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Antimicrobial Agents and Chemotherapy, August 2009, p. 3384-3390, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01347-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Aude A. Ferran, Anne-Sylvie Kesteman, Pierre-Louis Toutain, and Alain Bousquet-Mélou*

UMR181 Physiopathologie et Toxicologie Expérimentales, INRA, ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 chemin des Capelles, BP 87 614, 31076 Toulouse Cedex 3, France

Received 8 October 2008/ Returned for modification 27 December 2008/ Accepted 27 May 2009

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 (105 CFU) or high (108 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 (TMSW), 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 TMSW appeared to be a good predictor of the prevention of resistance for values less than 30%. When the TMSW 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 TMSW 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.

* Corresponding author. Mailing address: UMR181 Physiopathologie et Toxicologie Expérimentales, INRA, ENVT, Ecole Nationale Vétérinaire de Toulouse, 23 chemin des Capelles, BP 87 614, 31076 Toulouse Cedex 3, France. Phone: 33 (0) 5 61 19 39 25. Fax: 33 (0) 5 61 19 39 17. E-mail: a.bousquet-melou{at}envt.fr

{triangledown} Published ahead of print on 1 June 2009.

Antimicrobial Agents and Chemotherapy, August 2009, p. 3384-3390, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01347-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kesteman, A.-S., Ferran, A. A., Perrin-Guyomard, A., Laurentie, M., Sanders, P., Toutain, P.-L., Bousquet-Melou, A. (2009). Influence of Inoculum Size and Marbofloxacin Plasma Exposure on the Amplification of Resistant Subpopulations of Klebsiella pneumoniae in a Rat Lung Infection Model. Antimicrob. Agents Chemother. 53: 4740-4748 [Abstract] [Full Text]  


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