Abstract
Large-scale, placebo-controlled, cluster-randomized trials in high-mortality settings in several African countries demonstrated a 14-18% reduction in childhood mortality following twice-annual mass drug administration (MDA) of azithromycin among children aged 1-59 months [1-3]. Azithromycin MDA also selects for antimicrobial resistance (AMR), particularly macrolide resistance in treated populations [4-6]. It is unknown whether the genetic selection of AMR from azithromycin MDA could spill over to neighboring untreated populations. If present, such geographic spillover effects could lead the trials to underestimate the risks of AMR selection from azithromycin MDA. Here, we assessed between-village geographic spillover effects of genotypic resistance to macrolides and other antibiotic classes in rectal swabs collected from 1200 children in 30 monitoring villages in Niger after two years of MDA in 594 surrounding villages. We found no evidence of geographic spillover of macrolide resistance in untreated villages, as the genetic load of AMR remained at baseline levels in placebo-treated villages regardless of surrounding azithromycin treatment intensity. Sensitivity analyses confirmed the robustness of findings to the metric used to quantify the effect of proximal azithromycin MDAs on macrolide AMR, and no geographic spillover effects were detected for AMR to other antibiotic classes. Our results suggest that azithromycin MDA-induced selection of macrolide AMR is localized to treated villages without extending to children in neighboring, untreated villages, mitigating some concerns about geographic spillover of AMR to untreated populations. This analysis illustrates the value of randomized trial designs in assessing indirect effects of large-scale public health interventions.