title: Pharmacokinetic/pharmacodynamic analysis of the influence of inoculum size on the selection of resistance in Escherichia coli by a quinolone in a mouse thigh bacterial infection model.
abstract: Maintaining quinolone concentrations outside the mutant selection window (MSW) between the MIC and mutant prevention concentration (MPC) was suggested by in vitro and in vivo studies to prevent the selection of resistant mutants. However, selection also may depend on the presence of resistant bacterial mutants at the start of treatment, which is highly dependent on the initial inoculum size. In this study, a mouse thigh bacterial infection model was used to test the influence of different exposures to marbofloxacin on the selection of resistant bacteria after infection with a low (10(5) CFU) or high (10(8) CFU) initial inoculum of Escherichia coli. The inoculum size was shown to influence the exposure to marbofloxacin and the values of pharmacokinetic/pharmacodynamic indices. When the abilities of the indices time within the MSW (T(MSW)), area under the concentration-time curve of 0 to 24 h divided by the MIC, and the maximum concentration of drug in plasma divided by the MIC to predict the selection of resistant bacteria were compared, only T(MSW) appeared to be a good predictor of the prevention of resistance for values less than 30%. When the T(MSW) was higher than 34%, the selection of resistant bacteria occurred less often in thighs initially infected with the low inoculum (11/24; 46%) than in those infected with the high inoculum (30/36; 80%), suggesting that the selection of resistant mutants depends on both the T(MSW) and inoculum size. The relevance of these results merits further investigation to test different strategies of antibiotic therapy depending on the expected bacterial burden at the infectious site.
authors.affiliation: UMR181 Physiopathologie et Toxicologie Expérimentales, INRA, ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 chemin des Capelles, BP 87 614, 31076 Toulouse Cedex 3, France.
authors.forename: Aude A
authors.initials: AA
authors.lastname: Ferran
authors.forename: Anne-Sylvie
authors.initials: AS
authors.lastname: Kesteman
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Toutain
authors.forename: Alain
authors.initials: A
authors.lastname: Bousquet-Mélou
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects* / Q000502:physiology; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D024841:Fluoroquinolones / Q000627:therapeutic use; D051379:Mice; D008826:Microbial Sensitivity Tests; D016133:Polymerase Chain Reaction; D015363:Quinolones / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D013848:Thigh / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D015363:Quinolones; D003520:Cyclophosphamide; C080260:marbofloxacin