In this clinical trial involving children 6 to 23 months of age with acute otitis media, children who were treated with amoxicillin-clavulanate, as compared with those who received placebo, had consistently more favorable short-term outcomes, including a sustained symptomatic response, an absence of otoscopic evidence of persistent middle-ear infection, and a reduced rate of residual middle-ear effusion. There were no suggestive or significant between-group differences in the use of analgesic drugs or health care resources.
The interaction that we found between age and treatment is probably attributable to chance, since it involves small numbers of children and runs counter to other findings.14 In both study groups, the rates of clinical failure were greatest among children who were most severely affected initially. Nonetheless, the relative reduction in the risk of clinical failure at day 10 to 12 with amoxicillin-clavulanate treatment, as compared with placebo, was as large among the children who were least severely affected -- those whose illnesses would have been considered nonsevere as previously defined -- as it was among children whose illnesses would have been considered severe.
The principal side effects of treatment both with amoxicillin-clavulanate and with rescue antimicrobial agents were diarrhea and dermatitis in the diaper area, but the side effects were usually not severe enough to result in discontinuation of the offending drug. Treatment with amoxicillin-clavulanate was not associated with a detectable increase in nasopharyngeal colonization with nonsusceptible strains of S. pneumoniae, although the power to detect such emergent resistance was limited.
In keeping with recent recommendations,15 we chose the resolution of symptoms as the primary outcome of interest. Because we had previously noted that symptoms often recurred after having seemingly resolved, we defined the time of resolution in two ways: the time at which an AOM-SOS score of 0 or 1 was first recorded and the time of the second of two successive recordings of an AOM-SOS score of 0 or 1. We also measured the symptom burden over time, and we used a combination of symptomatic response and middle-ear findings to categorize overall outcomes as either clinical success or clinical failure.
The differences in symptom scores between the two study groups were modest but consistent through the first 10 days of follow-up; the differences were observed mainly among the children with the most severe symptoms initially. In contrast, between-group differences in the overall clinical response, which included the symptomatic response and findings on otoscopic examination, were substantial and were observed not only among the children who had the most severe symptoms initially but also among the children who had the least severe symptoms.
To our knowledge, a disparity of this nature has not been reported previously. These observations, together with the fact that among infants and young children, acute otitis media may be entirely asymptomatic16,17 and the fact that symptoms may not differentiate acute otitis media from other respiratory illnesses,18 suggest that overall clinical response constitutes the more telling measure of outcome. Regardless of the initial severity of symptoms, however, it is uncertain whether children who have become asymptomatic but have otoscopic findings that suggest persistent infection are thereby at increased risk for illness later.
Also uncertain is the clinical significance of persistent middle-ear effusion in the apparent absence of infection. Because in young children otitis media with effusion is often a forerunner of acute otitis media,19 it is possible that the higher prevalence of persistent effusion among the children in the placebo group than among children in the amoxicillin-clavulanate group might have placed the children in the placebo group at greater risk for recurrent infection.
The differences in outcome in this trial between the children who were treated with amoxicillin-clavulanate and the children who received placebo were greater than the differences seen in most previous trials of antimicrobial agents -- not because of better outcomes among the children treated with antimicrobial agents but because of higher rates of clinical failure among the children who received placebo. This finding, in turn, seems to be attributable to the stringent diagnostic criteria that we used to ensure that we would study only children in whom the diagnosis of acute otitis media was quite certain.
In conclusion, among children 6 to 23 months of age with acute otitis media, treatment with amoxicillin-clavulanate for 10 days affords a measurable short-term benefit, irrespective of the apparent severity of the illness. The benefit must be weighed against concern not only about the side effects of the medication but also about the contribution of antimicrobial treatment to the emergence of bacterial resistance. These considerations underscore the need to restrict treatment to children whose illness is diagnosed with the use of stringent criteria.
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