but also may lead to permanent disability or even death. 6 Pharmaceutical cost are the fastest growing health care expense. Cost of the drug play a crucial role in patient care especially in developing countries. 10

Pharmacoeconomic analysis is comparison with of two or more drug therapies with respect to their costs and consequences. 11

In the light of above mentioned information, monitoring and evaluation of prescription patterns of antimicrobial agents are one of the recommended

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Introduction strategies to control resistance and also to improve the prescribing practices. 2

ADRs due to antibiotics are the most common in the our country because these are the most commonly used drug in therapy. 12 It is always safe to keep the numbers of drugs per prescription low to minimize the risk of drug interactions, development of bacterial resistance and cost in hospital. It is always good to have a complete prescription with name, age, sex, and diagnosis with drug treatment using less number of drugs, correct dose and administration duration.

There is need to conduct many studies to educate the prescribers, the rational drug therapy for safety and benefit to the patient.13

Till date no study on utilization pattern, safety profile and economic outcome of antimicrobial use has been conducted in this institution. Hence it was thought worthwhile to conduct a study to evaluate the utilization pattern, safety profile and cost analysis of antimicrobial use in the Medical ICU of this institute.

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Review of Literature Review of Literature Review of literature

Intensive care has been defined as “a service for patients with potentially recoverable conditions who can benefit from more detailed observation and invasive treatment than can safely be provided in general wards or high dependency areas.” The most commonly supported organ is the lung, but facilities should also exist for the diagnosis, prevention, and treatment of other organ dysfunction.14

The Intensive Care Unit (ICU) management of patients is targeted towards, 15

• Respiratory system

• Cardiovascular system

• Alimentary system

• Nosocomial infection and infection surveillance

• Anticoagulation

• Patient comfort

Common Reasons for ICU Care

There are many reasons a patient may need care in an ICU. Some of the more common problems and conditions that may bring a patient to an ICU or that may develop while a patient is under ICU care. 15

A. Pneumonia

B. Urinary tract infection(UTI)

C. Blood stream infection(BSI)

D. Shock

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E. Acute Respiratory Distress Syndrome (ARDS)

F. Chronic Respiratory failure

G. Renal failure

H. Neurological conditions

I. Bleeding & clotting

J. Multi Organ Dysfunction Syndrome(MODS)

K. Nosocomial Infection(NI)

A. Pneumonia

The most common nosocomial infection in ICU patients is pneumonia and is usually associated with mechanical ventilation (ventilator-associated pneumonia/VAP). Common risk factors for nosocomial pneumonia are old age, premature infants, chronic lung disease, previous abdominal thoracic surgery, endotracheal intubation, duration of mechanical ventilation, nasogastric tube, immunosuppression, prior antibiotic use, supine position, poor pulmonary toilet, increased gastric pH and aspiration. 16 The common causative agents were Pseudomonas aeruginosa , Klebsiella pneumoniae , Streptococcus pneumoniae , Haemophilus influenzae , Escherichia coli , Moraxella catarrhalis and Staphylococcus aureus . Although less frequently isolated, Streptococcus pneumoniae had become a worldwide problem because of its increasing resistance to penicillins and most other beta-lactams. They are often very difficult to diagnose because of multiple causes of pulmonary infiltrates, including ARDS, pulmonary hemorrhage or embolus and cardiogenic shock. 17

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B. Urinary tract infections (UTIs)

Nosocomial UTIs were the second most common infection in the ICU and constituted a major source for nosocomial septicemia and related mortality.

Usually, UTI presented with fever or with other signs of systemic illness.

Common risk factors included indwelling bladder catheters, duration of catheterization and other factors like female gender, old age, premature infants, diabetes mellitus, renal failure, and metal colonization. Both condom catheters and transurethral catheters posed significant risk for UTI. 18 The microorganisms usually responsible for catheter-associated UTIs were derived from the fecal flora of the patient or originated from the hospital environment, and included Escherichia coli , Enterococcus spp., Pseudomonas aeruginosa ,

Klebsiella pneumoniae , Proteus mirabilis and Candida albicans .17

C. Bloodstream infections (BSIs)

BSIs are usually the third most common nosocomial infection in ICUs, and are commonly divided into primary and secondary. Primary BSIs were associated with intravascular devices like catheters, and secondary BSIs arose from an infection at another site (e.g., an intra-abdominal infection). There were several sources of bacteraemia, mainly nosocomial pneumonia, UTI and other foci of infection such as skin and soft tissue infections (particularly in burn patients) and surgical wounds. 19 Gram positive organisms like MRSA and coagulase-negative staphylococci are more likely causative agents, particularly in relation to the presence of IV devices, central lines or peripheral IV catheters. Coagulase-negative staphylococci produce an extracellular slime

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Review of Literature matrix in which bacteria are embedded and which interferes with the penetration of antibiotics and hence cannot be eliminated by traditional antimicrobial therapy. 20

D. Shock

Shock is an acute or hyperacute physiological derangement, a systemic syndrome characterized by signs and symptoms, which are the response of different organs to a situation of hypoperfusion for their cells basic metabolic needs. Perfusion means oxygen and nutrients delivery via blood flow.21 Shock results from four potential, and not necessarily exclusive, pathophysiological mechanisms, 22

• Hypovolemia shock: Internal or external fluid loss

• Cardiogenic Shock: Acute myocardial infarction, end-stage

cardiomyopathy, advanced valvular heart disease, myocarditis, or cardiac

arrhythmias

• Obstruction Shock: Pulmonaryem embolism, cardiac tamponade, or

tension pneumothorax

• Distributive factors: severe sepsis or anaphylaxis from the release of

inflammatory mediators

Whatever causes it, shock is a situation of relative hypoxaemia due to failure of the circulation in delivering and distributing enough oxygen for the oxidative processes leading to ATP formation. 21

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E. Acute respiratory distress syndrome (ARDS)

Acute lung injury (ALI) is a clinical syndrome of severe dyspnea of rapid onset, hypoxemia, and diffuse pulmonary infiltrates leading to respiratory failure, a ratio of arterial oxygen tension to fraction of inspired oxygen

(PaO 2 /FiO 2 ) of 201-300 mmHg, in the absence of cardiac failure.

ALI/ARDS results from direct causes like pneumonia, aspiration of gastric contents, pulmonary contusion, etc. and indirect causes like sepsis, trauma, fractures, pancreatitis, burns, etc. is usually treated with some AMAs.

Reductions in ARDS/ALI mortality are largely the result of general advances in the care of critically ill patients and in ventilatory strategies. 23

F. Renal Failure

Acute renal failure (ARF) is associated with pre persistent high mortality in critically ill patients in intensive care units. It is failure of the kidneys (renal failure) to eliminate fluid and waste from the patient’s body.

Sepsis, dehydration, toxic substances, and hypertension are some of the causes.

In case of severity dialysis is done. 24

H. Neurological Conditions

ICUs in neuroscience centres tend to deal with the management of primary diseases of the central and peripheral nervous system which may cause encephalopathy, raised intracranial pressure (ICP), ventilatory, autonomic and bulbar insufficiency or profound neuromuscular weakness. 25

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I. Bleeding and Clotting

Many critically ill patients develop hemostatic abnormalities, ranging from isolated thrombocytopenia or prolonged global clotting tests to complex defects, such as disseminated intravascular coagulation. 26

J. Multiple Organ Dysfunction Syndrome – MODS

MODS is defined as the concurrent dysfunction of two or more organs or systems including respiratory, cardiovascular, haematological, neurological, gastrointestinal, hepatic and renal . A common and deadly condition, is frequently observed in ICU. 27

K. Nosocomial infection

A nosocomial infection is defined as an infection that is not present or incubating when the patient is admitted to hospital or other health care facility.

Nosocomial infections in the ICU is about 2 to 5 times higher than in the general in-patient hospital population. 28 Patients may present with a community-acquired, bacteraemia-related illness, but the majority develop bacteraemia as a secondary nosocomial event. This occurs as a consequence of host defence alteration through their underlying diseases, extensive use of invasive procedures like surgery, tubes, catheters, drains, etc., and coexisting endogenous or exogenous immunosuppression. The incidence of nosocomial bacteraemia in ICU patients ranges from 2.5% to 26%. Associated mortality remains high at 21–56%. 29

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Therapeutic Measures in ICU

A. Fluid & Electrolytes

B. Cardiovascular Drug

C. Corticosteroid

D. GIT Drug

E. Insulin Therapy

F. Bronchodilators

G. Anticonvulsants

H. Sedatives and analgesics

I. Antimicrobial agents

Antimicrobial Agents

Antimicrobial drugs have caused a dramatic change not only of the treatment of infectious diseases but of a fate of mankind. 30 Infections are very common in critically ill patients because of immobility, invasive procedures, compromised immune status and exposure to cross infections. 31 Once the source of sepsis is known, the antimicrobial therapy should be tailored according to the possible infecting pathogens and their relative antibiotic susceptibilities. 32

The infections usually encountered are pneumonia, bloodstream and urinary tract infections. Pneumonia and bloodstream infections were the most common serious infections in ICUs. 16

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The term “antimicrobials” include all agents that act against all types of microorganisms – bacteria (antibacterial), viruses (antiviral), fungi (antifungal) and protozoa (antiprotozoal).7

If an improper antimicrobial agent happens to be chosen for the treatment of infection with drug-resistant microorganisms, the therapy may not achieve beneficial effect, and moreover, may lead to a worse prognosis. 30

Every institution should have an antibiotic policy and guideline in place which should be based on local susceptibility pattern of pathogens. Guidelines will help physicians to prescribe rationally and to choose the best effective, most appropriate empiric antibiotic for the patient. 4

History of AMAs

Table 1: Historical landmark and the scientist s who contribut ed to AMA 30

Year Scientist Drug Noble Prize Year

1910 Paul Ehrlich Arsphenamine

(salvarsan)

1935 Gerhard Domagk Sulfanilamide 1939

1928 Alexander Fleming Penicillin 1945

1943 Selman Abraham Streptomycin 1952 Waksman

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Table 2: Discovery of AMA 30

1910 Arsphenamine

1928 Penicillin

1935 Sulfanilamide

1943 Streptomycin

1944 Aminoglycosides

1949 Chloramphenicol

1950 Tetracyclines

1952 Macrolides ⁄Lincosamides⁄ Streptogramins

1956 Glycopeptides

1957 Rifamycins

1959 Nitromidiazoles

1960 Penicillinase-stable methicillin

1960s Cephems

1962 Nalidixic acid

1962 Quinolones

1968 Trimethoprim

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1984 Norfloxacin

2000 Oxazolidinones

2003 Lipopeptides

Definitions 7,33

Antibiotic is a low molecular substance produced by a microorganism that at a low concentration inhibits or kills other microorganisms.

Antimicrobial is any substance of natural, semisynthetic or synthetic origin that kills or inhibits the growth of microorganisms but causes little or no damage to the host.

Initial antimicrobial use (<72 hours of starting therapy) was defined as any antimicrobial treatment initiated for empiric coverage while microbiologic results were pending or for definitive therapy in which a pathogen was already known.

Empiric antimicrobial use was defined as antimicrobial use that occurred within 72 hours of initiation of therapy while microbiologic cultures results were pending or antimicrobial use in situations after 72 hours of initiation when microbiologic cultures did not yield a pathogen.

Definitive (therapeutic) antimicrobial use was defined as any antimicrobial use at a time when microbiologic culture results and susceptibility data were available. This could have occurred at initiation of therapy or after empiric antimicrobial use was initiated once microbiologic culture results were available.

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End antimicrobial usage was defined as the final choice of antimicrobial regimen selected for the indication being treated. This category includes definitive antimicrobial use in which a pathogen was isolated or empiric antimicrobial use in which no pathogen was ever isolated or microbiologic cultures were never obtained.

Epidemiology:

In India the infectious disease burden was among the highest in the world and recent report showed the inappropriate and irrational use of antimicrobial agents against these diseases, which led to increase in development of antimicrobial resistance. 34

Antimicrobial use in hospitalized patients was common, with patients receiving antibiotics on 70% of their ICU days, and patients on the general inpatient wards receiving antimicrobials on ≥40% of their inpatient days. 33

World Health Organization has proposed regional strategy on antimicrobial resistance with the goal to minimize the morbidity and mortality due to antimicrobial resistant infection, to preserve the effectiveness of antimicrobial agents in the treatment and prevention of microbial infections. 34

For monitoring use and misuse of antibiotics: Schedule H of the drug and cosmetics act contains a list of 536 drugs which are required to be dispensed on the prescriptions of a registered medical practitioner. 35

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Classification of AMA

Patients in ICU were commonly prescribed multiple broad spectrum antibiotics. 32

Antimicrobial drugs can be classified in many ways, based on, 36

A. Chemical structure

B. Mechanism of Action

C. Type of organism against which primarily active

D. Spectrum of activity

E. Type of action

F. Source of Antibiotics

A. Chemical structure

Table 3: Antimicrobial drugs classified based on chemical structure

Sulfonamides and related drugs Sulfadiazine, Sulfones—Dapsone

(DDS), Paraaminosalicylic acid (PAS).

