Should we be using oral fluoroquinolones for AOM?

June 2006

The fluoroquinolone antibiotics are potentially a useful class of antibiotics for the pediatric population.

They are used extensively for numerous infectious diseases in adults, both for ambulatory infections and for more serious illnesses requiring hospitalization.

An important differentiating characteristic in these populations, however, includes concerns pediatric clinicians are likely to have about the adverse effect profile of the fluoroquinolones. The primary concern relates to the potential for fluoroquinolone-induced arthrotoxicity in infants and children. As described below, however, the clinical significance of this adverse effect is low, although the perception among clinicians persists. This does not imply that the fluoroquinolones can be used frequently in infants and children, for other concerns may arise with their widespread use.

Nine fluoroquinolone products are commercially available: ciprofloxacin, gatifloxacin (Tequin, Bristol-Myers Squibb), gemifloxacin (Factive, Oscient), levofloxacin (Levaquin, Ortho-McNeil), lomefloxacin (Maxaquin, Searle and Co.), moxifloxacin (Avelox, Bayer), norfloxacin (Noroxin, Merck), sparfloxacin (Zagam, Rhone-Poulenc Rorer) and ofloxacin (Floxin, Ortho-McNeil). As a class, the fluoroquinolone antibiotics possess several beneficial characteristics, including a broad antibacterial spectrum and a good pharmacokinetic profile (good oral absorption and once/twice daily dosing).

Differences among the agents exist, including enhanced activity against gram-positive pathogens in the more recently introduced fluoroquinolones. Another important difference includes FDA-approved labeling for use in children. Only ciprofloxacin has a pediatric indication (1 to 17 years of age); it is indicated for use as second-line therapy for chronic urinary tract infection and pyelonephritis due to Escherichia coli. Ciprofloxacin, gatifloxacin and levofloxacin are available commercially as an oral solution (ciprofloxacin is also available generically).

A characteristic of the fluoroquinolones is their broad spectrum of antimicrobial activity, as they display activity toward many gram-negative, gram-positive and atypical bacterial pathogens. The fluoroquinolones are active against most Enterobacteriaceae. Ciprofloxacin provides activity against Pseudomonas aeruginosa, and because of this and its good oral bioavailability, ciprofloxacin is a useful antibiotic for select pediatric infections (eg, pulmonary exacerbations in cystic fibrosis). The fluoroquinolones also provide good activity against other clinically significant gram-negative bacteria, including Haemophilus influenzae and Moraxella catarrhalis (including -lactamase producing strains). The more recently introduced fluoroquinolones (referred to as fourth-generation), such as gatifloxacin, additionally provide activity against Streptococcus pneumoniae, including many penicillin-nonsusceptible strains. Fluoroquinolones are active against important atypical pathogens, including Chlamydia trachomatis, Mycoplasma pneumoniae and Legionella pneumophilia.

The adverse effect of the fluoroquinolone antibiotics likely feared most by pediatric clinicians is arthrotoxicity, and it is because of this that most of the fluoroquinolones are not labeled for use in children (with the exception of ciprofloxacin), nor have they been widely studied in children.

Nalidixic acid (NegGram), a related quinolone antibiotic, is labeled for use in children (3 months to 12 years of age) with urinary tract infections. Its antimicrobial spectrum is limited compared with the fluoroquinolone agents. Although several case reports of potential arthrotoxicity were reported earlier with nalidixic acid, subsequent evaluations of nalidixic acid have shown that even high-dose and long-term use in children does not result in arthropathy. The potential for this adverse effect prompted animal studies of other quinolone agents. These studies revealed that all quinolone agents produce changes in immature cartilage of weight-bearing joints in several juvenile animal species. These changes have been shown in part to be permanent in the tested animals. Despite these findings, however, several of the fluoroquinolone antibiotics have been used clinically in numerous children, and evaluations (open-label and controlled) of the potential for arthrotoxicity have been conducted and the results published.

Norfloxacin has been labeled for use in children in Japan since 1993, and no reports of arthropathy have been documented. One of the most frequent evaluated clinical uses of fluoroquinolones in children, particularly ciprofloxacin, is treatment of pulmonary infection in cystic fibrosis due to P. aeruginosa. Most of these evaluative studies used clinical signs and symptoms for assessment of arthrotoxicity, several studies have used more sensitive measures, including MRI, ultrasonography and histopathologic analysis. One case report evaluated knee tissue samples of two deceased cystic fibrosis patients, who had been given multiple courses of ciprofloxacin (no evidence of arthrotoxicity was noted). These evaluations demonstrate that there is no unequivocal documentation of quinolone-induced arthropathy in infants and children. Arthrotoxicity as demonstrated in juvenile animals is limited to these tested species. Clinical reports of arthralgia temporally related to fluoroquinolone use have been reversible and without permanent sequelae. It is likely that these reports were coincidental (eg, arthropathy associated with cystic fibrosis) and not drug-induced adverse effects.

