Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA; Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA.
Department of Pharmacy, Mayo Clinic, Rochester, MN, USA.
Int J Antimicrob Agents. 2017 Sep;50(3):482-486. doi: 10.1016/j.ijantimicag.2017.04.008. Epub 2017 Jun 28.
Alterations in cefepime pharmacokinetic (PK) exposure and decreased bacterial susceptibility increase the risk of treatment failure. The impact of susceptible-dose-dependent (SDD) minimum inhibitory concentrations (MICs), i.e. 4-8 µg/mL, on target attainment rates for cefepime in febrile neutropenia (FN) is unclear. We sought to identify optimal cefepime regimens against SDD cefepime MICs in FN using a modelling and simulation approach. Creatinine clearance (CL) and body surface area (BSA) covariate-adjusted models of clearance were evaluated. Monte Carlo simulations representing 10 000 patients were completed to assess various dosing strategies (i.e. 3-8 g/day infused over 0.5-24 h, replaced every 6-24 h) and predict probabilities of target attainment (PTAs) for unbound cefepime. Nine patients received cefepime 2 g every 8 h (q8h) (0.5-h infusion). A two-compartment PK model with BSA- and CL-adjusted clearance was fit to the data. Mean population values for total clearance (6.3 ± 1.1 L/h), intercompartmental clearance (6.9 ± 2.8 L/h), and central (14.8 ± 3.8 L) and peripheral (10.9 ± 4.6 L) distribution volumes were all estimated with <50% CV. Simulated dosing regimens of 3-4 g/day administered as continuous infusions and doses of 2 g administered q6h (0-5 h infusion) to q8h (4-h infusion) achieved ≥90% PTA at MICs up to 8 µg/mL. Simulated regimens of 1 g q8h (4-h infusion) or 1 g q6h (0.5-h infusion) achieved ≥90% PTA only against MICs up to 4 µg/mL. High-dose prolonged infusion or more frequent cefepime regimens may be necessary to treat FN organisms with SDD MICs.
头孢吡肟药代动力学（PK）暴露的改变和细菌敏感性的降低会增加治疗失败的风险。对于发热性中性粒细胞减少症（FN），敏感剂量依赖性（SDD）最低抑菌浓度（MIC），即 4-8μg/mL，对头孢吡肟的靶达标率的影响尚不清楚。我们试图通过建模和模拟方法确定针对 FN 中 SDD 头孢吡肟 MIC 的最佳头孢吡肟方案。评估了清除率的肌酐清除率（CL）和体表面积（BSA）协变量调整模型。完成了代表 10000 名患者的蒙特卡罗模拟，以评估各种给药方案（即 3-8g/天输注 0.5-24 小时，每 6-24 小时更换一次），并预测未结合头孢吡肟的靶达标率（PTAs）的概率。9 名患者接受头孢吡肟 2g 每 8 小时（q8h）（0.5 小时输注）。采用 BSA 和 CL 调整清除率的两室 PK 模型拟合数据。总清除率（6.3±1.1L/h）、隔室清除率（6.9±2.8L/h）以及中央（14.8±3.8L）和外周（10.9±4.6L）分布容积的人群平均值均以 <50%CV 估计。每天 3-4g 的模拟给药方案作为连续输注给药，每天 2g 的剂量 q6h（0-5h 输注）至 q8h（4h 输注）在 MIC 高达 8μg/mL 时达到≥90%的 PTA。每天 1g q8h（4h 输注）或 1g q6h（0.5h 输注）的模拟方案仅在 MIC 高达 4μg/mL 时达到≥90%的 PTA。对于具有 SDD MIC 的 FN 病原体，可能需要高剂量延长输注或更频繁的头孢吡肟方案。
