Department of Pharmacy, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Front Cell Infect Microbiol. 2022 Jul 7;12:874401. doi: 10.3389/fcimb.2022.874401. eCollection 2022.
The study aimed to evaluate and compare the pharmacokinetic/pharmacodynamic (PK/PD) exposure to vancomycin in the novel optimal two-step infusion (OTSI) intermittent infusion (II) continuous infusion (CI) mode, for MRSA bloodstream infections occurring in critical patients.
With PK/PD modeling and Monte Carlo simulations, the PK/PD exposure of 15 OTSI, 13 II, and 6 CI regimens for vancomycin, at 1, 2, 3, 4, 5, and 6 g daily dose, was evaluated. Using the Monte Carlo simulations, the vancomycin population PK parameters derived from critical patients, the PD parameter for MRSA isolates [i.e., minimum inhibitory concentration (MIC)], and the dosing parameters of these regimens were integrated into a robust mdel of vancomycin PK/PD index, defined as a ratio of the daily area under the curve (AUC) to MIC (i.e., AUC/MIC), to estimate the probability of target attainment (PTA) of these regimens against MRSA isolates with an MIC of 0.5, 1, 2, 4, and 8 mg/L in patients with varying renal function. The PTA at an AUC/MIC ratio of >400, 400-600, and >600 was estimated. A regimen with a PTA of ≥90% at an AUC/MIC ratio of 400-600, which is supposed to maximize both efficacy and safety, was considered optimal.
At the same daily dose, almost only the OTSI regimens showed a PTA of ≥90% at an AUC/MIC ratio of 400-600, and this profile seems evident especially in patients with creatinine clearance () of ≥60 ml/min and for isolates with an MIC of ≤2 mg/L. However, for patients with of <60 ml/min and for isolates with an MIC of ≥4 mg/L, the II regimens often displayed a higher or even ≥90% PTA at an AUC/MIC ratio of >400 and of >600. The CI regimens frequently afforded a reduced PTA at an AUC/MIC ratio of >400 and of >600, regardless of and MIC.
The data indicated that the OTSI regimens allowed preferred PK/PD exposure in terms of both efficacy and safety, and thus should be focused more on, especially in patients with of ≥60 ml/min and for isolates with an MIC of ≤2 mg/L.
本研究旨在评估和比较新型优化两步输注（OTSI）间歇性输注（II）连续输注（CI）模式下万古霉素在重症患者耐甲氧西林金黄色葡萄球菌（MRSA）血流感染中的药代动力学/药效学（PK/PD）暴露情况。
通过 PK/PD 建模和蒙特卡罗模拟，评估了 15 种 OTSI、13 种 II 和 6 种 CI 万古霉素方案在 1、2、3、4、5 和 6 g/d 日剂量下的 PK/PD 暴露情况。使用蒙特卡罗模拟，将从重症患者中获得的万古霉素群体 PK 参数、MRSA 分离株的药效学参数[即最小抑菌浓度（MIC）]以及这些方案的给药参数整合到一个稳健的万古霉素 PK/PD 指数模型中，该模型定义为每日 AUC 与 MIC 的比值（即 AUC/MIC），以估计这些方案对 MIC 为 0.5、1、2、4 和 8 mg/L 的不同肾功能患者中 MRSA 分离株的目标达标率（PTA）。估计了 AUC/MIC 比值>400、400-600 和>600 时的 PTA。AUC/MIC 比值为 400-600 时 PTA≥90%的方案被认为是最佳方案，因为该方案在疗效和安全性方面都能达到最大化。
在相同的日剂量下，几乎只有 OTSI 方案在 AUC/MIC 比值为 400-600 时显示出≥90%的 PTA，而且这种情况在清除率（）≥60 ml/min 的患者和 MIC≤2 mg/L 的分离株中似乎更为明显。然而，对于清除率<60 ml/min 的患者和 MIC≥4 mg/L 的分离株，II 方案在 AUC/MIC 比值>400 和>600 时通常显示出更高甚至≥90%的 PTA。CI 方案在 AUC/MIC 比值>400 和>600 时经常显示出较低的 PTA，无论清除率和 MIC 如何。
数据表明，OTSI 方案在疗效和安全性方面提供了更优的 PK/PD 暴露，因此应更加关注该方案，尤其是清除率≥60 ml/min 的患者和 MIC≤2 mg/L 的分离株。
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