Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de Investigación Lascaray Ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.
Bioaraba, Microbiology, Infectious Disease, Antimicrobial Agents, and Gene Therapy, Vitoria-Gasteiz, Spain.
Blood Purif. 2023;52(5):464-473. doi: 10.1159/000529264. Epub 2023 Mar 1.
Continuous renal replacement therapies (CRRTs) are frequently used in critically ill patients; however, there are scarce in vitro and in vivo studies showing the extracorporeal elimination of ceftaroline and avibactam. The aim of this study was to assess, through an in vitro model, the extracorporeal elimination of ceftaroline and avibactam by continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodiafiltration (CVVHDF), and continuous veno-venous hemodialysis (CVVHD), using a polysulfone hemofilter.
Simulated in vitro experiments were performed using a multiFiltrate machine with a 1.4 m2 Ultraflux® AV600S polysulfone hemofilter. Isofundin® without or with bovine serum albumin was circulated as vehicle for ceftaroline or avibactam. Pre-filter, post-filter, and effluent samples were taken over a period of 60 min, and they were immediately stored at 4°C until processed in the same day. The quantification of ceftaroline and avibactam in the samples was performed by high-performance liquid chromatography with ultraviolet detection. Protein binding, extraction coefficient (EC), and extracorporeal clearance (CLCRRT) were calculated.
The elimination of both ceftaroline and avibactam during the three extracorporeal modalities followed first-order pharmacokinetics. Regardless of the CRRT technique, EC values for both molecules were around 1, similar to the unbound fraction of avibactam (0.96) and higher than the unbound fraction of ceftaroline (0.79). CLCRRT of ceftaroline ranged from 15.63 to 17.66 mL/min when CVVH and CVVHD were used with a flow rate of 1,000 mL/h, and from 29.25 to 32.95 mL/min for the CVVHDF modality with a flow rate of 2,000 mL/h. For avibactam, CLCRRT ranged from 15.07 to 18.82 mL/min for CVVH and CVVHD, and from 33.74 to 34.13 mL/min for CVVHDF.
Avibactam and ceftaroline are extensively removed through the polysulfone membrane, and a dose adjustment may be recommended for patients under CRRT to ensure pharmacodynamic target achievement.
连续肾脏替代疗法（CRRT）在重症患者中经常使用；然而，体外和体内研究很少显示头孢他啶和阿维巴坦的体外清除率。本研究的目的是通过体外模型评估头孢他啶和阿维巴坦通过连续静脉-静脉血液滤过（CVVH）、连续静脉-静脉血液透析滤过（CVVHDF）和连续静脉-静脉血液透析（CVVHD）的体外清除率，使用聚砜膜血液滤器。
使用带有 1.4 m2 Ultraflux® AV600S 聚砜膜血液滤器的多滤器机器进行模拟体外实验。Isofundin® 无或有牛血清白蛋白循环作为头孢他啶或阿维巴坦的载体。在 60 分钟的时间内采集预滤器、后滤器和流出物样本，并立即在 4°C 下储存，直到当天处理。通过高效液相色谱法与紫外检测法对样本中的头孢他啶和阿维巴坦进行定量。计算蛋白结合率、萃取系数（EC）和体外清除率（CLCRRT）。
三种体外模式下头孢他啶和阿维巴坦的消除均遵循一级药代动力学。无论 CRRT 技术如何，两种分子的 EC 值均在 1 左右，与阿维巴坦的未结合部分（0.96）相似，高于头孢他啶的未结合部分（0.79）。当使用 1000 mL/h 的流速进行 CVVH 和 CVVHD 时，头孢他啶的 CLCRRT 范围为 15.63 至 17.66 mL/min，而当使用 2000 mL/h 的流速进行 CVVHDF 时，CLCRRT 范围为 29.25 至 32.95 mL/min。对于阿维巴坦，CVVH 和 CVVHD 的 CLCRRT 范围为 15.07 至 18.82 mL/min，CVVHDF 为 33.74 至 34.13 mL/min。
阿维巴坦和头孢他啶通过聚砜膜大量清除，对于接受 CRRT 的患者，可能需要调整剂量以确保达到药效学目标。
