TY - JOUR
T1 - The gastrointestinal antibiotic resistome in pediatric leukemia and lymphoma patients
AU - MacDonald, Tamara
AU - Dunn, Katherine A.
AU - MacDonald, Jane
AU - Langille, Morgan G. I.
AU - van Limbergen, Johan E.
AU - Bielawski, Joseph P.
AU - Kulkarni, Ketan
N1 - Funding Information: This research was funded by a Nova Scotia Health Research Foundation (now Research Nova Scotia) establishment grant, Beatrice Hunter Health Research Institute New Investigator grant, and JD Irving Foundation grant to KK. KAD was funded in part by a IWK Research Associateship and JM was funded by an IWK summer research award. Acknowledgments Publisher Copyright: Copyright © 2023 MacDonald, Dunn, MacDonald, Langille, Van Limbergen, Bielawski and Kulkarni.
PY - 2023
Y1 - 2023
N2 - Introduction: Most children with leukemia and lymphoma experience febrile neutropenia. These are treated with empiric antibiotics that include β-lactams and/or vancomycin. These are often administered for extended periods, and the effect on the resistome is unknown. Methods: We examined the impact of repeated courses and duration of antibiotic use on the resistome of 39 pediatric leukemia and lymphoma patients. Shotgun metagenome sequences from 127 stool samples of pediatric oncology patients were examined for abundance of antibiotic resistance genes (ARGs) in each sample. Abundances were grouped by repeated courses (no antibiotics, 1-2 courses, 3+ courses) and duration (no use, short duration, long and/or mixed durationg) of β-lactams, vancomycin and “any antibiotic” use. We assessed changes in both taxonomic composition and prevalence of ARGs among these groups. Results: We found that Bacteroidetes taxa and β-lactam resistance genes decreased, while opportunistic Firmicutes and Proteobacteria taxa, along with multidrug resistance genes, increased with repeated courses and/or duration of antibiotics. Efflux pump related genes predominated (92%) among the increased multidrug genes. While we found β-lactam ARGs present in the resistome, the taxa that appear to contain them were kept in check by antibiotic treatment. Multidrug ARGs, mostly efflux pumps or regulators of efflux pump genes, were associated with opportunistic pathogens, and both increased in the resistome with repeated antibiotic use and/or increased duration. Conclusions: Given the strong association between opportunistic pathogens and multidrug-related efflux pumps, we suggest that drug efflux capacity might allow the opportunistic pathogens to persist or increase despite repeated courses and/or duration of antibiotics. While drug efflux is the most direct explanation, other mechanisms that enhance the ability of opportunistic pathogens to handle environmental stress, or other aspects of the treatment environment, could also contribute to their ability to flourish within the gut during treatment. Persistence of opportunistic pathogens in an already dysbiotic and weakened gastrointestinal tract could increase the likelihood of life-threatening blood borne infections. Of the 39 patients, 59% experienced at least one gastrointestinal or blood infection and 60% of bacteremia’s were bacteria found in stool samples. Antimicrobial stewardship and appropriate use and duration of antibiotics could help reduce morbidity and mortality in this vulnerable population.
AB - Introduction: Most children with leukemia and lymphoma experience febrile neutropenia. These are treated with empiric antibiotics that include β-lactams and/or vancomycin. These are often administered for extended periods, and the effect on the resistome is unknown. Methods: We examined the impact of repeated courses and duration of antibiotic use on the resistome of 39 pediatric leukemia and lymphoma patients. Shotgun metagenome sequences from 127 stool samples of pediatric oncology patients were examined for abundance of antibiotic resistance genes (ARGs) in each sample. Abundances were grouped by repeated courses (no antibiotics, 1-2 courses, 3+ courses) and duration (no use, short duration, long and/or mixed durationg) of β-lactams, vancomycin and “any antibiotic” use. We assessed changes in both taxonomic composition and prevalence of ARGs among these groups. Results: We found that Bacteroidetes taxa and β-lactam resistance genes decreased, while opportunistic Firmicutes and Proteobacteria taxa, along with multidrug resistance genes, increased with repeated courses and/or duration of antibiotics. Efflux pump related genes predominated (92%) among the increased multidrug genes. While we found β-lactam ARGs present in the resistome, the taxa that appear to contain them were kept in check by antibiotic treatment. Multidrug ARGs, mostly efflux pumps or regulators of efflux pump genes, were associated with opportunistic pathogens, and both increased in the resistome with repeated antibiotic use and/or increased duration. Conclusions: Given the strong association between opportunistic pathogens and multidrug-related efflux pumps, we suggest that drug efflux capacity might allow the opportunistic pathogens to persist or increase despite repeated courses and/or duration of antibiotics. While drug efflux is the most direct explanation, other mechanisms that enhance the ability of opportunistic pathogens to handle environmental stress, or other aspects of the treatment environment, could also contribute to their ability to flourish within the gut during treatment. Persistence of opportunistic pathogens in an already dysbiotic and weakened gastrointestinal tract could increase the likelihood of life-threatening blood borne infections. Of the 39 patients, 59% experienced at least one gastrointestinal or blood infection and 60% of bacteremia’s were bacteria found in stool samples. Antimicrobial stewardship and appropriate use and duration of antibiotics could help reduce morbidity and mortality in this vulnerable population.
KW - antibiotic resistance genes
KW - leukemia
KW - lymphoma
KW - microbiome
KW - pediatric
KW - resistome
UR - http://www.scopus.com/inward/record.url?scp=85149819018&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fcimb.2023.1102501
DO - https://doi.org/10.3389/fcimb.2023.1102501
M3 - Article
C2 - 36909730
SN - 2235-2988
VL - 13
JO - Frontiers in cellular and infection microbiology
JF - Frontiers in cellular and infection microbiology
M1 - 1102501
ER -