The impact of prophylactic azithromycin on the developing preterm gut microbiome and resistome

Early-life antibiotic exposure can profoundly impact the developing preterm gut microbiome and resistome, with short- and long-term consequences for health. In a large multi-center (n = 28) study of 693 preterm infants, we investigated the effects of 10 d of prophylactic intravenous azithromycin on the gut microbiome and antibiotic resistance genes (ARGs). The AZithromycin ThErapy for Chronic Lung Disease of Prematurity (AZTEC) study was a double blind, randomized, placebo-controlled trial of preterm infants (born < 30 weeks of gestation), treated from birth for 10 d with either intravenous azithromycin or placebo, and sampled longitudinally for 21 d or discharge. Using 16S rRNA gene sequencing, antibiotic susceptibility testing, and quantitative PCR, we show azithromycin reduced microbial diversity and the relative abundance of health-associated Bifidobacterium and increased relative abundances of pathobionts Staphylococcus and Enterobacter/Klebsiella. This early azithromycin treatment increased the number of macrolide-resistant genes, including the presence of erm (C), which persisted for the duration of the study. Probiotic use (at individual unit discretion) increased alpha diversity and Bifidobacterium relative abundance, but did not fully mitigate the effects of azithromycin receipt. Combined azithromycin and probiotics further increased the enrichment of Enterobacter/Klebsiella and total ARGs, including erm(C). These findings highlight the impacts of antibiotic and probiotic use, both important in balancing infection control issues and microbiome disruption and antimicrobial resistance.