title: Ex vivo pharmacodynamics of amoxicillin-clavulanate against beta-lactamase-producing Escherichia coli in a yucatan miniature pig model that mimics human pharmacokinetics.
abstract: The objective of the present study was to investigate the potential bactericidal activity of amoxicillin-clavulanate against beta-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 beta-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 beta-lactamase-producing strains, the existence of a clavulanate concentration threshold of 1.5 to 2 micro g/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 beta-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.
authors.affiliation: Laboratoire d'Antibiologie, Institut de Bactériologie, Université Louis Pasteur, Hôpitaux Universitaires de Strasbourg, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bronner
authors.forename: Valérie
authors.initials: V
authors.lastname: Murbach
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Peter
authors.forename: Dominique
authors.initials: D
authors.lastname: Levêque
authors.forename: Hassan
authors.initials: H
authors.lastname: Elkhaïli
authors.forename: Yves
authors.initials: Y
authors.lastname: Salmon
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dhoyen
authors.forename: Henri
authors.initials: H
authors.lastname: Monteil
authors.forename: Gary
authors.initials: G
authors.lastname: Woodnutt
authors.forename: François
authors.initials: F
authors.lastname: Jehl
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013556:Swine, Miniature; D001618:beta-Lactamases / Q000096:biosynthesis*
chemical_list: D019980:Amoxicillin-Potassium Clavulanate Combination; D001618:beta-Lactamases