用蒙特卡洛模拟优化耐甲氧西林金黄色葡萄球菌感染的肾功能不全低龄患儿万古霉素的给药方案

Optimum dosage regimen of vancomycin in MRSA-infected young children with various renal dysfunction based on Monte Carlo Simulation

目的应用蒙特卡洛模拟评价万古霉素在肾功能正常与不全低龄耐甲氧西林金黄色葡萄球菌(MRSA)感染患儿中的给药方案。方法收集2013—2014年成都地区万古霉素对MRSA菌株的最低抑菌浓度值(MIC)和其在2个月~2岁中国低龄患儿中药动学资料,经Crystal Ball软件模拟5 000例次得到相应目标获得概率(PTA)与累计反应分数(CFR)。结果万古霉素对MRSA的MIC分布频率,MIC为0.03、0.06、0.12、0.25、0.50 mg·L^(-1)时各占12.79%,MIC为1、2 mg·L^(-1)时各占29.07%、6.98%。万古霉素达满意抗菌活性的最低剂量:肾功能正常者(A组),MIC为0.03~0.06、0.12和0.25 mg·L^(-1)时分别予30、37.5和80 mg·kg^(-1)·d^(-1),MIC为0.5~2 mg·L^(-1)时即使80 mg·kg^(-1)·d^(-1)也不能达满意抗菌活性;肾功能轻度不全者[B组,估算的肾小球滤过率(e GFR)为60~89 m L·min^(-1)·1.73 m^(-2)],MIC为0.03~0.12、0.25和0.5 mg·L^(-1)时分别予30、40和80 mg·kg^(-1)·d^(-1),MIC为1~2 mg·L^(-1)时即使80 mg·kg^(-1)·d^(-1)也不能达满意抗菌活性;肾功能中度不全者(C组,e GFR为30~59 m L·min^(-1)·1.73 m^(-2)),MIC为0.03~0.25、0.5 mg·L^(-1)时分别予30、50 mg·kg^(-1)·d^(-1),MIC为1~2 mg·L^(-1)时即使80 mg·kg^(-1)·d^(-1)也不能达满意抗菌活性。各方案下A、B组对MRSA的CFR均<90%。结论感染MRSA的肾功能正常与轻度不全低龄患儿经验性应用万古霉素时可考虑联合用药,结合各MIC分布频率和达满意抗菌活性的最低剂量可知,大多数肾功能正常低龄患儿按40 mg·kg^(-1)·d^(-1)给药剂量偏低,绝大多数肾功能中度不全者应用50~80 mg·kg^(-1)·d^(-1)可获得满意抗菌活性。

Objective To optimize dosage regimen of vancomycin in MRSA-infected young children with various renal dysfunction using Monte Carlo simulation. Methods The MIC distribution for vancomycin against MRSA in Chengdu during 2012—2014 and the popula-tion pharmacokinetic data of vancomycin reported previously were collected. The PTA and CFR of 5000 patients were simulated by u-sing Crystal Ball software. Results The MIC distribution of vancomycin against MRSA was 12. 79% for 0. 03,0. 06,0. 12,0. 25,0. 50 mg·L - 1 and 29. 07% for 1 mg·L - 1 ,6. 98% for 2 mg·L - 1 ,respectively. The lowest dose of vancomycin with satisfactory antibacteri-al activity was as follows：For normal renal function（group A）,if MIC between 0. 03-0. 06,0. 12 and 0. 25 mg·L - 1 ,vancomycin dos-age will be 30,37. 5 and 80 mg·kg - 1 ·d - 1;while MIC between 0. 5-2 mg·L - 1 ,giving vancomycin 80 mg·kg - 1 ·d - 1 could not a-chieve a satisfactory antibacterial activity. For mild renal insufficiency（group B,eGFR = 60-89 mL·min - 1 ·1. 73 m - 2 ）,if MIC be-tween 0. 03-0. 12,0. 25 and 0. 5 mg·L - 1 ,vancomycin dosage will be 30,40 and 80 mg·kg - 1 ·d - 1;while MIC between 1-2 mg· L - 1 ,80 mg·kg - 1 ·d - 1 could not achieve a satisfactory antibacterial activity. For moderate renal insufficiency（group C,eGFR = 30-59 mL·min - 1 ·1. 73 m - 2 ）,if MIC between 0. 03-0. 25 and 0. 5 mg·L - 1 ,vancomycin dosage will be 30 and 50 mg·kg - 1 ·d - 1;while MIC between 1-2 mg·L - 1 ,80 mg·kg - 1 ·d - 1 could not achieve a satisfactory antibacterial activity. The CFR were both 〈 90% in group A and B. Conclusions Drug combination should be considered for MRSA-Infected young children with normal renal function and mild renal insufficiency. 40 mg·kg - 1 ·d - 1 is insufficient to achieve target levels in most pediatric patients with normal renal func-tion. For the patients with moderate renal impairment,almost all obtained satisfactory antibacterial activity at 50-80 mg·kg - 1 ·d - 1 .