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. 2023 Jun 15;11(3):e0509322.
doi: 10.1128/spectrum.05093-22. Epub 2023 May 23.

Prevalence and Clinical Consequences of Colistin Heteroresistance and Evolution into Full Resistance in Carbapenem-Resistant Acinetobacter baumannii

Hadas Kon  1 , Amichay Hameir  1 , Amir Nutman  1   2 , Elizabeth Temkin  1 , Alona Keren Paz  1 , Jonathan Lellouche  1   3 , David Schwartz  1 , David S Weiss  4 , Keith S Kaye  5 , George L Daikos  6   7 , Anna Skiada  6   7 , Emanuele Durante-Mangoni  8   9 , Yael Dishon Benattar  10   11 , Dafna Yahav  2   12 , Vered Daitch  2   13 , Mariano Bernardo  14 , Domenico Iossa  8 , Lena E Friberg  15 , Ursula Theuretzbacher  16 , Leonard Leibovici  2   13 , Yaakov Dickstein  10 , Dina Pollak  17 , Sigal Mendelsohn  17 , Mical Paul  10 , Yehuda Carmeli  1   2
Affiliations

Prevalence and Clinical Consequences of Colistin Heteroresistance and Evolution into Full Resistance in Carbapenem-Resistant Acinetobacter baumannii

Hadas Kon et al. Microbiol Spectr. .

Abstract

Colistin heteroresistance (HR) refers to a bacterial population comprised of several subpopulations with different levels of resistance to colistin. In this study, we discuss the classic form of HR, in which a resistant subpopulation exists within a predominantly susceptible population. We investigated the prevalence of colistin HR and its evolution into full resistance among 173 clinical carbapenem-resistant Acinetobacter baumannii isolates and examined the effect of HR on clinical outcomes. To determine HR, we performed population analysis profiling. Our results showed a high prevalence of HR (67.1%). To examine evolution of HR strains into full resistance, the HR strains were grown in colistin-containing broth, transferred onto colistin-containing plates, and colonies on these plates were transferred into colistin-free broth. Many of the HR strains (80.2%) evolved into full resistance, 17.2% reverted to HR, and 2.6% were borderline. We used logistic regression to compare 14-day clinical failure and 14-day mortality between patients infected by HR versus susceptible non-HR carbapenem-resistant A. baumannii. In the subgroup of patients with bacteremia, HR was significantly associated with 14-day mortality. IMPORTANCE To our knowledge, this is the first large-scale study to report on HR in Gram-negative bacteria. We described the prevalence of colistin HR in a large sample of carbapenem-resistant A. baumannii isolates, the evolution of many colistin HR isolates to a resistant phenotype following colistin exposure and withdrawal, and the clinical consequences of colistin HR. We found a high prevalence of HR among clinical carbapenem-resistant A. baumannii isolates; most evolved into a resistant phenotype following colistin exposure and withdrawal. In patients treated with colistin, evolution of HR A. baumannii into full resistance could lead to higher rates of treatment failure and contribute to the reservoir of colistin-resistant pathogens in health care settings.

Keywords: Acinetobacter baumannii; carbapenem-resistance; colistin; heteroresistance; population analysis profiling.

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Conflict of interest statement

The authors declare a conflict of interest. E.D.M. reports grants and/or personal fees from Pfizer, M.S.D., Rosh, Anglini, Nordic Pharma, and Sanofi-Aventis. G.L.D. reports grants and/or personal fees from Pfizer, Menarini, and M.S.D. K.S.K. reports grants and/or personal fees from Spero Therapeutics, Q.P.E.X., and MicuRx. M.P. reports grants and/or personal fees from Shionogi and Pfizer. Y.C. reports grants and/or personal fees from Allecra Therapeutics, Genentech, Nabriva Therapeutics, Pfizer, PPD, Q.P.E.X. Biopharma, Roche Pharmaceuticals, Spero Therapeutics, VenatoRX Pharmaceuticals. All other authors have no interests to declare.

Figures

FIG 1
FIG 1
Population analysis profile of (A) a colistin-resistant reference strain, (B) HR strains and (C) susceptible non-HR strains. A to C show box plots of the number of colonies able to grow in the presence of each colistin concentration (CFU/mL). The horizontal line represents the average colony count (value presented outside the box), the box represents the upper and lower quartile and the vertical lines represent the highest and lowest value. Counts below 20 CFU/mL were considered insignificant (in figure C some points were not shown because the colony count was below the limit of 20 CFU/mL).
FIG 2
FIG 2
Panels A and B refer to HR isolates only. Panel C represents the entire study sample. (A) Frequencies of resistant cells of the HR isolates from the unselected stage (FU), colistin stage (FC) and withdrawal stage (FW) at 8*MIC-i. (B) Determination of evolution into full resistance or reversion into HR. Bottom right quarter are fully resistant and top left quarter are reverted. Three borderline isolates marked in orange. (C) Distribution of HR and susceptible non-HR isolates, including distribution of evolution into full resistance or reverted to HR.
FIG 3
FIG 3
Schematic illustration of experiments conducted in this study to determine heteroresistance (HR) and evolution to full resistance: (A) Population analysis profiling (PAP) assay (unselected stage), (B) Selection of the resistant population (colistin stage) and (C) withdrawal of antibiotic pressure (withdrawal stage).
See this image and copyright information in PMC

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