Objective  To systematically review the efficacy and safety of azithromycin versus amoxicillin and clavulanate potassium in the treatment of otitis media in children.

Methods  PubMed, Embase, Cochrane Library, CNKI, WanFang Data and VIP databases were electronically searched to collect randomized controlled trials (RCTs) of azithromycin versus amoxicillin and clavulanate potassium in the treatment of otitis media in children from inception to February 28, 2025. Two researchers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. Meta-analysis was then performed using RevMan 5.3 software.

Results  A total of 21 RCTs involving 6,092 patients were included. The results of Meta-analysis showed that there was no statistically significant difference in the total effective rate after completion of treatment [RR=0.99, 95%CI (0.96, 1.03), P=0.72] and the total effective rate during follow-up period [RR=0.99, 95%CI (0.94, 1.04), P=0.10] between amoxicillin and clavulanate potassium group and azithromycin group. The results of subgroup analysis showed there was no statistically significant difference in the total effective rate between amoxicillin and clavulanate potassium group and azithromycin group in children under two years old or 2 years old and above (P>0.05). The incidence of diarrhea [RR=0.41, 95%CI (0.28, 0.60), P<0.001], vomiting [RR=0.49, 95%CI (0.28, 0.87), P=0.02], nausea [RR=0.46, 95%CI (0.27, 0.78), P=0.004], loose stools [RR=0.44, 95% CI (0.24, 0.79), P=0.006], rash [RR=0.62, 95%CI (0.39, 0.96), P=0.03], fungal dermatitis [RR=0.32, 95%CI (0.18, 0.57), P<0.001], dermatitis [RR=0.31, 95%CI (0.14, 0.67), P=0.003] in the azithromycin group were all lower than those in the amoxicillin and clavulanate potassium group, and the difference was statistically significant.

Conclusion  The current evidence shows that azithromycin versus amoxicillin and clavulanate potassium are equally effective in treating otitis media in children, but azithromycin is considered safer. Due to the limited quality and quantity of included studies, more high-quality studies are required to verify the above conclusions.

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