Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Clinical Pharmacology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
J Antimicrob Chemother. 2024 Nov 4;79(11):2801-2808. doi: 10.1093/jac/dkae290.
Ceftazidime/avibactam is a key antibiotic for carbapenemase-producing Enterobacterales (CPE) Gram-negative infections, but current dosing may be suboptimal to grant activity. This study explores the population pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) ceftazidime/avibactam for maximizing treatment efficacy in critically ill patients.
A retrospective analysis of adult patients receiving CI ceftazidime/avibactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modelling identified the most accurate method for estimating ceftazidime/avibactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive joint PK/PD target attainment of ceftazidime/avibactam.
The European Kidney Function Consortium (EKFC) equation best described kidney function for ceftazidime/avibactam clearance. The findings challenge the current approach of only reducing the ceftazidime/avibactam dose based on kidney function by identifying dose adjustments in patients with augmented kidney function. Our CI ceftazidime/avibactam dosing strategies, adjusted by TDM, showed promise for achieving optimal aggressive joint PK/PD targets and potentially improving clinical/microbiological outcomes against KPC- and OXA-48-producing Enterobacterales. The risk of neurotoxicity associated with these strategies appears acceptable.
This study suggests that adjusting ceftazidime/avibactam dosing regimen based solely on eCLcr might be suboptimal for critically ill patients. Higher daily doses delivered by CI and adjusted based on TDM have the potential to improve aggressive joint PK/PD target attainment and potentially clinical/microbiological outcomes. Further investigations are warranted to confirm these findings and establish optimal TDM-guided dosing strategies for ceftazidime/avibactam in clinical practice.
头孢他啶/阿维巴坦是治疗产碳青霉烯酶肠杆菌科（CPE）革兰氏阴性感染的关键抗生素，但目前的剂量可能无法达到最佳疗效。本研究旨在探讨连续输注（CI）头孢他啶/阿维巴坦的群体药代动力学/药效学（PK/PD），以最大限度地提高危重症患者的治疗效果。
对接受 CI 头孢他啶/阿维巴坦治疗并进行两种药物治疗药物监测（TDM）的成年患者进行回顾性分析。群体 PK/PD 模型确定了基于肾功能估计头孢他啶/阿维巴坦清除率的最准确方法，蒙特卡罗模拟研究了各种 CI 给药方案与头孢他啶/阿维巴坦强化联合 PK/PD 目标达成之间的关系。
欧洲肾脏功能联合会（EKFC）方程最能描述头孢他啶/阿维巴坦清除率的肾功能。这些发现挑战了仅根据肾功能降低头孢他啶/阿维巴坦剂量的当前方法，通过确定肾功能增强患者的剂量调整，发现了一种新的方法。我们通过 TDM 调整的 CI 头孢他啶/阿维巴坦给药策略，有望实现最佳强化联合 PK/PD 目标，并可能改善对产 KPC 和 OXA-48 的肠杆菌科的临床/微生物学结果。这些策略相关的神经毒性风险似乎是可以接受的。
本研究表明，仅根据 eCLcr 调整头孢他啶/阿维巴坦剂量方案可能对危重症患者不太理想。通过 CI 给予更高的每日剂量，并根据 TDM 进行调整，有可能提高强化联合 PK/PD 目标的达成率，并可能改善临床/微生物学结果。需要进一步的研究来证实这些发现，并为临床实践中头孢他啶/阿维巴坦建立最佳 TDM 指导的给药策略。
