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Home , Enoxacin, Fleroxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin

18th Expert Committee on the Selection and Use of Essential Medicines (2011)

Fluoroquinolone Use in Paediatrics: Focus on Safety and Place in Therapy

Jennifer A. Goldman, M.D. 1,2, Gregory L. Kearns, Pharm.D., Ph.D. 1,3,4

Departments of Pediatrics 1 and Pharmacology 3, University of Missouri – Kansas City and the Divisions of Pediatric Infectious Disease 2 and Clinical Pharmacology and Medical Toxicology, 4 Children’s Mercy Hospital, Kansas City, MO, USA

Commissioned work for the Guidelines Group for the Revision of the “Guidance for National Programmes on the Management of Tuberculosis in Children”, World Health Organization, 30-31 March 2010, Geneva, Switzerland

1 I. Introduction

The first quinolone, , was developed in the 1960s and was used (off- label) in pediatric therapeutics without restriction. Consequent to their broad spectrum of antimicrobial (including anti-mycobacterial) effect and perceived excellent safety profile, there was considerable hope and expectation that this class of would find an important place in pediatric therapeutics. However, reports of quinolone-associated injury in weight bearing joints of juvenile animals resulted not only in an apparent contraindication to their use in human infants and children but also, completely derailed their formal development by pharmaceutical companies for use in pediatrics. While this situation resulted from a genuine concern for safety seemingly supported by relevant experimental findings, it served initially to remove a potentially useful class of antimicrobial agents from pediatric use. Despite the concerns associated with fluoroquinolone use in children, the favorable characteristics of this (eg., excellent oral and tissue penetration, broad antimicrobial spectrum, well characterized and predictable concentration-effect relationships, relative low incidence of development of microbial resistance) resulted in their increasing use in infants and children; initially as secondary or tertiary antimicrobial choices and three decades later, as a potential first line modality of treatment recommended in standard pediatric compendia used throughout the world (eg., monographs in Medicines for Children, Royal College of Paediatrics and Child Health and Neonatal and Paediatric Pharmacists Group, 2003; Pediatric Dosage Handbook, 16th edition, Lexicomp Corporation, 2009). For example, previous recommendations from the American Academy of Pediatrics (Red Book, 28th edition, American Academy of Pediatrics, 2009) indicate that fluoroquinolones may be useful for treating in pediatric patients where no other (appropriate) oral agent is available, the is caused by a multidrug-resistant (such as Pseudomonas sp. and strains) or prolonged oral treatment of gram- negative bacterial infections (eg., chronic osteomyelitis, exacerbations in patients with , infections in immunocompromised patients) is needed. Consequently, there appears to now be a real place in the pediatric therapeutic armamentarium for this class of antimicrobial agents. However, an overriding caveat for their use in children continues to entail a critical assessment of the risk vs. benefit ratio where adverse event data derived from animal models may not be completely/accurately extrapolated to developing humans. The purpose of this review of the fluoroquinolones is to synthesize available information of pertinence with respect to their use in children. The and pharmacodynamics of the drugs will be discussed as well as their general safety profile and the current and potential future roles for representative agents in this class in treating serious infections that can commonly occur in infants and children.

II. Clinical Pharmacology Fluoroquinolones are a class of antimicrobials that selectively target the action of bacterial II and IV. Inhibition of the activity of these enzymes disables DNA replication which in turn, inhibits bacterial replication. Presently, four generations of fluoroquinolone antibiotics exist as illustrated by the following table:

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First generation nalidixic acid Second generation ciprofloxacin, , , , , , Third generation , , , Fourth generation ,

