Study Population

Figure 1. Figure 1. Enrollment, Randomization, and Follow-up of Children in the Trial. The Acute Otitis Media–Severity of Symptoms (AOM-SOS) scale consists of seven discrete items — tugging of ears, crying, irritability, difficulty sleeping, diminished activity, diminished appetite, and fever. Parents are asked to rate these symptoms, as compared with the child’s usual state, as “none,” “a little,” or “a lot,” with corresponding scores of 0, 1, and 2. Total scores range from 0 to 14, with higher scores indicating greater severity of symptoms. The respiratory-infection season was defined as October 1 through May 31.

Table 1. Table 1. Selected Demographic and Clinical Characteristics of the Children, According to Treatment Group.

We screened 1569 children, of whom 896 were eligible for the clinical trial and 520 underwent randomization (Figure 1). Enrollment was then discontinued, because the external data and safety monitoring board for the study considered that the primary objective of the study had been realized. Selected demographic and clinical characteristics of the children are shown in Table 1 and in Table S1 in the Supplementary Appendix. There were no significant differences between enrolled children and children whose parents withheld consent, except with respect to race and ethnic group (Table S1 in the Supplementary Appendix).

End-of-treatment assessments for the index episode were completed for 238 of 257 children (93%) in the 10-day group and for 229 of 258 (89%) in the 5-day group (P=0.18). The mean (±SD) duration of follow-up was 4.4±2.0 months in the 10-day group and 3.9±2.2 months in the 5-day group (P=0.007). Of 470 children for whom medication data for the index episode were available, 435 (93%) reportedly received all scheduled medication doses during the first 3 days of treatment, and 418 (89%) also received at least 80% of doses overall.

Clinical Failure and Prognostic Factors in Index Episode

Table 2. Table 2. Clinical-Failure Rates for the Index Episode of Acute Otitis Media at or before the End-of-Treatment Visit, According to Selected Characteristics at Entry.

Table 2 summarizes the results for the index episode of acute otitis media. Clinical failure was observed in a greater percentage of children treated with amoxicillin–clavulanate for 5 days than of those treated for 10 days (77 of 229 children [34%] vs. 39 of 238 [16%]; difference, 17 percentage points [based on unrounded data]; 95% confidence interval, 9 to 25; number needed to treat to prevent clinical failure, 6). Because the upper boundary of this confidence interval — namely 25 percentage points — was greater than 10 percentage points, the prespecified established criterion for the noninferiority of 5-day treatment was not met.

The results in subgroups consistently favored the group of children assigned to receive the 10-day treatment. We found an interaction between treatment and estimates of episode severity that were based on history of pain and fever; the magnitude of the difference between the 10-day group and the 5-day group in the percentage of children with clinical failure was greater among those with probably severe illness than among those with probably nonsevere illness (Table 2). In contrast, we did not find interactions between treatment and other indexes of severity, namely AOM-SOS scores, infection in both ears versus one ear, and degrees of tympanic-membrane bulging. At the times of clinical failure, AOM-SOS scores greater than 8 were noted only in the 5-day group, although the between-group difference did not reach significance (Table S2 in the Supplementary Appendix).

Overall, in the two groups combined, clinical-failure rates were greater among children with exposure to three or more children for 10 or more hours per week than among those with less exposure (P=0.02) and greater among children with bilateral acute otitis media than in those with unilateral acute otitis media (P<0.001). Within the two groups, clinical-failure rates were higher according to the number of children’s characteristics (none, one, or two) that were considered to be unfavorable on the basis of clinical experience or findings in earlier studies (Table 2)4,14 or that were found in the current study to be associated with significant odds ratios. Results in the per-protocol analysis were similar to those in the intention-to-treat analysis.

Symptomatic Response in Index Episode

Table 3. Table 3. Symptomatic Response in Index Episode of Acute Otitis Media as Measured by AOM-SOS Score.

Table 3 summarizes, for the index episode, key measures of symptomatic response according to parent-recorded AOM-SOS scores. The mean symptom scores over the period from day 6 to day 14 were 1.61 in the 5-day group and 1.34 in the 10-day group (P=0.07); the mean scores at the day-12-to-14 assessment were 1.89 versus 1.20 (P=0.001). The percentage of children whose symptom scores decreased more than 50% (indicating less severe symptoms) from baseline to the end of treatment was lower in the 5-day group than in the 10-day group (181 of 227 children [80%] vs. 211 of 233 [91%], P=0.003). Within each treatment group, scores were higher (i.e., less favorable) in children who had been categorized on the basis of otoscopic findings as having clinical failure than in those who had been categorized as having clinical success. Over the period from day 6 to day 14, the mean scores were higher in children whose scores at entry had been greater than 8 than in children whose scores had been 8 or less (mean scores in the 10-day group, 1.6±2.0 vs. 1.0±1.3; P=0.02; mean scores in the 5-day group, 1.9±2.2 vs. 1.3±1.6; P=0.02).

