Colistin Heteroresistance Is Largely Undetected among Carbapenem-Resistant Enterobacterales in the United States

• Type of Material: Article
• Authors: Victor I. Band, Emory University; Sarah Satola, Emory University; Richard D. Smith, University of Maryland; David A. Hufnagel, Emory University; Chris Bower, Georgia Emerging Infections Program; Andrew B. Conley, Georgia Institute of Technology; Eileen Burd, Emory University; Monica Farley, Emory University; Jesse Jacob, Emory University; David Weiss, Emory University
• Language: English
• Date: 2021-01-26
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Band et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/mBio.02881-20
• Title of Journal or Parent Work: mBio
• Volume: 12
• Issue: 1
• Grant/Funding Information: This work was supported by the National Institutes of Health (grants RO1 AI141883 and RO1 AI1418661) and the Department of Veteran’s Affairs (grant BX002788). D.S.W. is supported by a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease award. The Multi-Site Gram-Negative Surveillance Initiative is funded by the U.S. Centers for Disease Control and Prevention.
• Keywords: antibiotic resistance; heteroresistance; Enterobacteriaceae; CRE; polymyxins; colistin; Enterobacterales
• Research Categories: Health Sciences, Immunology; Health Sciences, Public Health; Health Sciences, Epidemiology

Abstract

Heteroresistance is a form of antibiotic resistance where a bacterial strain is comprised of a minor resistant subpopulation and a majority susceptible subpopulation. We showed previously that colistin heteroresistance can mediate the failure of colistin therapy in an in vivo infection model, even for isolates designated susceptible by clinical diagnostics. We sought to characterize the extent of colistin heteroresistance among the highly drug-resistant carbapenem-resistant Enterobacterales (CRE). We screened 408 isolates for colistin heteroresistance. These isolates were collected between 2012 and 2015 in eight U.S. states as part of active surveillance for CRE. Colistin heteroresistance was detected in 10.1% (41/408) of isolates, and it was more common than conventional homogenous resistance (7.1%, 29/408). Most (93.2%, 38/41) of these heteroresistant isolates were classified as colistin susceptible by standard clinical diagnostic testing. The frequency of colistin heteroresistance was greatest in 2015, the last year of the study. This was especially true among Enterobacter isolates, of which specific species had the highest rates of heteroresistance. Among Klebsiella pneumoniae isolates, which were the majority of isolates tested, there was a closely related cluster of colistin-heteroresistant ST-258 isolates found mostly in Georgia. However, cladistic analysis revealed that, overall, there was significant diversity in the genetic backgrounds of heteroresistant K. pneumoniae isolates. These findings suggest that due to being largely undetected in the clinic, colistin heteroresistance among CRE is underappreciated in the United States.