Bronner Stéphane, Murbach Valérie, Peter Jean-Daniel, Levêque Dominique, Elkhaïli Hassan, Salmon Yves, Dhoyen Nathalie, Monteil Henri, Woodnutt Gary, Jehl François
Laboratoire d'Antibiologie, Institut de Bactériologie, Université Louis Pasteur, Hôpitaux Universitaires de Strasbourg, France.
Antimicrob Agents Chemother. 2002 Dec;46(12):3782-9. doi: 10.1128/AAC.46.12.3782-3789.2002.
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.
本研究的目的是调查阿莫西林-克拉维酸对产β-内酰胺酶的大肠杆菌菌株的潜在杀菌活性，并阐明酶产生对活性的影响程度。六只成年尤卡坦小型猪静脉注射1.1g阿莫西林-克拉维酸，静脉输注30分钟。测定血清样本的药代动力学参数，并与已发表的人类数据（静脉注射剂量2.2g）进行比较。两种物种的参数具有可比性，因此，小型猪构成了阿莫西林-克拉维酸药效学研究的良好模型。因此，该模型被用于阿莫西林-克拉维酸对四种不同水平产β-内酰胺酶的大肠杆菌菌株的体外药效学研究。将大肠杆菌菌株与药代动力学研究中血清样本的系列稀释液（1:2至1:256）一起培养，并在暴露1、3和6小时后测定存活细菌的数量。低于最低抑菌浓度和最低杀菌浓度的阿莫西林-克拉维酸对产生低水平青霉素酶的菌株具有显著的杀菌效力。对于高产或中产β-内酰胺酶的菌株，证明存在1.5至2μg/ml的克拉维酸浓度阈值，低于该阈值则没有杀菌活性。存活细菌指数表明阿莫西林（在克拉维酸存在下）存在浓度和时间依赖性的联合作用，其随测试菌株产生的β-内酰胺酶量的变化而变化。本研究表明阿莫西林-克拉维酸对低水平和中等水平产青霉素酶的大肠杆菌菌株有效。这些发现有待在小型猪实验感染模型中得到证实。