In addition, a number of other adverse events associated with fluoroquinolone agents include achilles tendon ruptures, electrocardiogram changes and problems in glucose homeostasis.

Potential uses

Despite their relationship with arthrotoxicity in juvenile animal species, several fluoroquinolone agents have been evaluated in controlled clinical studies. Published evaluations have demonstrated that the fluoroquinolones have efficacy in children with cystic fibrosis bronchopulmonary infection, complicated urinary tract infection (ciprofloxacin is FDA-labeled for this use), chronic suppurative otitis media, neonatal meningitis, febrile neutropenia and enteric infections. It is recommended, however, that these uses be reserved for cases where conventional antibiotics are likely to be ineffective (eg, multidrug resistant pathogens, drug allergy). Unique characteristics of ciprofloxacin, good oral absorption and availability as an oral suspension plus activity against P. aeruginosa allow this fluoroquinolone to be very useful for treatment in patients with cystic fibrosis.

As discussed above, an important advantage of the fluoroquinolones is their expanded antimicrobial spectrum against many clinically significant pathogens responsible for infectious illness in children. Surveillance studies have documented the fluoroquinolones to be very active against the major pathogens responsible for acute otitis media (AOM). A recent surveillance study of respiratory tract pathogens (Jones, 2000) demonstrated gatifloxacin to have excellent activity against -lactamase producing H. influenzae and M. catarrhalis. Gatifloxacin also demonstrated excellent activity against S. pneumoniae, including penicillin-nonsusceptible strains (97% of penicillin-nonsusceptible isolates were susceptible in vitro to gatifloxacin). Of 15 antibiotics tested, only vancomycin and quinupristin-dalfopristin (Synercid, Monarch) demonstrated greater activity against penicillin-nonsusceptible S. pneumoniae. A recent study (Jones, 2003) has additionally evaluated antimicrobial activity of gatifloxacin in correlation with its pharmacodynamic-pharmacokinetic characteristics. As resistance from S. pneumoniae occurs in a stepwise manner, gatifloxacin’s increased favorable pharmacodynamic-pharmacokinetic profile allows it to continue to provide activity against single-step mutants (ie, isolates possessing resistance-conferring genetic regions), which are likely to be resistant to earlier generation fluoroquinolone agents.

Acute otitis media treatment

The pharmacodynamic and pharmacokinetic characteristics of gatifloxacin allow it to be potentially of great use for AOM, as it displays excellent activity against the major otic pathogens. Gatifloxacin has been evaluated in several controlled studies of AOM in children. Pichichero reviewed data from four clinical trials of gatifloxacin treatment of recurrent AOM or AOM treatment failure (defined as AOM occurring within 14 days after the last dose of antibiotic for a previous episode or as lack of response after at least two full days of treatment for the current episode). Two trials were phase-2 open label trials, and two other trials were comparative (compared with amoxicillin-clavulanate – one trial normal dose [40 mg/kg/day], one trial high-dose [80 mg/kg/day]). These four trials included 867 children given gatifloxacin. Tympanocentesis was optional for the phase-3 comparative trials, and was required before and during treatment for one noncomparative trial, and before the other noncomparative trial. Overall, gatifloxacin clinical efficacy was high – 89% in the noncomparative trials. In the comparative trials gatifloxacin clinical efficacy was greater than amoxicillin/clavulanate: 91% vs. 81% for AOM treatment failure, 89% vs. 69% for AOM treatment failure and age 2 years and younger, and 90% vs. 75% for severe AOM in children 2 years and younger, respectively (P<0.05 for all comparisons). There was no difference in clinical cure rate among clinically evaluable patients receiving high-dose amoxicillin/clavulanate or gatifloxacin. Gatifloxacin provided good activity against penicillin-nonsusceptible S. pneumoniae (88% bacteriologic eradication rate, as based upon follow-up tympanocentesis or presumed eradication with clinical cure). Of 12 subjects who had clinical failure with ceftriaxone (nine had received three-day therapy), nine achieved clinical cure with gatifloxacin. No evidence of arthrotoxicity was seen during these trials or during one-year of follow-up. Although these studies are limited by lack of documentation of bacteriologic cure in all evaluated subjects, they do provide useful data on the potential clinical usefulness of gatifloxacin.