Of these agents, ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin are the most widely used.8 The mechanism of action for the fluoroquinolones conveys activity that is bactericidal in nature. They have activity against a broad range of gram positive and negative organisms. The drugs in this class are uniformly active against the Enterobacteriaceae, and many strains of Listeria, , and mycobacteria. The newer quinolones have enhanced activity against staphylococci, streptococci and anaerobes.23 In general, the older generation compounds have more activity against gram negative and provide less gram positive coverage. The converse is true with 3rd and 4th generation fluoroquinolones which demonstrate an expanded spectrum against gram positive organisms. In regards to their activity against Mycobacterium tuberculosis, moxifloxacin and gatifloxacin demonstrate more potent in vitro activity than ciprofloxacin or levofloxacin.24 Expanded use of the fluoroquinolones brings with it increasing concern for the development of microbial resistance. There are several potential mechanisms for the development of resistance. These include the development of mutations in the genes that encode bacterial topioisomerase II and IV (which result in altered binding affinity of the drug and reduced action) and the development of bacterial efflux transporters (which reduce intracellular drug exposure). A plasmid carrying the gene qnrA has also been discovered which leads to an inherent mechanism of resistance.14 As with most antimicrobial agents, a primary determinant of fluoroquinolone efficacy resides with obtaining a sufficient exposure of the offending pathogen to the drug for a sufficient time for it to have its intrinsic biological effects. Thus, the application of pharmacodynamic principles (eg., the relationship between drug intrinsic activity, attained concentration-time profile and host factors) has become an important tool when selecting antibiotics.23 This is especially true for the fluoroquinolones as reflected by in vivo studies which have examined the exposure-response relationship using the pharmacodynamic surrogate of the ration of the area under the plasma concentration vs. time curve (AUC, a parameter reflecting general systemic exposure) and the minimum inhibitory concentration (MIC). In studies examining the pharmacodynamics of ciprofloxacin in seriously ill patients, investigators determined that an AUC/MIC below 125 was associated with inadequate antibacterial activity, a ratio between 125-250 was associated with “acceptable” activity and that an AUC/MIC between 250-500 produced optimal antibacterial activity.9 Also, the attainment of peak serum concentration to MIC ratios of ≥ 10:1 for fluoroquinolones has been shown to increase the probability of successful treatment outcomes as well as reduce the frequency of emerging resistant during therapy. While the aforementioned pharmacodynamic optima (ie. AUC/MIC of > 125 and Cmax:MIC ratio of ≥ 10:1) appear reasonable based on data from critically ill adult patients with gram negative respiratory infection, they appear to be different for other conditions where fluoroquinolones might be used. For example, in adult outpatients with community acquired respiratory infections caused by , an AUC/MIC ratio of ≥ 25 appears predictive of

3 bacterial eradication.16 Thus, treatment strategies and the prospective design of fluoroquinolone dosing regimens are best accomplished using a target exposure strategy which is based upon pharmacodynamic principles, knowledge of both host factors and microbial susceptibility and an understanding of the pharmacokinetic properties of a given agent. The pharmacokinetics of many of the available fluoroquinolone antibiotics have been previously characterized in both adult and pediatric patient populations.16 As a class, these agents are rapidly absorbed from the small intestine and their bioavailability is quite high, ranging from 70 to 95%. Peak plasma concentrations of later generation agents (eg., gatifloxacin, levofloxacin, moxifloxacin) are generally attained between one and two hours after oral administration and their bioavailability does not appear to be markedly impacted by concurrent ingestion with food. They demonstrate relatively low binding to circulating plasma proteins and as a result of their excellent penetration into tissue, have apparent volumes of distribution which far exceed the total body water space (eg., average apparent volume of distribution for ciprofloxacin ~ 2.3 L/kg).11 The biotransformation of the fluoroquinolones is drug dependent with many of the early generation compounds (eg., ciprofloxacin) being extensively metabolized in the as compared to later generation compounds (eg., levofloxacin, gatifloxacin, gemifloxacin) which are predominantly excreted unchanged in the .24 As compared to early generation compounds, the newer fluoroquinolones (i.e. gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin) generally have longer elimination half lives 16 which facilitates the use of longer dosing intervals. As a direct result of their relatively restricted use in pediatric patients, there is a relative paucity of pharmacokinetic data for the fluoroquinolones generated from populations of infants and children with the exception of studies conducted in patients with cystic fibrosis. A previous review concerning the clinical pharmacology of the fluoroquinolones in pediatric patients has denoted that the systemic clearance of drugs within this class may be increased in young children.19 This phenomenon appears to be quite compound dependent. As reviewed by Algasham and Nahata, 1 the average elimination half life of ciprofloxacin in children appears to be shorter than reported from studies in adults and consequently, supported a need for thrice daily dosing. In contrast, the elimination half life of ciprofloxacin in infants has been reported to be prolonged relative to data from older children and associated with a higher plasma AUC (ie., higher systemic exposure from a given dose which infers reduced plasma clearance). As well, the oral bioavailability of ciprofloxacin in younger children has been reported to be reduced as compared to older children and young adults. 1 Similar to ciprofloxacin, the pharmacokinetics of levofloxacin appear to be age dependent. As reported by Chien, et al. 6, levofloxacin elimination (as reflected by apparent elimination half life plasma clearance) in children aged five years and younger appeared to be significantly different from values obtained in older children and from historical data generated in an adult cohort. The summary data are presented in the following table: Summary of Levofloxacin Pharmacokinetic Estimates in Pediatric and Adult Subjects Receiving a Single Intravenous Dose (7 mg/kg) of Levofloxacin [adapted from Chien S, et al. 2005]

