A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration
A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration
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DOI：
10.1128/aac.01655-19
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发表时间：
2020-01-01
影响因子：
4.9
通讯作者：
Roberts, Jason A.
中科院分区：
文献类型：
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作者：
Sime, Fekade B.;Lassig-Smith, Melissa;Roberts, Jason A.
本研究的目的是描述危重患者接受持续静脉-静脉血液滤过（CVVHDF）的头孢唑氮-他唑巴坦的最佳给药方案。我们对临床适应症为头孢唑氮-他唑巴坦和CVVHDF的成人危重患者进行了前瞻性观察药代动力学研究。通过色谱分析，从连续过滤前血液、过滤后血液和超滤样品中测量非结合药物浓度。使用Pmetrics进行群体药代动力学建模和给药模拟。四室药代动力学模型充分描述了6例患者的数据。头孢唑烷和他唑巴坦的平均（+/-标准差[SD]）提取率分别为0.76 +/- 0.08和0.73 +/- 0.1。平均+/- SD筛分系数分别为0.94 +/- 0.24和1.08 +/- 0.30。模型估计CVVHDF清除率分别为2.7 +/- 0.8和3.0 +/- 0.6升/小时。剩余非cvvhdf清除率分别为0.6 +/- 0.5和3.3 +/- 0.9升/小时。在最初的24小时内，每8小时低至0.75 g的剂量，考虑到40% fT (>MIC)（游离药物浓度高于MIC的时间百分比）目标，对铜绿假单胞菌的经验覆盖率累积分数反应为b> = 85%。对于100% fT (>MIC)，每8 h至少需要1.5 g的剂量。在每8小时1.5 g和3.0 g的模拟方案中，头孢ozane稳态浓度的中位数（四分位数范围）分别为28（21至42）和56(42至84)mg/l。相应的他唑巴坦浓度分别为6.1（5.5 ~ 6.7）和12.1 (11.0 ~ 13.4)mg/l。我们建议对CVVHDF的危重患者采用前负荷方案，单次负荷剂量为3.0 g，然后每8小时0.75 g，血液和透析液流速研究。
The aim of this work was to describe optimized dosing regimens of ceftolozane-tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for ceftolozane-tazobactam and CVVHDF. Unbound drug concentrations were measured from serial prefilter blood, postfilter blood, and ultrafiltrate samples by a chromatographic assay. Population pharmacokinetic modeling and dosing simulations were performed using Pmetrics. A four-compartment pharmacokinetic model adequately described the data from six patients. The mean (+/- standard deviation [SD]) extraction ratios for ceftolozane and tazobactam were 0.76 +/- 0.08 and 0.73 +/- 0.1, respectively. The mean +/- SD sieving coefficients were 0.94 +/- 0.24 and 1.08 +/- 0.30, respectively. Model-estimated CVVHDF clearance rates were 2.7 +/- 0.8 and 3.0 +/- 0.6 liters/h, respectively. Residual non-CVVHDF clearance rates were 0.6 +/- 0.5 and 3.3 +/- 0.9 liters/h, respectively. In the initial 24 h, doses as low as 0.75 g every 8 h enabled cumulative fractional response of >= 85% for empirical coverage against Pseudomonas aeruginosa, considering a 40% fT (>MIC) (percentage of time the free drug concentration was above the MIC) target. For 100% fT (>MIC), doses of at least 1.5 g every 8 h were required. The median (interquartile range) steady-state trough ceftolozane concentrations for simulated regimens of 1.5 g and 3.0 g every 8 h were 28 (21 to 42) and 56 (42 to 84) mg/liter, respectively. The corresponding tazobactam concentrations were 6.1 (5.5 to 6.7) and 12.1 (11.0 to 13.4) mg/liter, respectively. We suggest a front-loaded regimen with a single 3.0-g loading dose followed by 0.75 g every 8 h for critically ill patients undergoing CVVHDF with study blood and dialysate flow rates.