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Mutation Rate and Evolution of Fluoroquinolone Resistance in Escherichia coli Isolates from Patients with Urinary tract infections
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
2003 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 47, no 10, 3222-3232 p.Article in journal (Refereed) Published
Abstract [en]

Escherichia coli strains from patients with uncomplicated urinarytract infections were examined by DNA sequencing for fluoroquinoloneresistance-associated mutations in six genes: gyrA, gyrB, parC,parE, marOR, and acrR. The 54 strains analyzed had a susceptibilityrange distributed across 15 dilutions of the fluoroquinoloneMICs. There was a correlation between the fluoroquinolone MICand the number of resistance mutations that a strain carried,with resistant strains having mutations in two to five of thesegenes. Most resistant strains carried two mutations in gyrAand one mutation in parC. In addition, many resistant strainshad mutations in parE, marOR, and/or acrR. No (resistance) mutationwas found in gyrB. Thus, the evolution of fluoroquinolone resistanceinvolves the accumulation of multiple mutations in several genes.The spontaneous mutation rate in these clinical strains variedby 2 orders of magnitude. A high mutation rate correlated stronglywith a clinical resistance phenotype. This correlation suggeststhat an increased general mutation rate may play a significantrole in the development of high-level resistance to fluoroquinolonesby increasing the rate of accumulation of rare new mutations.

Place, publisher, year, edition, pages
2003. Vol. 47, no 10, 3222-3232 p.
National Category
Natural Sciences
URN: urn:nbn:se:uu:diva-96329DOI: 10.1128/AAC.47.10.3222-3232.2003OAI: oai:DiVA.org:uu-96329DiVA: diva2:170869
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2011-07-18Bibliographically approved
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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