Leibovitz and colleagues evaluated gatifloxacin in 160 children (6 to 48 months of age) with recurrent or nonresponsive AOM (AOM occurring <14 days after completing antibiotic treatment or not improving after >48 hours of therapy). Bacteriologic and clinical cure rates were evaluated (middle ear fluid obtain pretreatment and days three to five of therapy). Eighty-nine patients were microbiologically evaluable. H. influenzae was the most predominant pathogen identified (61% of isolates), followed by S. pneumoniae (30%). Of the S. pneumoniae isolates, 72% were nonsusceptible to penicillin (42% fully resistant). The drugs eradicated 98% of all pathogens, including 100% eradication for H. influenzae and 94% eradication for S. pneumoniae (92% eradication rate for penicillin-nonsusceptible isolates). No articular adverse events were noted during this trial. Despite this trial and the previous studies, gatifloxacin is not labeled for use in children. The manufacturer, Bristol-Meyers Squibb, applied for licensure in children, but withdrew its application because of disagreements over a proposed risk management program sought by the FDA.

Conclusion

The fluoroquinolones can play an important role in the therapy of select pediatric infectious diseases.

While pediatric clinicians may continue to harbor concerns over the potential for fluoroquinolones to cause arthrotoxic adverse effects, a more important concern – widespread bacterial resistance – should be considered, as resistance to the fluoroquinolones would likely result if they were largely embraced for their potential benefits and used extensively in children. Although resistance to fluoroquinolones has been noted in a small percentage of S. pneumoniaeisolates worldwide, many infectious disease experts fear that widespread use of fluoroquinolones in children would likely drive this resistance rate upward. An important consideration includes the concept that nasopharyngeal colonization with high-density populations of pneumococci occurs more often in children than in adults. Studies have shown that bacterial genetic material coding for fluoroquinolone resistance can pass horizontally from normal oral flora, such as viridans group streptococci (Streptococcus mitis, Streptococcus oralis). Frequent exposure to fluoroquinolones in children may allow resistance mutations to transfer from these oral flora to S. pneumoniae.

Even though the above studies reveal the potential for clinical benefit of the fluoroquinolone antibiotics in the treatment of common pediatric infections, such as AOM, infectious disease experts, including authors of the studies reviewed here, caution against the routine use of gatifloxacin and other fluoroquinolone for common infections. Select fluoroquinolone, such as ciprofloxacin, may be used appropriately for specific indications, such as bronchopulmonary exacerbations in cystic fibrosis. Thus, the answer to the title of this column is no.

If prescribing gatifloxacin or other fluoroquinolones, it would behoove pediatricians to discuss with the parents the drug label caution and the published literature relating use of these antibiotics in the pediatrician population. Further studies of gatifloxacin’s role in AOM and other important infectious diseases should be undertaken. Pediatric labeling by the FDA might be beneficial to the pediatric community.

For more information:

• Marchant CD. Gatifloxacin therapy for children: an antibiotic still in the “back room.” Clin Infect Dis. 2005;41:479-480.
• Pichichero ME. Safety and efficacy of gatifloxacin therapy for children with recurrent acute otitis media and/or AOM treatment failure. Clin Infect Dis. 2005;41:470-478.
• Schaad UB. Fluoroquinolone antibiotics in infants and children. Infectious Disease Clinics of North America 2005;19:617-628.
• Dagan R. Potential role of fluoroquinolone therapy in childhood otitis media. Pediatr Infect Dis J. 2004;23:390-398.
• Jones RN. Worldwide antimicrobial susceptibility patterns and pharmacodynamic comparisons of gatifloxacin and levofloxacin against Streptococcus pneumoniae: report from the antimicrobial resistance rate epidemiology study team. Antimicrobial Agents Chemother. 2003;47:292-296.
• Leibovitz E. Bacteriologic and clinical efficacy of oral gatifloxacin for the treatment of recurrent/nonresponsive acute otitis media: an open label, noncomparative, double tympanocentesis study. Pediatric Infect Dis J. 2003;22:943-949.
• Mandell LA. The battle against emerging antibiotic resistance: should fluoroquinolones be used to treat children? Clin Infect Dis. 2002;35:721-727.
• Jones RN. In vitro activity of newer fluoroquinolones for respiratory tract infections and emerging patterns of antimicrobial resistance: data from the SENTRY antimicrobial surveillance program. Clin Infect Dis. 2000;31(Suppl 2):S16-23.
• Burkhardt J. Quinolone arthropathy in animals versus children. Clin Infect Dis. 1997;25:1196-1204.