Diaminopyrimidines Trimethoprim, Pyrimethamine

Quinolones Nalidixic acid, Norfloxacin,

Ciprofloxacin, Prulifloxacin, etc

β-Lactam antibiotics Penicillins, Cephalosporins,

Monobactams, Carbapenems

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Tetracyclines Oxytetracycline, Doxycycline, etc

Nitrobenzene derivative Chloramphenicol

Aminoglycosides Streptomycin, Gentamicin, Amikacin,

Neomycin, etc.

Macrolide antibiotics Erythromycin, Clarithromycin,

Azithromycin, etc

Lincosamide antibiotics Lincomycin, Clindamycin

Glycopeptide antibiotics Vancomycin, Teicoplanin

Oxazolidinone Linezolid.

Polypeptide antibiotics Polymyxin-B, Colistin, Bacitracin,

Tyrothricin

Nitrofuran derivatives Nitrofurantoin, Furazolidone.

Nitroimidazoles Metronidazole, Tinidazole, etc.

Nicotinic acid derivatives Isoniazid, Pyrazinamide, Ethionamide

Polyene antibiotics Nystatin, Amphotericin- B, Hamycin

Azole derivatives Miconazole, Clotrimazole,Ketoconazole,

Fluconazole

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Others Rifampin, Spectinomycin, Sod. fusidate,

Cycloserine, Viomycin, Ethambutol,

Thiacetazone, Clofazimine, Griseofulvin

B. Mechanism of action

Table 4: Antimicrobial drugs classified based on Mechanism of action

Inhibit cell wall synthesis Penicillins, Cephalosporins,

Cycloserine, Vancomycin, Bacitracin

Cause leakage from cell Polypeptides—Polymyxins, Colistin, Bacitracin. membranes

Polyenes—Amphotericin B, Nystatin,

Hamycin

Inhibit protein synthesis Tetracyclines, Chloramphenicol,

Erythromycin, Clindamycin, Linezolid

Cause misreading of m-RNA Aminoglycosides— Streptomycin,

code and affect permeability Gentamicin, etc

Inhibit DNA gyrase Fluoroquinolones—Ciprofloxacin and

others.

Interfere with DNA function Rifampin

Interfere with DNA synthesis Acyclovir, Zidovudine

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Interfere with intermediary Sulfonamides, Sulfones, PAS,

metabolism Trimethoprim, Pyrimethamine,

Metronidazole

C. Type of organisms against which primarily active

Table 5: Antimicrobial drugs classified based on Type of organisms

Antibacterial Penicillins, Aminoglycosides,

Erythromycin, Fluoroquinolones

Antifungal Griseofulvin, Amphotericin B,

Ketoconazole

Antiviral Acyclovir, Amantadine, Zidovudine

Antiprotozoal Chloroquine, Pyrimethamine,

Metronidazole, Diloxanide

Anthelmintic Mebendazole, Pyrantel,

Niclosamide, Diethyl carbamazine

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D. Spectrum of activity

Table 6: Antimicrobial drugs classified based on spectrum of activity

Narrow-spectrum PenicillinG, Erythromycin

Broad-spectrum Tetracyclines, Chloramphenicol,

Extended spectrum penicillins Newer cephalosporins, aminoglycosides,

fluoroquinolones

E. Type of action

Table 7: Antimicrobial drugs classified based on Type of action

Primarily bacteriostatic Sulfonamides, Erythromycin,

Tetracyclines, Clindamycin,

Chloramphenicol, Linezolid,

Ethambutol

Primarily bactericidal Penicillins, Cephalosporins,

Aminoglycosides, Vancomycin,

Ciprofloxacin, Rifampin, Metronidazole,

Isoniazid, Cotrimoxazole, Pyrazinamide

Some primarily static drugs may become cidal at higher concentrations

(as attained in the urinary tract), e.g. erythromycin, nitrofurantoin. On the other

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F. Source of Antibiotics:

Table 8: Antimicrobial drugs classified based on Orgin

Fungi Penicillin, Griseofulvin, Cephalosporin

Bacteria Polymyxin B, Tyrothricin, Colistin

Aztreonam, Bacitracin

Actinomycetes Aminoglycosides , Macrolides

Tetracyclines, Polyenes, Chloramphenicol

Individual classes of Drugs:

A. Beta – Lactam Antibiotics 37

The β lactam antibiotics are useful and frequently prescribed antimicrobial agents- Penicillins, cephalosporins, monobactams and carbapenems have a β lactam ring in their molecular structure. These bactericidal antibiotics act primarily on the bacterial cell wall by inhibition of synthesis of the bacterial peptidoglycan. Although some bacteria produce β lactamase and have developed resistance, these drugs on the whole remain useful in treating many different types of infections.

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Penicillins 37

Penicillin is active against Streptococci, Neisserriae, Spirochaetes, some anaerobes including Clostridia and a few other organisms. About 80 - 90% of the Staphylococcus aureus are β lactamase producers and hence are resistant to penicillin G and aminopenicillins. The prevalence of penicillinase producing

Neisseria gonorrhoea is on the increase. There are reports of decreased susceptibility of pneumococci and streptococci to penicillin from other parts of the world. The only serious disadvantage of penicillins is hypersensitivity reaction.

Penicillin formulations available are:

1. Penicillin G (Crystalline Penicillin or Benzyl Penicillin) – for intravenous

(IV) use. Needs to be given frequently (4 – 6 hourly).

2. Procaine Penicillin – Intramuscular (IM) preparation with a longer duration of action. Needs to be administered less frequently i.e. daily.

3. Benzathine Penicillin – given IM provides low levels of penicillin in the circulation for 3-4 weeks.

4. Penicillin V (Phenoxymethyl Penicillin) – an oral preparation, intrinsically less active than Penicillin G

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Penicillin is the drug of choice for the treatment of the following infections:

1. Streptococcal infections e.g. tonsillopharyngitis

2. Infections due to Streptococcus pneumoniae.

3. Meningococcal infections e.g. meningitis, septicaemia

4. Syphilis

5. Clostridial infections, anthrax, diphtheria

6. Leptospirosis

Aminopenicillins 37

Ampicillin and amoxycillin are destroyed by staphlococcal β lactamases but have a slightly broader spectrum than penicillins because of their activity against some gram negative bacilli like E .coli, salmonella sp and shigella sp .

They also have better activity against H.influenzae and enterococci compared with penicillin. Although initially sensitive, resistance to these drugs among

E.coli is now widespread. Many strains of H.influenzae also produce β lactamases, which can destroy these drugs.

Amoxycillin is better absorbed than ampicillin and has a longer half life and hence is preferred for oral therapy. These drugs are used in empirical treatment of respiratory infections and in the treatment of susceptible urinary tract infections. They may be used for typhoid fever.

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Anti –Staphylococcal Penicillins 37

These are narrow spectrum penicillins, resistant to Staphylococcal β lactamases . Methicillin, oxacillin, and cloxacillins fall into this category. Of these only cloxacillin, flucloxacillin and dicloxacillin are clinically useful and are to be used only for proven or suspected staphylococcal infections.

Flucloxacillin, suitable for oral administration, can cause cholestatic jaundice in some patients. Some staphylococci have developed resistance to this group, by mechanisms other than β lactamase. These methicillin resistant

Staphylococcus aureus (MRSA) will be resistant to all other β lactams (i.e. all penicillin, cephalosporins, monobactams and carbapenems).

Anti – Pseudomonal Penicillins 37

Newer penicillins with a high grade of activity against gram negative bacteria including pseudomonas, e.g. piperacillin, ticarcillin

β lactam and β lactamase inhibitor combinations

Eg Clavulanic acid, Sulbactam

Augmentin is a preparation containing amoxycillin and clavulanic acid.

Clavulanic acid has minimal antibacterial activity but inhibits β lactamase effectively. This combination is useful in the treatment of β lactamase producing bacteria. Sulbactam is another β lactam inhibitor used in combination with penicillins.

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Combinations are more expensive and so should be used only while treating infections with known β lactamase producers. Amoxycillin/ clavulanic acid combination can cause cholestasis.

Cephalosporins 37

The cephalosporins have been traditionally divided into to three generations based on their spectrum of activity. In general, cephalosporins are less prone to hypersensitivity reactions, are more stable to staphylococcal penicillinases and have a broader spectrum than penicillins. However, they are expensive and have very little action on enterococci . None of them are effective against MRSA.

First generation cephalopsorins include among others, cephalexin(oral), cephalothin and cefazolin (parenteral). The spectrum of activity is similar, being effective against penicillinase producing staphylococci and other Gram-positive cocci (except MRSA and enterococci) and a few gram- negative enteric bacilli. There is no special advantage for any one first generation cephalosporins over another. They are not usually first choice for any infection. They may be used in some patients with penicillin hypersensitivity - those without immediate (IgE mediated) hypersensitivity.

Second generation drugs Cephamandole (parenteral), cefuroxime axetil and cefaclor (oral) are more stable to some Gram-negative β-lactamase.

Their activity against Gram-positive organisms is similar to, or less than, that of the first generation cephalosporins and they have varying degrees of activity

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Review of Literature against anaerobes. These drugs have a limited role in therapy and are more expensive.

Third generation cephalosporins (ceftriaxone, ceftazidime, cefotaxime) is active against gram-negative bacilli. They have some activity on gram-positive cocci and that against anaerobes varies. A major advantage of these agents is their ability to reach the central nervous system. Ceftazidime has specific antipseudomonal activity. Ceftriaxone and cefotaxime are useful in hospital-acquired and any other gramnegative septicaemia and meningitis.

Monobactams (Aztreonam) and Carbapenem (Imipenem) 37

Aztreonam is active against gram-negative bacteria including pseudomonas and β-lactamase producing enterobacteriaceae. Carbapenems have a much broader spectrum, including gram-positive, gram-negative and some anaerobic bacteria.

B. Aminoglycosides 37

This group of antibiotics (gentamicin, tobramycin, netilmicin, amikacin,

Kanamycin, neomycin, streptomycin) act by inhibiting protein synthesis in bacteria. They have good activity against aerobic gram-negative bacilli, including brucella. When given together with penicillin, they have good activity against enterococci. Streptomycin is useful against mycobacteria.

Aminoglycosides are not absorbed when given orally and should be administered parenterally for systemic effects. Aminoglycosides are ototoxic

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Review of Literature and nephrotoxic. The therapeutic index is low and blood levels need to be monitored if used for prolonged courses of either directed or empirical therapy for longer than 3 days. In spite of this disadvantage, they are used widely for their action on gram-negative bacilli.

Gentamicin is the least expensive and has good activity against 90% of gram-negative bacilli. It is the aminoglycoside of choice for empirical treatment of severe gram-negative sepsis including nosocomial infections.

The primary indication for aminoglycosides is as short-term empirical therapy pending the outcome of investigations. Their value as empirical drugs relates to their rapid bactericidal activity and the comparatively low levels of resistance in many community and health care–associated Gram-negative pathogens. When used empirically, no further doses should be given beyond 48 hours and if continuing empirical IV therapy is required (ie an organism is not grown) therapy should be changed to an alternative less toxic drug. Monitoring of aminoglycoside plasma concentrations is not required if the clinical plan is to cease therapy within 72 hours of commencement.

Aminoglycosides are indicated for directed therapy in only a few circumstances. These include, but are not restricted to:

• Infections when resistance to other safer antimicrobials has been shown

• Combination therapy for serious Pseudomonas aeruginosa infections and

brucellosis

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• Low doses as synergistic treatment for streptococcal and enterococcal

endocarditis.

Monitoring plasma concentrations of aminoglycosides is recommended in these patients and should commence on the first dose of directed therapy.

The recommended initial dose of gentamicin is 4-6mg/kg/day as a single daily dose given slowly over 20 minutes. However single daily dose is not recommended in pregnant women and endocarditis. The first dose is given irrespective of renal function as follows:

Age Initial dose of gentamicin

Neonates less than 34 weeks postconception 3mg/kg

Neonates 34-44 weeks postconception 3.5mg/kg

Infants and children less than 10 years 7.5mg/kg to maximum of 320mg

10-29 years 6mg/kg to maximum of 560mg

30-59 years 5mg/kg to maximum of 480mg

Greater than 60 years 4mg/kg to maximum of 400mg

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After the first dose, subsequent doses of the same size should be given for up to 3 days at intervals determined by the patient’s renal function as follows:

Estimated creatinine Dosing interval Maximum number of

clearance doses

Greater than 60ml/min 24 hours 3 (at 0, 24 and 48 hours)

40-60 ml/min 36 hours 2 (at 0 and 36 hours)

30-40 ml/min 48 hours 2 (at 0 and 48 hours)

Less than 30 ml/min No further doses 1 (at 0 hours)

For prolonged courses (longer than 3 days), it is important to determine trough serum gentamicin levels periodically (at least twice a week) and to adjust the dosage to maintain the desirable serum levels. In general trough levels not exceeding 0.5 to 1 µg/mL are sought.

C. Tetracyclines 37

Tetracyclines also act by inhibiting protein synthesis and have broad spectrum of activity. This includes staphylococci, neisseriae, H.influenzae, some members of enterobacteriaceae, mycoplasma, clamydiae, rickettsiae and spirochaetes . For chlamydial and rickettsial infections this is the drug of choice.

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This group also has action against protozoa like Entamoeba histolytica and plasmodium sp . The spectrum of activity of different tetracyclines is similar, but they are different in their pharmacokinetics. Most tetracyclines are excreted through the kidneys except doxycycline, which is safer in patients with renal impairment, but caution is required in patients with hepatic disease.

