Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, CT, USA.
Heart & Vascular Institute, Hartford HealthCare, Hartford, CT, USA.
Int J Antimicrob Agents. 2022 Jul;60(1):106603. doi: 10.1016/j.ijantimicag.2022.106603. Epub 2022 May 14.
This study determined the pharmacokinetics of cefepime in patients requiring extracorporeal membrane oxygenation (ECMO) support to guide dosage selection. Cefepime population pharmacokinetics where characterized in Pmetrics for R for six critically ill patients receiving ECMO. Simulation was employed to determine the fT>MIC and total trough concentration of varying regimens in each patient to evaluate ability to achieve optimal pharmacodynamic exposure and thresholds for cefepime-associated neurotoxicity. Of the six participants, two required continuous veno-venous hemodiafiltration (CVVHDF) while four had a CrCL between 92-199 ml/min. All patients received 2 g q8h as a 3h infusion. A two-compartment model fitted the data best with median (range) parameter estimates as follows: clearance, 5.99 (4.10-10.29) L/h; volume of central compartment, 10.08 (2.45-15.14) L; and intercompartment transfer constants (k), 3.58 (2.01-4.99) and k, 1.70 (1.00-2.88) . The 2g q8h (3h infusion) regimen resulted in >70% fT>MIC in all patients up to an MIC of 16 µg/mL, whereas 2g q12h (0.5h) resulted in 5/6 patients achieving 70% ƒT>MIC at 8 µg/mL but only 1/6 at 16 µg/mL. Aggressive dosing regimens resulted in trough concentrations exceeding conservative neurotoxicity thresholds. No patient demonstrated signs or symptoms of neurotoxicity during treatment. For ECMO patients with normal to augmented renal clearance similar to those presented here, or those receiving CVVHDF, these data support dosing regimens of 2g q8h (3h infusions) to empirically target MICs up to 16 µg/mL. Larger studies are needed to determine how ECMO affects cefepime pharmacokinetics.
本研究旨在确定接受体外膜肺氧合 (ECMO) 支持的患者中头孢吡肟的药代动力学，以指导剂量选择。使用 Pmetrics for R 对接受 ECMO 的六名危重症患者进行了头孢吡肟群体药代动力学研究。模拟用于确定每个患者不同方案的 fT>MIC 和总谷浓度，以评估实现最佳药效学暴露和头孢吡肟相关神经毒性阈值的能力。在六名参与者中，两名需要持续静脉-静脉血液透析滤过 (CVVHDF)，而四名患者的 CrCL 在 92-199 ml/min 之间。所有患者均接受 2 g q8h 作为 3h 输注。两室模型最适合数据，中位数（范围）参数估计如下：清除率，5.99（4.10-10.29）L/h；中央室容积，10.08（2.45-15.14）L；和隔室转移常数（k），3.58（2.01-4.99）和 k，1.70（1.00-2.88）。2g q8h（3h 输注）方案在所有患者中，MIC 高达 16μg/ml 时，fT>MIC 均超过 70%，而 2g q12h（0.5h）时，5/6 名患者在 8μg/ml 时达到 70%ƒT>MIC，但只有 1/6 名患者在 16μg/ml 时达到 70%ƒT>MIC。强化剂量方案导致谷浓度超过保守神经毒性阈值。在治疗过程中，没有患者出现神经毒性的迹象或症状。对于这里介绍的具有正常至增强肾清除率的 ECMO 患者或接受 CVVHDF 的患者，这些数据支持 2g q8h（3h 输注）的剂量方案，以经验性靶向 MIC 高达 16μg/ml。需要更大的研究来确定 ECMO 如何影响头孢吡肟的药代动力学。
