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

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 Citation Lapp Z, Han JH, Wiens J, Goldstein EJC, Lautenbach E, Snitkin ES. 2021. Patient and microbial genomic factors associated with carbapenem-resistant Klebsiella pneumoniae extraintestinal colonization and infection. mSystems 6:e00177-21. https://doi.org/10 . 1128/mSystems.00177-21. Editor David W. Cleary, University of Southampton Copyright © 2021 Lapp et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license. Address correspondence to Evan S. Snitkin, esnitkin@med.umich. edu. Are patient characteristics or bacterial genomic variation more predictive of healthcare infection with carbapenemresistant Klebsiella pneumoniae? Received 22 February 2021 Accepted 23 February 2021 Published 16 March 2021 March/April 2021 Volume 6 Issue 2 e00177-21 msystems.asm. org 1 RESEARCH ARTICLE