Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection

ABSTRACT Antibiotic resistance is a growing crisis and a grave threat to human health. It is projected that antibiotic-resistant infections will lead to 10 million annual deaths worldwide by the year 2050. Among the most significant threats are carbapenem-resistant Enterobacteriaceae (CRE), includin...

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Autores principales:	Victor I. Band, Sarah W. Satola, Eileen M. Burd, Monica M. Farley, Jesse T. Jacob, David S. Weiss
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Klebsiella antibiotic resistance clonal heteroresistance colistin heteroresistance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4df6b58123384c9b8d143a505d46fe8b
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spelling	oai:doaj.org-article:4df6b58123384c9b8d143a505d46fe8b2021-11-15T15:53:27ZCarbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection10.1128/mBio.02448-172150-7511https://doaj.org/article/4df6b58123384c9b8d143a505d46fe8b2018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02448-17https://doaj.org/toc/2150-7511ABSTRACT Antibiotic resistance is a growing crisis and a grave threat to human health. It is projected that antibiotic-resistant infections will lead to 10 million annual deaths worldwide by the year 2050. Among the most significant threats are carbapenem-resistant Enterobacteriaceae (CRE), including carbapenem-resistant Klebsiella pneumoniae (CRKP), which lead to mortality rates as high as 40 to 50%. Few treatment options are available to treat CRKP, and the polymyxin antibiotic colistin is often the “last-line” therapy. However, resistance to colistin is increasing. Here, we identify multidrug-resistant, carbapenemase-positive CRKP isolates that were classified as susceptible to colistin by clinical diagnostics yet harbored a minor subpopulation of phenotypically resistant cells. Within these isolates, the resistant subpopulation became predominant after growth in the presence of colistin but returned to baseline levels after subsequent culture in antibiotic-free media. This indicates that the resistance was phenotypic, rather than due to a genetic mutation, consistent with heteroresistance. Importantly, colistin therapy was unable to rescue mice infected with the heteroresistant strains. These findings demonstrate that colistin heteroresistance may cause in vivo treatment failure during K. pneumoniae infection, threatening the use of colistin as a last-line treatment for CRKP. Furthermore, these data sound the alarm for use of caution in interpreting colistin susceptibility test results, as isolates identified as susceptible may in fact resist antibiotic therapy and lead to unexplained treatment failures. IMPORTANCE This is the first report of colistin-heteroresistant K. pneumoniae in the United States. Two distinct isolates each led to colistin treatment failure in an in vivo model of infection. The data are worrisome, especially since the colistin heteroresistance was not detected by current diagnostic tests. As these isolates were carbapenem resistant, clinicians might turn to colistin as a last-line therapy for infections caused by such strains, not knowing that they in fact harbor a resistant subpopulation of cells, potentially leading to treatment failure. Our findings warn that colistin susceptibility testing results may be unreliable due to undetected heteroresistance and highlight the need for more accurate and sensitive diagnostics.Victor I. BandSarah W. SatolaEileen M. BurdMonica M. FarleyJesse T. JacobDavid S. WeissAmerican Society for MicrobiologyarticleKlebsiellaantibiotic resistanceclonal heteroresistancecolistinheteroresistanceMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Klebsiella antibiotic resistance clonal heteroresistance colistin heteroresistance Microbiology QR1-502
spellingShingle	Klebsiella antibiotic resistance clonal heteroresistance colistin heteroresistance Microbiology QR1-502 Victor I. Band Sarah W. Satola Eileen M. Burd Monica M. Farley Jesse T. Jacob David S. Weiss Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection
description	ABSTRACT Antibiotic resistance is a growing crisis and a grave threat to human health. It is projected that antibiotic-resistant infections will lead to 10 million annual deaths worldwide by the year 2050. Among the most significant threats are carbapenem-resistant Enterobacteriaceae (CRE), including carbapenem-resistant Klebsiella pneumoniae (CRKP), which lead to mortality rates as high as 40 to 50%. Few treatment options are available to treat CRKP, and the polymyxin antibiotic colistin is often the “last-line” therapy. However, resistance to colistin is increasing. Here, we identify multidrug-resistant, carbapenemase-positive CRKP isolates that were classified as susceptible to colistin by clinical diagnostics yet harbored a minor subpopulation of phenotypically resistant cells. Within these isolates, the resistant subpopulation became predominant after growth in the presence of colistin but returned to baseline levels after subsequent culture in antibiotic-free media. This indicates that the resistance was phenotypic, rather than due to a genetic mutation, consistent with heteroresistance. Importantly, colistin therapy was unable to rescue mice infected with the heteroresistant strains. These findings demonstrate that colistin heteroresistance may cause in vivo treatment failure during K. pneumoniae infection, threatening the use of colistin as a last-line treatment for CRKP. Furthermore, these data sound the alarm for use of caution in interpreting colistin susceptibility test results, as isolates identified as susceptible may in fact resist antibiotic therapy and lead to unexplained treatment failures. IMPORTANCE This is the first report of colistin-heteroresistant K. pneumoniae in the United States. Two distinct isolates each led to colistin treatment failure in an in vivo model of infection. The data are worrisome, especially since the colistin heteroresistance was not detected by current diagnostic tests. As these isolates were carbapenem resistant, clinicians might turn to colistin as a last-line therapy for infections caused by such strains, not knowing that they in fact harbor a resistant subpopulation of cells, potentially leading to treatment failure. Our findings warn that colistin susceptibility testing results may be unreliable due to undetected heteroresistance and highlight the need for more accurate and sensitive diagnostics.
format	article
author	Victor I. Band Sarah W. Satola Eileen M. Burd Monica M. Farley Jesse T. Jacob David S. Weiss
author_facet	Victor I. Band Sarah W. Satola Eileen M. Burd Monica M. Farley Jesse T. Jacob David S. Weiss
author_sort	Victor I. Band
title	Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection
title_short	Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection
title_full	Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection
title_fullStr	Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection
title_full_unstemmed	Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection
title_sort	carbapenem-resistant <italic toggle="yes">klebsiella pneumoniae</italic> exhibiting clinically undetected colistin heteroresistance leads to treatment failure in a murine model of infection
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/4df6b58123384c9b8d143a505d46fe8b
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Carbapenem-Resistant <italic toggle="yes">Klebsiella pneumoniae</italic> Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection

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