title: Influence of inoculum size and marbofloxacin plasma exposure on the amplification of resistant subpopulations of Klebsiella pneumoniae in a rat lung infection model.
abstract: We tested the hypothesis that the bacterial load at the infection site could impact considerably on the pharmacokinetic/pharmacodynamic (PK/PD) parameters of fluoroquinolones. Using a rat lung infection model, we measured the influence of different marbofloxacin dosage regimens on selection of resistant bacteria after infection with a low (10(5) CFU) or a high (10(9) CFU) inoculum of Klebsiella pneumoniae. For daily fractionated doses of marbofloxacin, prevention of resistance occurred for an area-under-the-concentration-time-curve (AUC)/MIC ratio of 189 h for the low inoculum, whereas for the high inoculum, resistant-subpopulation enrichment occurred for AUC/MIC ratios up to 756 h. For the high-inoculum-infected rats, the AUC/MIC ratio, C(max)/MIC ratio, and time within the mutant selection window (T(MSW)) were not found to be effective predictors of resistance prevention upon comparison of fractionated and single administrations. An index corresponding to the ratio of the time that the drug concentrations were above the mutant prevention concentration (MPC) over the time that the drug concentrations were within the MSW (T(>MPC)/T(MSW)) was the best predictor of the emergence of resistance: a T(>MPC)/T(MSW) ratio of 0.54 was associated with prevention of resistance for both fractionated and single administrations. These results suggest that the enrichment of resistant bacteria depends heavily on the inoculum size at the start of an antimicrobial treatment and that classical PK/PD parameters cannot adequately describe the impact of different dosage regimens on enrichment of resistant bacteria. We propose an original index, the T(>MPC)/T(MSW) ratio, which reflects the ratio of the time that the less susceptible bacterial subpopulation is killed over the time that it is selected, as a potentially powerful indicator of prevention of enrichment of resistant bacteria. This ratio is valid only if plasma concentrations achieve the MPC.
authors.affiliation: UMR181 Physiopathologie et Toxicologie Expérimentales, INRA, ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles, BP 87 614, 31 076 Toulouse Cedex 3, France.
authors.forename: Anne-Sylvie
authors.initials: AS
authors.lastname: Kesteman
authors.forename: Aude A
authors.initials: AA
authors.lastname: Ferran
authors.forename: Agnès
authors.initials: A
authors.lastname: Perrin-Guyomard
authors.forename: Michel
authors.initials: M
authors.lastname: Laurentie
authors.forename: Pascal
authors.initials: P
authors.lastname: Sanders
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Toutain
authors.forename: Alain
authors.initials: A
authors.lastname: Bousquet-Mélou
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D008168:Lung / Q000382:microbiology*; D008297:Male; D008826:Microbial Sensitivity Tests; D051381:Rats
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; C080260:marbofloxacin