Public health campaigns targeting infectious diseases in children may inadvertently reshape the microbial resistance landscape in ways that could compromise future antibiotic effectiveness. The implications extend far beyond immediate treatment outcomes to fundamental questions about how mass drug interventions alter human microbiomes across populations. This cluster-randomized trial in Niger examined resistance patterns in 1,742 children aged 1-59 months who received either azithromycin or placebo through mass distribution programs. The intervention specifically selected for macrolide resistance genes within gut bacteria of treated children, demonstrating how population-level antibiotic exposure creates selective pressure even in asymptomatic individuals. Notably, this resistance development remained confined to the macrolide class, with no cross-resistance detected for other antibiotic families in either gut or nasopharyngeal samples. The research represents one of the most comprehensive examinations of resistance emergence during mass drug administration, using advanced genomic sequencing to track specific resistance determinants rather than relying solely on phenotypic testing. These findings illuminate a critical tension in global health strategy. Mass azithromycin distribution has proven remarkably effective at reducing childhood mortality from infectious diseases, particularly in resource-limited settings. However, this study quantifies the resistance cost of such interventions, showing that even beneficial public health measures carry evolutionary consequences for microbial communities. The resistance remained class-specific rather than broadly multi-drug resistant, suggesting the selective pressure was targeted rather than creating pan-resistant organisms. For health-conscious adults, this research underscores how antibiotic exposure anywhere in the ecosystem potentially affects resistance patterns globally, emphasizing the importance of judicious antibiotic use even when individual risk seems minimal.