Tetracycline should be used with caution in patients with pre–existing hepatic or renal disease, as they can lead to worsening of function. Doxycycline has a longer half-life than tetracycline. Because of their effect on growing bones and teeth, these drugs are contraindicated in pregnancy, lactating mothers and in children.

D. Chloramphenicol 37

Also a broad-spectrum antibiotic, it acts by inhibiting protein synthesis.

The spectrum includes both aerobes and anaerobes. It can be used topically, orally or parentally. Bioavailability after oral administration is as good as parenteral use and the oral preparation can be used to initiate treatment in emergencies if the injection is not available. Chloramphenicol is not safe in pregnancy and in neonates as it may cause Grey baby syndrome. This drug can also cause bone marrow suppression. Its use as far as possible should be limited to specific indications like typhoid fever, invasive salmonellosis, meningitis, brain abscess and occasionally anaerobic infections.

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E. Macrolides 37

Erythromycin, roxithromycin, azithromycin and clarithromycin act by inhibiting protein synthesis. They have similar antimicrobial spectra but differ in their pharmacokinetics and adverse effects. They are active against gram- positive organisms, H.influenzae, neisseriae, mycoplasma sp, chlamydia and rikettsiae . They also act on toxoplasma, which is a protozoa.

Erythromycin is absorbed orally and is distributed well. It does not cross the blood brain barrier. The main adverse reaction is gastric irritation. Some patients develop jaundice. Parenteral preparations can cause phlebitis and occasional cardiac arrhythmias (in high doses).

Its main use is in respiratory infections and as an alternative to penicillin in those hypersensitive to penicillin. It is the drug of choice in neonatal and obstetric chlamydial infection and is used in campylobacter infection.

The newer macrolides have better bioavailability and fewer side effects.

Azithromycin, in addition to its use similar to that of erythromycin, is also used to treat toxoplasmosis. Clarithromycin is used in treating mycobacterium avium complex (MAC) infections and H.Pylori.

F. Quinolones 37

These drugs interfere with transcription of DNA. The first drug to be used in this group, nalidixic acid, had a very narrow spectrum mainly limited to gram-negative bacilli. This drug is used widely in the treatment of UTI, since

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Review of Literature high concentration attained in urine (20–50 times that in plasma), Norfloxacin and ciprofloxacin have a broader spectrum of activity. Norfloxacin is used in the treatment of urinary and gastrointestinal infections. Ciprofloxacin reaches high levels in the blood and is very effective against enterobacteriaceae, pseudomonas sp , and mycobacteria . Ciprofloxacin is not very effective against

Streptococcus pneumoniae . It is therefore useful in treating gram-negative infections like hospital acquired septicaemias and gram-negative pneumonias.

It is also useful in treating chloramphenicol resistant Salmonella typhi infections. Bacterial resistance develops rapidly if these agents are widely used.

They are well absorbed when given orally and have a good penetration into cells like macrophages. They do not cross the blood brain-barrier. Unlike many other antibiotics they reach the prostate.

Nalidixic acid can cause GI upset and skin reactions. Quinolones have many adverse effects including dizziness, depression, and they can precipitate seizures. They may interact with many other drugs, for example theophylline.

Quinolones is not recommended in pregnant women, infants, children and breastfeeding mothers.

G. Rifampicin 37

Rifampicin is used in the treatment of tuberculosis and infections with

S.aureus. Rifabutin is used in the treatment and prophylaxis of MAC infection.

Since resistance emerges rapidly, these drugs should always be used in combination with other antibiotics. Rifampicin colours urine, tears and other

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Review of Literature body fluids red. It can accelerate the metabolism of other drugs including oral contraceptives, warfarin, and phenytoin.

H. Nitroimidazoles 37

Metronidazole and tinidazole are active against all anaerobic bacteria and protozoa like T. vaginalis, G. lamblia and E. hystolitica . Metronidazole is well absorbed and can be administered IV, orally or rectally. The rectal preparation produces high levels and can be used to treat serious infections. It crosses the blood brain barrier.

Metronidazole is usually well tolerated. Common minor side effects include nausea, vomiting, metallic taste in mouth and disulfiram like reaction with alcohol.

Tinidazole has longer half-life and therefore can be administered less frequently.

I. Glycopeptides 37

Vancomycin acts by inhibiting peptidoglycan (cell wall) synthesis. All gram-positive organisms are susceptible. However, the drug is reserved for treating Gram-positive infections resistant to β lactams (MRSA and Ampicillin/

Gentamicin resistant enterococci) and some patients hypersensitive to β lactams. Its oral use for antibiotic associated diarrhoea should be limited to those caused by Clostridium difficle and unresponsive to metronidazole.

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Vancomycin is given IV slowly over at least over one hour (10mg/ min) to prevent anaphylactoid reaction. Renal toxicity can occur, especially if given with aminoglycosides. Therefore, pay attention to dosage schedules and monitor serum levels and renal function.

Antimicrobial Resistance (AMR)

Factors contributing to the development of Antimicrobial Resistance:

Antimicrobial resistance can be defined as loss or decreased responsiveness to the conventional doses of AMAs, which is a commonly encountered problem in the ICU involving various factors like,38, 39

A. Cross transmission

B. Host defense

C. Antimicrobial use

D. Duration of hospital stay

E. Use of invasive devices

A. Cross transmission

Several factors unique to ICUs contribute to cross transmission of antimicrobial-resistant pathogens. The urgent nature of critical care often does not allow for necessary aseptic precautions or hand washing. Hence, antimicrobial-resistant pathogens are carried from patient to patient via unwashed hands of health care workers. The large number and wide variety of health care workers attending to patients needs have inconsistent training and compliance with hand washing, gloving and gowning, the degree of asepsis

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Review of Literature used in maintaining invasive devices and the level of crowding in ICUs may impact on the cross transmission of these pathogens. Introduction of antimicrobial-resistant bacteria into an ICU may occur upon transfer of critically ill patients who are unknowingly colonized or infected with such bacteria from other facilities. 40

B. Host defense

Colonization of ICU patients with antimicrobial-resistant pathogens can lead to clinical infection because of breakdown of normal host defenses. ICU patients are particularly susceptible to nosocomial infections because the normal skin and mucosal barriers to infection are commonly compromised by the use of invasive devices. It is no surprise that the incidence of nosocomial infections in ICU patients is correlated with the use of invasive devices. 41 In addition, ICU patients often have severe underlying illnesses, suppressed immune systems, malnutrition and a history of frequent hospitalization. These patients may be more likely to be colonized or infected with an antimicrobial- resistant pathogen from exposures during a previous health care encounter. All of these factors, especially the need to use antimicrobial agents in ICU patients, contribute to the increased risk of developing nosocomial infections with antimicrobial-resistant pathogens. 42

C. Antimicrobial use

Perhaps no other factor is more important in the development of antimicrobial resistance than antimicrobial use. Many studies have established a correlation between antimicrobial use and antimicrobial resistance at the

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Review of Literature hospital level. At least 7 days of mechanical ventilation, previous antibiotic use and previous use of broad-spectrum antibiotics (third-generation cephalosporins, fluoroquinolones, carbapenem, or a combination) were the most important risk factors associated with the development of ventilator- associated pneumonia caused by antibiotic-resistant pathogens. 43

D. Duration of stay

Prolonged length of hospital stay also seems to predispose patients to infection with antibiotic-resistant bacteria. This may be due, in part, to the greater likelihood over time of becoming colonized with such bacteria from either horizontal nosocomial transmission or endogenous emergence of resistance. 39

E. Use of invasive devices

Invasive devices such as endotracheal tubes, intravascular catheters, and urinary catheters also seem to encourage resistant infections. 39

Drug-resistant organisms

WHO report on the global status of AMR and surveillance, information was compiled on resistance to antibacterial drugs commonly used to treat infections caused by nine bacteria of international concern. 38

• Escherichia coli : resistance to third-generation cephalosporins, including

resistance conferred by extended spectrum beta-lactamases (ESBLs), and

to fluoroquinolones

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• Klebsiella pneumoniae : resistance to third-generation cephalosporins,

including resistance conferred by ESBLs, and to carbapenems

• Staphylococcus aureus : resistance to beta-lactam antibacterial drugs

(methicillin, methicillin-resistant S. aureus)

• Streptococcus pneumoniae : resistance or nonsusceptibility to penicillin (or

both)

• Nontyphoidal Salmonella (NTS): resistance to fluoroquinolones

• Shigella species : resistance to fluoroquinolones

• Neisseria gonorrhoeae : decreased susceptibility to third-generation

cephalosporins.

Clinical Implications of Increasing Antimicrobial Resistance

In general, infections caused by multidrug resistant pathogens are associated with higher in-hospital mortality rates, longer duration of hospital stay and increased health care costs and may also increase the likelihood of initial inadequate antimicrobial treatment as these pathogens may not be susceptible to initial empirical therapy. 38

Antimicrobial Resistance Monitoring

Antimicrobial resistance in pathogens causing important communicable diseases has become a matter of great public health concern globally including our country. Resistance has emerged even to newer, more potent antimicrobial agents like carbapenems. The factors responsible for this are widespread use and availability of practically all the antimicrobials across the counter meant

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Review of Literature for human, animal and industrial consumption. There are definite policies / guidelines for appropriate use of antimicrobials at national level in specific national health programmes being run in the country e.g. RNTCP, National

AIDS control programme, etc. For other diseases of public health importance like enteric fever, diarrhoeal disease, respiratory infections, etc the individual hospitals are following their own antimicrobial policies and hospital infection control guidelines. 33

To monitor antimicrobial resistance it is necessary to have regulations for use and misuse of antibiotics in the country, creation of national surveillance system for antibiotic resistance, mechanism of monitoring prescription audits, regulatory provision for monitoring use of antibiotics in human, veterinary & industrial sectors and identification of specific intervention measures for rational use of antibiotics. Work plan for monitoring of antimicrobial resistance in the country. Briefly the action plan of various

ToRs[Terms of Reference] is as follows: 33

A. For monitoring use and misuse of antibiotics : 33

Schedule H of the drug and cosmetics act contains a list of 536 drugs which are required to be dispensed on the prescriptions of a registered medical practitioner. In order to have separate regulation to check unauthorized sale of antibiotics, a separate schedule as Schedule H1 may be introduced under the

Drugs and Cosmetics Rules to regulate sale of antibiotics exclusively.

Corresponding provisions under the Rules could be framed for their implementation. A system of colour coding of third generation antibiotics and 373737 | P a g e

Review of Literature all newer molecules like Carbapenems (Ertapenem, Imipenem, Meropenem),

Tigecycline, Daptomycin may be put in place restricting their access to only tertiary hospitals. Appropriate steps should be taken to curtail the availability of fixed dose combination of antibiotics in the market

B. Hospital based sentinel Surveillance System for monitoring antibiotic 33

Resistance will be set up with the identification of one of more Central

Institutions under the ministry of health as coordinating centers at the National

Level. The design for AMR surveillance consists of,

• Identification of pathogens/diseases of public health importance

• Creation of network of Antibiotic Susceptibility Testing (AST)

• Standardizing methodology for microbial identification and AST

• The laboratories will perform AST using standardized methods and

carbapenem resistant isolates will be stocked and sent to designated central

laboratory for further analysis, like identification of NDM-1 [New Delhi

Metallo-Lactamase ]isolates.

• Strengthen Quality Systems in the network laboratories

C. For documenting prescription patterns and establishing a monitoring system 33

• To study the consumption of various antibiotics in tertiary care public

hospitals in Delhi under central government

• To study the trends in antibiotic use in these hospitals of Delhi

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• Data generated will be used for intervention studies for rational use of

antibiotics.

D. For enforcement and enhancement of regulatory provisions for use of antibiotics in human, veterinary and industrial use. 33

• In India, the antibiotics are used widely in food animals as growth

promoters and to prevent and treat infection. Non-therapeutic usage of

antibiotics has been especially common in poultry production. However,

there is no regulatory provision regarding the use of antibiotics in

livestock.

• Establish intersectoral coordination committee with experts from various

sectors.

• Develop regulations on usage of antimicrobials in poultry and other

animals as well as the requisite labeling requirements in food.

E. For promoting rational use of drugs various strategies suggested are: 33

• Educational strategy: Training, printing materials, media-based approach

• Managerial strategy: Monitoring & supervision, generic substitution,

patient cost sharing (economic incentives) etc

• Regulatory strategy: Enforcement, sanction, drug withdrawal, market

control etc

• Formulation & implementation of an antibiotic policy

With quality assured laboratory data in real time develop antibiotic policies that are standard national / local treatment guidelines advocating

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Review of Literature evidence based immunotherapy or combination therapy. This must include consideration of spectrum of antibiotics, pharmacokinetics/ pharmacodynamics, adverse effects monitoring, cost and special needs of individual patient groups

Newer Concepts in Antimicrobial Therapy

Procalcitonin as a Biomarker in Sepsis 31

Procalcitonin is the best studied biomarker for guiding antibiotic treatment duration in the hospital setting. Procalcitonin measurements integrated in clinical algorithms have been shown to reduce the duration of antibiotic courses by 25-65% in hospitalized and more severely ill patients with

Community Acquired Pneumonia(CAP) and sepsis.

