蒙特卡洛模拟评价革兰阴性菌感染的β-内酰胺给药方案

Evaluation of β-lactam treatment regimens for Gram-negative infections using Monte Carlo simulation

为评价7种β-内酰胺药物对革兰阴性菌感染的给药方案,本文用药动学/药效学的蒙特卡洛模拟,获取药效学指标(f%T>MIC)的累积效应分数(CFR)。其中,亚胺培南/西司他丁、美罗培南的CFR最高,二者0.5gtid对铜绿假单胞菌的抑菌CFR分别为76.12%和80.56%,而敏感率为74.7%和78.4%,对产超广谱β-内酰胺酶(ESBLs)菌和易产头孢菌素酶(AmpC)菌株的杀菌CFR和敏感率均达100%;头孢他啶1gtid对产ESBLs肺炎克雷伯菌、哌拉西林钠/三唑巴坦钠3.375gqid对鲍曼不动杆菌的抑菌CFR(53.89%、47.59%)与敏感率(53.2%、47.5%)基本一致;增加头孢吡肟的剂量和给药次数可提高CFR值,2gtid对产气肠杆菌、枸橼酸杆菌属的杀菌CFR为92.83%、96.99%,大于敏感率(67.3%、78.8%)。因此,对产ESBLs菌和易产AmpC酶菌株,选用方案为亚胺培南/西司他丁0.5gtid或美罗培南0.5gtid;对产ESBLs大肠埃希菌,可选哌拉西林钠/三唑巴坦钠3.375gq4h;对产气肠杆菌、枸橼酸杆菌属,或选用头孢吡肟2gtid;对铜绿假单胞菌、鲍曼不动杆菌感染的经验治疗需考虑联合用药。基于PK/PD的蒙特卡洛模拟,可用以评价抗感染治疗的效果,优化给药方案设计。

The Monte Carlo simulation based on pharmacokinetics/pharmacodynamics was used to get the cumulative fraction of response（CFR）of pharmacodynamic target（f%T〉MIC）to evaluate the treatment regimens of sevenβ-lactams for Gram-negative infections.The CFRs of imipenem/cilastatin and meropenem were the highest,both antibacterial CFRs of 0.5 g tid against Pseudomonas aeruginosa were 76.12%and 80.56%,respectively.Meanwhile the sensitivity rates were 74.7%and 78.4%.All of bactericidal CFRs and sensitivity rates reached 100%for producing ESBLs strains and producing AmpC enzyme strains.The antibacterial CFRs of ceftazidime 1 g tid against producing ESBLs Klebsiella pneumoniae（53.89%）and piperacillin sodium/tazobactam sodium 3.375 g qid against Acinetobacter baumannii（47.59%）were basically coincident with the sensitivity rates（53.2%,47.5%）,the CFRs of cefepime were improved with the dose and frequency increased,and the bactericidal CFRs of cefepime 2 g tid（92.83%,96.99%）were higher than the sensitivity rates（67.3%,78.8%）against Enterobacter aerogenes and Citrobacter spp.For these reasons,imipenem/cilastatin 0.5 g tid or meropenem 0.5 g tid may be selected against producing ESBLs strains and producing AmpC enzyme strains,or piperacillin sodium/tazobactam sodium 3.375 g q4h against producing ESBLs Escherichia coli,or cefepime 2 g tid against Enterobacter aerogenes and Citrobacter spp.The drug combination should be considered for theβ-lactam empirical treatment of Pseudomonas aeruginosa infection and Acinetobacter baumannii infection.Monte Carlo simulation based on PK/PD can be used to evaluate the effect of anti-infective treatment,and optimize the antibiotic dosage design.