The effects of antibiotic exposures on the gut resistome during hematopoietic cell transplantation in children

Abstract

Antibiotic resistance is a global threat driven primarily by antibiotic use. We evaluated the effects of antibiotic exposures on the gut microbiomes and resistomes of children at high risk of colonization by antibiotic-resistant bacteria. We performed shotgun metagenomic sequencing of 691 serially collected fecal samples from 80 children (<18 years) undergoing hematopoietic cell transplantation. 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. We identified 372 unique antibiotic resistance genes (ARGs); the most frequent ARGs identified encode resistance to tetracyclines (n = 88), beta-lactams (n = 84), and fluoroquinolones (n = 79). Both aerobic and anaerobic antibiotic exposures were associated with a decrease in the number of bacterial species (aerobic, β = 0.71, 95% CI: 0.64, 0.79; anaerobic, β = 0.66, 95% CI: 0.53, 0.82) and the number of unique ARGs (aerobic, β = 0.81, 95% CI: 0.74, 0.90; anaerobic, β = 0.73, 95% CI: 0.61, 0.88) within the gut metagenome. However, only antibiotic regimens that included anaerobic activity were associated with an increase in acquisition of new ARGs (anaerobic, β = 1.50; 95% CI: 1.12, 2.01) and an increase in the relative abundance of ARGs in the gut resistome (anaerobic, β = 1.62; 95% CI: 1.15, 2.27). Specific antibiotic exposures were associated with distinct changes in the number and abundance of ARGs for individual antibiotic classes. Our findings detail the impact of antibiotics on the gut microbiome and resistome and demonstrate that anaerobic antibiotics are particularly likely to promote acquisition and expansion of antibiotic-resistant bacteria.

Keywords

• Shotgun metagenomic sequencing
• antibiotic resistance
• antimicrobial stewardship
• anaerobic bacteria
• piperacillin-tazobactam
• metronidazole