Antibiotics are routinely used as part of the management of
severe acute malnutrition and are known to reduce gut microbial diversity in non-malnourished children. We evaluated gut microbiomes in children participating in a randomized controlled trial (RCT) of
azithromycin versus
amoxicillin for
severe acute malnutrition. Three hundred one children aged 6 to 59 months with uncomplicated
severe acute malnutrition (mid-upper arm circumference < 11.5 cm and/or weight-for-height Z-score < -3 without clinical complications) were enrolled in a 1:1 RCT of single-dose
azithromycin versus a 7-day course of
amoxicillin (standard of care). Of these, 109 children were randomly selected for microbiome evaluation at baseline and 8 weeks. Rectal swabs were processed with metagenomic
DNA sequencing. We compared alpha diversity (inverse Simpson's index) at 8 weeks and evaluated relative abundance of microbial taxa using DESeq2. Of 109 children enrolled in the microbiome study, 95 were followed at 8 weeks. We found no evidence of a difference in alpha diversity between the
azithromycin and
amoxicillin groups at 8 weeks controlling for baseline diversity (mean difference -0.6, 95% CI -1.8 to 0.6, P = 0.30). Gut microbiomes did not diversify during the study. Differentially abundant genera at the P < 0.01 level included Salmonella spp. and Shigella spp., both of which were overabundant in the
azithromycin compared with
amoxicillin groups. We found no evidence to support an overall difference in gut microbiome diversity between
azithromycin and
amoxicillin among children with uncomplicated
severe acute malnutrition, but potentially pathogenic bacteria that can cause invasive
diarrhea were more common in the
azithromycin group. Trial Registration: ClinicalTrials.gov NCT03568643.