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Selection of strong mutators and of rifampicin-resistant mutants, during evolution of fluoroquinolone resistance in urinary tract Escherichia coli.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-96330OAI: oai:DiVA.org:uu-96330DiVA: diva2:170870
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2011-07-08
In thesis
1. Mutations and Mutation Rate in the Development of Fluoroquinolone Resistance
Open this publication in new window or tab >>Mutations and Mutation Rate in the Development of Fluoroquinolone Resistance
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The emergence of multidrug resistant bacteria world wide is a serious problem, and very few new drugs are under development. The selection of resistant bacteria is affected by factors such as mutation rate, biological fitness cost and the rate of fitness compensation. This thesis is focused on how mutation rate affects resistance to fluoroquinolones and on exploring a dosing strategy that might slow resistance development.

In a set of urinary tract Escherichia coli isolates MIC values above the breakpoint for the fluoroquinolones norfloxacin and ciprofloxacin carried at least three resistance-associated mutations. In these isolates the number of resistance mutations correlated with the mutation rate. During step-wise selection for decreased susceptibility to fluoroquinolones, the accumulation of mutations in E. coli was associated with an increasing biological cost both in vitro and in vivo. However, in some lineages an additional selection step for resistance was associated with a partial restoration of fitness. During step-wise selections we found, as expected, that reduced ciprofloxacin susceptibility frequently hitchhiked with a strong mutator phenotype. More surprisingly, we also found that reduced susceptibility was frequently associated with the emergence of rifampicin-resistant populations. We hypothesise that this correlation reflects selection for fitness-compensating mutations in RNA polymerase.

Mutant prevention concentration (MPC) dosing has been proposed as a strategy to reduce the selection of resistant bacterial populations. Based on limited data it had been thought that MPC might be a simple multiple of MIC, which can easily be determined. However, we showed for a collection of susceptible urinary tract E. coli that MPC could not be predicted from MIC and must be measured directly for relevant populations. Using an in vitro kinetic model we also showed that the pharmacodynamic index that best predicted prevention of resistance development in wild type E. coli was an AUC/MPC of > 22 for ciprofloxacin.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 102 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 357
Microbiology, Mutation rate, Fluoroquinolone, Resistance, Biological fitness, Urinary tract infection, Escherichia coli, MPC, Mikrobiologi
urn:nbn:se:uu:diva-8275 (URN)978-91-554-6997-9 (ISBN)
Public defence
2007-12-01, B21, BMC, Husargatan 3, 75124 Uppsala, 10:15
Available from: 2007-11-01 Created: 2007-11-01Bibliographically approved

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Hughes, Diarmaid
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