Impact of antibiotics to off-target infant gut microbiota and resistance genes in cohort studies

Background: Young children are frequently exposed to antibiotics for otitis media and respiratory infections, with the potential for collateral consequences on the gut microbiome. The impact of antibiotic exposures to off-target microbes (i.e., bacteria not targeted by antibiotic treatment) and antibiotic resistance genes (ARGs) is unknown. Methods: We used metagenomic sequencing data from paired stool samples collected prior to antibiotic exposure and at 1 year from over 200 infants and a difference-in-differences approach to assess the relationship between subsequent exposures and the abundance or compositional diversity of off-target microbes and ARGs while adjusting for covariates. Results: By 1 year, the relative abundance of multiple species and ARGs differed by antibiotic exposure. Compared to infants never exposed to antibiotics, Bacteroides vulgatus relative abundance increased by 1.72% (95%CI:0.19,3.24) while Bacteroides fragilis decreased by 1.56% (95%CI:-4.32,1.21). Bifidobacterium species also exhibited opposing trends suggesting differential antibiotic selection. Overall, antibiotic exposure was associated with a dose-dependent decrease in alpha diversity of off-target microbes. ARGs associated with antibiotic exposure included class A beta-lactamase gene CfxA6. Among infants attending day care, Escherichia coli and ARG abundance were both positively associated with antibiotic use. Conclusion: Further quantifying impacts to off-target microbes and ARGs has implications for antibiotic stewardship