Dalla Costa T, Nolting A, Rand K, Derendorf H
Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Int J Clin Pharmacol Ther. 1997 Oct;35(10):426-33.
The aim of the study was to investigate the in vitro antiinfective effect of piperacillin-tazobactam (PIP-TZB) combinations on Escherichia coli in simulations of free concentration time profiles of both drugs, similar to those obtained in human tissue after i.v. bolus administrations.
An in vitro dilution model was used to expose E. coli ATCC 35218 (beta-lactamase producer) to various piperacillin-tazobactam concentration profiles obtained after i.v. bolus multiple dose, using different dose ratio combinations (1:4, 1:8, 1:16) and dosing regimens, ranging from once-a-day to 4 times a day. The antimicrobial effect was evaluated by determination of the number of bacteria over time. The concentration of PIP in the model was determined by HPLC.
A modified Emax model was used to describe the pharmacodynamic effect. The model was linked with the piperacillin concentrations determined experimentally to provide a pharmacokinetic-pharmacodynamic (PK-PD) model. The EC50 for piperacillin alone averaged 5.66 +/- 0.29 micrograms/ml. The EC50 for all doses of piperacillin combined with 0.5 g of tazobactam were dose-dependent and averaged 1.70 +/- 0.56, 3.95 +/- 1.02, and 6.14 +/- 1.24 micrograms/ml for PIP 2, 4, and 8 g, respectively. By increasing the dose of TZB in combination with a fixed dose of PIP, a decreased EC50 was observed.
The PK-PD model allowed a detailed evaluation of the dosing regimens investigated. The results suggested that for these combinations, 3 times a day administration is as effective as 4 times a day. Pharmacodynamic activity of the combinations can be prolonged by sufficiently high inhibitor concentrations.
本研究旨在模拟静脉推注给药后人体组织中哌拉西林-他唑巴坦（PIP-TZB）两种药物的游离浓度-时间曲线，研究其对大肠杆菌的体外抗感染作用。
采用体外稀释模型，将大肠埃希菌ATCC 35218（β-内酰胺酶产生菌）暴露于静脉推注多次给药后获得的不同哌拉西林-他唑巴坦浓度曲线下，使用不同剂量比组合（1:4、1:8、1:16）和给药方案，给药频率从每日1次至每日4次。通过测定不同时间的细菌数量来评估抗菌效果。模型中PIP的浓度通过高效液相色谱法测定。
采用改良的Emax模型描述药效学效应。该模型与实验测定的哌拉西林浓度相关联，以提供药代动力学-药效学（PK-PD）模型。单独哌拉西林的EC50平均为5.66±0.29微克/毫升。所有剂量的哌拉西林与0.5克他唑巴坦联合使用时，EC50呈剂量依赖性，哌拉西林2克、4克和8克时的EC50分别平均为1.70±0.56、3.95±1.02和6.14±1.24微克/毫升。通过增加他唑巴坦剂量与固定剂量的哌拉西林联合使用，观察到EC50降低。
PK-PD模型允许对所研究的给药方案进行详细评估。结果表明，对于这些组合，每日3次给药与每日4次给药效果相同。足够高的抑制剂浓度可延长组合药物的药效学活性。
