Falcone Marco, Menichetti Francesco, Cattaneo Dario, Tiseo Giusy, Baldelli Sara, Galfo Valentina, Leonildi Alessandro, Tagliaferri Enrico, Di Paolo Antonello, Pai Manjunath P
Infectious Diseases Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.
Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy.
J Antimicrob Chemother. 2021 Mar 12;76(4):1025-1031. doi: 10.1093/jac/dkaa549.
Avibactam is a β-lactamase inhibitor that is combined with aztreonam against Enterobacterales co-expressing serine- and metallo-β-lactamases (MBL). Optimal dosing of aztreonam with avibactam is not well-defined in critically ill patients and contingent on ceftazidime/avibactam product labelling.
To identify a pragmatic dosing strategy for aztreonam with avibactam to maximize the probability of target attainment (PTA).
We conducted a prospective observational pharmacokinetic study. Five blood samples were collected around the fourth dose of aztreonam or ceftazidime/avibactam and assayed for all three drugs. Population pharmacokinetic (PK) analysis coupled with Monte Carlo simulations were used to create a dosing nomogram for aztreonam and ceftazidime/avibactam based on drug-specific pharmacodynamic (PD) targets.
A total of 41 participants (59% male) median age of 75 years (IQR 63-79 years) were enrolled. They were critically ill (46%) with multiple comorbidities and complications including burns (20%). Population PK analysis identified higher volume of distribution and lower clearance (CL) compared with typical value expectations for aztreonam and ceftazidime/avibactam. Estimated glomerular filtration (eGFR) rate using the CKD-EPI equation predicted CL for all three drugs. The need for high doses of aztreonam and ceftazidime/avibactam above those in the existing product labels are not predicted by this analysis with the exception of ceftazidime/avibactam for patients with eGFR of 6-15 mL/min, in whom suboptimal PTA of ≤71% is predicted.
Pragmatic and lower daily-dose options are predicted for aztreonam and ceftazidime/avibactam when the eGFR is <90 mL/min. These options should be tested prospectively.
阿维巴坦是一种β-内酰胺酶抑制剂，与氨曲南联合用于对抗共表达丝氨酸和金属β-内酰胺酶（MBL）的肠杆菌科细菌。在重症患者中，氨曲南与阿维巴坦的最佳给药剂量尚未明确界定，且取决于头孢他啶/阿维巴坦产品标签。
确定氨曲南与阿维巴坦的实用给药策略，以最大化目标达成概率（PTA）。
我们开展了一项前瞻性观察性药代动力学研究。在氨曲南或头孢他啶/阿维巴坦的第四剂给药前后采集五份血样，并对所有三种药物进行检测。采用群体药代动力学（PK）分析结合蒙特卡洛模拟，基于药物特异性药效学（PD）目标创建氨曲南和头孢他啶/阿维巴坦的给药剂量图。
共纳入41名参与者（59%为男性），中位年龄75岁（四分位间距63 - 79岁）。他们病情严重（46%），伴有多种合并症和并发症，包括烧伤（20%）。群体PK分析显示，与氨曲南和头孢他啶/阿维巴坦的典型预期值相比，分布容积更高，清除率（CL）更低。使用CKD - EPI方程估算的肾小球滤过率（eGFR）可预测所有三种药物的CL。除了eGFR为6 - 15 mL/min的患者使用头孢他啶/阿维巴坦时预测PTA低于最佳值（≤71%）外，该分析未预测需要高于现有产品标签剂量的高剂量氨曲南和头孢他啶/阿维巴坦。
当eGFR < 90 mL/min时，预计氨曲南和头孢他啶/阿维巴坦有实用且较低的每日剂量选择。这些选择应进行前瞻性测试。
