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
• carbapenem

Acknowledgments

We thank the Duke University School of Medicine for the use of the Microbiome Core Facility, which provided DNA extraction, and the Sequencing and Genomic Technologies Shared Resource, which provided library preparation and shotgun metagenomic sequencing. We especially thank all the children and families who participated in this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The metagenomic data will be uploaded to the Sequence Read Archive prior to publication. The deidentified metadata and analytic script are also publicly available (https://github.com/smh114/Pediatric_HCT_Gut_Resistome).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2333748

Additional information

Funding

Research reported in this publication was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1AI104681. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was additionally supported by the National Institute of Child Health and Human Development of the National Institutes of Health (T32 HD094671 and K12HD105253 to S.M.H.), the National Human Genome Research Institute of the National Institutes of Health (T32 HG008955 to S.M.H.), the Translating Duke Health Ending Disease Where it Begins Working Group (to S.M.H.), the local efforts of the Duke Children’s Office of Development and its Children’s Miracle Network Hospitals fundraising corporate partnerships and programs (to S.M.H.), and a National Institutes of Health Career Development Award (K23-AI135090 to M.S.K.).