Antimicrobial agents used in ICU

Antimicrobial agents are used for prevention and the treatment of various infections. These are used empirically for the treatment of infections without culture sensitivity test . ICU is a designated ward of a hospital where critically ill patient are monitored and treated. Patients may require ventilator support in many critical condition due to respiratory failure and there is higher risk of hospital acquired infections in these patients. Antimicrobial agents are prescribed in ICU for prevention and treatment of critical illnesses and hospital acquired infections. According to American Thoracic Society guideline cephalosporins, carbapenem, piperacillin+tazobactam, aminoglyocsides,

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Review of Literature quinolones (levofloxacin, ciprofloxacin), vancomycin and linezolid are prescribed empirically in patients to prevent hospital acquired infections. 44

A. Prophylactic use of antimicrobial agents

Infections are an everyday problem in the intensive care unit (ICU) and antibiotics are therefore commonly used in this setting. Besides treatment of infections, antibiotics are administered as prophylaxis to prevent or limit major infections in critically ill patients.

Antimicrobial prophylaxis for nonsurgical patients is generally not recommended except in certain specific situations like neutropenia and for preventing ventilator-associated pneumonia 45

For surgical prophylaxis during ICU management, administration of

AMA one hour before the procedure demonstrated the lowest surgical site infection (SSI) rates. Ideally, the antimicrobial should be administered as near to the incision time as possible to achieve low SSI rates. 46

B. Choice of antimicrobial agent for prophylaxis 47,48

Choice of antimicrobial agents involves several considerations like patient specific factors (presumed source of infection, presence of comorbid conditions, previous antibiotic administration), microbiological factors (most likely pathogen and their susceptibility pattern), and pharmacological factors

(bioavailability, distribution to the site of infection and potential drug toxicity).

Bactericidal AMAs are usually preferred. 47

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In critically ill patients, such as those in septic shock, febrile neutropenic patients and patients with bacterial meningitis, empiric therapy should be initiated immediately after or concurrently with collection of diagnostic specimens. Therefore, a common approach is to use broad-spectrum antimicrobial agents as initial empiric therapy, sometimes with a combination of antimicrobial agents with the intent to cover multiple possible pathogens commonly associated with the specific clinical syndrome. This is true for both community- and hospital-acquired infections. 48

For example, in an otherwise healthy young adult with suspected bacterial meningitis who is seen in the emergency department, the most likely pathogens would be Streptococcus pneumoniae and Neisseria meningitidis , and thus a combination of a third-generation cephalosporin (ceftriaxone) plus vancomycin would be recommended as empiric therapy.

Hospital-acquired infections are frequently related to the presence of invasive devices and procedures that result in loss of the normal barriers to infection, as is the case with intravascular catheter–associated bacteremia, ventilator-associated pneumonia, and catheter-associated urinary tract infections. They are commonly caused by drug-resistant organisms, both gram- positive (eg, methicillin- resistant Staphylococcus aureus ) and gram negative

(eg, Pseudomonas aeruginosa ) bacteria.

Antimicrobial susceptibility testing measures the ability of a specific organism to grow in the presence of a particular drug in vitro and is performed using guidelines established by the Clinical and Laboratory Standards Institute.

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The goal of AST is to predict the clinical success or failure of the antibiotic being tested against a particular organism. Data are reported in the form of minimum inhibitory concentration (MIC), which is the lowest concentration of an antibiotic that inhibits visible growth of a microorganism, and are interpreted by the laboratory as “susceptible,” “resistant,” or “intermediate,” according to Clinical and Laboratory Standards Institute criteria.

C. Empirical Therapy 48

Empirical or presumptive anti-infective therapy is based on a clinical diagnosis combined with evidence from the literature and from the educated experience of the probable pathogens causing the infection. Definitive therapy depends on the microbiologic diagnosis by isolation or other direct evidence of pathogen.

(i).The timing of initial therapy should be guided by the patient’s condition and urgency of the situation.

In critically ill patients e.g. patients in septic shock or bacterial meningitis therapy should be initiated immediately after or concurrently with collection of diagnostic specimens.

In other conditions where patient is stable, antimicrobial therapy should be deliberately withheld until appropriate specimens have been collected and submitted to the microbiology laboratory e.g when treating a patient of osteomyelitis or sub-acute endocarditis.

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(ii). Empiric vs definitive antimicrobial therapy 48

Initial therapy for infection is often empiric and guided by the clinical presentation. Therefore, a common approach is to use broad spectrum antimicrobial agents as initial empiric therapy with the intent to cover multiple possible pathogens commonly associated with the specific clinical syndrome.

Once laboratory results of microbiology tests are available with identification of pathogen along with antimicrobial susceptibility data, every attempt should be made to narrow the antibiotic spectrum. This is a critically helpful and integral component of antimicrobial therapy because it can reduce cost and toxicity and significantly delay the emergence of antimicrobial resistance in the community. Antimicrobial agents with a narrower spectrum should be directed at the most likely pathogens for the duration of therapy for infections such as community-acquired pneumonia, urinary tract infections, soft tissue infections etc. in an OPD setting because specific microbiological tests are not routinely performed or available or affordable

(iii). Bactericidal vs Bacteriostatic Therapy 48

A commonly used distinction among antibacterial agents is that of bactericidal vs bacteriostatic agents. Bactericidal drugs, which cause death and disruption of the bacterial cell, include drugs that primarily act on the cell wall

(eg, β-lactams), cell membrane (eg, daptomycin), or bacterial DNA (eg, fluoroquinolones). Bacteriostatic agents inhibit bacterial replication without killing the organism. Most bacteriostatic drugs, including sulfonamides,

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Review of Literature tetracyclines, and macrolides, act by inhibiting protein synthesis. Bactericidal agents are preferred in the case of serious infections such as endocarditis and meningitis to achieve rapid cure.

(iv). Use of Antimicrobial Combinations 48

Synergy between antimicrobial agents - when studied in vitro, the combined effect of the agents is greater than the sum of their independent activities when measured separately. When infections are thought to be caused by more than one organism, a combination regimen may be preferred because it would extend the antimicrobial spectrum beyond that achieved by a single agent. Combination therapy is used in this setting to ensure that at least 1 of the administered antimicrobial agents will be active against the suspected organism(s)

For example, the combination of certain β-lactams and aminoglycosides exhibits synergistic activity against a variety of gram-positive and gram- negative bacteria and is used in the treatment of serious infections, for which rapid killing is essential (eg, treatment of endocarditis caused by Enterococcus species with a combination of penicillin and gentamicin).

(v). Host factors 48

Host factor like age, physiological state of the patient (e.g. pregnancy and lactation), organ function (e.g. renal or hepatic function), genetic variation

(e.g. G6PD deficiency), allergy or intolerance must be kept in mind while prescribing antimicrobial therapy. Due consideration should be give to the

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Review of Literature efficacy of an antimicrobial agent at the site of infection (e.g. first and second- generation cephalosporins and macrolides do not cross the blood-brain barrier and are not recommended for central nervous system infections.

Fluoroquinolones achieve high concentrations in the prostate and are preferred oral agents for the treatment of prostatitis)

(a). Age 48

Patients at both extremes of age handle drugs differently, primarily due to differences in body size and kidney function. Most pediatric drug dosing is guided by weight. In geriatric patients, the serum creatinine level, and the creatinine clearance should be estimated by factoring in age and weight for these patients.

(b). Pregnancy and Lactation 48

Special considerations for the use of antimicrobial agents in pregnancy relate to both the mother and the fetus. In the case of the developing fetus, many antimicrobial agents can be either teratogenic or otherwise toxic to the fetus. Penicillins, cephalosporins, and macrolides have historically been the most commonly used antimicrobial agents considered safe in pregnancy. In contrast, agents such as sulfonamides and nitrofurantoin, tetracyclines and chloramphenicol, have well-described fetal or neonatal adverse effects and should be avoided.

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(c). Renal and Hepatic Function 48

Because the kidney and the liver are the primary organs responsible for elimination of drugs from the body, it is important to determine how well they are functioning during antimicrobial administration- to prevent accumulation and toxicity in patients with reduced renal or hepatic function.

(d). Genetic Variation 48

Example is that of glucose-6-phosphate dehydrogenase (G6PD) deficiency, which can result in hemolysis in individuals when exposed to certain antimicrobial agents, such as dapsone, primaquine, and nitrofurantoin.

These drugs should be avoided in those known to be deficient in G6PD, and it is advisable to test for this predisposition in patients who might have a higher risk of G6PD deficiency (eg, African Americans) before prescribing these agents.

(e). History of Allergy or Intolerance 48

A history of antimicrobial allergy or intolerance should be routinely obtained in the evaluation and management of infection

(f). History of Recent Antimicrobial Use 48

Eliciting a history of exposure to antimicrobial agents in the recent past

(approximately 3 months) can also help in selection of antimicrobial therapy. A recently used antimicrobial agent, it is likely to be resistant to that drug and/or drug class, and an alternative agent should be used.

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Route of administration 48

The choice of route of administration is determined by the site and severity of infections as well as the cost of treatment. Since ICM (Intensive care management) involves critically ill patients, the AMAs are generally administered by injectable routes like IM or IV & Oral.

Aerosolized Antibiotics 31

Intermittent aerosolization of antibiotics into the respiratory tract has been used in patients with P. aeruginosa pneumonia, particularly in the setting of cystic fibrosis. Tobramycin and colistin have been used in pneumonia caused by MDR Pseudomonas.

Recently, amikacin, nebulized with special devices has been used for

MDR gram-negative pneumonia that was unresponsive to standard therapy.

Duration of antimicrobial therapy 28,49

The duration of antimicrobial therapy is determined by the effective clinical or bacteriological control of infection. The optimal duration of antimicrobial therapy is generally 7-10 days for community-acquired pneumonia. However, no data is available for ICU-acquired infections. Hence, individual ICUs follow different strategies, using short course (4-7 days) or long course (10-14 days) of either monotherapy or multiple antimicrobial therapy. Longer duration combination therapy may be needed for deep seated infections such as endocarditis, necrotizing fasciitis, osteomyelitis and fecal peritonitis.

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Antimicrobial dosing

The dose of AMA should be adequate or appropriate on the basis of patient body weight or BMI, and the administration may be repeated intraoperatively if the operative procedure is prolonged beyond 2 half-lives after the first dose to ensure adequate antimicrobial levels until wound closure.

Most procedures can be “covered” by a single dose of a first- or second- generation cephalosporin. Inappropriate selection of the antimicrobial agent or inappropriate dosing regimen, can increase the prevalence of antibiotic resistant strains, prolong hospital stay, cause adverse reactions, and negatively affect an institution’s pharmacy budget for antibiotics.50 The American Society of

Health-System Pharmacists (ASHP) recommends continued prophylaxis for up to 72 hours after cardiothoracic surgery. 45 For nonsurgical prophylaxis like prevention of VAP, short courses of narrow-spectrum agents particularly active against Hemophilus spp. and pneumococci should be employed 51

Guidelines and strategies for optimizing the use of AMAs in the ICU 52

• AMAs should be used only when there is clinical and / or microbiological

evidence / suspicion of infection.

• Protocols for empirical use of AMAs may be developed by consensus

based on expert opinion.

• Samples of infected material should be obtained prior to initiating

empirical therapy.

• A rapid result from the laboratory of microbiology should be pursued.

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• A definitive therapy should be initiated when the causative organism is

isolated.

• The effectiveness of antimicrobial therapy should be monitored.

• Duration of treatment should be limited according to clinical and / or

microbiological response.

• Effective steps should be taken for preventing the emergence of multidrug

resistant organisms.

• Adverse drug events or drug interactions should be closely monitored.

• Hospital infection control committee should be organized to formulate and

implement antimicrobial policy and to monitor the compliance of the

policy.

• Medical staff should be aware of the need for the compliance of

antimicrobial policies and guidelines.

• National antimicrobial policy should be consulted whenever necessary.

Table 9: Dosage Guide For Commonly Used Antimicrobial Agents 49

ANTIBIOTICS ADVERSE REACTION ROUTE ADULT DOSE

Amikacin Nephrotoxicity, Ototox icity Intravenous 15mg/Kg/day q 8 -12 1.5mg/Kg hours, max doses

Amoxycillin Fever, rash, diarrhea, abdominal Oral 250-500mg q 8 hourly

cramps, AST ALT elevation

Amoxycillin- Rash, diarrhea, abdominal, AST Oral, 375mg 8hourly clavunate ALT elevation Intravenous 625-1000mg12 hourly (co-amoxyclav)

Ampicillin Hypersensitivity reaction, Intravenous 500 mg -1gm q 6 hourly

nausea, diarrhea, exfoliative or dermatitis, infectious Oral mononucleosis rash, interstitial nephritis.

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Azithromycin Le ukopenia, transient elevation Oral 500mg daily

of liver enzymes, renal toxicity Azetronam Rash, Diarrhoea , vomiting, Intravenous 1-2g q 8 hourly, Max

AST, ALT elevation dose 8gm in 24 hours

Benzathine penicillin Hypersensitivity and J arisch Intramuscular 1.2 -2.4 million

Herxheimer reaction, haemolytic units/dose

anemia, seizures with high doses in renal failure Cefadroxil Rash ,eosinophilla Oral 500mg bid or 1 g bid

Cefazolin Leukopenia, eosinophilia, Intravenous 0.52gm q 6 -8 hourly

rash, transient elevation of liver enzymes renal toxicity

Cefepime Same as third generation Intravenous 1-4gm/day 2-3 doses

cephalosporins. Adjust dose in renal failure.