4 Age Group Cmax t1/2 AUC Vss CL CLR (μg/mL) (h) (μg•h/mL) (L/kg) (L/h/kg) (L/h/kg) Pediatric subjects, Single IV dose, 7 mg/kg 0.5−2 y 5.19±1.26 4.1±1.3 21.5±6.12 1.56±0.30 0.35±0.13 NA (n=6) 2−5 y 6.02±1.07 4.0±0.8 22.7±4.66 1.50±0.21 0.32±0.08 NA (n=7) 5−10 y 6.11±0.88 4.8±0.8 29.2±6.40 1.57±0.44 0.25±0.05 0.18±0.07 (n=9) 10–12 y 6.12±1.19 5.4±0.8 39.8±11.3 1.44±0.35 0.19±0.05 0.15±0.06 (n=7) 12−16 y 6.15±1.55 6.0±2.1 40.5±7.56 1.56±0.53 0.18±0.03 0.11±0.04 (n=11) Adults, Single IV dose, 500 mg* 18–45 y 6.18±1.04 6.0±1.0 48.3±5.40 1.27±0.12 0.15±0.02 NA (n=23)

NA = Not Available All data presented as Mean±Standard Deviation *Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Data on file.

The almost two-fold difference in levofloxacin clearance observed in this study between infants and children less than five years and those > 12 years of age led the authors to recommend a dose of 10 mg/kg every 12 hours for infants and young children (as opposed to a dose of 10 mg/kg daily for adolescents and adults) so as to enable attainment of a systemic exposure likely to produce desired antimicrobial effect. Finally, this study reported similar plasma concentration vs. time profiles for levofloxacin in children receiving oral and intravenous doses of the drug which suggested excellent oral bioavailability of the liquid formulation in pediatric patients. In contrast to the previous data on ciprofloxacin and levofloxacin, gatifloxacin does not appear to have age-dependent pharmacokinetics. In a study of 76 pediatric patients (age range 0.5 to 16 years) who received a single oral dose of gatifloxacin suspension of 5, 10 or 15 mg/kg (maximum dose 600 mg), Capparelli, et al.4 did not find a statistically significant association between age and either the apparent oral clearance (mean±SD value = 5.5±2.1 ml/min/kg) or plasma elimination half life (5.1±1.4 hr). As well, these authors reported an apparent proportional relationship between gatifloxacin dose and AUC, and comparable relative oral bioavailability of the suspension and tablet formulation of the drug. Data from this study supported a recommendation for gatifloxacin dosing of 10 mg/kg every 24 hours in both infants and children to attain potentially therapeutic systemic exposures.

