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Selection of ciprofloxacin resistance in Escherichia coli in an in vitro kinetic model: relation between drug exposure and mutant prevention concentration
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. (Klinisk bakterologi)
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.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2006 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 57, no 6, 1116-1121 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 57, no 6, 1116-1121 p.
Keyword [en]
antibiotic resistance, MPC, PK/PD, E. coli
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95847DOI: 10.1093/jac/dkl135PubMedID: 16624874OAI: oai:DiVA.org:uu-95847DiVA: diva2:170204
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2017-12-14Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 302
Keyword
Biology, Fluoroquinolone, Escherichia coli, Resistance, Gyrase, Topoisomerase IV, MPC, Fitness compensation, Urinary Tract Infection, Biologi
Identifiers
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
Opponent
Supervisors
Available from: 2007-04-27 Created: 2007-04-27 Last updated: 2011-07-18Bibliographically approved
2. Relation Between Drug Exposure and Selection of Antibiotic Resistant Bacteria
Open this publication in new window or tab >>Relation Between Drug Exposure and Selection of Antibiotic Resistant Bacteria
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The worldwide increase in antibiotic resistance is a concern for public health. When the appropriate antibiotic dosage is determined, the priorities are efficacy and toxicity. The aim of this thesis was to gain knowledge about the most efficient dosing regimens in order to minimize the emergence and selection of antibiotic-resistant mutants. We also wanted to assess the impact of antibiotic selective pressure and host to host transmission for the dissemination of resistance.

Escherichia coli bacteria with different levels of cefotaxime susceptibility were competed in an in vitro kinetic model, demonstrating a complex selection of low-level resistance influenced e.g. by the time duration of selective concentrations and the rise of new mutants. We also constructed a mathematical model incorporating biologically relevant parameters and showed its usefulness when assessing the risks of resistance development.

When E. coli populations with pre-existing fluoroquinolone-resistant mutants were exposed to simulated serum concentrations, several currently used doses of fluoroquinolones clearly enhanced the development and selection of resistance.

The mutant prevention concentration (MPC) was measured for several E. coli isolates with different fluoroquinolone susceptibilities, and because of fluctuating antibiotic concentrations in the human body, the pharmacokinetics was considered when evaluating MPC. Results indicate that the area under the serum concentration time curve in relation to the MPC may be a useful predictor for emergence of resistance.

In the commensal flora of healthy human couples we noted a high frequency of trimethoprim-resistant E. coli. There was also an extensive sharing and transmission of E. coli clones. Treating the female with trimethoprim reduced the number of intestinal E. coli which might have facilitated the transmission from the male partner. These findings suggest that the rate of transmission is high and effectively contributes to the spread of both susceptible and antibiotic-resistant E. coli in intrafamilial settings.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 184
Keyword
Microbiology, Pharmacokinetics, Pharmacodynamics, Antibiotic resistance, Selection, Transmission, Mathematical model, Escherichia coli, Mikrobiologi
Identifiers
urn:nbn:se:uu:diva-7197 (URN)91-554-6685-0 (ISBN)
Public defence
2006-11-10, Hörsalen, Klinisk Bakteriologi, Akademiska Sjukhuset ing D1, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-10-20 Created: 2006-10-20 Last updated: 2011-07-22Bibliographically approved

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