Cefixime Diarrhoea, Leukopenia, renal Oral 400mg/day in toxicity, transient elevation 1-2 divided doses. of liver enzymes.

Cefotaxime Arrythmia, transient Intravenous 1-2gm 6-8 hourly elevation of liver

enzymes, renal toxicity.

Ceftazidime Hypersensitivity reaction, Intraveous 1-2g q 8 -12 hourly

dizziness, rash, diarrhea, Intramuscular (IV)

colitis, exfoliative dermatitis, thrombocytopenia

Ceftriaxone Gall bladder sludging Intravenous 1-2gm q 12-24 hourly , transient elevation of liver enzymes, renal

toxicity

Cefuroxime Leukopenia, eosinophilia, Intravenous 750mg- 1.5g

allergic reaction, transient q 8 hourly

elevation of liver enzymes , renal toxicity

Cefuroxime Leukopenia, eosinophilia, Oral 250 -500md bid allergic reaction, transient elevation of liver enzymes , renal toxicity

Cephalexin Transient neutropenia, Oral 250 -500mg q 8 hourly

AST and ALT elevation, arthralgia, rash, eosinophilia.

Chloramphenicol Bone marrow Oral 50mg/kg/day in

suppression, aplastic Intravenous 4 divided doses

anaemia, grey baby syndrome, hemolysis in G6PD

Ciprofloxacin Nausea, vomiting, Oral 250-750mg q 12 hrly abdominal discomfort, Intravenous

arthralgia, photosensitivity transient elevation of liver enzymes

Clarithromycin Transient elevation of Intravenous 250 -500mg bid liver enzymes, renal Oral

toxicity, nausea, abdominal cramps

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Clindamycin Diarrhea, nausea, Oral 150 -300 mg q 6 -8 h

pseudomembranous colitis, Intravenous (oral, iv)

skin rash, Erythema Severe infections multiforme , raised ALT 300-600 mg 8 hrly IV

AST, thrombocytopenia, leucopenia

Dose related neutropenia, Oral 250-500mg/kg/day in elevated AST, ALT, Intravenous 3-4 divided doses Cloxacillin Cholecystitis interstitial 1-2 gram q 6 hourly nephritis.

Cotrimoxazole Megaloblastic anaemia, Oral 160mg (Trimetho- distrurbance, rash, prim) erythema mutliforme major/minor

Ertapenem Diarrhoea, nausea, vomiting, Intravenous 13 years and above headache, hallucination, Intramuscular 1gm IV infusion/ IM

seizures, arrhythmia, once daily pseudomembranous colitis, in 3-5 ml of lidocain dose reduction in renal failure CI if hypersensitivity

to lidocaine/ β lactam

Erythromycin Arrhythmia Jaundice Oral 250-500mg q 6 hourly

Furazolidine Avoid alcohol, tyramine Oral 100mg 3-4 times a day

containing food, Mao inhibitors, Nausea headache, dizziness, fall in BP, urticarial, safety in pregnancy unknown

Gentamicin Nephrotoxicity Intravenous 1.3-6 mg/kg/day

ototoxicity and optic Intramuscular

neuritis

Imipenemcilastin Nausea, diarrhea, rash Oral 500mg once daily

Intravenous

Linezolid Peripheral and optic Oral 400-600 mg q 12 h neuropathy, Intravenous

thrombocytopenia, hypertension, myelosuppression, colitis.

Meropenem Hypotension, transient Intravenous 1.5-3gm/day in elevation of liver enzymes, Oral 3 divided doses

renal modification in renal 6gm/day failure in meningitis

Metronidazole Nausea, metallic taste, Intravenous 500-700 q 8 hourly disulfuran like Oral reaction with alcohol, peripheral neuropathy

Nalidixic acid Hepatotoxicity, myalgia, Oral 1gm 4 times/day leukopenia, vertigo, rash, dizziness, pseudotumor cerebri, seizure, avoid in G6PD deficiency

Nitofurantoin Discoloration of urine, Oral 50-100 mg q 6 hourly

vertigo, rash, (5-7mg/kg/day in methemoglobinemia, 4 divided doses cholestatic jaundice, max dose 400mg)

hepatocellular damage and neuropathy. Avoid at term and labour.

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200-400 mg twice daily Norfloxacin Sam as quinolones Oral

Ofloxacin Leukopenia, transient Oral 200 -400 q 12 hourly of liver enzymes, Intravenous

renal toxicity. May precipitate psychosis/seizures,pho tosensitivity.

Penicillin G Hypersensitivity reaction like Oral 2-24 million units day anaphylaxis rare. nonfatal Intravenous in divided doses

reactions are like serum q 4-6 hrly IV

sickness, rash contact dermatitis seen in 1 in 1000 adults. Jarisch Herxheimer reaction, haemolytic anaemia with high doses

Penicillin V Rash, haemolytic Oral 250 -500 mg

anaemia interstitial every 6-8 hourly.

nephritis, seizure with high doses.

Piperacillin – Leukopenia, transient Intravenous 4.5 gm q 8hourly

Tazobactum elevation of liver

enzymes, renal toxicity.

Teicoplanin Hypersensitivity Intravenous 400mg once daily reactions, rash, less Intramuscular (6-30mg/kg/day)

nephrotoxic as compares to Vancomycin

Tigecycline Nausea, vomiting, allergic Intravenous 100mg followed by

reactions, photosensitivity, 50mg every 12 hrly pseudo tumor cerebri, infusion over 30-60 pancreatitis. minutes. No dose adjustment to renal failure Vancomycin Red man syndrome, oto-toxicity, Intravenous 0.5gm q 6 hourly or

nephrotoxicity 1gm q 12 hourly

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Drug utilization study (DUS)

Drugs prescribed in clinical practice are mainly based on the evidence provided by the pre marketing and post marketing period. Data created from the post marketing period are needed to provide an adequate basis for improving drug therapy. Studies on drug utilization are a potential tool used to evaluate health systems. Tremendous improvement in the marketing of new drugs, variation in the pattern of drug prescribed, delayed adverse effects and cost of drug have increased the importance of DUS. 53

The principal focus of DUS is to imply prescription of drug in an optimal dose on the right indication with the correct information and at an affordable price thereby facilitating rational use of drugs in a population. DUS contribute to rational drug use by increasing our understanding of how drugs are used, generate early signals of irrational use of drugs and enable us to intervene to improve drug therapy. 54

Definition: 53

“Drug utilization is defined as the marketing, distribution, prescription and use of drugs in a society with special emphasis on the resulting medical, social and economic consequences.”

Assessment of drug use indicators:

The indicators of prescribing practices measure the performance of health care providers in several key dimensions related to the appropriate use of

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Review of Literature drugs. They measure general prescribing tendencies within a given setting, independent of specific diagnosis. 55

WHO prescribing indicators: 56

• Average number of drugs per prescription - measure the degree of

polypharmacy. Combination drugs are counted as one

• Percentage of drugs prescribed by generic name

• Percentage of drugs prescribed from essential drug list

• Percentage of encounters with an antibiotic prescribed

• Percentage of encounters with an injection prescribed to measure overall

level of use of injection which is commonly over used and costly form of

drug therapy.

Complementary indicators: 56

• Average drug cost per encounter

• Percentage of drug cost spent on injection

Normal Values: 56

• Average number of drug per encounter 2-3

• Percentage of encounter with an injection prescribed 16-20%

• Percentage of drugs prescribed by generic name- 100%

• Percentage of drugs prescribed from EDL 80-100%

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• Percentage of encounters with antibiotics prescribed should not be above

40%

Factors influencing drug utilization: 54

1. Population related factor: change in total population, change in population

demographic, change in health status of a population

2. System related factor: change and transition associated with health system

reform and restructuring changes in policies and programs

3. Research and technology related: new treatment approach

4. Pharmaceutical industry: development of new drug product, promotion of

drugs to physician, drug sampling, direct to consumer advertising

5. Practice and people related: change in prescribing and dispensing practice

Uses of DUS: 54

i. Facilitate rational use of drug

ii. Increase our understanding of how drugs are being used iii. Generate hypothesis that set the agenda for further investigation and

thus avoid prolonged irrational use of drugs iv. Assess whether interventions intended to improve drug use have had the

desired impact

v. By comparing data from different localities may identify and promotion

of best practice

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Measurement of DUS in a hospital - quantitative study

Analysis of the data obtained included the following measurements a) Number of drugs: Average number of drugs and maximum number of drugs prescribed for each patient. b) Selection of drugs:

i. Most commonly used drugs in the order of frequency.

ii. Order of frequency in the utilization of AMAs. iii. Order of frequency of other drugs. c) Cost involved for the patient & hospital:

i. Cost of drugs for single day and during total duration of study.

ii. Cost of individual group of drugs. iii. Frequency of distribution for total cost of drug therapy.

The Anatomical Therapeutic chemical (ATC) classification system 57

In the ATC classification system the drugs are divided into different groups according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties.

The main purpose of ATC classification is as a tool for prescribing drug utilization statistics and it is recommended by the WHO to be used in international comparisons.

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Concept of DDDs from WHO 58

The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults.

DDD is a unit of measurement and does not necessarily correspond to the recommended or prescribed daily dose (PDD). Doses for individual patients and patient groups will often differ from the DDD as they must be based on individual characteristics (e.g. age and weight) and pharmacokinetic considerations.

Drug utilization figures should ideally be presented as numbers of

DDDs per 1000 inhabitants per day or, when drug use by inpatients is considered, as DDDs per 100 bed-days. For anti-infectives (or other drugs normally used for short periods), it is often considered to be most appropriate to present the figures as numbers of DDDs per 1000 inhabitant per year.

DDDs/1000 inhabitants/ day

Prescription data presented in DDD/1000 inhabitants/day may provide a rough estimate of the proportion of the study population that may be treated daily with certain drugs. As an example, 10 DDDs/1000 inhabitants/day indicates that 1% of the population on average might get a certain drug or group of drugs every day.

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Pharmacovigilance

Pharmacovigilance is an important post-marketing tool in ensuring the safety of pharmaceutical product. It involves evaluating information gathered from the health care providers, pharmaceutical company and patients in order to understand the risks and benefits of a particular drug. These activities: 59

• Identify new information about adverse effects of the drug

• Prevent harm to the patient

Major role of pharmacovigilance is to identify and evaluate safety signals. Safety signal refers to concern about an excess of adverse events compared to that would be expected with a product use. 59

Defination:

Pharmacovigilance: 60

“Pharmacovigilance is the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects particularly long term and short term side effects of medicines.”

Adverse Event (AE) /Adverse experience: 59

Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment is called as AE.

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Adverse Drug Reaction (ADR): 59

A response which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function. An adverse drug reaction, contrary to an adverse event, is characterized by the suspicion of a causal relationship between the drug and the occurrence, i.e. judged as being at least possibly related to treatment by the reporting or a reviewing health professional. Any response to a medicinal product which is noxious and unintended is ADR.

Serious adverse event or serious adverse drug reaction:

A serious adverse event or reaction is any untoward medical occurrence that at any dose results in death or is life threatening. Life threatening refers to an event in which patient was at risk of death at the onset of event like:

• Inpatient hospitalization or prolongation of existing hospitalization

• Persistent or significant disability

• Congenital anomaly or birth defect

Objectives: 59,60

The main objectives of National Pharmacovigilance Program are as following

• To foster the culture of Adverse Event notification and reporting

• To establish a viable and broad based ADR monitoring programs in India

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• To create an ADR database for the Indian population

• To create awareness of ADR monitoring among people

• To ensure optimum safety of drug products in Indian market

• To create infrastructure for ongoing regulatory review of Periodic Safety

Updates Regulators (PSURs)

• To promote rational and safe use of medicines.

• To contribute the knowledge of value, detriment, efficiency and hazard of

medicines.

• To encourage edification and clinical training.

• To endorse healthy communication to the community.

• To increase public protection from the new products.

Clinical importance: 61

New drug released into market lack long term safety data. Prescribed drugs response varies due to interactions with drug and food. Awareness about pharmacovigilance and practice according to it has a large impact on health care quality. Information on clinical, pathological and epidemiological information related to adverse reaction help us to fully understand adverse effects of drugs and for identifying patients at risk. ADR have the potential to provide insight into structure-activity relationship, pharmacokinetic, pharmacodynamic and genetic factors affecting the action of drugs. This may provide lead for other novel indications of the drug. Knowledge acquired following stringent monitoring on adverse effect of drug can prevent

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Review of Literature unnecessary suffering by patients and decrease financial loss of the patient due to inappropriate use of drug.

Antimicrobial Allergy 48

The term antimicrobial allergy is frequently used synonymously with adverse reaction or adverse effect, allergic reactions constitute only one subset of adverse reactions to antimicrobial agents.

Table 10: Classification of the Adverse Effects of Antimicrobial Drugs

Allergy

Toxicity

Direct Drug-drug interaction

Therapeutic failure

Effects on commensal flora - Human &

Animal

Clostridium difficile infection Increased Indirect chance of infection with drug-resistant

pathogens

Effect on environmental flora

Allergic or hypersensitivity reactions can be either immediate (IgE- mediated) or delayed and usually manifest as a rash; anaphylaxis is the most severe manifestation of IgE-mediated allergy.

