Patient and Microbial Genomic Factors Associated with Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Extraintestinal Colonization and Infection

ABSTRACT Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a critical-priority antibiotic resistance threat that has emerged over the past several decades, spread across the globe, and accumulated resistance to last-line antibiotic agents. While CRKP infections are associated with high mortality,...

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Autores principales:	Zena Lapp, Jennifer H. Han, Jenna Wiens, Ellie J. C. Goldstein, Ebbing Lautenbach, Evan S. Snitkin
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	infection Klebsiella pneumoniae machine learning antibiotic resistance genomic epidemiology hospital infections Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/481c670b99294686ac2d4fe074c8248d
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spelling	oai:doaj.org-article:481c670b99294686ac2d4fe074c8248d2021-12-02T17:07:47ZPatient and Microbial Genomic Factors Associated with Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Extraintestinal Colonization and Infection10.1128/mSystems.00177-212379-5077https://doaj.org/article/481c670b99294686ac2d4fe074c8248d2021-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00177-21https://doaj.org/toc/2379-5077ABSTRACT Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a critical-priority antibiotic resistance threat that has emerged over the past several decades, spread across the globe, and accumulated resistance to last-line antibiotic agents. While CRKP infections are associated with high mortality, only a subset of patients acquiring CRKP extraintestinal colonization will develop clinical infection. Here, we sought to ascertain the relative importance of patient characteristics and CRKP genetic background in determining patient risk of infection. Machine learning models classifying colonization versus infection were built using whole-genome sequences and clinical metadata from a comprehensive set of 331 CRKP extraintestinal isolates collected across 21 long-term acute-care hospitals over the course of a year. Model performance was evaluated based on area under the receiver operating characteristic curve (AUROC) on held-out test data. We found that patient and genomic features were predictive of clinical CRKP infection to similar extents (AUROC interquartile ranges [IQRs]: patient = 0.59 to 0.68, genomic = 0.55 to 0.61, combined = 0.62 to 0.68). Patient predictors of infection included the presence of indwelling devices, kidney disease, and length of stay. Genomic predictors of infection included presence of the ICEKp10 mobile genetic element carrying the yersiniabactin iron acquisition system and disruption of an O-antigen biosynthetic gene in a sublineage of the epidemic ST258 clone. Altered O-antigen biosynthesis increased association with the respiratory tract, and subsequent ICEKp10 acquisition was associated with increased virulence. These results highlight the potential of integrated models including both patient and microbial features to provide a more holistic understanding of patient clinical trajectories and ongoing within-lineage pathogen adaptation. IMPORTANCE Multidrug-resistant organisms, such as carbapenem-resistant Klebsiella pneumoniae (CRKP), colonize alarmingly large fractions of patients in regions of endemicity, but only a subset of patients develop life-threatening infections. While patient characteristics influence risk for infection, the relative contribution of microbial genetic background to patient risk remains unclear. We used machine learning to determine whether patient and/or microbial characteristics can discriminate between CRKP extraintestinal colonization and infection across multiple health care facilities and found that both patient and microbial factors were predictive. Examination of informative microbial genetic features revealed variation within the ST258 epidemic lineage that was associated with respiratory tract colonization and increased rates of infection. These findings indicate that circulating genetic variation within a highly prevalent epidemic lineage of CRKP influences patient clinical trajectories. In addition, this work supports the need for future studies examining the microbial genetic determinants of clinical outcomes in human populations, as well as epidemiologic and experimental follow-ups of identified features to discern generalizability and biological mechanisms.Zena LappJennifer H. HanJenna WiensEllie J. C. GoldsteinEbbing LautenbachEvan S. SnitkinAmerican Society for MicrobiologyarticleinfectionKlebsiella pneumoniaemachine learningantibiotic resistancegenomic epidemiologyhospital infectionsMicrobiologyQR1-502ENmSystems, Vol 6, Iss 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	infection Klebsiella pneumoniae machine learning antibiotic resistance genomic epidemiology hospital infections Microbiology QR1-502
