Fratoni Andrew J, Kois Abigail K, Gluck Jason A, Nicolau David P, Kuti Joseph L
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
Heart & Vascular Institute, Hartford HealthCare, Hartford, CT, USA.
J Antimicrob Chemother. 2024 May 2;79(5):1118-1125. doi: 10.1093/jac/dkae079.
Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO.
Patients with infection supported on ECMO received 4-6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC-MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0-24/MIC ≥ 8 for relebactam, and ≥40% fT > MIC for imipenem for each approved dosing regimen.
Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ± standard deviation parameters were: CL0, 15.21 ± 6.52 L/h; Vc, 10.13 ± 2.26 L; K12, 2.45 ± 1.16 h-1 and K21, 1.76 ± 0.49 h-1 for imipenem, and 6.95 ± 1.34 L/h, 9.81 ± 2.69 L, 2.43 ± 1.13 h-1 and 1.52 ± 0.67 h-1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L.
Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa.
体外膜肺氧合（ECMO）是一种挽救生命的治疗方式，但有可能改变抗菌药物的药代动力学（PK）。亚胺培南/西司他丁/瑞来巴坦是一种用于治疗某些多重耐药革兰氏阴性菌感染的抗生素。在此，我们描述了在接受ECMO支持的重症患者中亚胺培南和瑞来巴坦的群体药代动力学。
根据估计的肌酐清除率，接受ECMO支持且有感染的患者按照当前处方信息接受4 - 6剂亚胺培南/西司他丁/瑞来巴坦。在抗生素最后一剂给药后采集血样。通过液相色谱 - 串联质谱法测定浓度。使用Pmetrics对有无协变量的群体PK模型进行拟合。对1000名患者进行蒙特卡洛模拟，评估每种批准给药方案下瑞来巴坦的fAUC0 - 24/MIC≥8以及亚胺培南的fT＞MIC≥40%的联合达标概率（PTA）。
7名接受ECMO支持的患者纳入PK分析。以肌酐清除率作为亚胺培南和瑞来巴坦清除率的协变量的二室模型对数据拟合最佳。亚胺培南的平均±标准差参数为：CL0，15.21±6.52 L/h；Vc，10.13±2.26 L；K12，2.45±1.16 h-1和K21，1.76±0.49 h-1；瑞来巴坦的参数为6.95±1.34 L/h，9.81±2.69 L，2.43±1.13 h-1和1.52±0.67 h-1。根据肌酐清除率模拟每种批准剂量的亚胺培南/西司他丁/瑞来巴坦，在MIC高达2 mg/L时达标概率≥90%。
预计在接受ECMO支持的患者中按照药品说明书给药的亚胺培南/西司他丁/瑞来巴坦能够达到足以治疗包括铜绿假单胞菌在内的敏感革兰氏阴性菌分离株的暴露水平。
