In recent decades, there has been extensive development, clinical investigation, licensure and use of fluoroquinolone (FQ) antibiotics, yet none has been licensed for pediatric use since naladixic acid in 1962. Compared with naladixic acid, these new FQs, including ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin and gemifloxacin, have a wide spectrum of antimicrobial activity and favorable pharmacologic properties,1 but concerns for adverse events have prevented licensure in children. Moreover widespread use of FQ in children would likely further increase the prevalence of FQ resistant pathogens, already described with adult use. Nonetheless physicians who care for children may find themselves faced with therapeutic situations where FQ offer significant benefits for their patients.
MECHANISM OF ACTION, ANTIBACTERIAL SPECTRUM, PHARMACOLOGY
Quinolones inhibit bacterial DNA synthesis by targeting the enzymatic activities of DNA gyrase and topoisomerase IV.1 All quinolones have excellent activity against Gram-negative bacteria, particularly Enterobacteriaceae, Haemophilus spp., Moraxella catarrhalis and Neisseria spp. They also have activity against many strains of Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus but weak activity against methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci. Ciprofloxacin is the most potent available FQ against Gram negatives. Levofloxacin, gatifloxacin, moxifloxacin and gemifloxacin are more active against Gram-positive organisms, including Streptococcus pneumoniae. Atypical pathogens, including Mycoplasma spp., Chlamydia spp., Legionella spp. and Ureaplasma urealyticum, are susceptible to FQ. The early fluoroquinolones had limited activity against anaerobes; however, the new FQ (eg, moxifloxacin and gatifloxacin) have improved anaerobic activity. They also have activity against mycobacteria and excellent intracellular penetration. Concentrations of FQ in bile, lung and urine are higher than serum; whereas concentrations in saliva, bone and cerebrospinal fluid (CSF) are usually lower than in serum. However, CSF concentrations are clinically useful for treatment of meningitis.
Resistance is acquired by spontaneous chromosomal mutations that alter genes encoding DNA gyrase and topoisomerase IV. Resistance can also occur by genetically mediated alterations in drug permeability.1 Both Gram-negative pathogens, such as P. aeruginosa, Escherichia coli and Salmonella, and Gram-positive pathogens, such as Staphylococcus aureus and S. pneumoniae, develop resistance by spontaneous mutation. Widespread use of fluoroquinolones for community-acquired infections favors the survival of resistant strains and the prevalence of FQ resistance. In Hong Kong, Ho et al2 reported a 3.8% resistance rate of S. pneumoniae to levofloxacin, among the highest reported worldwide. This rate increased to 15.2% among penicillin-resistant isolates. Resistance rates in the United States and Europe have been <3%,3,4 but clinically important resistance, ie, clinical failure of levofloxacin therapy in patients hospitalized with pneumococcal pneumonia has been documented.5 There is a concern that extensive use of FQ in children will increase the rate of resistance, given that children are a major reservoir of pneumococci.6
Licensed FQ are generally well tolerated in adults with an overall incidence of 4–8% adverse reactions with gastrointestinal and central nervous system manifestations being more common and photosensitivity and drug interactions less so. However, several quinolones have been withdrawn from the market because of serious adverse reactions; notably, grepafloxacin caused prolonged QT syndrome, and trovofloxacin was withdrawn after fatal liver toxicity. In the pediatric population, a major concern has been the potential for cartilage abnormalities due to the cartilaginous lesions noted in weight-bearing joints of juvenile animals treated with FQ. However, studies in children failed to identify arthropathy by nuclear magnetic resonance imaging.7 A comprehensive review including over 7000 children (5 days to 24 years of age) who received ciprofloxacin, ofloxacin or nalidixic acid failed to show any association between quinolone use and arthropathy.8 In a multicenter nonblinded observational cohort study comparing adverse events among pediatric patients receiving ciprofloxacin and pefloxacin with those among patients receiving other antibiotics, musculoskeletal symptoms (large joint arthralgias, myalgias) occurred more frequently in the FQ group (3.8% versus 0.4%), but no severe or persistent musculoskeletal lesions were observed.9 In a prospective observational study, 116 neonates with sepsis were treated with ciprofloxacin, and no short term hematologic, renal or hepatic adverse events were noted; additionally there was no associated clinical arthropathy or growth impairment at 1 year of follow-up.10 To date, no controlled studies have documented bone and joint sequelae from FQ use, and the available evidence does not show a causal relationship between FQ treatment and joint damage in humans. Nevertheless concern persists. An application for gatifloxacin licensure for pediatric use was withdrawn, because the Food and Drug Administration proposed risk management procedures that precluded reasonable pediatric use.11
Although clinical use of FQ does not require FDA approval, the lack of FDA approval and the perceived concerns about safety and limited published experience suggest that FQ should be used with caution. Furthermore oral suspensions are often lacking, and pharmacokinetics with appropriate dosing information in children are often unknown. Criteria guiding use of FQ in children should be: (1) a life-threatening or difficult to treat infection; and (2) inability to use other antibacterial agents because of drug allergy, drug toxicity or antimicrobial resistance. Examples of potential FQ use in children are as follows.