spellingShingle	infection Klebsiella pneumoniae machine learning antibiotic resistance genomic epidemiology hospital infections Microbiology QR1-502 Zena Lapp Jennifer H. Han Jenna Wiens Ellie J. C. Goldstein Ebbing Lautenbach Evan S. Snitkin Patient and Microbial Genomic Factors Associated with Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Extraintestinal Colonization and Infection
description	ABSTRACT Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a critical-priority antibiotic resistance threat that has emerged over the past several decades, spread across the globe, and accumulated resistance to last-line antibiotic agents. While CRKP infections are associated with high mortality, only a subset of patients acquiring CRKP extraintestinal colonization will develop clinical infection. Here, we sought to ascertain the relative importance of patient characteristics and CRKP genetic background in determining patient risk of infection. Machine learning models classifying colonization versus infection were built using whole-genome sequences and clinical metadata from a comprehensive set of 331 CRKP extraintestinal isolates collected across 21 long-term acute-care hospitals over the course of a year. Model performance was evaluated based on area under the receiver operating characteristic curve (AUROC) on held-out test data. We found that patient and genomic features were predictive of clinical CRKP infection to similar extents (AUROC interquartile ranges [IQRs]: patient = 0.59 to 0.68, genomic = 0.55 to 0.61, combined = 0.62 to 0.68). Patient predictors of infection included the presence of indwelling devices, kidney disease, and length of stay. Genomic predictors of infection included presence of the ICEKp10 mobile genetic element carrying the yersiniabactin iron acquisition system and disruption of an O-antigen biosynthetic gene in a sublineage of the epidemic ST258 clone. Altered O-antigen biosynthesis increased association with the respiratory tract, and subsequent ICEKp10 acquisition was associated with increased virulence. These results highlight the potential of integrated models including both patient and microbial features to provide a more holistic understanding of patient clinical trajectories and ongoing within-lineage pathogen adaptation. IMPORTANCE Multidrug-resistant organisms, such as carbapenem-resistant Klebsiella pneumoniae (CRKP), colonize alarmingly large fractions of patients in regions of endemicity, but only a subset of patients develop life-threatening infections. While patient characteristics influence risk for infection, the relative contribution of microbial genetic background to patient risk remains unclear. We used machine learning to determine whether patient and/or microbial characteristics can discriminate between CRKP extraintestinal colonization and infection across multiple health care facilities and found that both patient and microbial factors were predictive. Examination of informative microbial genetic features revealed variation within the ST258 epidemic lineage that was associated with respiratory tract colonization and increased rates of infection. These findings indicate that circulating genetic variation within a highly prevalent epidemic lineage of CRKP influences patient clinical trajectories. In addition, this work supports the need for future studies examining the microbial genetic determinants of clinical outcomes in human populations, as well as epidemiologic and experimental follow-ups of identified features to discern generalizability and biological mechanisms.
format	article
author	Zena Lapp Jennifer H. Han Jenna Wiens Ellie J. C. Goldstein Ebbing Lautenbach Evan S. Snitkin
author_facet	Zena Lapp Jennifer H. Han Jenna Wiens Ellie J. C. Goldstein Ebbing Lautenbach Evan S. Snitkin
author_sort	Zena Lapp
title	Patient and Microbial Genomic Factors Associated with Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Extraintestinal Colonization and Infection
title_short	Patient and Microbial Genomic Factors Associated with Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Extraintestinal Colonization and Infection
title_full	Patient and Microbial Genomic Factors Associated with Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Extraintestinal Colonization and Infection
title_fullStr	Patient and Microbial Genomic Factors Associated with Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Extraintestinal Colonization and Infection
title_full_unstemmed	Patient and Microbial Genomic Factors Associated with Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Extraintestinal Colonization and Infection
title_sort	patient and microbial genomic factors associated with carbapenem-resistant <named-content content-type="genus-species">klebsiella pneumoniae</named-content> extraintestinal colonization and infection
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/481c670b99294686ac2d4fe074c8248d
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Patient and Microbial Genomic Factors Associated with Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Extraintestinal Colonization and Infection

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