美罗培南对产碳青霉烯酶肠杆菌科细菌的药效学研究

Pharmacodynamics of Meropenem Against Carbapenemase-producing Enterobacteriaceae

关键词:  美罗培南  碳青霉烯酶  肠杆菌科  蒙特卡罗模拟  药效学

Key words:  meropenem  carbapenemase  enterobacteriaceae  Monte Carlo simulation  pharmacodynamics

摘要:

目的 评价美罗培南对产碳青霉烯酶肠杆菌科细菌（carbapenemase-producing Enterobacteriaceae，CPE）的药效学，为临床选择治疗方案提供参考。方法 选取CPE的MIC为0.5，1，2，4，8，16，32，64 mg·L^-1，从文献中获得美罗培南在健康志愿者和ICU老年患者中的药动学参数，应用蒙特卡罗模拟分析美罗培南的30 min传统输注（traditional infusion，TI）、3 h延长输注（prolonged infusion，PI）给药方案，具体为1 000 mg q6h TI、1 000 mg q6h PI、2 000 mg q8h TI、2 000 mg q8h PI、1500 mg q6h TI、1 500 mg q6h PI，比较不同给药方案获得的药效学达标概率（probability of target attainment，PTA）。结果 当药效学目标为40% T>MIC时，如美罗培南对CPE的MIC ≤ 4 mg·L^-1，在健康人中6种给药方案获得的PTA均为100%，在ICU老年患者中6种给药方案获得的PTA>97%；如美罗培南对CPE的MIC=8 mg·L^-1，在健康人中2 000 mg q8h PI、1 500 mg q6h TI、1 500 mg q6h PI 3种给药方案获得的PTA>90%，分别为100%，99.48%，100%，在ICU老年患者中6种给药方案获得的PTA均>90%；如美罗培南对CPE的MIC=16 mg·L^-1，在健康人中6种给药方案获得的PTA均<16%，在ICU老年患者中6种给药方案获得的PTA<90%。如美罗培南对CPE的MIC=8 mg·L^-1，当药效学目标为100% T>MIC时，在ICU老年患者中1 500 mg q6h PI获得最高的PTA，为61.62%，其次为2 000 mg q8h PI，获得的PTA为46.95%。结论 当美罗培南对CPE的MIC ≤ 8 mg·L^-1时，适合应用美罗培南进行治疗。选用高剂量PI方案可获得更高的药效学PTA，1 500 mg q6h PI可能为最理想的给药方案，可作为治疗CPE时的经验治疗方案。

Abstract:

OBJECTIVE To evaluate the pharmacodynamics of meropenem against carbapenemase-producing Enterobacteriaceae(CPE) and provide reference for clinical treatment. METHODS The MIC of CPE was 0.5, 1, 2, 4, 8, 16, 32, and 64 mg·L^-1. Pharmacokinetic parameters of meropenem in healthy volunteers and elderly patients in ICU were obtained from the literature. Monte Carlo simulation was performed to analyze 30 min traditional infusion (TI) and 3 h prolonged infusion (PI) of meropenem. Dosing regimens of 1 000 mg q6h TI, 1 000 mg q6h PI, 2 000 mg q8h TI, 2 000 mg q8h PI, 1 500 mg q6h TI, and 1 500 mg q6h PI were used to compare probability of target attainment(PTA). RESULTS When the pharmacodynamic target was 40%T> MIC, if the MIC of meropenem for CPE did not exceed 4 mg·L^-1, the PTA obtained by six regimens in healthy people was 100%, and the PTA obtained by six regimens in elderly ICU patients was more than 97%. If the MIC of meropenem for CPE was 8 mg·L^-1, the PTA obtained by three regimens of 2 000 mg q8h PI, 1 500 mg q6h TI and 1 500 mg q6h PI in healthy people were 100%, 99.48%, and 100% respectively, while the PTA obtained by the six regimens in elderly ICU patients was more than 90%. If the MIC of meropenem for CPE was 16 mg·L^-1, the PTA obtained by the six regimens in healthy people was less than 16%, and the PTA obtained by the six regimens in elderly ICU patients was less than 90%. When the pharmacodynamic target was 100%T>MIC, if the MIC of meropenem for CPE was 8 mg·L^-1, the highest PTA was obtained in the elderly ICU patients with 1500 mg q6h PI (61.62%), followed by 2 000 mg q8h PI(46.95%). CONCLUSION When the MIC of meropenem for CPE does not exceed 8 mg·L^-1, meropenem is suitable for treatment. High-dose regimen of PI can achieve optimum PTA. Meropenem regimen of 1 500 mg q6h PI may be the most ideal drug regimen and can be recommended as an empirical treatment regimen for CPE.