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In-Human Multiyear Evolution of Carbapenem-Resistant Klebsiella pneumoniae Causing Chronic Colonization and Intermittent Urinary Tract Infections: A Case Study

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a frequent pathogen of the urinary tract, but how CRKP adapts in vivo over time is unclear. We examined 10 CRKP strains from a patient who experienced chronic colonization and recurrent urinary tract infections over a period of 4.5 years. We perfo...

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Autores principales: Kalu, Michelle, Tan, Karen, Algorri, Marquerita, Jorth, Peter, Wong-Beringer, Annie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241548/
https://www.ncbi.nlm.nih.gov/pubmed/35531657
http://dx.doi.org/10.1128/msphere.00190-22
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author Kalu, Michelle
Tan, Karen
Algorri, Marquerita
Jorth, Peter
Wong-Beringer, Annie
author_facet Kalu, Michelle
Tan, Karen
Algorri, Marquerita
Jorth, Peter
Wong-Beringer, Annie
author_sort Kalu, Michelle
collection PubMed
description Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a frequent pathogen of the urinary tract, but how CRKP adapts in vivo over time is unclear. We examined 10 CRKP strains from a patient who experienced chronic colonization and recurrent urinary tract infections over a period of 4.5 years. We performed whole-genome sequencing and phenotypic assays to compare isolates that had evolved relative to the first isolate collected and to correlate genetic and phenotypic changes over time with the meropenem-containing regimen received. Phylogenetic analysis indicated that all 10 strains originated from the same sequence type 258 (ST258) clone and that three sublineages (SL) evolved over time; strains from two dominant sublineages were selected for detailed analysis. Up to 60 new mutations were acquired progressively in genes related to antibiotic resistance, cell metabolism, and biofilm production over time. Doubling of meropenem MICs, increases in biofilm production and bla(KPC) expression, and altered carbon metabolism occurred in the latter strains from the last sublineage compared to the initial strain. Subinhibitory meropenem exposure in vitro significantly induced or maintained high levels of biofilm production in colonizing isolates, but isolates causing infection were unaffected. Despite acquiring different mutations that affect carbon metabolism, overall carbon utilization was maintained across different strains. Together, these data showed that isolated urinary CRKP evolved through multiple adaptations affecting carbon metabolism, carbapenem resistance, and biofilm production to support chronic colonization and intermittent urinary tract infections. Our findings highlight the pliability of CRKP in adapting to repeated antibiotic exposure and should be considered when developing novel therapeutic and stewardship strategies. IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae (CRKP) can cause a variety of infections such as recurrent urinary tract infections (rUTI) with the ability to change with the host environment over time. However, it is unclear how CRKP adapts to the urinary tract during chronic infections and colonization. Here, we studied the evolution of CRKP strains from a patient who experienced chronic colonization and recurrent UTIs over a period of 4.5 years despite multiple treatment courses with meropenem-containing regimens. Our findings show the flexibility of CRKP strains in developing changes in carbapenem resistance, biofilm production, and carbon metabolism over time, which could facilitate their persistence in the human body for long periods of time in spite of repeated antibiotic therapy.
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spelling pubmed-92415482022-06-30 In-Human Multiyear Evolution of Carbapenem-Resistant Klebsiella pneumoniae Causing Chronic Colonization and Intermittent Urinary Tract Infections: A Case Study Kalu, Michelle Tan, Karen Algorri, Marquerita Jorth, Peter Wong-Beringer, Annie mSphere Research Article Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a frequent pathogen of the urinary tract, but how CRKP adapts in vivo over time is unclear. We examined 10 CRKP strains from a patient who experienced chronic colonization and recurrent urinary tract infections over a period of 4.5 years. We performed whole-genome sequencing and phenotypic assays to compare isolates that had evolved relative to the first isolate collected and to correlate genetic and phenotypic changes over time with the meropenem-containing regimen received. Phylogenetic analysis indicated that all 10 strains originated from the same sequence type 258 (ST258) clone and that three sublineages (SL) evolved over time; strains from two dominant sublineages were selected for detailed analysis. Up to 60 new mutations were acquired progressively in genes related to antibiotic resistance, cell metabolism, and biofilm production over time. Doubling of meropenem MICs, increases in biofilm production and bla(KPC) expression, and altered carbon metabolism occurred in the latter strains from the last sublineage compared to the initial strain. Subinhibitory meropenem exposure in vitro significantly induced or maintained high levels of biofilm production in colonizing isolates, but isolates causing infection were unaffected. Despite acquiring different mutations that affect carbon metabolism, overall carbon utilization was maintained across different strains. Together, these data showed that isolated urinary CRKP evolved through multiple adaptations affecting carbon metabolism, carbapenem resistance, and biofilm production to support chronic colonization and intermittent urinary tract infections. Our findings highlight the pliability of CRKP in adapting to repeated antibiotic exposure and should be considered when developing novel therapeutic and stewardship strategies. IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae (CRKP) can cause a variety of infections such as recurrent urinary tract infections (rUTI) with the ability to change with the host environment over time. However, it is unclear how CRKP adapts to the urinary tract during chronic infections and colonization. Here, we studied the evolution of CRKP strains from a patient who experienced chronic colonization and recurrent UTIs over a period of 4.5 years despite multiple treatment courses with meropenem-containing regimens. Our findings show the flexibility of CRKP strains in developing changes in carbapenem resistance, biofilm production, and carbon metabolism over time, which could facilitate their persistence in the human body for long periods of time in spite of repeated antibiotic therapy. American Society for Microbiology 2022-05-09 /pmc/articles/PMC9241548/ /pubmed/35531657 http://dx.doi.org/10.1128/msphere.00190-22 Text en Copyright © 2022 Kalu et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Kalu, Michelle
Tan, Karen
Algorri, Marquerita
Jorth, Peter
Wong-Beringer, Annie
In-Human Multiyear Evolution of Carbapenem-Resistant Klebsiella pneumoniae Causing Chronic Colonization and Intermittent Urinary Tract Infections: A Case Study
title In-Human Multiyear Evolution of Carbapenem-Resistant Klebsiella pneumoniae Causing Chronic Colonization and Intermittent Urinary Tract Infections: A Case Study
title_full In-Human Multiyear Evolution of Carbapenem-Resistant Klebsiella pneumoniae Causing Chronic Colonization and Intermittent Urinary Tract Infections: A Case Study
title_fullStr In-Human Multiyear Evolution of Carbapenem-Resistant Klebsiella pneumoniae Causing Chronic Colonization and Intermittent Urinary Tract Infections: A Case Study
title_full_unstemmed In-Human Multiyear Evolution of Carbapenem-Resistant Klebsiella pneumoniae Causing Chronic Colonization and Intermittent Urinary Tract Infections: A Case Study
title_short In-Human Multiyear Evolution of Carbapenem-Resistant Klebsiella pneumoniae Causing Chronic Colonization and Intermittent Urinary Tract Infections: A Case Study
title_sort in-human multiyear evolution of carbapenem-resistant klebsiella pneumoniae causing chronic colonization and intermittent urinary tract infections: a case study
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241548/
https://www.ncbi.nlm.nih.gov/pubmed/35531657
http://dx.doi.org/10.1128/msphere.00190-22
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