Mass azithromycin distribution and antibiotic resistance in the gut and nasopharynx: a cluster-randomized trial

Repeated semiannual azithromycin mass drug administration (MDA) to children has been shown to reduce all-cause childhood mortality. However, antibiotic resistance is a major public health concern as the program is being implemented in sub-Saharan Africa. In the double-blind, cluster-randomized, placebo-controlled trial (AVENIR) in Niger, we evaluated the impact of azithromycin MDA targeting different age groups on mortality and on the gut and nasopharyngeal microbiome and resistome of children in participating communities. A total of 3,000 communities were randomized in a 1:1:1 allocation to 3 arms: 2 years of semiannual MDA of (1: child-azithromycin) azithromycin to 1-59-month olds, (2: infant-azithromycin) azithromycin to 1-11-month olds and placebo to 12-59-month olds or (3: placebo) placebo to 1-59-month olds. Mortality (co-primary endpoint) and safety data have previously been published. Here we report on resistance (the co-primary endpoint). One hundred fifty communities (50 per arm) were selected for this analysis. A total of 4,382 rectal and 4,402 nasopharyngeal samples were included. The co-primary outcomes included changes in gut and nasopharynx macrolide AMR. The trial met its primary AMR endpoint for the gut but not for the nasopharynx. The gut macrolide AMR burden in fold change between arms was highest in child-azithromycin compared with placebo (1.16, 95% confidence interval (CI): 1.06-1.28; P < 0.01), followed by child-azithromycin compared with infant-azithromycin (1.13, 95% CI: 1.02-1.23; P = 0.01), and infant-azithromycin compared with placebo (1.04×, 95% CI: 0.94-1.15×; P = 0.66). There were no statistically significant differences in macrolide AMR selection fold change in the nasopharynx between arms: 2.14 (95% CI: 0.93-4.99) for child-azithromycin versus placebo, 2.08 (95% CI: 0.93-4.69) for infant-azithromycin versus placebo, and 1.03 (95% CI: 0.46-2.30) for child-azithromycin versus infant-azithromycin. Close monitoring of AMR should be an essential component of MDA for childhood mortality. ClinicalTrials.gov registration: NCT04224987.