Population Pharmacokinetics of Unbound Ceftolozane and Tazobactam in Critically III Patients without Renal Dysfunction
Population Pharmacokinetics of Unbound Ceftolozane and Tazobactam in Critically III Patients without Renal Dysfunction
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DOI：
10.1128/aac.01265-19
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发表时间：
2019-10-01
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.
评价危重患者的给药方案需要该人群的药代动力学数据。这项前瞻性观察性研究旨在描述未结合头孢洛扎和他唑巴坦在无肾损害的重症患者中的群体药代动力学，并评估推荐给药方案治疗全身感染的充分性。根据临床医生建议，患者接受1.5或3.0 g头孢洛扎-他唑巴坦。测定未结合的头孢洛扎和他唑巴坦血浆浓度，并使用Pmetrics分析数据，随后进行Monte Carlo模拟。二室模型充分描述了12例患者的数据。尿肌酐清除率（CLCR）和体重分别描述了清除率和中心分布容积（V）的患者间变异性。未结合头孢洛扎和他唑巴坦的平均+/-标准差（SD）参数估计值分别为CL 7.2 +/- 3.2和25.4 +/- 9.4 L/h，V 20.4 +/- 3.7和32.4 +/- 10 L，未结合的头孢洛扎或他唑巴坦从中枢至外周室的分布速率常数（Kcp）为0.46 +/- 0.74和2.96 +/- 8.6 h（-1），未结合的头孢洛扎或他唑巴坦从外周室到中央室的分布速率常数（Kpc）为0.39 +/- 0.37和26.5 +/- 8.4 h（-1）。每8小时（q8 h）给药1.5 g和3.0 g时，定向治疗对铜绿假单胞菌的部分靶向达到率（FTA）>= 85%（MIC = 85%）。对于40%时间的目标，游离药物浓度高于MIC（40%fT（>MIC）），建议间歇输注3g q8 h，除非存在高度敏感病原体，在这种情况下可以使用1.5 g剂量。如果需要更高的100% fT（>MIC）目标，则1.5 g负荷剂量加4.5 g连续输注可能足够。
Evaluation of dosing regimens for critically ill patients requires pharmacokinetic data in this population. This prospective observational study aimed to describe the population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal impairment and to assess the adequacy of recommended dosing regimens for treatment of systemic infections. Patients received 1.5 or 3.0 g ceftolozane-tazobactam according to clinician recommendation. Unbound ceftolozane and tazobactam plasma concentrations were assayed, and data were analyzed with Pmetrics with subsequent Monte Carlo simulations. A two-compartment model adequately described the data from twelve patients. Urinary creatinine clearance (CLCR) and body weight described between-patient variability in clearance and central volume of distribution (V), respectively. Mean +/- standard deviation (SD) parameter estimates for unbound ceftolozane and tazobactam, respectively, were CL of 7.2 +/- 3.2 and 25.4 +/- 9.4 liters/h, V of 20.4 +/- 3.7 and 32.4 +/- 10 liters, rate constant for distribution of unbound ceftolozane or tazobactam from central to peripheral compartment (Kcp) of 0.46 +/- 0.74 and 2.96 +/- 8.6 h(-1), and rate constant for distribution of unbound ceftolozane or tazobactam from peripheral to central compartment (Kpc) of 0.39 +/- 0.37 and 26.5 +/- 8.4 h(-1). With dosing at 1.5 g and 3.0 g every 8 h (q8h), the fractional target attainment (FTA) against Pseudomonas aeruginosa was >= 85% for directed therapy (MIC = 85%. For a target of 40% of time the free drug concentration is above the MIC (40% fT(>MIC)), 3g q8h by intermittent infusion is suggested unless a highly susceptible pathogen is present, in which case 1.5-g dosing could be used. If a higher target of 100% fT(>MIC) is required, a 1.5-g loading dose plus a 4.5-g continuous infusion may be adequate.