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Antimicrobial Agents and Chemotherapy, November 2009, p. 4740-4748, Vol. 53, No. 11
0066-4804/09/$08.00+0 doi:10.1128/AAC.00608-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Influence of Inoculum Size and Marbofloxacin Plasma Exposure on the Amplification of Resistant Subpopulations of Klebsiella pneumoniae in a Rat Lung Infection Model
Anne-Sylvie Kesteman,1,2
Aude A. Ferran,1
Agnès Perrin-Guyomard,2
Michel Laurentie,2
Pascal Sanders,2
Pierre-Louis Toutain,1 and
Alain Bousquet-Mélou1*
UMR181 Physiopathologie et Toxicologie Expérimentales, INRA, ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 Chemin des Capelles, BP 87614, 31076 Toulouse Cedex 3, France,1 Laboratory for the Research and Investigation of Veterinary Drugs and Disinfectants, AFSSA Fougères, La Haute Marche, BP 90203, Javené 35302 Fougères, France2
Received 5 May 2009/ Returned for modification 17 July 2009/ Accepted 1 September 2009
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 (105 CFU) or a high (109 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, Cmax/MIC ratio, and time within the mutant selection window (TMSW) 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/TMSW) was the best predictor of the emergence of resistance: a T>MPC/TMSW 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/TMSW 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.
* Corresponding author. Mailing address: 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. Phone: 33 (0)561193925. Fax: 33 (0)561193917. E-mail: a.bousquet-melou{at}envt.fr
Published ahead of print on 8 September 2009.
Antimicrobial Agents and Chemotherapy, November 2009, p. 4740-4748, Vol. 53, No. 11
0066-4804/09/$08.00+0 doi:10.1128/AAC.00608-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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