Fouad Aliaa, Kobic Emir, Nicolasora Nelson P, Bastin Melissa L Thompson, Adams Paul M, Shen Yuwei, Fratoni Andrew J, Ye Xiaoyi, Kuti Joseph L, Nicolau David P, Asempa Tomefa E
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
Department of Pharmacy, Banner-University Medical Center, Phoenix, Arizona, USA.
Open Forum Infect Dis. 2024 Oct 21;11(10):ofae451. doi: 10.1093/ofid/ofae451. eCollection 2024 Oct.
Cefiderocol is the first antibiotic with effluent flow rate-based dosing recommendations outlined in the product label for patients receiving continuous renal replacement therapy (CRRT). We aimed to investigate the population pharmacokinetics of cefiderocol among patients receiving CRRT and validate these dosing recommendations.
A multicenter, prospective cefiderocol pharmacokinetic study among intensive care unit patients receiving CRRT was conducted (2022-2023). Blood sampling was performed at steady-state and cefiderocol concentrations were assayed by validated liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analyses were conducted in Pmetrics using R software. The free time above the minimum inhibitory concentration ( T > MIC) and total daily area under the concentration time curve (AUC) were calculated.
Fourteen patients with effluent flow rates ranging from 2.1 to 5.1 L/h were enrolled. Cefiderocol concentrations best fitted a 2-compartment model. Mean ± standard deviation (SD) parameter estimates for clearance, central compartment volume, and intercompartment transfer constants (k and k) were 3.5 ± 1.5 L/hour, 10.7 ± 8.4 L, 3.9 ± 1.8 hours, and 2.2 ± 2.2 hours, respectively. With simulations based on product label dosing recommendations, all patients achieved 100% T > MIC up to MIC 8 mg/L with an AUC (mean ± SD) of 1444 ± 423 mg × hour/L. Cefiderocol was well tolerated among the 14 patients.
The current package insert dosing recommendations resulted in pharmacodynamically optimized cefiderocol exposures. Cefiderocol concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUC was within the range observed in patients in the phase 3 clinical trials, suggestive of a safe and therapeutic drug profile.
头孢地尔是首个在产品标签中针对接受持续肾脏替代治疗（CRRT）的患者给出基于流出液流速给药建议的抗生素。我们旨在研究接受CRRT的患者中头孢地尔的群体药代动力学，并验证这些给药建议。
在2022年至2023年期间，对接受CRRT的重症监护病房患者进行了一项多中心、前瞻性头孢地尔药代动力学研究。在稳态时进行血样采集，并用经过验证的液相色谱 - 串联质谱法测定头孢地尔浓度。使用R软件在Pmetrics中进行群体药代动力学分析。计算高于最低抑菌浓度的自由时间（T > MIC）和浓度 - 时间曲线下的每日总面积（AUC）。
纳入了14名流出液流速在2.1至5.1 L/h之间的患者。头孢地尔浓度最适合二室模型。清除率、中央室容积以及室间转运常数（k12和k21）的平均±标准差（SD）参数估计值分别为3.5±1.5 L/小时、10.7±8.4 L、3.9±1.8小时和2.2±2.2小时。根据产品标签给药建议进行模拟，所有患者在MIC高达8 mg/L时均达到100% T > MIC，AUC（平均±SD）为1444±423 mg×小时/L。14名患者对头孢地尔耐受性良好。
当前包装说明书中的给药建议使头孢地尔的暴露在药效学上得到优化。在每个流出液流速下，所有患者的头孢地尔浓度均超过相关的MIC断点，且AUC在3期临床试验患者中观察到的范围内，提示其具有安全且有效的药物特性。
