Acute otitis media (AOM) is one of the most common childhood illnesses requiring medical attention. By the age of 3 years >75% of children have had at least one episode of AOM.1 The standard first choice for treatment of AOM in the United States is amoxicillin. However, in settings in which the pathogen is likely to be beta-lactamase-producing Haemophilus influenzae or Moraxella catarrhalis, an antibiotic that is beta-lactamase-stable must be used.2 Cefixime, a third generation oral cephalosporin, has potent in vitro activity against beta-lactamase-producing strains of H. influenzae and M. catarrhalis3, 4 and has demonstrated response rates ranging from 76 to 95% in AOM clinical trials.5-8 Response rates for other beta-lactamase-stable antibiotics are comparable.9 Another beta-lactamase-stable antibiotic that is commonly used for empiric therapy of AOM is amoxicillin/clavulanate. In this study we compared the efficacy, safety and patient/parental acceptability of once daily cefixime with amoxicillin/clavulanate administered three times a day in infants and children with AOM.
MATERIALS AND METHODS
This prospective, randomized, open label, comparative clinical trial of cefixime vs. amoxicillin/clavulanate in the treatment of AOM was conducted at 14 sites in the United States. The study protocol was approved by the Central Research Institutional Review Committee. Informed, written consent was obtained from the parents or guardians of the study participants.
Study patients were required to be between the ages of 6 months and 12 years and to have a diagnosis of AOM based on clinical symptoms (at least one of the following: otalgia, irritability or fever), otoscopic examination (at least one of the following: bulging tympanic membrane, inflammation, evidence of retrotympanic bubbles or effusion or lack of motility response to positive or negative pressure) and, if possible, tympanometric measurements (patients with type B curves). Exclusion criteria included a history of hypersensitivity to cephalosporins, severe gastrointestinal disorders such as irritable bowel syndrome, preexisting sensorineural hearing loss, ruptured tympanic membrane and underlying conditions that might increase susceptibility to severe, chronic infections.
Patients who qualified for this study were randomly assigned to treatment with either cefixime (8 mg/kg once daily) or amoxicillin/clavulanate (40 mg/kg/day in three divided doses) for 10 days. No other antibacterials were permitted during the course of the study unless clinical failure was documented.
Tympanometry (when possible) and physical, clinical and otoscopic examinations were performed at the screening visit, at the end of therapy (within 48 h after the last dose) and, for those patients with favorable outcomes at the end of therapy, at posttherapy follow-up (2 weeks after study completion). Clinical responses were designated as cure (complete abatement of symptoms and no evidence of AOM), improvement (improvement of symptoms and no otoscopic or tympanometric evidence of AOM), failure (no demonstrable response to therapy at the end-of-therapy visit), relapse (clinical improvement at the end of therapy followed by recrudescence of signs and symptoms at the posttherapy visit) or nonevaluable.
All study participants were observed and questioned at each visit for possible adverse experiences. All patients who received at least one dose of either study drug were included in the safety analysis.
Compliance with therapy was evaluated by reviewing the daily medication diary card completed by the parent or guardian and by measuring the remaining study drug. To evaluate acceptability parents and guardians were asked to complete a questionnaire on the convenience of the treatment and the willingness of the child to take the medicine. A scale ranging from 1 (disliked) to 3 (liked a lot) was used for the acceptability evaluation.
Statistical tests were conducted using two-tailed testing at the 0.05 significance level. The primary efficacy analysis focused on the posttherapy evaluation and included only patients who had received a study drug for at least 5 consecutive days of the 10-day therapeutic course; the intent-to-treat analysis included any patient who had received one dose or more of either study drug. Analysis of variance was used to examine the effect of age, number of previous AOM episodes and study center site and region on response rates. Categorical data were analyzed for differences in frequency between the two treatment groups using chi square testing.
