Division of Intensive Care Unit, Hyogo College of Medicine, Hyogo, Japan.
Department of Infection Control and Prevention, Hyogo College of Medicine, Hyogo, Japan.
Int J Antimicrob Agents. 2018 May;51(5):745-751. doi: 10.1016/j.ijantimicag.2018.01.021. Epub 2018 Feb 6.
The purpose of this study was to identify the optimum dosing regimen of linezolid in sepsis patients with and without renal dysfunction and sepsis patients on low-dose continuous renal replacement therapy (CRRT) using a pharmacokinetics/pharmacokinetics (PK/PD) approach.
Sepsis patients with and without renal dysfunction (creatinine clearance < 50 mL/min), and sepsis patients on low-dose CRRT (dose: 800 mL/h) were studied. The PK data were modeled using a two-compartment model, and then used for simulation. The target PK/PD was the 24-h area under the concentration-time curve to minimum inhibitory concentration ratio of ≥ 80. Dosing regimens were evaluated using cumulative fraction of response (CFR) and safety probability (trough level < 7 µg/mL) by Monte Carlo simulation.
Twenty-seven patients, including 8 patients with preserved renal function, 9 patients with renal dysfunction, and 10 patients on CRRT, were studied. The proposed regimen to attain CFR ≥ 90% was 800 mg every 12 h (safety probability 82.4%) for patients with preserved renal function. By contrast, the target CFR was attained with a decreased regimen in patients with renal dysfunction and those on CRRT [600 mg every 24h (safety probability 68.6%) and 800 mg every 24h (42.1%)].
We identified different dosage strategies to achieve target linezolid concentrations according to renal function and use of CRRT in sepsis patients. Because of unassured safety probability in patients without preserved renal function, dosing regimens should be adjusted based on the therapeutic drug monitoring.
本研究旨在通过药代动力学/药效学（PK/PD）方法，确定伴有或不伴有肾功能障碍的脓毒症患者以及接受低剂量连续性肾脏替代治疗（CRRT）的脓毒症患者中利奈唑胺的最佳给药方案。
研究了伴有和不伴有肾功能障碍（肌酐清除率<50 mL/min）的脓毒症患者，以及接受低剂量 CRRT（剂量：800 mL/h）的脓毒症患者。使用两室模型对 PK 数据进行建模，然后进行模拟。目标 PK/PD 为 24 小时浓度-时间曲线下面积与最小抑菌浓度比值≥80。通过蒙特卡罗模拟评估累积反应分数（CFR）和安全性概率（谷浓度<7 µg/mL）来评估给药方案。
共纳入 27 例患者，其中 8 例肾功能正常，9 例肾功能障碍，10 例接受 CRRT。对于肾功能正常的患者，建议每 12 小时给予 800mg 以达到 CFR≥90%（安全性概率 82.4%）。相比之下，肾功能障碍和接受 CRRT 的患者的目标 CFR 可通过降低剂量方案达到[600mg 每 24 小时（安全性概率 68.6%）和 800mg 每 24 小时（42.1%）]。
我们根据肾功能和脓毒症患者使用 CRRT 的情况，确定了实现利奈唑胺目标浓度的不同剂量策略。由于肾功能正常患者的安全性概率不确定，应根据治疗药物监测调整给药方案。
