亚胺培南、美罗培南、头孢哌酮-舒巴坦和哌拉西林-他唑巴坦对医院获得革兰阴性菌感染治疗方案的蒙特卡洛模拟评估

The reliability of using impenem, meropenem, cefoperazone-sulbactam and piperacillin-tazobactam to treat nosocomial Gram-negative bacterial infections with Monte Carlo simulation

目的 通过蒙特卡洛模拟评估亚胺培南、美罗培南、头孢哌酮-舒巴坦、哌拉西林-他唑巴坦对医院获得革兰阴性菌感染治疗方案的合理性.方法 收集医院感染的革兰阴性菌,肉汤稀释法测定MIC,与4种药物常用给药方案所得的药代动力学参数进行蒙特卡洛模拟,评估给药方案的合理性.结果 共收集菌株2 541株,其中肠杆菌科2 093株,非发酵菌448株;亚胺培南和美罗培南对肠杆菌科细菌的MIC90多低于1 mg/L,两个复方制剂则多为64 mg/L;4种药物对鲍曼不动杆菌MIC50在32 mg/L以上.蒙特卡洛模拟发现,碳青霉烯类药物累计应答率（CFR）明显高于复方制剂,亚胺培南和美罗培南1g8h1次给药所获得CFR分别为74.69％和81.42％,头孢哌酮-舒巴坦2g8h1次和哌拉西林-他唑巴坦4g6h1次（两药剂量均指不含酶抑制剂的剂量）CFR分别为49.59％和27.66％.结论 亚胺培南和美罗培南适合于临床针对革兰阴性菌院内感染的经验治疗,哌拉西林-他唑巴坦需要增加剂量或者延长输注时间获得满意的药物浓度高于MIC的时间（T＞ MIC）;头孢哌酮-舒巴坦需要更多研究以确定其临床应用方案的有效性.

Objective To evaluate the reliability of using imipenem,meropenem,cefoperazonesulbactam,piperacillin-tazobactam in the treatment of hospital-acquired Gram-negative bacterial infections with Monte Carlo simulation（MCS）.Methods The MIC of the four agents collected from hospital-acquired infections were detected in accordance with broth dilution method of Clinical and Laboratory Standard Institute （CLSI）.MCS were conducted with MICs and the pharmacokinetics parameters of the four agents based on conventional dose regimens.The cumulative fraction of response （CFR） of time over MIC target attainment in different dosing regimen were generated.Results A total of 2 541 strains,including 2 093 strains of Enterobacteriaceae and 448 strains of glucose non-fermentative bacilli were collected.The MIC90 of imipenem and meropenem against Enterobacteriaceae were less than 1 mg/L in general,whereas MICg0 of two agents with β-1actamase inhibitors was around 64 mg/L.As to glucose non-fermenting bacteria,MICs of all the four agents were very high,especially to Acinetobacter baumannii,which indicated MIC50 more than 32 mg/L.MCS revealed that carbapenems had significantly higher CFR than those with β-1actamase inhibitors.Imipenem and meropenem （1 g,q8 h） obtained CFRs of 74.69% and 81.42%,respectively.The CFR of cefoperazone-sulbactam （2 g,q8 h） and piperacillin-tazobactam （4 g,q6 h） （both excluding β-1actamase inhibitors） were just 49.59% and 27.66% respectively,which increased after excluding A.baumannii in piperacillin-tazobactam.Conclusions The conventional dose regimens of imipenem and meropenem are reliable for the empiric therapy of Gram-negative hospital-acquired bacterial infections.Piperacillin-tazobactam is suggested to use with higher doses or prolonged infusion time to satisfy the time of drug concentration exceeded the MIC （T 〉 MIC） requirement.More clinical studies of cefoperazone-sulbactam should be conducted to optimize its regimen and guarantee its efficacy.