Lister P D, Prevan A M, Sanders C C
Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
Antimicrob Agents Chemother. 1997 Apr;41(4):721-7. doi: 10.1128/AAC.41.4.721.
An in vitro pharmacokinetic model was used to study the pharmacodynamics of piperacillin-tazobactam and piperacillin-sulbactam against gram-negative bacilli producing plasmid-encoded beta-lactamases. Logarithmic-phase cultures were exposed to peak antibiotic concentrations observed in human serum after the administration of intravenous doses of 3 g of piperacillin and 0.375 g of tazobactam or 0.5 g of sulbactam. Piperacillin and inhibitor were either dosed simultaneously or piperacillin was dosed sequentially 0.5 h after dosing with the inhibitor. In studies with all four test strains, the pharmacodynamics observed after simultaneous dosing were similar to those observed with the sequential regimen. Since the ratio between piperacillin and tazobactam was in constant fluctuation after sequential dosing, these data suggest that the pharmacodynamics of the piperacillin-inhibitor combinations were not dependent upon maintenance of a critical ratio between the components. Furthermore, when regrowth was observed, the time at which bacterial counts began to increase was similar between the simultaneous and sequential dosing regimens. Since the pharmacokinetics of the inhibitors were the same for all regimens, these data suggest that the length of time that the antibacterial activity was maintained over the dosing interval with these combinations was dictated by the pharmacokinetics of the beta-lactamase inhibitor in the combination. The antibacterial activity of the combination appeared to be lost when the amount of inhibitor available fell below some critical concentration. This critical concentration varied depending upon the type and amount of enzyme produced, as well as the specific inhibitor used. These results indicate that the antibacterial activity of drug-inhibitor combinations, when dosed at their currently recommended ratios, is more dependent on the pharmacokinetics of the inhibitor than on those of the beta-lactam drug.
采用体外药代动力学模型研究哌拉西林 - 他唑巴坦和哌拉西林 - 舒巴坦对产生质粒编码β - 内酰胺酶的革兰氏阴性杆菌的药效学。对数生长期培养物暴露于静脉注射3 g哌拉西林和0.375 g他唑巴坦或0.5 g舒巴坦后在人血清中观察到的抗生素峰值浓度。哌拉西林和抑制剂要么同时给药，要么在给予抑制剂0.5小时后依次给予哌拉西林。在对所有四种测试菌株的研究中，同时给药后观察到的药效学与序贯给药方案观察到的相似。由于序贯给药后哌拉西林与他唑巴坦的比例不断波动，这些数据表明哌拉西林 - 抑制剂组合的药效学不依赖于各组分之间维持临界比例。此外，当观察到细菌再生长时，同时给药和序贯给药方案中细菌计数开始增加的时间相似。由于所有给药方案中抑制剂的药代动力学相同，这些数据表明这些组合在给药间隔期间维持抗菌活性的时间长度由组合中β - 内酰胺酶抑制剂的药代动力学决定。当可用抑制剂量降至某个临界浓度以下时，组合的抗菌活性似乎丧失。该临界浓度因产生的酶的类型和量以及所用的特定抑制剂而异。这些结果表明，按目前推荐比例给药时，药物 - 抑制剂组合的抗菌活性更多地取决于抑制剂的药代动力学，而不是β - 内酰胺药物的药代动力学。
