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The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Emory Univ, Dept Biol, Atlanta, GA 30322 USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0001-6640-2174
2019 (English)In: Nature Microbiology, E-ISSN 2058-5276, Vol. 4, no 3, p. 504-514Article in journal (Refereed) Published
Abstract [en]

When choosing antibiotics to treat bacterial infections, it is assumed that the susceptibility of the target bacteria to an antibiotic is reflected by laboratory estimates of the minimum inhibitory concentration (MIC) needed to prevent bacterial growth. A caveat of using MIC data for this purpose is heteroresistance, the presence of a resistant subpopulation in a main population of susceptible cells. We investigated the prevalence and mechanisms of heteroresistance in 41 clinical isolates of the pathogens Escherichia coli, Salmonella enterica, Klebsiella pneumoniae and Acinetobacter baumannii against 28 different antibiotics. For the 766 bacteria-antibiotic combinations tested, as much as 27.4% of the total was heteroresistant. Genetic analysis demonstrated that a majority of heteroresistance cases were unstable, with an increased resistance of the subpopulations resulting from spontaneous tandem amplifications, typically including known resistance genes. Using mathematical modelling, we show how heteroresistance in the parameter range estimated in this study can result in the failure of antibiotic treatment of infections with bacteria that are classified as antibiotic susceptible. The high prevalence of heteroresistance with the potential for treatment failure highlights the limitations of MIC as the sole criterion for susceptibility determinations. These results call for the development of facile and rapid protocols to identify heteroresistance in pathogens.

Place, publisher, year, edition, pages
2019. Vol. 4, no 3, p. 504-514
National Category
Microbiology
Identifiers
URN: urn:nbn:se:uu:diva-379034DOI: 10.1038/s41564-018-0342-0ISI: 000459201400019PubMedID: 30742072OAI: oai:DiVA.org:uu-379034DiVA, id: diva2:1295408
Funder
Swedish Research Council, 2017-01527
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved

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Nicoloff, HervéHjort, KarinAndersson, Dan I

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