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Antimicrobial Agents and Chemotherapy, December 2002, p. 3782-3789, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3782-3789.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Ex Vivo Pharmacodynamics of Amoxicillin-Clavulanate against ß-Lactamase-Producing Escherichia coli in a Yucatan Miniature Pig Model That Mimics Human Pharmacokinetics

Stéphane Bronner,1 Valérie Murbach,1 Jean-Daniel Peter,1 Dominique Levêque,1 Hassan Elkhaïli,1 Yves Salmon,1 Nathalie Dhoyen,1 Henri Monteil,1 Gary Woodnutt,2 and François Jehl1*

Laboratoire d'Antibiologie, Institut de Bactériologie, Université Louis Pasteur, Hôpitaux Universitaires de Strasbourg, F67000 Strasbourg, France,1 SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania2

Received 30 March 2001/ Returned for modification 22 November 2001/ Accepted 29 August 2002

The objective of the present study was to investigate the potential bactericidal activity of amoxicillin-clavulanate against ß-lactamase-producing Escherichia coli strains and to elucidate the extent to which enzyme production affects the activity. Six adult Yucatan miniature pigs received a single intravenous dose of 1.1 g of amoxicillin-clavulanate as an intravenous infusion over 30 min. The pharmacokinetic parameters were determined for the serum samples and compared to the published data for humans (2.2-g intravenous dose). The parameters were comparable for the two species, and therefore, the miniature pig constitutes a good model for pharmacodynamic study of amoxicillin-clavulanate. Therefore, the model was used in an ex vivo pharmacodynamic study of amoxicillin-clavulanate against four strains of Escherichia coli producing ß-lactamases at different levels. The E. coli strains were cultured with serial dilutions (1:2 to 1:256) of the serum samples from the pharmacokinetic study, and the number of surviving bacteria was determined after 1, 3, and 6 h of exposure. Amoxicillin-clavulanate at concentrations less than the MIC and the minimal bactericidal concentration had marked bactericidal potency against the strain that produced low levels of penicillinase. For high-level or intermediate-level ß-lactamase-producing strains, the existence of a clavulanate concentration threshold of 1.5 to 2 µg/ml, below which there was no bactericidal activity, was demonstrated. The index of surviving bacteria showed the existence of mixed concentration- and time-dependent actions of amoxicillin (in the presence of clavulanate) which varied as a function of the magnitude of ß-lactamase production by the test strains. This study shows the effectiveness of amoxicillin-clavulanate against low- and intermediate-level penicillinase-producing strains of E. coli. These findings are to be confirmed in a miniature pig experimental infection model.

* Corresponding author. Mailing address: Laboratoire d'Antibiologie, Institut de Bactériologie, Université Louis Pasteur, Hôpitaux Universitaires de Strasbourg, 3, rue Koeberlé, F67000 Strasbourg, France. Phone: (33) 3 90 24 37 81. Fax: (33) 3 88 25 11 13. E-mail: francois.jehl{at}medecine.u-strasbg.fr.

Antimicrobial Agents and Chemotherapy, December 2002, p. 3782-3789, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3782-3789.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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