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In a recent national study of the prevalence of adverse drug effects, antibiotics were implicated in 19% of all emergency department visits for drug related adverse events, and 79% of all antibiotic-associated adverse events were classified as allergic reactions. Historical details should be elicited to help distinguish allergic from nonallergic reactions. Nonallergic drug toxicity is usually, but not always, associated with higher doses and/or prolonged use and is particularly noted in patients with poor kidney or liver function that results in impaired clearance. Examples include nephrotoxicity with aminoglycosides, neurotoxicity of penicillins, and peripheral neuropathy with prolonged use of metronidazole.

Cost analysis of AMA:

ICU beds account for 20-40% of all hospital costs and three to ten times the cost of a hospitalization on a regular inpatient unit. Antimicrobial cost accounted for 50 -70% of the total drug expenditure in ICU. Patients those admitted to ICU had to borrow money or sell their assets. Our study revealed that cost of drug therapy and antimicrobial agents per patient in ICU were higher as compared to developing country but lower as compared to developed country.44 Irrational prescription of antimicrobials is the major health care problem and burden to the society, which leads to development of resistance and increase in health care cost. 62

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Studies on utilization of AMAs in ICU of Indian Hospital:

Gajbhiye et.al. noted that, DUS have the potential to make objective evaluation and analysis of health professionals work and provide them with feedback to stimulate thinking about their practice and finding ways to improve physicians’ own performance. 63Study by Drupad HS et al. stated that, antimicrobials were extensively used in ICU to treat the complicated cases.

They also observed that irrational prescription and polypharmacy of antimicrobial led to emergence of drug resistance and therapy failure and increased the patient mortality and morbidity. 62 The common indication for

AMAs on the study by Badar et.al. study are 64.9% for infection, followed by symptomatic 24%, prophylactic 11%. 64

The priority actions recommended on Ghanshani et.al. study were,65

(1) National surveillance of antibiotic use and antibiotic resistance

(2) Increasing use of diagnostic tests, especially microbiological tests

(3) Strengthening of infection control committees in hospitals

(4) Restricting the use of antibiotics for nontherapeutic use.

Studies on safety & cost of AMAs in ICU:

Shelat et.al. in his study stated that, cost of drug therapy and antimicrobial agents per patient in ICU were higher as compared to developing country but lower as compared to developed country. Cost of antimicrobials was accounted more than 30% of cost of total drug therapy, But the limitation in this study was, laboratory cost, hospitalization cost, ICU equipment cost,

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Review of Literature staff cost, indirect cost like transport cost, loss of wages were not calculated. 44

The alarming increase in AMAs use and along with it, the increasing antibiotic resistance will lead to increased morbidity, mortality, and treatment cost. 3

Studies on utilization of AMAs expressed as DDDs per 1000 inhabitants per day:

A study done by Anand et.al. says ATC/DDD based studies were superior for comparing the use of drugs between hospitals or on regional levels.

He also states that DDD/100 bed-days is proposed by WHO to analyze and compare the utilization of drugs. 4 Gidamudi et.al. concluded in his study that,

DDD/1000 inhabitants/day may provide a rough estimate of the proportion of the study population that may be treated with certain drugs. He also observed,

DDDs for most anti-infectives were based on the treatment of moderately severe infection. In some hospitals much higher doses were frequently used and this must be considered when using the DDD as a unit of measurement. 66

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Aims and Objectives Aims and Objectives

Aims and Objectives

Aim : To assess the utilization pattern, safety profile and economic outcome of antimicrobials in Medical ICU of the institution.

Objectives:

1) To determine utilization of antimicrobials in medical ICU using WHO Drug use indicators and ATC/DDD method expressed in terms of DDD/1000 inhabitants/day. 2) To analyze the prescribing trends of antimicrobials in medical ICU. 3) To assess safety profile. 4) To evaluate the prescription costs - in patients admitted in ICU based on cost per DDD.

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Materials and Methods

Materials and Methods

Methodology

Materials and methods:

Study design:

This study was a Prospective cross sectional observational study.

Study setting:

This study was conducted at Intensive Medical Care Unit (IMCU),

Department of General Medicine, Sree Mookambika Institute of Medical

Sciences, Kulasekharam, Kanyakumari District, Tamilnadu

Study period:

This study was done during the period February 2016 to February 2017.

Inclusion criteria:

• Patients prescribed with antimicrobial drugs in Medical ICU

• Patient with age more than 18 years of either sex

Exclusion criteria:

• Patients not receiving any AMAs.

• Patient not willing to give written informed consent

Institutional Human Ethics Committee Approval:

Ethical clearance was obtained from Institutional Human Ethics Committee

(IHEC) Ref. No. SMIMS/IHEC/2016/A/21 (Appendix I) .

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Materials and Methods

Study Procedure:

The study was carried out after getting approval from Institutional

Human Ethics Committee (IHEC). Patients admitted in medical ICU department satisfying the inclusion and exclusion criteria was enrolled in the study. They were explained about the study and written informed consent

(Appendix II) was obtained from each patient or attenders before recruiting them into the study. Details from the prescriptions in the case file were recorded in case record forms (Appendix III). The demographic data of the patients, presenting complaints, detail of AMAs used and adverse effect of

AMAs were recorded. Details of AMAs included dose, route and frequency of medication

Assessment of drug use indicators

Following drugs use indicators were assessed according to WHO guidelines.

Prescribing Indicators: a) Average number of drugs per encounter (problem)

Total number of different drugs prescribed Number of encounters surveyed

b)Percentage of drugs prescribed by generic name

Number of drugs prescribed by generic name X100

Total number of drug prescribed

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Materials and Methods

c) Percentage of encounters with injection prescribed

Number of encounters with injection prescribed X100 Number of encounter surveyed d) Percentage of drugs prescribed from Essential drug list(EDL)

Number of drugs prescribed from EDL X100 Total number of drugs prescribed

Complementary Indicators a) Average drugs cost per encounter per day

Total cost of all drugs prescribed

Number of encounter surveyed

b) Percentage of drugs cost spent on injections

Total cost spent on injections prescribed X100 Total drug cost

The data collected was compared with WHO values given below,

• Average number of drugs per encounter 2-3

• Percentage of encounter with an injection prescribed 16-20%

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Materials and Methods

• Percentage of drugs prescribed by generic name- 100%

• Percentage of drugs prescribed from EDL 80-100%

• Percentage of encounters with antibiotics prescribed should not be above

40%

Essential Drugs from National List of essential medicine(2015) India 67

Defined Daily Dose(DDD) Calculation

The utilization of AMAs was analyzed by ATC/DDD method. DDD was calculated as per guidelines for ATC classification and DDD assignment

(2013)as given by WHO collaborator centre for drugs. Statistics methodology,

Oslo, Norway(Appendix IV).

The consumption data are given in DDD/1000 inhabitants/day. The

DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults.

DDD/1000 patients in ICU/day is calculated as

Total amount of drug used during study period(mg) X 1000

DDD(mg) X duration of study(in days) X Total sample size

Cost per DDD was calculated for AMAs as given below

Cost of one tablet or injection X DDD(mg)

Strength of one tablet or one ampoule of Antimicrobial injection(mg)

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Materials and Methods

CIMS was used for calculating cost in Indian rupees.

Prescribing pattern of AMAs was evaluated by

• Average number of drugs and maximum number of drugs prescribed for

each patient.

• Percentage of patients on monotherapy or combination of AMAs.

• Utilization of various classes of AMAs.

• Order of frequency in the utilization of AMAs

• Order of frequency of other drug used

• Cost of individual class of AMAs for a single day and during total duration

of the stay

• Adverse effects related to treatment with AMAs.

Safe profile was assessed using WHO causality assessment. Prescription of patients admitted in ICU was also evaluated for cost per DDD.

In the present study, the target drug were the systemic antibacterial agents belonging to class J01 of the ATC/DDD classification system. The systemic antimycotic (J02), the antimycobacterial (J04) and the systemic antiviral (J05) drugs were not included in the study. The antimicrobials were classified using WHO Anatomical Therapeutic Chemical (WHO-ATC) classification system.

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Materials and Methods

Analysis of data

The data collected were entered into Microsoft Excel and subsequently analyzed. Descriptive statistics, was used for data analysis.

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Results Results

Observations and Results

Prospective evaluation of prescriptions of 123 patipatientsents admittedadmitted in medical ICU at Sree Mookambika Institute of Medical Sciences, between February 2016 and February 2017 was done and the dadatata were analanalyzed.yzed.

Baseline Demographic ch aracteristics

Table 11: Age Distribution of the patients

Age (years) Number Percentage (%)

Less than 20 4 3.25 21-40 17 13.82 41 -60 41 33.33 61-80 55 44.72 Above 80 6 4.88 Total 123 100 .00 The age range of study population was from 18 -85 years. Mean age of study population was 57.7 years. Maximum number of patients in the age group of 61 - 80 years were admitted in medical ICU.

Fig 1: Age wi se distribution of the patients

45 44.72 40 33.33 35 30 25 20 13.82 15 10 3.25 4.88

Percentage of(%)patients Percentage 5 0 Less than 21-40 41-60 61-80 Above 80 20 Age group (Years)

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Sex Distribution

Table 12: Gender wise distribution of patients

Gender Number Percentage (%) Male 82 66.67 Female 41 33.33 Total 123 100.00

Fig 2: Age wise distribution of male and female patientpatientss

38 40

35

30 23 25 18 17 20 14 Male 15 Female

Number of Patients of Number 10 3 3 4 5 1 2

0 Less than 21 -40 41 -60 61 -80 Above 81 20

Age group (yrs )

Male preponderance was higher in all age groups.

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Fig 3: Most common causes of infection on system based

Respiratory… 24.39% CNS 19.51% GIT 13.82%

Dermatology 12.2% Poisoning 10.57%

Cardiac 6.5% Genito Urinary 4.88% Renal 4.88% Causes of admission of Causes Blood 2.44% Endocrine 0.81%

0 5 10 15 20 25

Percentage (%)

A wide spectrum of clinical diagnosis was observed . O ut of 123 patients, highest number of patients were admitted for Respiratory infection. (n=30,

24.39%.)

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Tab 13: Frequency of co -morbidity found in patients

Patients with number of Number Percentag e(%) comorbidities 1 comorbidity 44 35.77 2 comorbidity 16 13.01 ≥3 comorbidity 13 10.57 No comorbidity 50 40.65 Total 123 100.00

Fig 4: Frequency of co -morbidity found in patients

35.77% 40.65% 1 comorbidity 2 comorbidity ≥3 comorbidity Nil comorbidity

13.01% 10.57%

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Prescribing Indicators Data a) Average number of drugs per encounter

Total number of different drugs prescribed 939 = = 7.63 Number of encounters surveyed 123 b) Percentage of drugs prescribed by generic name

Number of drugs prescribed by generic name X 100 Total number of drugs prescribed

288 = X 100 939

= 30.67% c) Percentage of encounters with an injection prescribed

Number of encounters with an injection prescribed X 100 Number of encounter surveyed 123 = X 100 = 100% 123 d) Percentage of drugs prescribed from Essential Drug List (EDL)

Number of drugs prescribed from EDL X 100 Total number of drugs prescribed

849 = X 100 = 90.41% 939

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Results

Complementary Indicator Data a) Average drug cost per encounter per day

Total cost of all drugs prescribed 25487 = Number of encounters surveyed 123

The total cost of AMAs in our study wasRs.25487/- for 123 encounters.

Therefore average drug cost per encounter per day was Rs. 110.8 b) Percentage of drugs cost spent on injections

Cost spent on injections prescribed X 100 Total drug cost

10939.95 = X 100 = 42.92% 25487 The total amount spent on antimicrobial injection was Rs. 10939.95/- for 123 encounters. Therefore the percentage of drugs cost spent on injections was

42.92%.

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Table 14:Summary of Prescribing Indicators Data

Prescribing Indicator Average / Percent WHO Standard assessed Average number of 7.63 2-3 drugs per encounter Percentage of drugs 30.67% 100% prescribed by generic name Percentage of 100% 16-20% encounters with injections Percentage of drugs 90.41% 80-100% prescribed from EDL

Polypharmacy was observed in the prescriptions (7.63) compared to WHO value (2-3).

There was no tendency to prescribe drugs by generic name (30.67%), most of the drugs were prescribed by branded name.

There was also overuse of injections which led to increase in cost spent on injections (Rs. 10939.95) for 123 encounters.

There was a tendency to prescribe drugs from EDL (90.41%) which is similar to WHO value (80-100%).

