Pathways through which water, sanitation, hygiene, and nutrition interventions reduce antibiotic use in young children: a mediation analysis of a cluster-randomized trial

BackgroundLow-cost, household-level water, sanitation, and hygiene (WASH) and nutrition interventions can reduce pediatric antibiotic use, but the mechanism through which interventions reduce antibiotic use has not been investigated. MethodsWe conducted a causal mediation analysis using data from the WASH Benefits Bangladesh cluster-randomized trial (NCT01590095). Among a subsample of children within the WSH, nutrition, nutrition+WSH, and controls arms (N=1,409), we recorded caregiver-reported antibiotic use at ages 14 and 28 months and collected stool at age 14 months. Mediators included caregiver-reported child diarrhea, acute respiratory infection (ARI), and fever; and enteric pathogen carriage in stool measured by qPCR. Models controlled for mediator-outcome confounders. FindingsThe receipt of any WSH or nutrition intervention reduced antibiotic use in the past month by 5.5 percentage points (95% CI 1.2, 9.9) through all pathways, from 49.5% (95% CI 45.9%, 53.0%) in the control group to 45.0 % (95% CI 42.7%, 47.2%) in the pooled intervention group. Interventions reduced antibiotic use by 0.6 percentage points (95% CI 0.1, 1.3) through reduced diarrhea, 0.7 percentage points (95% CI 0.1, 1.5) through reduced ARI with fever, and 1.8 percentage points (95% CI 0.5, 3.5) through reduced prevalence of enteric viruses. Interventions reduced antibiotic use through any mediator by 2.5 percentage points (95% CI 0.2, 5.3). InterpretationOur findings bolster a causal interpretation that WASH and nutrition interventions reduced pediatric antibiotic use through reduced infections in a rural, low-income population. FundingBill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched for primary studies and systematic reviews that investigated mediation of antibiotic use by water, sanitation and hygiene interventions in Scopus using (TITLE-ABS-KEY(("WASH" OR "sanitation" OR "water" OR "hygiene" OR "nutrition") AND ("antibiot*") AND ("interven*") AND ("mediat*" OR "indirect effect*" OR "pathway" OR "mechanism") AND ("use" OR "practice*")). We included all publications until September 4, 2024. We restricted results to studies in English, focused on humans, and within medicine, agricultural and biological sciences, immunology or microbiology, or environmental science. Our search yielded 115 studies. We found no relevant research studies. Four review studies discussed the need for improved sanitation and drinking water as an AMR control strategy in LMICs. Two study protocols described longitudinal observational studies in LMICs that will explore the relationship between WASH and antibiotic resistance. Added value of this studyWe used causal mediation analysis to investigate mechanisms through which WASH and nutrition interventions reduced antibiotic use in young children in a community setting in rural Bangladesh. This study is rigorous because it leverages a randomized trial with high intervention adherence and includes objectively measured mediators. We found that WASH and nutrition interventions reduced antibiotic use via reduced diarrhea, ARI with fever, and enteric virus carriage. This study improves on previous studies by identifying a specific mechanism through which WASH and nutrition interventions reduced pediatric antibiotic use in an understudied setting and population. Implications of all the available evidenceIn a previous analysis of a randomized trial of WASH and nutrition interventions, we found that pediatric antibiotic use was lower in the intervention arms compared to control. Here, using causal mediation analysis, we identified several biologically plausible pathways through which interventions likely reduced antibiotic use. This analysis bolsters a causal interpretation that low-cost, household-level WASH and nutrition interventions can reduce pediatric antibiotic use in settings with similar infectious disease dynamics and antimicrobial access.