Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
Ghent University Hospital, Gent, Belgium.
Int J Antimicrob Agents. 2021 Apr;57(4):106299. doi: 10.1016/j.ijantimicag.2021.106299. Epub 2021 Feb 7.
To determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection.
ARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 μg/mL for ceftolozane and time that the unbound concentration exceeded the 1 μg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated.
Mean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (V) were 236 (118) hµg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) hµg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and V were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate.
In patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam. CLINICALTRIALS.
NCT02387372.
确定对于合并肾功能增强（ARC）和细菌感染的患者，已确立的头孢他洛滨/他唑巴坦（C/T）给药方案是否足够。
在一项 I 期药代动力学研究中，通过直接测量 11 例危重症患者的肌酐清除率（CrCl），确认了 ARC（CrCl≥130mL/min）。患者接受 3g C/T（头孢他洛滨 2g/他唑巴坦 1g）作为 60 分钟静脉输注。在输注开始后 0（预给药）、1、2、4、6 和 8 小时进行药代动力学采样。对浓度数据进行非房室分析。评估了以下药效学目标：游离（未结合）药物浓度超过头孢他洛滨最低抑菌浓度（fT>MIC）4μg/mL 的时间和他唑巴坦未结合浓度超过 1μg/mL 目标阈值（fT>阈值=1μg/mL）的时间超过给药间隔的 20%。评估了安全性。
头孢他洛滨的平均（SD）血浆浓度-时间曲线下面积从 0 到无穷大（AUCinf）、清除率和稳态时的分布容积（V）分别为 236（118）hμg/mL、10.4（4.5）L/h 和 30.8（10.8）L，对于他唑巴坦分别为 35.5（18.5）hμg/mL、35.3（16.5）L/h 和 54.8（20.1）L。与健康个体相比，ARC 患者的头孢他洛滨和他唑巴坦清除率和 V 更高。头孢他洛滨的平均估计 fT>MIC 为 4μg/mL 时为 86.4%；平均估计 tazobactam fT>阈值=1μg/mL 时为 54.9%。治疗中出现的不良事件为轻度至中度。
在 ARC 患者中，3g C/T 剂量符合头孢他洛滨和他唑巴坦的相应药效学目标。临床试验。
NCT02387372。