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Results

Utilization of AMAs (J01) expressed as number of DDDs/1000 patient/days and their cost/DDD in Medical ICU(MICU) Defined Daily Dose (DDD) Calculation: DDD/1000 patients in ICU/day Total amount of drug used during study period(mg) X 1000 DDD(mg) X duration of study(in days) X Total sample size Defined daily Dose (DDD) calculation as per the above formula for each AMAs

Antimicrobial Agents Preperation DDD/1000 patients in ICU/day Levofloxacin Oral 0.55 Levofloxacin Parenteral 0.15 Ciprofloxacin Oral 0.11 Ciprofloxacin Parenteral 0.57 Ceftriaxone Parenteral 6.45 Cefataxime Parenteral 0.75 Cefixime Oral 2.22 Ampicillin Parenteral 0.22 Meropenem Parenteral 1.25 Imipenem&cilastatin Parenteral 0.22 Cefoperazone(1000) Parenteral 0.66 &Sulbactam(500) Amoxicillin(500) Oral 0.13 &clavulanic acid(125) Amoxicillin(500) Parenteral 0.07 &clavulanic acid(125) Ti gecycline Parenteral 0.13 Doxycycline Oral 1.11 Amikacin Parenteral 0.22 Azithromycin Oral 1.55 Clindamycin Parenteral 0.33 Clindamycin Oral 0.35 Linezolid Parenteral 0.44 Linezolid Oral 0.44 Vancomycin Parenteral 0.35 Teicoplanin Parenteral 0.13 Metronidazole Parenteral 3.34 Nitrofurantoin Oral 0.46 Piperacillin&Tazoobactam Parenteral 3.5 Sulfamethoxazole(800) & Oral 0.62 Trimethoprim(160) DDDs are used to measure antibiotic use overtime and to monitor their trends in MICU

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Results

Table 15: Utilization of AMAs expressed as number of DDD/1000 patients/day and cost/DDD

ATC Code AMAs DDD/1000 AMAs patients/day Cost/DDD * (Rs) J01MA12 Levofloxacin(O) 0.55 7 J01MA12 Levofloxacin(P) 0.15 129 J01MA02 Ciprofloxacin(O) 0.11 20 J01MA02 Ciprofloxacin(P) 0.57 40 J01DD04 Ceftriaxone(P) 6.45 122 J01DH02 Cefotaxime(P) 0.75 176 J01DD08 Cefixime(O) 2.22 40 J01CA01 Ampicillin(P) 0.22 64 J01DH02 Meropenem(P) 1.25 3800 J01AA12 Tigecycline(P) 0.13 6460 J01 AA02 Doxycycline(O) 1.11 3 J01GB06 Amikacin(P) 0.22 124 J01FA10 Azithromycin(O) 1.55 18.6 J01FF01 Clindamycin(O) 0.33 56 J01FF01 Clindamycin(P) 0.35 504 J01XX08 Linezolid(O) 0.44 156 J01XX08 Linezolid(P) 0.44 580 J01XA01 Vancomycin(P) 0.35 1556 J01XA02 Teicoplanin(P) 0.13 1067 J01XD01 Metronidazole(P) 3.34 42 J01XE01 Nitrofurantoin(O) 0.46 2 Total 21.21 14966.6

O- Oral, P- Parenteral

* Cost of one tablet or one ampoule of injection X DDD(mg)

Strength of one tablet or one ampoule of Antimicrobial injection(mg)

Beta-lactam antibiotics (11.97 DDDs/1000 Patients/day) were more utilized than other AMAs. Among the beta-lactam antibiotics, cephalosporins were most frequently utilized drugs (10.08 DDDs/1000 patients/day).

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Results

Table 16: Utilization of Fixed Drug Combination AMAs expressed as number of DDD/1000 patients/day and cost/DDD

ATC Code AMAs DDD/1000 AMAs patients/day Cost/DDD* (Rs) J01DD62 Cefoperazone(500) 0.66 960 &Sulbactam(500) (P) J01CR02 Amoxicillin(500) 0.13 20.80 &clavulanic acid(125) (O) J01DD08 Amoxicillin(1000) 0.07 332.50 &clavulanic acid(250) (P) J01EE01 Sulfamethoxazole(800) & 0.62 2 Trimethoprim(160) (O) J01CR05 Piperacillin&Tazobzctam (P) 3.5 1151

J01 DH51 Imipenem& cilastatin (P) 0.22 3340 Total 5.2 5806.30

O- Oral

P- Parenteral

Total cost/DDD for all AMAs was Rs.20772.90. Total cost/DDD for beta- lactam antibiotics was Rs. 402/-. But total cost/DDD for carbapenem was Rs.

7140/-.The cost/DDD wasRs 2623/- for glycopeptides (Vancomycin and teicoplanin).

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Results

Utilization of various classes of AMAs

Number of drugs per prescription

Table 17: Frequency of distribution of AMAs in each prescription

Prescription with Number of cases Percentage (%) AMAs Single drug 42 34.15 2 drugs 63 51.22 3 drugs 16 13.01 4 drugs 2 1.63 Total 123 100 .00 Most common pattern was 2 AMAs/prescription (n=63%) 51.22 % and least common was 4 drugs (n=2) 1. 63%.

Fig 5: Number of prescriptions containing Particular Antimicrobial group

121 120

100

80

60 45

40 14 12 8 20 6 6 6

0 Number of prescription Number

AMA group

Most commonly used antimicrobial group was Beta -lactam antibiotics (n=121) .

83 | P a g e Results

Table 18: Most commonly used Beta-lactam antibiotics

Betalactam antibiotics Frequency of Percentage (%) prescription of drugs Ampicillin 2 1.67 Ceftriaxone 56 46.67 Cefataxime 9 7.50 Cefixime 1 0.83 Meropanam 9 7.50 Imipenem 2 1.67 Sulford Forte 6.67 (cefoperazone+ sulbactam) 8 Piptaz (piperacillin+ tazobactam) 31 25.83 Augmentin (Amoxicillin + 1.67 clavulanic acid) 2 Total 120 100.00

As single drug, ceftriaxone (n=56;46.67%) was most frequently prescribed.

The combination drug commonly prescribed was Piperacillin + Tazobctam

(n=31; 25.83%).

84 | P a g e

Results

Table 19: Most commonly prescribed antibiotics injected

CommonlyPrescribedAntibiotic Frequency Percentage(%) Injection Ampicillin 2 1.07 Ceftriaxone 56 29.95 Cefataxime 9 4.81 Cefixime 1 0.53 Meropanam 9 4.81 Imipenem 2 1.07 Sulford Forte (cefoperazone+ sulbactam) 8 4.28 Piptaz (piperacillin+ tazobactam) 31 16.58 Augmentin (Amoxicillin + clavulanic acid) 2 1.07 Mertronidazole 45 24.06 Levofloxacin 2 1.07 Clindamycin 3 1.60 Amikacin 2 1.07 Linezolide 4 2.14 Ciprofl oxacin 4 2.14 Vancomycin 5 2.67 Teicoplanin 1 0.53 Tigecycline 1 0.53 Total 187 100.00

Most commonly prescribed antibiotic injection was Ceftriaxone (n=56,

29.95%), followed by metronidazole (n=45, 24.06%).

85 | P a g e

Results

Fig6:Number of prescription s containing one AMA prescribed

32 35

30

25

20

15

Number Prescription of Number 7 10

3 5

0 Cephalosporins Drugs Penicillins Carbapenem

86 | P a g e Results

Fig 7:Number of prescription containing 2 AMAs Prescribed

Ceftriaxone + Metronidazole 19 Piptaz + Metronidazole 8 Piptaz + Clindamycin 3 Piptaz + Azithromycin 3 Azithromycine + Levofloxacin 2 Sulford fort+ Metronidazole 2 Vancomycine +Meropenem 2 Ceftriaxone + Clindamycin 2 Meropenem +metronidazole 2 Ciprofloxacin + Metronidazole 2 Linezolid + Piptaz 2 Cefataxime + Metronidazole 2 Ceftriaxone + Azithromycine 2 Ceftriaxone + Vancomycin 2 Cefataxime + Linezolid 1 Metronidazole + Nitrofurantoin 1 Ceftriaxone + ciprofloxacin

Drugs 1 Piptaz + Doxycycline 1 Meropenem+ Doxycycline 1 Sulford fort + Augmentin 1 Sulford fort+ Azithromycin 1 Piptaz + Sepran DS 1 Linezolid + Ciprofloxacin 1 Tigecycline +Clindamycin 1 Meropenem + Linezolid 1

0 5 10 15 20

Number

87 | P a g e Results

Fig8: Number of prescription which contain 3 AMAs prescribed

Piptaz +Linezolid + Metronidazole 2

Levofloxacin+Azithromycine+Ceftrixone 2

Piptaz+Azithromycin+Ceftriaxon 1

Piptaz+ Azithromycin+ Teicoplanin 1

Doxycycline + Ceftriaxone+ Levofloxacin 1

Doxycycline + Azithromycin + Sulford fort 1

Cefataxime + Piptaz + Doxycycline 1

Drugs Cefataxime + Nitrofurantoin+ 1 Metronidazole Augmentin + Metronidazole + 1 Azithromycin Ampicillin+ Cefataxime + Sulford fort 1

Ampicillin + Metronidazole + Meropenem 1 Ampicillin + Metronidazole + 1 Levofloxacin

0 1 2 3

Number

Number of prescription s which contain four AMAs prescribed

In MICU the prescription with 4 AMAs were 2, in that one was with

Vancomycin + Ciprofloxacin + Clindamycin + Linezolid, and the other was

Ceftriaxone + Metronidazole + Ampicillin + Levofloxacin

88 | P a g e Results

Table 20:Percentage of prescription with single drug and combination of

AMAs

Prescription with Number Percentage (%) AMAs Monotherapy 42 34.15 Combination therapy 81 65.85 Total 123 100.00

Prescriptions with combination of AMAs were 65.85%. Ceftriaxone andmetronidazole were the most commonly prescribed 2 AMAs

(n= 19, 15.44% )

Most commonly prescribed single drug was Ceftriaxone (n= 26, 21.13%)

Table 21:Cost of individual class of AMAs for single day and during total duration of the stay

AMA Class Drug cost per Cost of drugs during encounterperday(Rs) total duration of stay(Rs) Sulfonamides (n=1) 4 20 Quinolones (n=12) 275 825 Beta- Lactam 14963 59892 (n=120) Broad spectrun 6466 19398 Antibiotics (n=6) Aminoglycoside 124 620 (n=2) Macrolides (n=14) 31 93 Lincosamide (n=7) 742 3710 Oxazolidinone (n=8) 736 2944 Glycopeptide (n=6) 2106 10530 Antiamoebic 12 60 Urinary Antiseptics 1 5 Total 25460 98097

89 | P a g e

Results

Table22: Frequency and percentage of encounter with ADRs

Type of ADR Number Percentage (%) Diarrhoea 2 15.38 Gastritis 3 23.08 Hypersensitivity 3 23.08 Nausea 4 30.77 Urticaria 1 7.69 Total 13 100.00

Table 23: Causality Assessment of ADRs according to WHO

WHO Causality Assessment Number of case Percentage(%) Scale Certain 3 23.09

Probable/Likely 4 30.77

Possible 2 15.38

Unlikely 2 15.38

Conditional/Unclassified 2 15.38

Total 13 100.00

90 | P a g e

Results

Fig 9: Percentage of encounters with ADRs as per WHO

30.77% 35.00 23.08% 30.00

25.00 15.38% 15.38% P 20.00 15.38% e r 15.00 c e 10.00 n 5.00 t a 0.00 g e

WHO causality assessment

The maximum ADRs observed were probable according to WHO causality assessment

91 | P a g e

Discussion Discussion

Discussion

The present study was undertaken to determine the utilization pattern, safety profile and cost analysis of AMAs in the Medical ICU, Sree

Mookambika Institute of Medical Sciences, Kulasekharam, Kanyakumari district. The DDD system was used to provide a tool for presenting drug utilization statistics, which allows measurement of drug consumption across therapeutic groups. It is difficult to treat patients in the ICU with multiple co- morbidities with less number of drugs as they require drugs for treatment of specific conditions as well as for prophylaxis, but it is also essential to keep a balance between the number of drugs and effective pharmacotherapy.

Among the organisms, aerobic gram-negative species and

Staphylococcus species are the most prevalent agents for infections. Most studies show that the high prevalence of gram-negative bacteria isolated from patients in ICUs is associated with a high rate of mortality. 17 In the present study no mortality was found with infections caused by the above organisms.

Of the 123 patients admitted in Medical ICU, Respiratory infection were

24.39%, CNS 19.51%, GIT 13.82%, Skin 12.20%, Poisoning 10.57%, Cardiac

6.50%, Genito urinary and Renal 4.88% each, Blood stream 2.44% and

Endocrine 0.81%. In a study by Mathur p et.al 19 , secondary bacteraemia in their ICUs was mostly due to LRT (Lower Respiratory Tract) infections which is consistent with this study.

929292 | P a g e

Discussion

Male preponderance was seen in this study similar to that by Gajbhiya VP et.al

63 on AMAs in the ICU of a rural tertiary care hospital. The most likely reason for this finding could be that in India male population has more access to medical facility compared to females, who even in critical illnesses are reluctant to utilize health care facilities, especially in those of lower socioeconomic strata. 4

A study by Anand et.al, 4 the maximum number of patients belonged to age group of 51–65 years (37%). In this study the maximum patients belonged to the age group of 61-80 years (44.72%).