Patient characteristics. The study enrolled 313 patients, with 158 receiving cefixime and 155 receiving amoxicillin/clavulanate. There were no statistically significant differences in demographic characteristics (Table 1) between the 2 groups. A total of 286 patients (148 in the cefixime group and 138 in the amoxicillin/clavulanate group) were clinically evaluable. Of the 27 patients considered nonevaluable, the most common reasons were missed follow-up visit and <50% administration of the study drug.
Clinical outcome. In the primary efficacy analysis the overall favorable clinical response (cure plus improvement) to cefixime was comparable with that of amoxicillin/clavulanate (Table 2). The secondary efficacy analyses by otoscopic, tympanometric and signs and symptoms data (including patient diaries) confirmed the comparable efficacy of the two treatments with respect to alleviating irritability and fever, relieving otalgia and improving otoscopic and tympanometric evaluations.
Analysis of variance revealed no site-by-treatment interaction. However, for both treatments there was a significant difference (P < 0.025) in the regional clinical response rates. The percentages of patients achieving favorable clinical response were lowest in the West (65.5% for cefixime; 63.5% for amoxicillin/clavulanate), moderate in the Central region (69.8% for cefixime; 82.1% for amoxicillin/clavulanate) and highest in the South (94.7% for cefixime; 84.2% for amoxicillin/clavulanate) and Northeast (90.3% for cefixime; 89.3% for amoxicillin/clavulanate).
There was no significant effect of age on therapy outcome, but relapse rates were significantly higher in children <2 years of age compared with older children (P = 0.0002) at the final visit. Overall relapse rates were 26% for cefixime and 29% for amoxicillin/clavulanate. Clinical outcome was significantly better in patients with one or fewer episodes of AOM in the year preceding study entry compared to patients with more than one episode during this period (P ≤ 0.006).
Assessment of patient diaries revealed that cefixime was significantly more acceptable to patients and parents than was amoxicillin/clavulanate (P = 0.0001) (Table 3). Children were more willing to take cefixime and liked its taste better than that of amoxicillin/clavulanate, and parents found cefixime administration to be easier and more convenient.
Adverse experiences. The overall adverse experience rate was significantly lower in the cefixime group (44%) than in the amoxicillin/clavulanate group (63%, P = 0.001). The most common adverse experiences were diarrhea and vomiting, both of which were more frequent with amoxicillin/clavulanate. Table 4 summarizes adverse experiences observed in 5% or more of patients in either treatment group.
AOM is one of the most common illnesses requiring medical attention during infancy and childhood. Hearing impairment that can result from AOM is a major concern, because this may negatively affect the child's language and intellectual development.10 Given the prevalence of AOM in young children and its potentially significant sequelae, aggressive antibacterial management to reduce the duration of morbidity and the frequency and severity of speech and language disability seems warranted. Because beta-lactamase is now commonly produced by strains of H. influenzae and M. catarrhalis isolated from the inflammatory effusion of patients with AOM, there is a need for therapeutic agents that resist hydrolysis by beta-lactamase of these bacteria. Both cefixime and amoxicillin/clavulanate exhibit good activity against beta-lactamase-producing strains and are effective in the management of AOM.11
In the current study of children with AOM, cefixime administered once daily was demonstrated to be as effective as amoxicillin/clavulanate administered three times a day in all efficacy analyses. An unanticipated and unexplained regional difference in efficacy was observed with both of the study drugs.
Although efficacy was similar, cefixime had a better adverse events profile and was better accepted by both patients and their parents than was amoxicillin/clavulanate. Our observation of cefixime acceptability agrees with blinded taste tests of commonly prescribed liquid formulations of oral antibiotics, which found that no antibiotic for empiric management of AOM tasted significantly better than cefixime.12, 13
In conclusion cefixime administered once daily is as effective as and had a better adverse events profile than amoxicillin/clavulanate in the management of childhood AOM. The taste and convenience of cefixime made this drug significantly more acceptable to patients and parents than amoxicillin/clavulanate.
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