Residual Middle-Ear Effusion and Recurrence

To compare the two study groups with regard to the prevalence of residual middle-ear effusion after the treatment of the index episode, we used the end-of-treatment assessment in children who had clinical success and the assessment after rescue treatment in children who had clinical failure. We found effusion in 139 of 226 children (62%) in the 10-day group (61 children with unilateral effusion and 78 with bilateral effusion) and in 141 of 216 (65%) in the 5-day group (49 with unilateral effusion and 92 with bilateral effusion) (P=0.35).

Overall, the percentage of children who had one or more recurrences of acute otitis media was greater among children with residual effusion than among those without residual effusion (48% vs. 29%, P<0.001); this was the case both among children who had clinical success (45% vs. 29%, P=0.01) and among those who had clinical failure (59% vs. 32%, P=0.008). Patterns were similar in the 10-day group and the 5-day group (Table S3 in the Supplementary Appendix). The groups did not differ significantly in the mean monthly rate of recurrence (0.14±0.18 episodes in the 10-day group and 0.12±0.19 in the 5-day group, P=0.22) or in the frequency distributions of the recurrences (P=0.56).

Overall, among children with recurrent episodes, the rate of clinical failure was consistently higher in the 5-day group than in the 10-day group (28% vs. 19%), and the criterion for noninferiority of the 5-day treatment was again not met. The rates of residual middle-ear effusion after treatment of recurrences were similar in the two groups.

Cumulative Duration of Antimicrobial Treatment

Cumulatively over the course of the 243-day respiratory-infection season, the mean numbers of days on which children received systemic antimicrobial treatment were 21±13 in the 10-day group and 15±12 in the 5-day group (P<0.001). Amoxicillin–clavulanate administered for the initial treatment of index and recurrent episodes of acute otitis media combined accounted for 70% of the days in the 10-day group and for 46% of the days in the 5-day group. The mean number of days on which an antimicrobial agent was administered for other reasons (mainly as rescue medication in children with clinical failure) was 6±9 in the 10-day group and 8±11 in the 5-day group (P=0.05).

Nasopharyngeal Colonization

Table 4. Table 4. Distribution of Acute Otitis Media Pathogens in Nasopharyngeal Cultures, According to Type of Visit.

Table 4 summarizes findings regarding children’s nasopharyngeal colonization with major pathogens for acute otitis media. After antimicrobial treatment for the index episode, the level of colonization with penicillin-susceptible strains of Streptococcus pneumoniae decreased in both the 10-day group and the 5-day group, and nonsusceptible strains now accounted for larger percentages of the remaining pneumococcal isolates. Over time, colonization with both susceptible strains and nonsusceptible strains returned to levels that were similar to those found at study entry. Colonization with susceptible strains and nonsusceptible strains of Haemophilus influenzae remained relatively unchanged throughout. These findings were also reflected in both the simple and conditional odds ratios — the latter of which may serve as a measure of community-wide effects of antimicrobial treatment on resistance13 — which did not differ significantly between the two treatment groups.

Among children whose nasopharyngeal isolates that were recovered during the index episode were either nonpathogens or penicillin-susceptible pathogens and for whom at least one subsequent culture was performed, 85 of 181 children (47%) in the 10-day group and 78 of 177 (44%) in the 5-day group were eventually found to be colonized with a penicillin-nonsusceptible pathogen (P=0.58).

Adverse Events and Other Measures

For all episodes within the first 16 days of follow-up, protocol-defined diarrhea (occurrence of three or more watery stools in 1 day or two watery stools daily for 2 consecutive days) occurred in 78 of 257 children (30%) in the 10-day group and in 75 of 258 (29%) in the 5-day group; dermatitis in the diaper area that required a prescription of a topical antifungal agent occurred in 85 of 257 (33%) and in 87 of 258 (34%), respectively. Diarrhea and dermatitis frequently occurred together. There were no significant between-group differences in the rates of use of other health care services, of missed work, or of special childcare arrangements because of children’s illness or in the levels of parental satisfaction.