Turnidge J D
Department of Microbiology and Infectious Diseases, Monash Medical Centre, Clayton, Victoria, Australia.
Diagn Microbiol Infect Dis. 1995 May-Jun;22(1-2):57-69. doi: 10.1016/0732-8893(95)00071-h.
Information about the pharmacodynamics of beta-lactams has accumulated rapidly over the last 20 years, and their application to cefotaxime are discussed in this review. Application of pharmacodynamics requires an integration of the pharmacokinetic and in vitro properties of the agent. Cefotaxime is similar to other beta-lactams in that it has little concentration-dependent killing and produces no postantibiotic effect against Gram-negative bacteria. However, it has a microbiologically active metabolite, deascetylcefotaxime, which can show synergy, partial synergy, or an additive effect in combination with the parent drug. More than any other technique, animal models have been able to elucidate the pharmacokinetic parameters that predict efficacy in vivo. They have shown that for beta-lactams it is the time that levels exceed the minimum inhibitory concentration (MIC) that is the most important determinant of efficacy. For bacteria to have no postantibiotic effect, plasma levels need to exceed the MIC for the whole of the dosing interval to achieve maximum killing at the site of infection. When applying these concepts as the most stringent criteria for efficacy using pharmacokinetic values from young, healthy volunteers, it can be shown that organisms with MICs of < or = 0.03 microgram/ml for a 1-g dose and 0.06 microgram/ml for a 2-g dose to achieve optimum efficacy with 12-h dosing of cefotaxime. However, two clinical studies have demonstrated trough levels much greater than would be predicted from these pharmacokinetic values, as a result of the effects of decreased renal function accompanying sepsis and older age. These studies showed that organisms with MICs < or = 1 microgram/ml for a 1-g dose or 2 micrograms/ml for a 2-g 12-h dose were covered for the whole of the dosing interval. Thus, all strains of Enterobacteriaceae and pathogenic Neisseria spp. that lack resistance mechanisms to third-generation cephalosporins would be covered using 12-h dosing schedules.
在过去20年里，关于β-内酰胺类药物药效学的信息迅速积累，本综述将讨论其在头孢噻肟上的应用。药效学的应用需要整合药物的药代动力学和体外特性。头孢噻肟与其他β-内酰胺类药物相似，其浓度依赖性杀菌作用较弱，对革兰氏阴性菌无抗生素后效应。然而，它有一个具有微生物活性的代谢产物，去乙酰头孢噻肟，与母体药物联合使用时可表现出协同、部分协同或相加作用。动物模型比任何其他技术都更能阐明预测体内疗效的药代动力学参数。研究表明，对于β-内酰胺类药物，药物水平超过最低抑菌浓度（MIC）的时间是疗效的最重要决定因素。为使细菌无抗生素后效应，血浆水平需要在整个给药间隔内超过MIC，以在感染部位实现最大杀菌效果。当将这些概念作为使用年轻健康志愿者药代动力学值的最严格疗效标准时，可以发现，对于1g剂量的头孢噻肟，MIC≤0.03μg/ml、2g剂量的MIC≤0.06μg/ml的微生物，采用每12小时给药方案可实现最佳疗效。然而，两项临床研究表明，由于脓毒症和老年导致肾功能下降所产生的影响，谷浓度远高于根据这些药代动力学值所预测的水平。这些研究表明，对于1g剂量的MIC≤1μg/ml或2g 12小时剂量的MIC≤2μg/ml的微生物，在整个给药间隔内均能被覆盖。因此，所有缺乏对第三代头孢菌素耐药机制的肠杆菌科菌株和致病性奈瑟菌属菌株，采用每12小时给药方案均可被覆盖。
