摘要目的 评价多黏菌素E甲磺酸钠(CMS)对感染泛耐药鲍曼不动杆菌(PDR-AB)或泛耐药铜绿假单胞菌(PDR-PA)重症患者的有效性及安全性.方法 筛选安徽省细菌耐药监测中心2012年9月至2015年9月收集的全省35家二级及以上医院重症加强治疗病房(ICU)分离的321株PDR-AB及204株PDR-PA,采用E试验检测多黏菌素E对PDR-AB及PDR-PA的最低抑菌浓度(MIC).采用蒙特卡罗方法模拟CMS的3种给药方案(1 MU q8h、2 MU q8h、3 MU q8h,MU为百万单位)达到药效学目标〔24 h药-时曲线下面积/MIC比值(AUC24/MIC)>60〕及出现药物相关性肾损伤的可能性,每种给药方案的模拟均依据患者的肾功能水平〔肌酐清除率(CLCr)分别为<60、≥60~90、≥90~120 mL/min〕进行分层分析.计算给药方案在特定MIC值获得的目标概率,即达标概率(PTA);并计算菌株群体对目标阈值的期望概率,即累积反应分数(CFR),选择其数值≥90%或≥80%作为最佳给药方案或次优给药方案;采用3种给药方案的稳态平均血药浓度达到4 mg/L以上的概率间接反映肾损伤事件的发生率.结果 多黏菌素E对321株PDR-AB及204株PDR-PA均敏感,对PDR-AB的MIC50和MIC90分别为0.5 mg/L和1.0 mg/L,对PDR-PA的MIC50和MIC90分别为0.5 mg/L和1.5 mg/L.采用建议剂量CMS(1 MU q8h)治疗CLCr<60 mL/min患者时,可获得较为理想的CFR(CFR-AB、CFR-PA分别为89.78%和81.06%),但伴随肾损伤的可能性高达32.51%,且对于MIC≥1 mg/L的菌株仍无法达到理想的疗效(PTA<66.56%);而该方案对于CLCr≥60~120 mL/min的患者无法获得满意的CFR(CFR-AB为56.97%~69.31%,CFR-PA为44.76%~56.94%).当CMS剂量增加至2 MU q8h时,CLCr≥60~120 mL/min的患者可以获得较高的CFR(77.45%~92.87%)和较低的肾损伤发生风险(<0.15%),但对于MIC≥1 mg/L的菌株PTA<75.36%.即使是肾功能正常(CLCr≥90~120 mL/min)的患者,最高剂量(3 MU q8h)也能获得较高的CFR(>89.24%),仅当感染菌株的MIC≥1.5 mg/L时PTA<76.20%,但伴随而来的是无法接受的肾损伤发生风险(>33.68%).结论 依据细菌的敏感性和患者的肾功能水平,在治疗过程中监测CMS药物浓度,才能在获得较好的抗感染疗效的同时保障药物使用的安全性.

abstractsObjective To evaluate the efficacy and safety of colistimethate sodium (CMS) for the treatment of critical patients infected by pan-drug resistantAcinetobacter baumannii (PDR-AB) or pan-drug resistant Pseudomonas aeruginosa (PDR-PA).Methods 321 isolates of PDR-AB and 204 isolates of PDR-PA from critical patients admitted to 35 intensive care units (ICUs) of grade two or above were collected from the Anhui Antimicrobial Resistance Investigation Net (AHARIN) program from September 2012 to September 2015, while the minimal inhibitory concentrations (MIC) of colistin were determined by the E-test. A series of Monte Carlo simulations was performed for CMS regimens (1 MU q8h, 2 MU q8h, and 3 MU q8h, and MU meant a million of unit), and the probability of achieving a 24-hour area under the drug concentration time curve (AUC24)/MIC ratio > 60 and risk of nephrotoxicity for each dosing regimen was calculated. Each simulation was run over three CLCr ranges: < 60, ≥ 60-90, ≥ 90-120 mL/min. The probability of target attainment (PTA)for the AUC24/MIC ratio was calculated using the partial MIC value, while the cumulative fraction of response (CFR) was determined by integrating each PTA with the MIC distributions, the value greater than or equal to 90% or more than 80% was set as the optimal dosing regimen or suboptimal dosing regimen respectively. The probability of average 24-hour serum concentrations up to 4 mg/L for three dosage regimens was used to predict the risks of nephrotoxicity.Results All 321 isolates of PDR-AB and 204 isolates of PDR-PA were susceptible to colistin, the MIC50/90 against PDR-AB were 0.5mg/L and 1.0 mg/L, and those against PDR-PA were 0.5 mg/L and 1.5 mg/L, respectively. When recommended dose (1 MU q8h) was used for patients with CLCr of < 60 mL/min, high CFR value (89.78% for PDR-AB, 81.06% for PDR-PA) were obtained, but with a high risks of nephrotoxicity (> 32.51%). Moreover, low value of PTA (< 66.56%) was yielded for isolates with MIC of ≥ 1 mg/L. Recommended dose also yielded a low CFR value (56.97%-69.31% for PDR-AB, 44.76%-56.94% for PDR-PA) in patients with CLCr of ≥ 60-120 mL/min. When dose was increased to 2 MU q8h, CFR (77.45%-92.87%) and the risks of nephrotoxicity (< 0.15%) was optimal for patients with CLCr ≥ 60-120 mL/min, but low value of PTA (< 75.36%) was also yielded for isolates with MIC of ≥ 1 mg/L. The most aggressive dose of 3 MU q8h provided high CFR (> 89.24%) even in patients with CLCr ≥ 90-120 mL/min, and PTA was < 76.20% only for isolates with MIC of ≥ 1.5 mg/L, but this dosing scheme was associated with unacceptable risks of nephrotoxicity (> 33.68%).Conclusion Measurement of MIC, individualized CMS therapy and therapeutic drug-level monitoring should be considered to achieve the optimal drug exposure and ensure the safety of CMS.