JAC Advance Access originally published online on July 16, 2007
Journal of Antimicrobial Chemotherapy 2007 60(4):795-801; doi:10.1093/jac/dkm265
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Dose-related selection of fluoroquinolone-resistant Escherichia coli
1 Antibiotic Research Unit, Department of Medical Sciences, Clinical Bacteriology and Infectious Diseases, Uppsala University, S-751 22 Uppsala, Sweden 2 Microbiology Programme, Department of Cell and Molecular Biology, Biomedical Centre, Uppsala University, S-751 24 Uppsala, Sweden
Received 11 April 2007; returned 21 May 2007; revised 25 June 2007; accepted 25 June 2007
* Corresponding author. E-mail: sara.olofsson{at}medsci.uu.se
Objectives: To investigate the effects of clinically used doses of norfloxacin, ciprofloxacin and moxifloxacin on survival and selection in Escherichia coli populations containing fluoroquinolone-resistant subpopulations and to measure the value of the pharmacodynamic index AUC/mutant prevention concentration (MPC) that prevents the growth of pre-existing resistant mutants.
Methods: Mixed cultures of susceptible wild-type and isogenic single (gyrA S83L) or double (gyrA S83L, 
marR) fluoroquinolone-resistant mutants were exposed to fluoroquinolones for 24 h in an in vitro kinetic model. Antibiotic concentrations modelled pharmacokinetics attained with clinical doses.
Results: All tested doses eradicated the susceptible wild-type strain. Norfloxacin 200 mg administered twice daily selected for both single and double mutants. Ciprofloxacin 250 mg administered twice daily eradicated the single mutant, but not the double mutant. 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 of ciprofloxacin was determined and based on those dose simulations that eradicated mutant subpopulations, an AUC/MPCwild-type of 35 prevented selection of the single mutant, whereas an AUC/MPCsingle mutant of 14 (equivalent to an AUC/MPCwild-type of 105) prevented selection of the double mutant.
Conclusions: All tested clinical dosing regimens were effective in eradicating susceptible bacteria, but ciprofloxacin 750 mg twice daily was the only dose that prevented the selection of single- and double-resistant E. coli mutants. Thus, among approved fluoroquinolone dosing regimens, some are significantly more effective than others in exceeding the mutant selection window and preventing the enrichment of resistant mutants.
Keywords: antibiotic resistance , MPC , PK/PD
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