PROJECT SUMMARY/ABSTRACT More than 2 million children under 5 die each year in sub-Saharan Africa (SSA). Children recently discharged from hospital suffer a particularly high risk of death and no interventions target this period. Recent clinical trials found 13%-49% mortality reductions associated with community-wide singe-dose azithromycin in SSA, and mechanisms of this effect are poorly understood. The Toto Bora trial (NIH/NICHD-HD079695) is a double-blind placebo-controlled randomized clinical trial (RCT) testing the effect of a 5-day course of azithromycin administered at hospital discharge to Kenyan children under 5 years on mortality and re-hospitalization in the subsequent 6-months. Utilizing samples from this trial, we have the unprecedented opportunity to elucidate mechanisms of post-discharge morbidity, mortality, and growth faltering AND determine mechanisms of azithromycin’s effect. We will test for enteropathogens and resistance genes in fecal samples and Escherichia coli collected from children at hospital discharge and 3-months thereafter using qPCR and link this molecular data to re-hospitalization, vital status, and anthropometric data collected throughout the 6-month post-discharge period. Results from this highly efficient nested study will inform targets for vaccines and pathogen-directed medications that could reduce post-discharge morbidity and mortality. Specific molecularly-determined pathogen or resistance markers that predict azithromycin’s effects on mortality, morbidity, and growth will elucidate mechanisms by which empiric azithromycin reduces child mortality and may identify specific populations who can be treated with azithromycin to maximize benefit while minimizing resistance.