Fouad Aliaa, McGrath Cole, Buyukyanbolu Ecem, Kuti Joseph L
Center for Anti-Infective Research and Development, Hartford Hospital, , Hartford, Connecticut, USA.
Antimicrob Agents Chemother. 2025 Jun 4;69(6):e0006125. doi: 10.1128/aac.00061-25. Epub 2025 May 5.
Cefepime-taniborbactam dosing in patients undergoing continuous renal replacement therapy (CRRT) is unknown. We employed an CRRT model to characterize transmembrane clearance (CL) and derive optimal dosing regimens for patients supported by CRRT. CL was determined in CVVH and CVVHD modes using the Prismaflex ST150 and HF1400 hemofilter sets. Samples were collected over 60 minutes to determine cefepime and taniborbactam concentrations at increasing effluent flow rates (ER). Sieving (SC) and saturation (SA) coefficients were measured and used to calculate CL. Multiple linear regression determined cefepime and taniborbactam CL as a function of ER, hemofilter, and mode. An established population pharmacokinetic model was integrated with the CL, and a 1,000 patient Monte Carlo Simulation was conducted to determine exposures of potential dosing regimens for pneumonia. The overall mean ± SD SC/SA across CRRT modes, hemofilters, and ERs were 1.13 ± 0.08 and 1.03 ± 0.07 for cefepime and taniborbactam, respectively. ER was the primary driver ( < 0.001) of CL for both drugs. For ER <3.5 L/h, cefepime and taniborbactam 1 g-0.25g q8h and 2 g-0.5g q12h as 4 h infusions achieved high probability of pharmacodynamic target attainment while keeping area under the curve exposures consistent with the proposed dose in pneumonia in non-CRRT patients. For ER ≥3.5 L/h, the optimum regimen was cefepime and taniborbactam 2 g-0.5 g q8h as a 4 h infusion. When incorporated into a population pharmacokinetic model, these CL data were used to propose dosing recommendations for cefepime and taniborbactam as a function of ER in patients undergoing CRRT.
接受持续肾脏替代治疗（CRRT）的患者中头孢吡肟-他尼硼巴坦的给药剂量尚不清楚。我们采用CRRT模型来表征跨膜清除率（CL），并为接受CRRT治疗的患者推导最佳给药方案。使用Prismaflex ST150和HF1400血液滤过器组件在连续性静脉-静脉血液滤过（CVVH）和连续性静脉-静脉血液透析滤过（CVVHD）模式下测定CL。在60分钟内收集样本，以确定在不断增加的流出液流速（ER）下头孢吡肟和他尼硼巴坦的浓度。测量筛分系数（SC）和饱和系数（SA）并用于计算CL。多元线性回归确定头孢吡肟和他尼硼巴坦的CL作为ER、血液滤过器和模式的函数。将已建立的群体药代动力学模型与CL相结合，并进行1000例患者的蒙特卡罗模拟，以确定肺炎潜在给药方案的暴露情况。在CRRT模式、血液滤过器和ER范围内，头孢吡肟和他尼硼巴坦的总体平均±标准差SC/SA分别为1.13±0.08和1.03±0.07。ER是两种药物CL的主要驱动因素（<0.001）。对于ER<3.5 L/h，头孢吡肟和他尼硼巴坦以1 g-0.25g每8小时一次和2 g-0.5g每12小时一次的剂量进行4小时输注，在保持曲线下面积暴露与非CRRT患者肺炎中拟议剂量一致的同时，实现了达到药效学靶点的高概率。对于ER≥3.5 L/h，最佳方案是头孢吡肟和他尼硼巴坦以2 g-0.5 g每8小时一次的剂量进行4小时输注。当纳入群体药代动力学模型时，这些CL数据用于提出接受CRRT治疗的患者中头孢吡肟和他尼硼巴坦作为ER函数的给药建议。
