Biannual azithromycin mass drug administration for reduction of childhood mortality: a systematic review and meta-analysis.

Background: Biannual mass drug administration of azithromycin (MDA-azithromycin) has been proposed as a strategy to reduce childhood mortality in high-mortality regions, particularly sub-Saharan Africa. However, its effectiveness across different age groups and potential risks, including antibiotic resistance, require further evaluation.

Methods: We systematically searched PubMed, Cochrane CENTRAL, Web of Science and ClinicalTrials.gov through September 2024 for randomized controlled trials (RCTs) comparing biannual MDA-azithromycin to placebo in children aged 1-59 months. The primary outcomes were mortality in children <1 year and 12-59 months. Secondary outcomes included adverse events and antibiotic resistance. Data were analysed using a random-effects model in Review Manager 5.4, with heterogeneity assessed via I2. Trial sequential analysis (TSA) evaluated cumulative evidence reliability, and the Cochrane RoB2 tool assessed risk of bias. PROSPERO registration: CRD42024589170.

Results: Five RCTs (691 235 children) were included. Among children <1 year, azithromycin showed a non-significant mortality reduction (RR: 0.90 [0.78, 1.04]; P = 0.14; I2 = 55%), with TSA indicating inconclusive evidence. Among children 12-59 months, MDA-azithromycin significantly reduced mortality (RR: 0.85 [0.79, 0.91]; P < 0.00001; I2 = 26%), with TSA confirming sufficient evidence. Adverse events were rare, but antibiotic resistance data were limited, warranting further monitoring. Evidence quality ranged from moderate to very low, with one trial at high risk of bias.

Conclusion: Biannual MDA-azithromycin significantly reduces mortality in children 12-59 months, supporting its use in high-mortality settings per WHO recommendations. Its impact on infants remains uncertain. Adverse events were minimal, but continued resistance surveillance is essential.