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Dose-related selection of fluoroquinolone-resistant Escherichia coli
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2007 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 60, no 4, 795-801 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: To investigate the effects of clinically used doses of norfloxacin,ciprofloxacin and moxifloxacin on survival and selection inEscherichia coli populations containing fluoroquinolone-resistantsubpopulations and to measure the value of the pharmacodynamicindex AUC/mutant prevention concentration (MPC) that preventsthe growth of pre-existing resistant mutants.

Methods: Mixed cultures of susceptible wild-type and isogenic single(gyrA S83L) or double (gyrA S83L, marR) fluoroquinolone-resistantmutants were exposed to fluoroquinolones for 24 h in an in vitrokinetic model. Antibiotic concentrations modelled pharmacokineticsattained with clinical doses.

Results: All tested doses eradicated the susceptible wild-type strain.Norfloxacin 200 mg administered twice daily selected for bothsingle and double mutants. Ciprofloxacin 250 mg administeredtwice daily eradicated the single mutant, but not the doublemutant. For that, 750 mg administered twice daily was required.Moxifloxacin 400 mg once daily eliminated the single mutant,but did not completely remove the double mutant. The MPC ofciprofloxacin was determined and based on those dose simulationsthat eradicated mutant subpopulations, an AUC/MPCwild-type of35 prevented selection of the single mutant, whereas an AUC/MPCsinglemutant of 14 (equivalent to an AUC/MPCwild-type of 105) preventedselection of the double mutant.

Conclusions: All tested clinical dosing regimens were effective in eradicatingsusceptible bacteria, but ciprofloxacin 750 mg twice daily wasthe only dose that prevented the selection of single- and double-resistantE. coli mutants. Thus, among approved fluoroquinolone dosingregimens, some are significantly more effective than othersin exceeding the mutant selection window and preventing theenrichment of resistant mutants.

Place, publisher, year, edition, pages
2007. Vol. 60, no 4, 795-801 p.
Keyword [en]
antibiotic resistance, MPC, PK/PD
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94999DOI: 10.1093/jac/dkm265ISI: 000249884400013PubMedID: 17635875OAI: oai:DiVA.org:uu-94999DiVA: diva2:169045
Available from: 2006-10-20 Created: 2006-10-20 Last updated: 2011-09-30Bibliographically approved
In thesis
1. 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 184
Microbiology, Pharmacokinetics, Pharmacodynamics, Antibiotic resistance, Selection, Transmission, Mathematical model, Escherichia coli, Mikrobiologi
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
Available from: 2006-10-20 Created: 2006-10-20 Last updated: 2011-07-22Bibliographically approved

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