应用蒙特卡洛模拟评价哌拉西林钠/他唑巴坦在新生儿脓毒血症中给药策略的效果研究

Evaluation of the effect of dosing strategy of piperacillin sodium tazobactam in neonatal sepsis by using Monte Carlo simulation

目的评价哌拉西林钠/他唑巴坦在新生儿脓毒血症中的给药策略及效果,为临床制定合理治疗方案提供参考。方法基于药动学/药效学(pharmacokinetics/Pharmacodynamics,PK/PD)理论,应用蒙特卡洛模拟,分别以血药浓度高于4倍最低抑菌浓度(Minimal inhibit concentration,MIC)的时间(100%T>4MIC)和血药浓度高于MIC的时间(100%T>MIC)为PK/PD目标指数,结合新生儿脓毒血症常见细菌为目标菌群,分别对哌拉西林钠/他唑巴坦100 mg/kg Q8h不同静脉滴注时间的给药方案进行模拟,在给药后8 h内每个小时对抗各目标菌群达到PK/PD指数的累积反应分数(Cumulative fraction of response,CFR),以CFR≥90%来判断给药效果。结果以100%T>4MIC为目标指数,哌拉西林钠/他唑巴坦100 mg/kg Q8h静脉滴注30 min方案,对大肠埃希菌在给药2 h后不能达到CFR≥90%,对肺炎克雷伯菌在给药1 h后不能达到CFR≥90%,对其他目标菌群,在给药后8 h内的任意时间点均无法达标;静脉滴注至1 h的给药方案相比之前的给药方案仅提高了肺炎克雷伯菌在给药后2 h内的CFR,对其他目标菌群结果没有发生改变;延长静脉滴注方案至3 h,所有目标菌群的CFR均较前方案有所提升,其中对大肠埃希菌在给药后2 h内CFR仍可高于90%。若以100%T>MIC为目标指数,哌拉西林钠/他唑巴坦100 mg/kg Q8h静脉滴注30 min,对大肠埃希菌在给药4 h后不能达到CFR≥90%,对肺炎克雷伯菌在给药2 h后不能达到CFR≥90%,对其他目标菌群,在给药后8 h内的任意时间点均无法达标;静脉滴注至1 h的给药方案相比之前的给药方案对所有目标菌群的CFR均未发生改变;延长静脉滴注方案至3 h,所有目标菌群的CFR均较前方案有所提升,其中对大肠埃希菌、肺炎克雷伯菌在给药后3 h内CFR仍可高于90%。结论在现有的药物敏感数据下,哌拉西林钠/他唑巴坦在新生儿脓毒血症治疗中仍可作为首选,但目前100 mg/kg Q8 h,静脉滴注30 min或1 h的给药方案值得商榷,静脉滴注延长至3h可显著提高治疗效果,需要时可结合临床及时调整治疗方案。

Objective To evaluate the administration regimen and effect of piperacillin sodium tazobactam in neonatal sepsis and to provide reference for clinical rational formulation.Methods Based on pharmacodynamics/pharmacokinetics(PK/PD)theory,using Monte Carlo simulation,taking 100%T>4MIC and 100%T>MIC as PK/PD target indexes,and taking the common bacteria of neonatal sepsis as the target flora,simulate the administration of piperacillin sodium tazobactam 100mg/kg Q8h at different intravenous infusion time.The cumulative fraction of response(CFR)to achieve PK/PD target indexes against each target flora every hour within 8 hours after administration was obtained.The effect of administration was determined by CFR≥90%.Results Taking 100%T>4MIC as the target index,piperacillin sodium tazobactam“100 mg/kg Q8h for intravenous drip for 30 minutes could not reach CFR≥90%for Escherichia coli after 2 hours of administration,and for Klebsiella pneumoniae,it could not reach CFR≥90%after 1 hour of administration.For other target flora,it could not reach the standard at any time within 8 hours after administration.The regimen of extending intravenous drip to 1 hour regimen only improved the CFR of Klebsiella pneumoniae within 2 hours of administration,and the results of other target flora did not change.In the regimen of extending intravenous drip to 3 hours,CFR of all target bacteria were improved compared with the previous regimen,and CFR of Escherichia coli was still higher than 90%within 2 h after administration.Taking 100%T>MIC as the target index,piperacillin sodium tazobactam 100 mg/kg Q8h for intravenous drip for 30 minutes could not reach CFR≥90%for Escherichia coli after 4 hours of administration,and for Klebsiella pneumoniae,it could not reach CFR≥90%after 2 hours of administration.For other target flora,it could not reach the standard at any time within 8 hours after administration.The regimen of extending intravenous drip to 1 hour did not change the CFR of all target flora.In the regimen of extending intravenous drip to 3 hours,CFR of all target bacteria were improved compared with the previous regimen,and CFR of Escherichia coli and Klebsiella pneumoniae could still be higher than 90%within 3 hours after administration.Conclusion Based on the available drug sensitive data,piperacillin sodium tazobactam can still be used as the first choice in the treatment of neonatal sepsis.However,the current administration regimen of 100 mg/kg Q8h intravenous infusion for 30 min or 1 h should be discussed,extending the intravenous drip to 3 hours can significantly improve the therapeutic effect,and the treatment regimen should be adjusted based on clinical practice.