The place of quinolones in paediatric anti-infective therapy

Fluoroquinolones are synthetic derivatives of nalidixic acid with a broad spectrum of antimicrobial activity, oral bioavailability and excellent tissue penetration. Although five agents are licensed in Canada (Table 1), none are approved for use in children, growing adolescents or pregnant women because of an association with arthropathy in the weight-bearing joints of some juvenile animal species (1). Since the last note on quinolones by a committee of the Canadian Paediatric Society was published in 1992 (2), paediatric experience with this class of antimicrobial agents has increased. This note briefly reviews some of the accumulating evidence for the use of fluoroquinolones in children in specific clinical settings. Fluoroquinolones licensed in Canada Systemic formulations listed; Quinolones are also available in a variety of ophthalmic and otic preparations Fluoroquinolones licensed in Canada Systemic formulations listed; Quinolones are also available in a variety of ophthalmic and otic preparations Quinolones inhibit DNA gyrase, an enzyme that is unique to bacteria and required for DNA replication, repair and recombination. The spectrum of organisms susceptible to quinolones includes most Gram-positive bacteria, including some streptococci and most Gram-negative bacteria such as Pseudomonas aeruginosa. While all fluoroquinolones are structurally similar, modifications have led to newer agents with activity against streptococci (including penicillin-resistant Streptococcus pneumoniae), increased activity against staphylococci (including methicillin-resistant strains), and activity against mycoplasma and chlamydia. Bacterial resistance to quinolones occurs through chromosomal mutations in DNA gyrase or the modification of the bacterial outer membrane, resulting in decreased drug permeability. Up to 20% of Pseudomonas auriginosa may be resistant to quinolones (3). Because quinolones can be given orally, they are appealing agents for use when P aeruginosa may be the etiological agent because the alternative option is intravenous therapy. Quinolones have been reported to be effective in children with febrile neutropenic episodes (4,5), urinary tract infections (6), chronic suppurative otitis media (7), exacerbation of cystic fibrosis (8,9) and enteric infections in developing countries (6). In a rabbit model, quinolones were efficacious in the treatment of meningitis due to S pneumoniae, including strains resistant to penicillin and other beta-lactams (10). According to case reports, quinolones have been successfully used in the treatment of central nervous system infections in infants and children. Although a review in the Cochrane Collaboration Issue 4 (11) found quinolone otic preparations to be more effective than nonquinolone agents in reducing ear discharge and eradicating bacteria associated with chronic otitis media with tympanic membrane perforation, the trials did not include children. A ciprofloxacin opthalmic solution was found to be similar in efficacy to a tobramycin ophthalmic solution in one multicentre study of acute bacterial conjunctivitis in children (12). Fluoroquinolones are generally well tolerated. The most commonly reported adverse events involve the gastrointestinal tract (nausea and diarrhea in 7% of patients), the central nervous system (eg, headache, dizziness, insomnia in 1% to 6% of patients) and skin (photosensitivity in 2% of patients). These adverse effects are reversible. Extensive exposure to ultraviolet light should be avoided during quinolone use. A slight prolongation of the Q-T interval in adult patients taking grepafloxacin and sparfloxacin has been reported (13); however, neither of these products are available in Canada. Drug interactions may occur with many agents, including antiarrhythmic agents, cimetidine, antacids, phenytoin and theophylline. Probably, the most worrisome side effect of quinolone use in children is the potential for arthropathy. While clearly demonstrated in various animal models, joint damage has not been a notable sequelae of quinolone use in humans. An exhaustive review of quinolone use in over 7000 children in all papers published to January 1997 identified 10 case reports of suspected quinoloneassociated arthropathy; all but one of the patients had a complete clinical recovery (14). Over 30 multipatient studies in skeletally immature children who received ciprofloxacin, nalidixic acid, norfloxacin or ofloxacin have shown no arthralgia beyond the level of severity expected as a part of their underlying illness (14). Eleven of the studies followed patients (n=530) to evaluate joint change for six months to 12 years and did not show quinolone-induced effects or alteration in linear growth. The authors concluded that the maximum risk of chondrotoxicity would not be greater than one in 2348 patients or approximately 0.04%. Paediatric studies published since 1997 (5,8,9,15) have not reported arthopathy. Quinolones offer certain paediatric patients with susceptible flora (eg, bronchopulmonary exacerbations in cystic fibrosis, chronic ear infections, complicated urinary tract infection) the option of an oral treatment regimen on an outpatient basis. Quinolones should be prescribed with prudence because the total number of children studied during and after quinolone use is less than 10,000. This means that rare but serious adverse events may not have been detected yet. Currently, there are no routine indications for the use of quinolones in the paediatric population. The costs and benefits of this class of agents must be considered in therapeutic decision-making in situations in which alternative safe treatments are not available. Given the limited experience of quinolone use in children, this class of anti-infective agents should only be considered when other safe and effective therapies are not available. The clinical settings in which other antimicrobial options may not be available include resistant microorganisms, inaccessibility of the intravenous route, or the wish on the part of a patient, parents or physician to choose an oral therapy rather than an intravenous route. In such cases, the costs and benefits of a therapeutic decision to use quinolones should be discussed with all parties, taking into consideration any new evidence available in the medical literature.

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