5 III. Data on safety and use of fluoroquinolones in children Soon after the first generation of quinolones was introduced, preclinical studies conducted in experimental animals (Beagle dogs) demonstrated damage to articular cartilage in weight-bearing joints.7 This continues to limit fluoroquinolone general use in pediatric patients consequent to a concern that similar effects (eg., damage to growth plate cartilage) might occur in growing children. Case reports of tendinitis and tendon rupture have also been reported in association with fluoroquinolone use. 7, 10, 12 Fluoroquinolone-associated tendon disorders are more likely to occur in the elderly (>60 years of age) with the Achilles tendon being the most common site affected. The time of onset of tendon symptoms following the initiation of treatment generally develops during the first 1-2 weeks following initiation of therapy while tendon rupture occurs within 2-3 weeks.12 In a case-control study by van der Linden et al, 22 the risk of Achilles tendon disorders associated with fluoroquinolone exposure was found to be relatively rare, with an overall excess risk of 3.2 cases per 1000 patient years. The concomitant use of appears to substantially increase the risk. A review of the literature reveals several large, retrospective studies evaluating the adverse events observed with fluoroquinolone use in children. Chuen et al. 7 performed a retrospective, observational study to assess the incidence and relative risk of tendon or joint disorders that occurred following the use of ofloxacin, levofloxacin, and ciprofloxacin. This study involved greater than 6000 children < 19 years of age with history of fluoroquinolone exposure and a “control group” of children exposed to , a which does not have known effects on cartilage, tendons or joints. The calculated risk for tendon or joint disorders was found to be no different in the children treated with fluoroquinolones when compared to those prescribed azithromycin. Chalumeau, et al. 5 reported results from a multicenter, observational, cohort study conducted in France which compared potential adverse events in a pediatric population of 276 pediatric patients who received fluoroquinolones and 249 “control” patients who received an antimicrobial other than a fluoroquinolone. Although short-term potential adverse events did occur more frequently in association with fluoroquinolone treatment, all events were transient and no severe or persistent musculoskeletal lesions were observed. The most common potential adverse event involved the followed by the musculoskeletal system, the skin and the CNS. In this patient cohort, musculoskeletal adverse events were more frequently associated with (18.2%) than ciprofloxacin (3.3%).5 A comparative study of levofloxacin in the treatment of children with community acquired demonstrated cure rates and safety profiles that were comparable to the other antibiotics used in the study.3 Noel, et al. 15 examined the comparative safety profile of levofloxacin in a cohort of 2,523 children treated with the drug from three large multi-center efficacy trials. Spontaneous (un-blinded) reports of one or more musculoskeletal events (arthritis, arthralgias, , gait abnormality) within sixty days of starting therapy were higher in levofloxacin-treated children when compared with those treated with non-fluoroquinolone antibiotics. The majority of musculoskeletal disorders reported were episodes of arthralgias in weight-bearing joints. Five participants from the levofloxacin group who had musculoskeletal complaints underwent either CT or MRI which failed to reveal any apparent structural abnormalities. As well, the data failed to reveal an association with long-term joint abnormalities or growth impairment and levofloxacin exposure.15 Other relatively rare but serious toxicities have been associated with fluoroquinolone use including: prolonged QT interval, photosensitivity, and acute liver failure. 14 The

6 frequency of their occurrence in pediatric patients can only be inferred from spontaneous reports emanating from use of these agents in adults.

IV. Place of therapy for fluoroquinolones in pediatrics Despite concerns of possible adverse effects, fluoroquinolones are being used in infants and children. In 2002, there were approximately 520,000 fluoroquinolone prescriptions written in the U.S. Over 13,000 of those prescriptions were written for children 2 to 6 years of age and nearly 3000 were written for children younger than 2 years of age.8 In most instances, the use of fluoroquinolones in pediatric patients is limited to specific clinical settings where their pharmacologic attributes are felt by the prescriber to outweigh potential risks for drug-associated adverse events. Examples of clinical settings where these drugs are felt to have utility include pulmonary exacerbations in patients with cystic fibrosis, infections associated with complicated urogenital anomalies, immunosuppressed patients, those with infectious diarrheal diseases and patients who develop infections secondary to multi-drug resistant organisms.10 Further delineation of fluoroquinolone use in pediatrics has been provided by the American Academy of Pediatrics through a published policy statement which recommended that their use be limited to the following: 1) exposure to aerosolized 2) urinary tract infections caused by or other multi-drug resistant, gram-negative bacteria 3) chronic suppurative or malignant caused by Pseudomonas aeruginosa 4) osteomyelitis or osteochondritis caused by Pseudomonas aeruginosa 5) exacerbation of pulmonary disease in patients with cystic fibrosis who have colonization with Pseudomonas aeruginosa and can be treated in an ambulatory setting 6) mycobacterial infections caused by isolates known to be susceptible to fluoroquinolones 7) Gram-negative bacterial infections in immunocompromised hosts in which oral therapy is desired or resistance to alternative agents is present 8) gastrointestinal tract infection caused by multidrug-resistant species, species, , or jejuni 9) documented bacterial septicemia or due to organisms with in vitro resistance to approved agents or in immunocompromised infants and children in whom parenteral therapy with other appropriate antimicrobial therapy has failed and 10) serious infections attributable to fluoroquinolone-susceptible pathogen(s) in children with life-threatening allergy to alternative agents.8 The clinical use of fluoroquinolones in children has been reviewed by Alghasham and Nahata.1 As denoted in the summary table below, there is ample evidence to support the utility of ciprofloxacin in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis where treatment has been associated with improved clinical outcomes. There also appears to be a role for this drug as part of maintenance therapy this particular patient population.

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* Citations to primary literature available in review by Alghasham and Nahata.1 Several efficacy studies of fluoroquinolones have also been performed in children with gastrointestinal infections caused by multi-drug resistant or shigellosis. Summarized results from these previously published studies 1 are contained in the following table. Collectively, clinical outcome data reveal a very high cure rate without the risk of relapse.

