Dose-related selection of fluoroquinolone-resistant Escherichia coli
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
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.
antibiotic resistance, MPC, PK/PD
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-94999DOI: 10.1093/jac/dkm265ISI: 000249884400013PubMedID: 17635875OAI: oai:DiVA.org:uu-94999DiVA: diva2:169045