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Dose-related selection of fluoroquinolones
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
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Article in journal (Refereed) Submitted
URN: urn:nbn:se:uu:diva-95848OAI: oai:DiVA.org:uu-95848DiVA: diva2:170205
Available from: 2007-04-27 Created: 2007-04-27Bibliographically approved
In thesis
1. Resistance to Fluoroquinolones in Escherichia coli: Prevention, Genetics and Fitness Costs
Open this publication in new window or tab >>Resistance to Fluoroquinolones in Escherichia coli: Prevention, Genetics and Fitness Costs
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotic-resistant bacteria are increasingly a major healthcare problem but very few new classes of antibiotics have been discovered or launched in recent decades. Approaches to dealing with the problem include learning how bacteria evolve to resistance and improving dosing regimens with current antibiotics so as to reduce the selection of resistant bacteria.

This thesis presents studies examining whether antibiotic dosing at high levels can prevent the selection of fluoroquinolone-resistant mutants in Escherichia coli. It also addresses the genetics of fluoroquinolone resistance in E. coli in relation to fitness costs for the resistant bacteria, and the evolution of E. coli to reduce the costs of resistance.

The mutant prevention concentration (MPC) of ciprofloxacin was measured for a set of clinical urinary tract infection E. coli strains showing that MPC could not be predicted from the minimum inhibitory concentration (MIC). Results from an in vitro kinetic model showed that an AUC/MPC >22 for ciprofloxacin was the single best pharmacodynamic index that predicted prevention of resistance emergence in the wild-type. Simulating currently approved dosing regimens for three different fluoroquinolones it was found that only a few were effective in preventing the selection of a small sub-population of pre-existing mutants.

Step-wise selection of fluoroquinolone resistance showed that the accumulation of mutations usually reduced bacterial fitness in vitro and in vivo. Systematic construction of isogenic resistant strains confirmed this result and revealed that some combinations of resistance mutations mutually compensate and increase both resistance and fitness. It was discovered that mutations altering RNA polymerase could ameliorate the fitness costs of fluoroquinolone resistance. Thus, the major fitness cost of fluoroquinolone resistance is due to defective transcription.

The finding that fluoroquinolone resistance mutations can increase resistance while mutually compensating their fitness costs, shows that resistance to fluoroquinolones can continue to evolve in the absence of antibiotic selection.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 76 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 302
Biology, Fluoroquinolone, Escherichia coli, Resistance, Gyrase, Topoisomerase IV, MPC, Fitness compensation, Urinary Tract Infection, Biologi
urn:nbn:se:uu:diva-7851 (URN)978-91-554-6884-2 (ISBN)
Public defence
2007-05-18, B21, BMC, Husargatan 3, 751 24 Uppsala, 10:15
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2011-07-18Bibliographically approved

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