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* Citations to primary literature available in review by Alghasham and Nahata.1

Fluoroquinolones penetrate well into the cerebral spinal fluid where the concentration can exceed 50% of the corresponding plasma drug concentration. This pharmacokinetic property in addition to the broad spectrum of antimicrobial activity has resulted in the use of these agents to treat meningitis caused by susceptible pathogens. While outcome data for this potential therapeutic indication are limited, there are case reports of effective treatment of meningitis with intravenous fluoroquinolones in pediatric patients.1 It has also been shown that a single dose of oral ciprofloxacin can successfully eradicate the nasopharyngeal carriage of Neisseria meningitidis to prevent the development of meningococcal disease.1 Fluoroquinolones continue to be evaluated as a treatment option in the setting of tuberculosis (TB) given the prevalence of the disease, its associated mortality and the fact that resistance to first line anti-mycobacterial drugs is commonplace. 21 As well, given that the

9 development of new drugs for the treatment of TB is slow, established drugs such as the fluoroquinolones are being revisited as possible therapeutic options. Currently, the fluoroquinolones are registered as second-line agents for TB therapy. Moxifloxacin and gatifloxacin have the lowest MICs and have shown the greatest bactericidal activity against M. tuberculosis. The potential of moxifloxacin and gatifloxacin to shorten TB treatment is currently being investigated in clinical trials.2

An evaluation of treatment of drug-resistant tuberculosis demonstrated that an aggressive, comprehensive management program can cure more than 60% of patients with extensively drug-resistant tuberculosis who are not HIV infected but who had received previous unsuccessful anti-tuberculosis treatments. As recently reviewed by Mitnick, et al. 13 fluoroquinolones (and particularly, moxifloxacin and levofloxacin) have an important therapeutic role in the treatment of multidrug-resistant tuberculosis.13 While there is limited in vivo efficacy data which characterizes the utility of this class of antimicrobials as second line tuberculosis treatment, a small prospective, randomized trial of moxifloxacin exhibited bactericidal activity that was comparable to that of as assessed by a reduction of mycobacterium in the sputum following therapy.17

V. Potential Places in Pediatrics for Fluoroquinolones In general, the fluoroquinolones remain an appealing class of antimicrobials due to their wide availability, desirable pharmacokinetic characteristics (eg., availability of formulations that enable flexible, accurate dosing over the entire pediatric age spectrum, good and predictable oral absorption, extensive tissue penetration), their broad antimicrobial spectrum (including effectiveness against multi-drug resistant organisms) and their generally excellent safety profile. Large retrospective studies as mentioned above have demonstrated efficacy and safety with documented adverse events being reversible with cessation of the drug. Although concerns remain about the potential of adverse cartilaginous effects on the young child, recent studies have not shown a significant increase in risk for children who are treated with fluoroquinolones. As denoted above, the complete evaluation of fluoroquinolone-associated joint involvement has been difficult to address given that spontaneous reports have been generally subjective with no biopsy or imaging data available to confirm structural injury. Also, there have been no large, randomized control trials in children which would be required to critically evaluate the safety of the fluoroquinolones in pediatric patients. In a commentary published in The Pediatric Infectious Disease Journal, Prof. Urs Schaad stated that “the triad of feared arthrotoxicity, potential bacterial resistance explosion and enormous requirements regarding adequate study and postmarketing control makes it unlikely that fluoroquinolones will ever be recommended for common infections in children.”20 Such an assertion could certainly be valid for developed counties where alternative antimicrobial agents, many of them more well studied in children than the fluoroquinolones, are widely available for consideration as first-line treatment for common childhood infectious diseases. In contrast, for areas of the world with restricted medical resources, the fluoroquinolones offer an attractive alternative for the treatment of serious infections, especially when situations either preclude parenteral drug administration or make it extremely difficult to provide. This is especially true for infections that have not responded to standard care (eg, patients with HIV disease and associated immunocompromise) and for those caused by pathogens where is a common problem (eg, tuberculosis). Though more data from controlled trials to further define the efficacy and

10 safety profile for this class of drugs in pediatric patients are desirable, existing information is sufficient to support their selection and to develop appropriate paradigms for their use in infants and children. General wide availability of the fluoroquinolones for use in pediatric patients guided by clear medical rationale and coupled with careful therapeutic monitoring is recommended. This will result in an appropriately expanded therapeutic armementarium for pediatric patients capable of significantly improving the outcome for those with life-treatening infections.

