Ceftaroline and Avibactam Removal by Continuous Renal Replacement Therapies: An in vitro Study

Abstract

Introduction: 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. Methods: 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 (CL_CRRT) were calculated. Results: 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). CL_CRRT 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, CL_CRRT ranged from 15.07 to 18.82 mL/min for CVVH and CVVHD, and from 33.74 to 34.13 mL/min for CVVHDF. Discussion: 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.