Kuti Joseph L, Horowitz Sheryl, Nightingale Charles H, Nicolau David P
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut 06102, USA.
Pharmacotherapy. 2005 Jul;25(7):935-41. doi: 10.1592/phco.2005.25.7.935.
To compare the pharmacodynamics of two beta-lactams--ceftazidime and meropenem--in healthy subjects versus patients.
Monte Carlo simulation based on published pharmacokinetic studies.
One hundred and ninety-seven participants (75 healthy volunteers and 122 patients) from published pharmacokinetic studies of ceftazidime or meropenem.
Data on total body clearance and volume of distribution for ceftazidime and meropenem in healthy subjects and patients were obtained from published studies. Monte Carlo simulations were performed based on the pharmacokinetics from each study for ceftazidime 1000 mg every 8 hours and meropenem 1000 mg every 8 hours against isolates of Escherichia coli , Klebsiella pneumoniae , Acinetobacter baumannii , and Pseudomonas aeruginosa collected from North and South America. We calculated the likelihood of obtaining bactericidal exposures (50% time above the minimum inhibitory concentration [MIC] for ceftazidime and 40% time above the MIC for meropenem) for each combination of pharmacokinetic study data and MIC distribution. Linear regression was used to compare target attainments for healthy subjects versus patients. Only three drug-pathogen combinations differed in target attainment between healthy subjects and patients: ceftazidime against P. aeruginosa in North America and meropenem against E. coli and P. aeruginosa in South America. The regression line of target attainment for patients versus healthy subjects had a slope of 1.04 (95% confidence interval [CI] 0.983-1.093) and a y intercept of -3.73 (95% CI -8.265-0.827, r2 = 0.992). The beta values for slope and intercept did not differ to a statistically significant extent between the regression line and the line of identity (p=0.264).
The pharmacodynamic target attainment calculated with healthy subject pharmacokinetic data was predictive of patient target target attainment for ceftazidime and meropenem.
比较两种β-内酰胺类药物（头孢他啶和美罗培南）在健康受试者与患者中的药效学。
基于已发表的药代动力学研究进行蒙特卡洛模拟。
来自已发表的头孢他啶或美罗培南药代动力学研究的197名参与者（75名健康志愿者和122名患者）。
从已发表的研究中获取健康受试者和患者中头孢他啶和美罗培南的总体清除率和分布容积数据。基于每项研究的药代动力学，对来自北美和南美的大肠杆菌、肺炎克雷伯菌、鲍曼不动杆菌和铜绿假单胞菌分离株进行蒙特卡洛模拟，头孢他啶每8小时给药1000mg，美罗培南每8小时给药1000mg。我们计算了每种药代动力学研究数据与MIC分布组合获得杀菌暴露（头孢他啶高于最低抑菌浓度[MIC]的时间为50%，美罗培南高于MIC的时间为40%）的可能性。采用线性回归比较健康受试者与患者的目标达成率。健康受试者与患者之间只有三种药物-病原体组合的目标达成率存在差异：北美地区头孢他啶对铜绿假单胞菌，以及南美地区美罗培南对大肠杆菌和铜绿假单胞菌。患者与健康受试者目标达成率的回归线斜率为1.04（95%置信区间[CI]0.983-1.093），y轴截距为-3.73（95%CI -8.265-0.827，r2 = 0.992）。回归线与恒等线之间斜率和截距的β值在统计学上无显著差异（p = 0.264）。
用健康受试者药代动力学数据计算的药效学目标达成率可预测患者使用头孢他啶和美罗培南的目标达成情况。