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REFERENCES 1. Alghasham AA, Nahata MC. Clinical use of fluoroquinolones in children. Ann Pharmacother 2000;34:347-359 2. Boogaard J, Kibiki GS, Kisanga ER, Boeree MJ, Aarnoutse RE. New drugs against tuberculosis; problems, progress, and evaluation of agents in clinical development. Antimicrob Ag Chemother 2009;53:849-862 3. Bradley JS, Arguedas A, Blumer JL, Saez-Llorens X, Melkote R, Noel GJ. Comparative study of levofloxacin in the treatment of children with community- acquired pneumonia. Pediatr Infect Dis J 2007;26:868-878 4. Capparelli EV, Reed MD, Bradley JS, Kearns GL, Jacobs RF, Damler BD, Blumer JL, Grasela DM. Pharmacokinetics of gatifloxacin in infants and children. Antimicrob Ag Chemother 2005;49:1106-1112 5. Chalumeau M, Tonnelier S, d’Athis P, Treluyer JM, Gendrel D, Breart G, Pons G. Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France. Pediatrics 2003;111;e714-e719 6. Chien S, Wells TG, Blumer JL, Kearns GL, Bradley JS, Bocchini JA Jr, Natarajan J, Maldonado S, Noel GJ. Levofloxacin pharmacokinetics in children. J Clin Pharmacol 2005;45:153-160 7. Chuen YL, Duffy C, Gerbino PG, Stryker S, Noel GJ. Tendon or joint disorders in children after treatment with fluoroquinolones or azithromycin. Pediatr Infect Dis J 2002;21:525-9 8. Committee on Infectious Diseases. The use of systemic fluoroquinolones. Pediatrics 2006;118:1287-1292 9. Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Ag Chemother 1993;37:1073-1081 10. Grady RW. Systemic quinolone antibiotics in children: a review of the use and safety. Expert Opin Drug Saf 2005;4:623-630 11. Lode H, Borner K, Koeppe P. Pharmacodynamics of fluoroquinolones. Clin Infect Dis 1998;27:33-39 12. Melhus A. Fluoroquinolones and tendon disorders. Expert Opin Drug Saf 2005;4:299- 309 13. Mitnick CD et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008;359:563-574 14. Murray TS, Baltimore RS. Pediatric uses of fluoroquinolone antibiotics. Pediatr Ann 2007;36:336-342 15. Noel GJ, Bradley JS, Kauffman RE, Duffy CM, Gerbino PG, Arguedas A, Bagchi P, Balis DA, Blumer JL. Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders. Pediatr Infect Dis J 2007;26:879-891 16. Noreddin AM, Haynes VL, Zhanel GG. Pharmacokinetics and pharmacodynamics of the new quinolones. J Pharm Pract 2005;18:432-443

12 17. Pletz MW, De Roux A, Roth A, Neumann KH, Mauch H, Lode H. Early bactericidal activity of moxifloxacin in treatment of pulmonary tuberculosis: a prospective, randomized study. Antimicrob Ag Chemother 2004;48:780-782 18. Sansone JM, Wilsman NJ, Leiferman EM, Conway J, Hutson P, Noonan KJ. The effect of fluoroquinolone antibiotics on growing cartilage in the lamb model. J Pediatr Orthop 2009;29:189-195 19. Schaad UB. Pediatric use of quinolones. Pediatr Infect Dis J 1999;18:469-470 20. Schaad UB. Will fluoroquinolones ever be recommended for common infections in children? Pediatr Infect Dis J 2007;26:865-867 21. Schaaf HS, Moll AP, Dheda K. Multidrug and extensively drug-resistant tuberculosis in Africa and South America: epidemiology, diagnosis and management in adults and children. Clin Chest Med 2009;30:667-683 22. Van der Linden PD, Sturkenboom MCJM, Herings RMC, Leufkens HGM, Stricker BHCh. Fluoroquinolones and risk of achilles tendon disorders: case-control study. Brit Med J 2002;324:1306-1307 23. Wright DH, Brown GH, Peterson ML, Rotschafer JC. Application of fluoroquinolone pharmacodynamics. J Antimicrob Chemother 2000;46:669-683 24. Yu, Victor et al. Antimicrobial Therapy and Vaccines. Volume II: Antimicrobial Agents. Maryland: ESun Technologies LLC, 2005.

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