Study design questions in treatment of children with acute otitis media.

Abstract

Arrieta et al. reported a difference in clinical outcome favoring high-dose azithromycin versus high-dose amoxicillin-clavulanate at days 28 to 32 (1). The authors' conclusion that the two drugs are comparable must be interpreted in the context of the study design. First, the study was powered to only be able to detect a >15% difference in overall clinical outcome, so very large numbers of patients are needed to show this difference. Second, 45% of patients had no pathogens. Third, high rates of spontaneous resolution of bacterial infection in AOM mask underlying differences in drug efficacy (12, 14). As expected with small, noninferiority studies (2, 12, 15), this study showed no differences in clinical outcome at days 12 to 16. There was a difference overall at days 28 to 32 (P 0.047), but no difference in the key group—culture-positive patients—which is consistent with other studies (14). Furthermore, high-dose amoxicillin-clavulanate was achieved by giving two medications: amoxicillin at 45 and clavulanate at 6.4 mg/kg/day plus amoxicillin at 45 mg/kg/day. High-dose amoxicillin-clavulanate (amoxicillin at 90 and clavulanate at 6.4 mg/kg/day) is now available as a single formulation, and recalculation of the results taking compliance into consideration results in the difference no longer being statistically significant (P = 0.19 instead of 0.047). The authors further conclude that clinical outcomes with both agents are comparable for both H. influenzae and Streptococcus pneumoniae. In fact, a difference of 14% was found with H. influenzae at days 12 to 16, a large difference that is quite noteworthy in light of the particularly high rates of spontaneous resolution in this organism (10, 11). AOM studies have shown azithromycin to have similar bacteriologic and clinical efficacy to placebo (5, 9, 13; A. Hoberman, R. Dagan, A. Rosenblut, E. Leibowitz, A. Huff, and B. Wynne, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. G-459, p. 279, 2003). A conclusion of comparability is clearly unwarranted. As for S. pneumoniae, clinical success with azithromycin at days 12 to 16 was 21 of 22 (95%) for macrolide-susceptible organisms versus 5 of 8 (63%) for macrolide-resistant organisms. This is similar to the results of a much larger study of regular-dose azithromycin in which the difference was statistically significant (Hoberman et al., 43rd ICAAC). While a bacteriologic diagnosis and outcome study requires only 30 patients per arm to differentiate a highly active agent from a placebo and 100 per arm from an agent with 60% bacteriologic efficacy, 234 and 780 patients per arm, respectively, are needed in bacteriologic diagnosis and clinical outcome studies (12). The study by Arietta et al. included <85 microbiologically evaluable patients per arm, which is far short of the 234 per arm needed to even distinguish an active agent from placebo based on clinical outcome. Bacteriologic outcome or considerably larger clinical outcome studies are clearly needed to determine if high-dose azithromycin offers any advantage (8). Given all that has been learned in recent years about the need for bacterial eradication and its relationship to clinical outcome (3-8, 11, 12; Hoberman et al., 43rd ICAAC), the continued overprescribing of antibiotics for this condition, and the ease of obtaining bacterial outcome data (8), it is disappointing that AOM studies are still being designed based only on clinical outcomes with small sample sizes. We therefore believe that the conclusion of these investigators that their data support consideration of high-dose azithromycin as an option for treating AOM in children who have failed first-line therapy or who experience recurrent episodes of AOM is not supported by the data presented.