Pseudomonas aeruginosa Infections.
Ciprofloxacin treatment of P. aeruginosa respiratory infections in children with cystic fibrosis has been widespread because it is an oral agent with activity against P. aeruginosa. Systemic ciprofloxacin therapy may be considered for chronic suppurative otitis media due to P. aeruginosa that cannot be managed by aural toilet and topical therapy with agents such as ofloxacin. Antimicrobial susceptibilities of P. aeruginosa need to be measured because strains with mutations in the target enzymes or efflux pump may preclude clinical usefulness of ciprofloxacin.
Complicated Acute Otitis Media.
Acute otitis media (AOM) that has failed treatment with conventional β-lactam antibiotics or β-lactam-allergic patients with AOM who fail macrolide therapy may benefit from FQ. In double tympanocentesis studies, gatifloxacin had high bacteriologic efficacy in children with AOM.12 However, lack of a liquid suspension limits this treatment option.
Resistant Gram-Negative Infections.
Fluoroquinolones may be indicated for drug-resistant strains of Gram-negative pathogens. For example, FQ may be recommended as initial therapy for typhoid fever in countries where β-lactam-resistant Salmonella typhi is prevalent. FQ can be used to treat invasive shigellosis when first line therapy fails. Antimicrobial susceptibilities must be determined, because FQ-resistant strains have been identified.
Fluoroquinolones have good CSF penetration and are efficacious in animal models of both Gram-positive and Gram-negative meningitis. Data on the clinical efficacy of FQ in the treatment of meningitis in humans are limited. However, trovafloxacin was comparable with ceftriaxone plus vancomycin in terms of clinical outcome, sequelae and death rates in 108 children treated for pneumococcal meningitis.13 In addition, quinolones were successfully used in the treatment of neonatal meningitis caused by antibiotic-resistant Enterobacteriaceae.14 The newer FQ may be considered for treatment of bacterial meningitis when standard therapy fails or when isolates are resistant to conventional antibiotic agents, such as enterobacteriaceae with extended spectrum β-lactamases.
The fluoroquinolones, including older agents such as ciprofloxacin and newer ones such as levofloxacin, gatifloxacin, moxifloxacin and gemifloxacin, have attractive properties including broad spectrum activity and favorable pharmacologic properties. Studies demonstrating cartilage abnormalities in juvenile animals suggest caution in the use of FQ in children, but clinical studies involving many thousands of children have failed to demonstrate bone or joint sequelae with clinical use of FQ. Fluoroquinolones should be considered in life-threatening and difficult to treat infections when alternative agents cannot be used because of antimicrobial resistance, allergy, toxicity or intolerance to alternative antimicrobial agents.
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14. Krčméry V, et al. Ciprofloxacin in treatment of nosocomial meningitis. Diagn Microbiol Infect Dis