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蒙特卡洛模拟在碳青霉烯类耐药菌感染头孢他啶-阿维巴坦给药方案评价中的应用
作者:王李1  房晓伟2  耿士窠2  潘爱军2  梅清2 
单位:1. 中国人民解放军联勤保障部队第901医院 急诊科, 安徽 合肥 230031;
2. 中国科学技术大学附属第一医院 重症医学科, 安徽 合肥 230001
关键词:头孢他啶 阿维巴坦 耐碳青霉烯类肠杆菌 耐碳青霉烯类铜绿假单胞菌 药代动力学 药效学 蒙特卡洛模拟 
分类号:R978.1
出版年·卷·期(页码):2020·39·第三期(281-286)
摘要:

目的:评价头孢他啶-阿维巴坦(CAZ-AVI)对耐碳青霉烯类肠杆菌(CRE)和耐碳青霉烯铜绿假单胞菌(CRPA)感染的有效性,优化其给药方案。方法:采用微量肉汤稀释法测定CAZ-AVI对392株CRE和149株CRPA的最低抑菌质量浓度(MIC)。采用蒙特卡洛模拟CAZ-AVI的3种给药方案(3 000 mg+750 mg q8h、2 000 mg+500 mg q8h、1 000 mg+250 mg q8h)达到药效学目标(%f T>MIC>70%)的可能性。每种方案的模拟依据肾功能水平进行分层分析,计算给药方案在特定MIC值获得的达标概率(PTA),并计算菌株群体对目标阈值的累积反应分数(CFR)。结果:CAZ-AVI对392株CRE的MIC50和MIC90分别为2 mg·L-1和 ≥ 128 mg·L-1;对149株CRPA的MIC50和MIC90分别为4 mg·L-1和 ≥ 128 mg·L-1。蒙特卡洛模拟结果显示,当MIC ≤ 8 mg·L-1时,常规剂量(2 000 mg)CAZ可使得所有患者获得>90%的PTA。当药物剂量增加至3 000 mg时,仅使MIC为16 mg·L-1且肌酐清除率(CRCL)>120 ml·min-1患者的PTA从38.6%提升至84.1%,而其他类型患者的获益增加不显著。对CRCL<60 ml·min-1的患者,仅需低剂量(1 000 mg)CAZ即可使得MIC ≤ 8 mg·L-1的患者获得100%的PTA。对于AVI,仅当CRCL>120 ml·min-1时,低剂量(250 mg)的方案难以获得理想的PTA值(22.2%),其余方案均可获得 ≥ 90%的PTA。但总体来看,没有任何一种给药方案可以获得80%以上的CFR。结论:CAZ-AVI对CRE和CRPA具有一定的抗菌活性,但在临床实际应用时应依据菌株敏感性和患者的肾功能水平制定个体化治疗方案。

Objective:To evaluate the efficacy of ceftazidime- avibactam (CAZ-AVI) for the treatment of carbapenem resistant Enterobacteriaceae (CRE) or carbapenem resistant Pseudomonas aeruginosa (CRPA) infections, and then optimize the drug administration. Methods:The minimal inhibitory concentration (MIC) of CAZ-AVI against 392 CRE isolates and 149 CRPA isolates were determined by broth microdilution method. A series of Monte Carlo simulations was performed to evaluate the possibility of achieving the pharmacodynamic target (%f T>MIC>70%) of the three CAZ-AVI regimens (3 000 mg+750 mg q8h, 2 000 mg+500 mg q8h, 1 000 mg+250 mg q8h). The simulation of each scheme was based on the level of renal function. The probability of target attainment (PTA) of the regimens was calculated at the fixed MIC value, and cumulative fraction of response (CFR) of the bacterial population to the threshold was also calculated. Results:The MIC50 and MIC90 against CRE was 2 mg·L-1 and ≥ 128 mg·L-1 respectively, and those against CRPA was 4 mg·L-1 and ≥ 128 mg·L-1, respectively. Monte Carlo simulation results showed that when MIC ≤ 8 mg·L-1, all patients could benefit from the conventional dose (2 000 mg) of CAZ and obtain a PTA of>90%.When the dosage was increased to 3 000 mg, the PTA of patients with MIC=16 mg·L-1 and creatinine clearance (CRCL) >120 ml·min-1 were increased from 38.6% to 84.1%, whereas the benefit of other patients was not increased significantly. For patients with CRCL< 60 ml·min-1, only a low dose (1 000 mg) of CAZ was needed to get a PTA of 100% when they infected with MICs of ≤ 8 mg·L-1. For AVI, most schemes obtained a PTA of ≥ 90%, except when the low dose (250 mg) was administrated to patients with CRCL of >120 ml·min-1 (PTA=22.2%). However, in general, there was no regimen that could obtain a CFR of higher than 80%. Conclusion:CAZ-AVI showed certain antibacterial activity against CRE and CRPA. The individual treatment should be made according to the sensitivity of strains and the level of patients' renal function.

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