An optimal extended-infusion dosing of cefepime and ceftazidime in critically ill patients with continuous renal replacement therapy

Purpose: This study aimed to determine optimal extended-infusion dosing regimens for cefepime and ceftazi-dime in critically ill patients receiving continuous renal replacement therapy using Monte Carlo Simulations (MCS). Materials and methods: Pharmacokinetic models were built using published pharmacokinetic/demographic data to predict drug disposition in 5000 virtual critically ill patients receiving continuous venovenous hemofiltration (CVVH) with the standard (20-30 mL/kg/h) and a higher (40 mL/kg/h) effluent rates. MCS was performed to as-sess the probability of target attainment (PTA) of four cefepime and ceftazidime doses administered over 4-h with the target of >-60% fT > 4xMIC. The lowest dose attaining PTA >-90% during the first 48-h was considered optimal. Additionally, risk of drug toxicity was assessed at 48-h using suggested neurotoxicity thresholds. Results: Cefepime 2 g loading dose (LD), then extended-infusion of 2 g q8hr was optimal in CVVH at 20 mL/kg/h and the same ceftazidime dose was optimal in CVVH at 20-30 mL/kg/h. Higher cefepime and ceftazidime doses were required to be optimal at higher effluent rates. This optimal dose particularly for cefepime likely increases neurotoxicity risk in most virtual patients with all CVVH settings. Conclusions: Cefepime and ceftazidime 2 g LD, followed by extended-infusion 2 g q8hr may be optimal in CVVH with standard effluent rates. (c) 2022 Published by Elsevier Inc.