Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Uppsala Pharmacometrics Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden.
J Antimicrob Chemother. 2022 Aug 25;77(9):2479-2488. doi: 10.1093/jac/dkac209.
PTA of protein-unbound ceftriaxone may be compromised in critically ill patients with community-acquired pneumonia (CAP) with augmented renal clearance (ARC). We aimed to determine an optimized ceftriaxone dosage regimen based on the probability of developing ARC on the next day (PARC,d+1; www.arcpredictor.com).
Thirty-three patients enrolled in a prospective cohort study were admitted to the ICU with severe CAP and treated with ceftriaxone 2 g once daily. Patients contributed 259 total ceftriaxone concentrations, collected during 1 or 2 days (±7 samples/day). Unbound fractions of ceftriaxone were determined in all peak and trough samples (n = 76). Population pharmacokinetic modelling and simulation were performed using NONMEM7.4. Target attainment was defined as an unbound ceftriaxone concentration >4 mg/L throughout the dosing interval.
A two-compartment population pharmacokinetic model described the data well. The maximal protein-bound ceftriaxone concentration decreased with lower serum albumin. Ceftriaxone clearance increased with body weight and PARC,d+1 determined on the previous day. A high PARC,d+1 was identified as a clinically relevant predictor for underexposure on the next day (area under the receiver operating characteristics curve 0.77). Body weight had a weak predictive value and was therefore considered clinically irrelevant. Serum albumin had no predictive value. An optimal PARC,d+1 threshold of 5.7% was identified (sensitivity 73%, specificity 69%). Stratified once- or twice-daily 2 g dosing when below or above the 5.7% PARC,d+1 cut-off, respectively, was predicted to result in 81% PTA compared with 47% PTA under population-level once-daily 2 g dosing.
Critically ill patients with CAP with a high PARC,d+1 may benefit from twice-daily 2 g ceftriaxone dosing for achieving adequate exposure on the next day.
社区获得性肺炎（CAP）合并增强型肾脏清除率（ARC）的危重症患者，游离型头孢曲松的药时曲线下面积（PTA）可能受损。我们旨在通过预测次日发生 ARC 的概率（PARC，d+1；www.arcpredictor.com），确定优化的头孢曲松剂量方案。
33 例入组前瞻性队列研究的 CAP 重症患者入住 ICU，接受头孢曲松 2 g 每日 1 次治疗。患者共采集了 259 个头孢曲松浓度，采集时间为 1 或 2 天（每天 ±7 个样本）。所有峰和谷样本（n=76）均测定游离型头孢曲松分数。采用 NONMEM7.4 进行群体药代动力学建模和模拟。定义靶浓度范围达标为整个给药间隔内游离头孢曲松浓度＞4mg/L。
两室模型能很好地描述数据。最大蛋白结合头孢曲松浓度随血清白蛋白降低而降低。头孢曲松清除率随体重和前一天的 PARC，d+1 增加。高 PARC，d+1 被确定为次日药物暴露不足的临床相关预测因子（受试者工作特征曲线下面积 0.77）。体重具有弱预测价值，因此被认为无临床意义。血清白蛋白无预测价值。确定最佳 PARC，d+1 阈值为 5.7%（敏感性 73%，特异性 69%）。当 PARC，d+1 低于或高于 5.7%时，分别分层每日 1 次或 2 次 2 g 给药，预计与人群水平每日 1 次 2 g 给药相比，PTA 分别为 81%和 47%。
PARC，d+1 较高的 CAP 危重症患者可能受益于头孢曲松每日 2 次 2 g 给药，以确保次日获得足够的暴露。
