基于蒙特卡洛模拟和药动学/药效学模型评价替加环素脑室注射治疗泛耐药鲍曼不动杆菌颅内感染的给药方案

Evaluation of tigecycline intraventricular injection regimens in extensively drug resistant Acinetobacter baumannii intracranial infection based on Monte Carlo simulation and pharmacokinetic/pharmacodynamic model

目的依据蒙特卡洛模拟和药动学/药效学(PK/PD)模型,评价及筛选替加环素脑室注射治疗泛耐药鲍曼不动杆菌(XDRAB)颅内感染的给药方案。方法通过山东第一医科大学第二附属医院电子病历系统,筛选出9例自2018年1月1日至2023年12月31日确诊为仅对替加环素或多黏菌素类抗菌药物敏感的XDRAB颅内感染患者,应用WHONET软件提取上述患者脑脊液标本中分离出的病原菌的药敏试验数据,统计药敏试验结果中替加环素对XDRAB的最小抑菌浓度(MIC)分布情况,并依据MIC分布情况设计替加环素脑室注射的不同给药方案:2 mg/12 h、3 mg/12 h、4 mg/12 h、5 mg/12 h、6 mg/12 h、10 mg/12 h,药物浓度分别为0.5 mg/mL和1.0 mg/mL,次数为1次。设定PK/PD指标目标靶值为游离药物脑脊液峰浓度(ƒC_(max))/MIC≥8,然后采用蒙特卡洛模拟不同给药方案在替加环素对XDRAB不同MIC值时的PK/PD指数达标情况[不同给药方案在特定MIC值的达标概率(PTA)和病原菌群体的累积反应分数(CFR)],最终筛选出最佳给药方案(筛选依据为PTA≥90%或CFR≥90%)。结果(1)共提取到9例患者27株病原菌的药敏试验数据,其中替加环素对XDRAB的MIC为2 mg/L的占比为55.56%、4 mg/L的占比为25.93%、8 mg/L的占比为18.52%。(2)当药物浓度分别为0.5 mg/mL或1.0 mg/mL时,6种给药方案在MIC为2 mg/L时的PTA均>90%;在MIC为4 mg/L时,除2 mg/12 h以外的其余5种给药方案的PTA均>90%;在MIC为8 mg/L时,5 mg/12 h、6 mg/12 h和10 mg/12 h给药方案的PTA>90%。(3)当药物浓度为0.5 mg/mL时,4 mg/12 h、5 mg/12 h、6 mg/12 h、10 mg/12 h给药方案的CFR>90%;当药物浓度为1 mg/mL时,4 mg/12 h、5 mg/12 h、6 mg/12 h、10 mg/12 h给药方案的CFR>92%。结论替加环素脑室注射治疗XDRAB颅内感染时,当MIC为2 mg/L时可选用2 mg/12 h给药方案,当MIC为4 mg/L时可选用3 mg/12 h给药方案,当MIC为8 mg/L时可选用5 mg/12 h给药方案,药物浓度为0.5 mg/mL或1 mg/mL均可。

Objective To evaluate and screen the regimens of tigecycline intraventricular injection in extensively drug resistant Acinetobacter baumannii(XDRAB)intracranial infection based on Monte Carlo simulation and pharmacokinetic/pharmacodynamic(PK/PD)model.Methods Nine patients with XDRAB intracranial infection confirmed as having susceptibility to tigecycline or polymyxin antimicrobials from January 1,2018 to December 31,2023 were screened from electronic medical record system in Second Affiliated Hospital of Shandong First Medical University.WHONET software was used to extract pathogen susceptibility data isolated from cerebrospinal fluid samples.Minimum inhibitory concentration(MIC)of tigecycline against XDRAB was analyzed by drug susceptibility test;different regimens for intraventricular tigecycline injection were designed based on MIC:2 mg/12 h,3 mg/12 h,4 mg/12 h,5 mg/12 h,6 mg/12 h,and 10 mg/12 h,with drug concentration of 0.5 mg/mL or 1.0 mg/mL once a day.Target value of PK/PD index was set as ƒC_(max)/MIC≥8;Monte Carlo was used to simulate the compliance of PK/PD index of tigecycline with different MIC against XDRAB for different dosed regimens(probability of target attainment[PTA]and cumulative fraction of response[CFR]);the best regiment was selected(screening basis:PTA≥90%or CFR≥90%).Results(1)A total of 27 strains of pathogenic bacteria from 9 patients were extracted from drug susceptibility test,in which MIC of tigecycline against XDRAB was 55.56% for 2 mg/L,25.93% for 4 mg/L,and 18.52% for 8 mg/L.(2)When the drug concentration was 0.5 mg/mL or 1.0 mg/mL,respectively,all 6 regimens had PTA>90% at 2 mg/L MIC;5 regimens,except for 2 mg/12 h,had PTA>90% at 4 mg/L MIC;regimens of 5 mg/12 h,6 mg/12 h,and 10 mg/12 h could achieve PTA>90% at 8 mg/L MIC.(3)When the drug concentration was 0.5 mg/mL,regimens of 4 mg/12 h,5 mg/12 h,6 mg/12 h,and 10 mg/12 h could achieve CFR>90%;when the drug concentration was 1 mg/mL,regimens of 4 mg/12 h,5 mg/12 h,6 mg/12 h,and 10 mg/12 h could achieve CFR>92%.Conclusion In intraventricular tigecycline injection for XDRAB intracranial infection,2 mg/12 h regimen is available in 2 mg/L MIC,3 mg/12 h regimen is available in 4 mg/L MIC,and 5 mg/12 h regimen is available in 8 mg/L MIC,with either 0.5 mg/mL or 1 mg/mL concentration.