Average number of drugs per prescription is an important index as it tends to measure the degree of polypharmacy, providing scope for review and educational intervention in prescribing practices. 55 In this study the average number of overall drugs per encounter was 7.63 which when compared with

WHO standard (2-3), is high. Poly pharmacy could enhance drug interaction which is not seen in this study. In a similar study performed in critical care unit of tertiary care teaching hospital in India, the average number of drugs per encounter was 13.54 which was high than ours.70 It is recognized that patients in ICU are generally prescribed more drugs than other patients. Besides patients had 1-3 co-morbid conditions. Atif M et.al 68 documented in his article that, there were several other reasons for higher number of drugs in a prescription, like, incompetency on the part of physicians, unavailability of clinical practice guidelines, financial incentives to the prescribers, lack of continuous medical education of the prescribers and the shortage of

939393 | P a g e

Discussion therapeutically correct drugs. Polypharmacy needs to be discouraged as a good number of ADRs results from drug-drug interactions.69

A study on AMAs utilization in ICU of a teaching hospital in South

India showed 57.8% as percentage of encounters in which antibiotics were prescribed. 4 All the 123 patients (100%) in this study were prescribed with

AMAs, as we included only patients receiving AMAs in medical ICU. Other studies showed 57.8% AMAs utilization of AMAs 4 and 83% received AMAs in a Bengaluru study by Patel MK et.al. 70

In Gajbhiye VP et.al. 63 study, the parenteral route was more common than the oral route and most commonly prescribed AMAs were in a combination parenteral form. The percentage of encounters in which injection was prescribed was 100% which is higher than the standard (16-20%). Possible reason for the high use of injection could be due to the serious conditions being treated in ICU and injectable forms produce faster onset of action. A study by

Christensen RF 71 in Uganda showed high use of antibiotic injection (48%).

There are high recommendations by WHO for generic prescription. The percentage of drugs prescribed by generic name was 30.67% which is low compared to the WHO standard (100%). It was noticed that most of the antimicrobial agents were prescribed by brand name which requires revision of current prescribing practice. Akl OA et.al 72 stated that, WHO deems generic prescription as a safety measure for patients as it clearly depicts and gives easy accessible information, and leads to better communication among healthcare

949494 | P a g e

Discussion providers. A national baseline study on drug use indicators in Ethiopia (2002) showed the percentage of drugs prescribed by generic name to be 87% which is higher than our finding (30.67%) 73

The percentage of drugs prescribed from the EDL in this study was

90.41%. The proposed optimal value for the percentage of drugs prescribed from the EDL by WHO was 100%. Rational prescribing means to prescribe drugs from the EDL issued by WHO because medicines in EDL are older, already tested in practice with established clinical use, and are of lower cost than the newer drugs. 72

In the present study the most frequent used AMA was ceftriaxone(46.67%) followed by Piperacillin & Tazobactam (25.83%). The most common AMA prescribed was ceftriaxone (22.7%) in the study by

Anand V et.al 4 and it also showed that the maximum utilization of AMA was cephalosporins and other beta
lactams followed by penicillins . In our study the most commonly prescribed antimicrobial group was beta lactam antibiotics

(64.17%). Among the betalactams, cephalosporins (39.57%) utilization was observed higher than penicillins(18.72%). Cephalosporins are commonly prescribed due to their relatively lower toxicity and broad spectrum activity.

In Malacarne et.al 47 study, there is widespread use of drug combinations. Antibiotic combinations are widely accepted if used appropriately in certain patients. The present study shows 65.85% of patients were prescribed with combination therapy of AMAs.

959595 | P a g e

Discussion

As two drugs therapy Cefotaxime + metronidazole (26.70%) were the most common empirical regimen used in the study by Patel MK et.al. 70 In this study- Ceftriaxone and metronidazole were the most commonly prescribed 2

AMAs (15.44%). This combination has synergetic activity and broader coverage of organisms for several serious gram negative infections.

In a study by Williams A et.al 74 the total cost of antibiotics prescribed in 200 patients was Rs 3, 99,016, an average of Rs 1995.08/patient. While in our study, the total cost of AMAs was Rs.25487/- for 123 encounters. The average drug cost per encounter per day was Rs. 110.8/patient. Shelat et.al 3 in his study stated that cost of drug therapy was lower compared to developed country. Cost spent on injections was Rs. 10939.95 (42.92% of total cost) which showed that higher cost was due to prescribing of injections especially carbapenem (7140/DDD) and glycopeptides (Vancomycin & Teicoplanin

2623/DDD). The cost/DDD for FDC was Rs.5806.03 which had increased the total cost.

Drug utilization studies have the potential to make objective evaluation and analysis of health professionals work and provide them with feedback to stimulate thinking about their practice and looking for ways to improve their own performance. 66 The DDD methodology has proved to be most useful in countries with a limited supply of drugs, and particularly in countries in which a small proportion of fixed dose combinations are marketed. 53 Prescription data presented in DDDs per 1000 inhabitant per day may provide a rough estimate of the proportion of the study population treated daily with a particular

969696 | P a g e

Discussion drug or group of drugs. As an example, the figure 10 DDDs inhabitants per day indicates that 1% of population on average might receive a certain drug or group of drugs daily.

There was high utilization of beta lactam antibiotics (11.77/DDD/1000 patients/day) in the present study. Among the beta lactam antibiotics, cephalosporins were most frequently utilized drug (10.08 DDD/1000 patients/day). Among the cephalosporins, ceftriaxone (6.45 DDD/1000 patients/day) was most utilized drug. These results appear to be in agreement with those from other Asian contries such as China, where cephalosporins and penicillins are the most utilized antibiotics. 75

The incidence of adverse drug events is not directly proportional to the number of drugs being taken, but increases remarkably as number of drugs rises. 69 In our study the frequency of ADRs were 13. The most common ADR was hypersensitivity. In a study by Shamna M et.al,76 the causality assessment of ADRs had been done using the Naranjo scale in which majority were probable (71.42%) with a less number of possible and definite reactions.

Similarly in our study more frequency was towards probable ADRs (30.77%).

Limitations of our study were small sample size, socioeconomic status of the patients was not analyzed. Indirect cost like expenditure on investigations and travelling expenses were not calculated which would have more information on total cost for controlling infection in ICU.

979797 | P a g e

Conclusion Conclusion

Conclusion

The pattern of antimicrobials used in medical ICU was studied in 123 subjects of Sree Mookambika Institute of Medical Science, from the period of

February 2016 to February 2017. From our study findings we were able to conclude that:

1. Mean age of study population was 57.7years.

2. Male preponderance was higher in all age groups.

3. Highest number of patients were admitted in ICU for Respiratory infection.

4. 59.35% were admitted with co-morbidity condition.

5. Average number of prescriptions per encounter was 7.63, which was

higher than the WHO standard (2-3)

6. Only 30.67% of drugs were prescribed with generic name, which was

lower than the WHO standard (100%)

7. All the patients included in the study were given medication through

injection.

8. 90.41% of drugs were from EDL, which showed similar to that of the

WHO standard (80-100%)

9. Average drug cost per encounter per day was Rs. 110.8/-

10. The percentage of drugs cost spent on injections was 42.92%, which was

higher than the WHO standard (40%).

11. Beta-lactam antibiotics (11.97 DDDs/1000 Patients/day) were more

utilized AMAs.

989898 | P a g e

Conclusion

12. Among beta-lactam antibiotics - cephalosporins were most frequently

utilized drugs (10.08 DDDs/1000 patients/day).

13. Most common pattern was 2 AMAs/prescription.

14. Ceftriaxone and metronidazole were the most commonly prescribed 2

AMAs.

15. Maximum ADR was probable (30.77%) as per WHO causality assessment

scale.

999999 | P a g e

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X

Annexure Annexure

XI Annexure

CONSENT FORM PART 2 OF 2 PARTICIPANTS CONSENT FORM The details of the study have been explained to me in writing. I am aware that the results of the study may not be directly beneficial to me but it will help in the advancement of medical sciences. I confirm that I have understood the study and had the opportunity to ask questions. I understand that my participation in the study is voluntary and that I am free to withdraw from the study at any time, without giving any reason and that it will not interfere with the normal course of treatment. I agree to make use of any data or results that arise from this study provided such a use is only for scientific purpose(s). I have been given an information sheet giving details of the study. I voluntarily consent to participate in the study with the title “Utilization pattern, Safety Profile and Cost analysis of Antimicrobials Prescribed in an Intensive Care Unit of a Teaching Hospital”. Serial No.: I.P. No. :

Name and signature of the Participant:

Address of the Participant:

Contact number of the participant:

Signature/Thumb impression of the participant / relative Witnesses:

1.

2.

Place: Kulasekharam Date:

XII Annexure

SREE MOOKAMBIKA INSTITUTE OF MEDICAL SCIENCES Kulasekharam, Kanyakumari District, Tamil Nadu, India – 629161 Department of Pharmacology

CASE RECORD

Title of the Study: “Utilization pattern, Safety Profile and Cost analysis of Antimicrobials Prescribed in an Intensive Care Unit of a Teaching Hospital”.

Subject number: I.P.No.: Date:

Name:

Age: Sex: M / F Socioeconomic status: BPL/APL Income: Address with contact number: Presenting complaints Diagnosis: Co-morbid conditions if any

Complications (if any):

Significant past history Investigation details

Details of medications prescribed in ICU

S.No Name Drugs Indi Dose Frequency Route Duration Adverse Cost(RS) of prescri catio Before/Aft effects /Regime drugs bed by ns er Food generic name

Signature of the Principal Investigator

XIII Annexure

ATC classification and DDD assignment (2013)as given by WHO collaborator centre for drugs:

Drugs ATC code DDD(mg) Levofloxacin (O) J01MA12 500 Levofloxacin (P) J01MA12 500 Ciprofloxacin (P) J01MA02 500 Ciprofloxacin (O) J01MA02 1000 Ampicillin (P) J01CA01 2000 Amoxicillin & Clavulanic acid (P) J01DD08 3000 Amoxicillin & Clavulanic acid (O) J01DD08 1000 Piperacillin & Tazobactam (P) J01CR05 14000 Meropenem (P) J01DH02 2000 Imipenem & Cilastin (P) J01DH51 2000 Cefoperazone & Sulbactam (P) J01DD62 4000 Ceftriaxone (P) J01DD04 2000 Cefotaxime (P) J01DD01 4000 Cefixime (O) J01DD08 400 Tigecycline (P) J01AA12 100 Doxycycline (O) J01AA02 100 Amikacin (P) J01GB06 1000 Azithromycin (O) J01FA10 300 Clindamycin (P) J01FF01 1800 Clindamycin (O) J01FF01 1200 Linezolid (P) J01XX08 1200 Linezolid (O) J01XX08 1200 Vancomycin (P) J01XA01 2000 Teicoplanin (P) J01XA02 400 Metronidazole (P) J01XD01 1500 Nitrofurantoin (O) J01XE01 200 Sulfamethoxazole & Trimethoprim (O) J01EE01 960

XIV ADR ASSESSMENT SCALES Scale 1: WHO CAUSALITY ASSESSMENT OF SUSPECTED ADVERSE DRUG REACTIONS (The Uppsala monitoring centre 2002)

Term Description A clinical event, including laboratory test abnormality, was occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to Certain withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary. A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent Probable/ Likely disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, but which could also be explained by Possible concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship Unlikely improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations. A clinical event, including laboratory test abnormality, reported as an adverse Conditional/ reaction, about which more data is essential for a proper assessment or the Unclassified additional data are under examination. A report suggesting an adverse reaction, which cannot be judged because Unassessible/ information is insufficient or contradictory, and which cannot be Unclassifiable supplemented or verified.

SUSPECTED ADVERSE DRUG REACTION REPORTING FORM For VOLUNTARY reporting of Adverse Drug Reactions by healthcare professionals

INDIAN PHARMACOPOEIA COMMISSION (AMC/ NCC Use only) (National Coordination Centre-Pharmacovigilance Programme of India) AMC Report No. Ministry of Health & Family Welfare Government of India Sector-23, Raj Nagar, Ghaziabad-201002 Worldwide Unique www.ipc.nic.in

A. PATIENT INFORMATION 12. Relevant tests / la boratory data with dat es 1. Patient Initials 2. Age at time of Event or 3. Sex M F ______date of birth ______4. Weight _Kgs

B. SUSPECTED ADVERSE REACTION 13 . Othe r re levant history in cluding pre-existing medical conditions (e.g. allergies, race, pregnancy, smoking, alcohol 5. Date of reaction started (dd/mm/yyyy) use, hepatic/ renal dysfunction etc) 6. Date of recovery (dd/mm/yyyy)

7. Describe reaction or problem

14. Seriousness of the reaction • Death (dd/mm/yyyy) • Congenital-anomaly • Life threatening • Required intervention • Hospitalization/prolonged to prevent permanen t • Disability impairment / damage • Other (specify)

15 . Outcomes • Fatal • Recovering • Unknown • Continuing • Recovered • Other (specify) C. SUSPECTED MEDICATION (S) S.No 8. Name Manufact Batch Exp. Date Dose Route Frequency Therapy dates (if known, Reason for use of (brand and ure r No ./ Lo t (if known)) use d use d give duration) prescribed for /or generic (if known) No . Date Date name) (if known) started stopped i. ii. iii. iv. S.No 9. Reaction abated after drug stopped or dose 10. Reaction reappeared after reintroduction As per C reduced Yes No Unknown NA Reduced dose Yes No Unknown NA If reintroduced dose i. ii. iii. iv. 11. Concomitant medical product including self D. REPORTER (see confidentiality section on first page) medication and herbal remedies with therapy dates 16. Name and Professional Address :_ (exclude those used to treat reaction) Pin code: E-mail ______Tel. No. (with STD code): ______Occ upation Signature ______

17. Causality Assessment 18. Date of this report (dd/mm/yyyy)