Résistance Evaluée contre la Vie des Enfants au Niger-Implementation et Recherche (REVENIR). Community antimicrobial resistance after azithromycin distribution: selection, spillover, co-selection

PROJECT SUMMARY/ABSTRACT Azithromycin mass drug administration (MDA) to children 1-59 months old reduces child mortality and is being considered for inclusion in child survival programs. However, azithromycin MDA leads to emergence of antimicrobial resistance (AMR). The World Health Organization (WHO) thus suggests azithromycin MDA be limited to children 1-11 months old to reduce the risk of AMR. Several high mortality West African countries have since initiated azithromycin MDA, though key questions about its impact on AMR remain. In particular, the impact of long-term selection pressure is not well understood – trachoma studies treating all ages found that AMR continues to increase with additional distributions, but studies treating only children suggest that resistance may plateau after an initial increase. Understanding AMR patterns with long-term MDA is essential to define the duration of future programs. In addition, spillover of AMR from treated to untreated groups is plausible, though has yet to be demonstrated in this context. If present, the risks of AMR with this intervention may be greater than anticipated. Similarly, previous studies on the impact of azithromycin MDA on co-selection for resistance in non-macrolide antibiotic classes have had mixed results. The emergence of co-selection with azithromycin MDA would amplify the risks of this intervention as well, threatening the efficacy of other essential antibiotics. The Bill & Melinda Gates Foundation-funded AVENIR trial is a large trial that randomizes more than 3,000 communities in Niger to 4 years of biannual MDA of 1) azithromycin to 1-11-month-olds with placebo to 12-59-month-olds, 2) azithromycin to 1-59-month-olds, or 3) placebo to 1-59-month-olds. AVENIR’s primary endpoints are mortality and AMR compared across the 3 arms. The trial will also collect rectal and nasopharyngeal samples from several treated and untreated groups in 150 communities after 2 and 4 years of distributions. In addition, AVENIR includes a subset of communities that received 5 years of azithromycin MDA in a prior study, resulting in very long-term distributions between the two studies. This presents a unique opportunity to study key questions beyond the scope of the main trial but essential to understanding how MDA drives community AMR. Our large sample size enables adequate power to elucidate the relationship between antibiotic use and population-level AMR emergence, including long-term effects, spillover effects to non-target groups, and co-selection in other antibiotic classes. Moreover, this project proposes metagenomic deep sequencing to characterize the respiratory and gut resistome in order to complement the proposed phenotypic AMR monitoring. We propose to leverage this trial-based infrastructure, large sample bank, and our lab’s high- throughput genomic approaches to provide evidence to directly impact mass azithromycin programs and the WHO guidelines on this intervention.