基于PK/PD理论及蒙特卡洛模拟评价和优化产超广谱β-内酰胺酶细菌的抗感染治疗方案

Evaluation and optimization of anti-infective therapeutic regimens of extended-spectrumβ-lactamases-producing bacteria based on PK/PD theory and Monte Carlo simulation

目的:分析评价不同抗菌药物给药方案对产超广谱β-内酰胺酶(extended-spectrumβ-lactamases,ESBLs)细菌的抗感染效果,为制订及优化抗菌药物治疗方案提供参考。方法:回顾性统计西安市中医医院2021—2022年产ESBLs细菌培养及药敏试验结果。基于药动学/药效学(PK/PD)理论,利用抗菌药物PK参数及最低抑菌浓度(minimal inhibitory cocentration,MIC)进行蒙特卡洛模拟,获得不同抗菌药物给药方案治疗产ESBLs细菌的达标概率(probability of target attainment,PTA)及累积反应分数(cumulative fraction of response,CFR),选择CFR≥90%/PTA≥90%的方案为经验性/目标性治疗产ESBLs细菌的最佳方案。结果:亚胺培南0.5 g q6h和1.0 g q8h/q6h静滴3.0 h,美罗培南0.5 g/1.0 g/2.0 g q8h静滴3.0 h,厄他培南1.0 g/2.0 g q24h静滴3.0 h,替加环素50 mg/75 mg/100 mg q12h,阿米卡星20 mg·kg^(-1)q24h,哌拉西林他唑巴坦4.5 g q8h/q6h静滴3.0 h给药方案的CFR均大于90%,推荐以上方案作为产ESLBs细菌引起的血流感染的初始经验性治疗选择,其他部位感染的给药方案应根据抗菌药物的PK特点进行调整。MIC为影响抗感染疗效的主要因素,根据MIC制订给药方案时,以PTA≥90%的方案为最优治疗选择。结论:缩短时间依赖性抗菌药物的给药间隔并延长输注时间至3.0 h,增加浓度依赖性抗菌药物的给药剂量,可显著提高PTA与CFR,达到提升抗感染治疗效果的目的。

OBJECTIVE To analyze and evaluate the anti-infective effects of different antimicrobial dosage regimens on extended-spectrum β-lactamases(ESBLs)-producing bacteria,and to provide reference for designing and optimizing antimicrobial agent therapeutic regimens.METHODS The results of bacterial culture and antimicrobial susceptibility testing of ESBLs-producing bacteria in Xi'an Hospital of Traditional Chinese Medicine from 2021 to 2022 were retrospectively analyzed.To obtain the probability of target attainment(PTA)and cumulative fraction of response(CFR)of various antimicrobial dosage regimens for the treatment of ESBLs-producing bacteria,Monte Carlo simulation based on PK/PD theory was carried out by using PK parameters of the antimicrobial agent and minimal inhibitory concentration(MIC).The regimen with CFR≥90%/PTA≥90%was selected as the best regimen for empirical/targeted treatment of ESBLs-producing bacteria.RESULTS The CFR of imipenem 0.5 g q6h and 1.0 g q8h/q6h with intravenous drip 3.0 h,meropenem 0.5 g/1.0 g/2.0 g q8h with intravenous drip 3.0 h,ertapenem 1.0 g/2.0 g q24h with intravenous drip 3.0 h,tigecycline 50 mg/75 mg/100 mg q12h,amikacin 20 mg·kg^(-1) q24h,and piperacillin tazobactam 4.5 g q8h/q6h with intravenous drip 3.0 h dosage regimens were all above 90%.These regimens were recommended as the initial empirical treatment options for bloodstream infection caused by ESBLs-producing bacteria.The dosage regimen for infections at other site should be adjusted based on the PK characteristics of antimicrobial agents.The key factor that impacted the efficacy of anti-infective therapy was MIC.The regimen with PTA≥90% should be chosen as the optimal treatment option when design dosage regimens based on the MIC.CONCLUSION To increase the efficacy of anti-infective therapy,the PTA and CFR can be significantly improved by shortening the administration interval and prolonging the infusion period to 3.0 h for time-dependent antimicrobial agents,and increasing the dosage for concentration-dependent antimicrobial agents.