Kuti Joseph L, Florea Naomi R, Nightingale Charles H, Nicolau David P
Center for Anti-Infective Research and Development, Hartford Hospital, Connecticut 06102, USA.
Pharmacotherapy. 2004 Jan;24(1):8-15. doi: 10.1592/phco.24.1.8.34804.
To compare the pharmacodynamics of meropenem and imipenem, both administered as 500 mg every 6 hours, against populations of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa.
Ten thousand-subject Monte Carlo simulation.
Variability in total body clearance (ClT), volume of distribution as calculated by the terminal elimination rate (Vdbeta), and minimum inhibitory concentration (MIC) distributions (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, A. baumannii, P. aeruginosa) were derived from the literature for both meropenem and imipenem. For the free drug concentrations, the percentage of the dosing interval that the drug concentrations remain above the MIC (%T>MIC) for each carbapenem-bacteria combination was calculated for 10,000 iterations, substituting a different ClT, Vdbeta, fraction of unbound drug, and MIC into the equation each time based on the probability distribution for each parameter. Probabilities of attaining targets of 30%, 50%, and 100% T>MIC were calculated.
Meropenem free drug %T>MIC exposure was significantly greater than that of imipenem against Enterobacteriaceae and P. aeruginosa, whereas imipenem exposure was greater for A. baumannii. For both agents, free drug %T>MIC exposure was greatest against Enterobacteriaceae and less for A. baumannii and P. aeruginosa. Probabilities of target attainment for 30% and 50% T>MIC were similar between drugs for most bacteria. At 100% T>MIC, meropenem target attainments were greater than those of imipenem against Enterobacteriaceae and P. aeruginosa, and imipenem attainment was higher for A. baumannii.
The probability of attaining lower pharmacodynamic targets for most gram-negative bacteria is similar for these carbapenems; however, differences become apparent as the pharmacodynamic requirement increases. Further study of the benefits of achieving this pharmacodynamic breakpoint with a higher probability of attaining targets is necessary.
比较美罗培南和亚胺培南（均每6小时给药500mg）对肠杆菌科细菌、鲍曼不动杆菌和铜绿假单胞菌群体的药效学。
一万受试者的蒙特卡洛模拟。
从文献中获取美罗培南和亚胺培南的总体清除率（ClT）、由终末消除率计算的分布容积（Vdbeta）以及最低抑菌浓度（MIC）分布（大肠埃希菌、肺炎克雷伯菌、阴沟肠杆菌、粘质沙雷菌、鲍曼不动杆菌、铜绿假单胞菌）的变异性。对于游离药物浓度，针对每种碳青霉烯-细菌组合，计算药物浓度在给药间隔内高于MIC的百分比（%T>MIC），进行10000次迭代，每次根据每个参数的概率分布，将不同的ClT、Vdbeta、游离药物分数和MIC代入方程。计算达到30%、50%和100% T>MIC目标的概率。
美罗培南游离药物%T>MIC暴露量在对抗肠杆菌科细菌和铜绿假单胞菌时显著高于亚胺培南，而亚胺培南对鲍曼不动杆菌的暴露量更大。对于两种药物，游离药物%T>MIC暴露量对抗肠杆菌科细菌时最高，对鲍曼不动杆菌和铜绿假单胞菌时较低。对于大多数细菌，两种药物达到30%和50% T>MIC目标的概率相似。在100% T>MIC时，美罗培南对肠杆菌科细菌和铜绿假单胞菌的目标达成率高于亚胺培南，而亚胺培南对鲍曼不动杆菌的达成率更高。
对于大多数革兰阴性菌，这些碳青霉烯类药物达到较低药效学目标的概率相似；然而，随着药效学要求的提高，差异变得明显。有必要进一步研究以更高的目标达成概率达到该药效学折点的益处。
