The Gut Resistome during Hematopoietic Stem Cell Transplantation in Children

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Abstract Background Children undergoing hematopoietic stem cell transplantation (HCT) are at high risk of acquiring antibiotic-resistant bacteria. Few prior studies examined antibiotic resistance genes (ARGs) within the gut metagenomes of children undergoing HCT. Methods We conducted a longitudinal study of children (age <18 years) undergoing HCT at a single institution. We performed shotgun metagenomic sequencing of fecal samples collected between days -30 and +100 relative to HCT. We evaluated the effects of aerobic (cefepime, vancomycin, fluoroquinolones, aminoglycosides, macrolides, and trimethoprim-sulfamethoxazole) and anaerobic (piperacillin-tazobactam, carbapenems, metronidazole, and clindamycin) antibiotic exposures on the diversity and composition of the gut microbiome and resistome. Findings Using metagenomic data from 693 fecal samples collected from 80 children, we identified 350 unique ARGs. The most frequent ARGs identified encode resistance to tetracycline (n=91), beta-lactams (n=80), and fluoroquinolones (n=76). Both aerobic and anaerobic antibiotic exposures were associated with a decrease in the number of bacterial species (aerobic, β=0.72, 95% CI: 0.66, 0.79; anaerobic, β=0.68, 95% CI: 0.61, 0.76) and the number of unique ARGs (aerobic, β=0.83, 95% CI: 0.76, 0.91; anaerobic, β=0.84, 95% CI: 0.76, 0.93) within the gut metagenome. However, only anaerobic antibiotics were associated with an increase in the number of newly acquired ARGs (29%, 95% CI: 10%, 52%) and the abundance of ARGs (95%, 95% CI: 59%, 138%) in the gut resistome. Specific antibiotic exposures were associated with distinct changes in the number and abundance of resistance genes for individual antibiotic classes. Interpretation The gut metagenome and resistome of children are highly dynamic throughout HCT, driven largely by antibiotic exposures. Compared to antibiotics without anaerobic activity, anaerobic antibiotics were associated with increased microbiome instability and expansion of the gut resistome. Funding Antibacterial Resistance Leadership Group, National Institutes of Health, Duke Children’s Health & Discovery Initiative, Children’s Miracle Network Hospitals

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