Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis
Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis
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DOI：
10.1128/aac.00988-17
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发表时间：
2017-10-01
影响因子：
4.9
通讯作者：
Beringer, Paul M.
中科院分区：
文献类型：
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作者：
Bensman, Timothy J.;Wang, Joshua;Beringer, Paul M.
涉及铜绿假单胞菌的急性肺加重（APE）与囊性纤维化（CF）患者的发病率和死亡率增加相关。耐药性是治疗的一个重大挑战。头孢他啶-阿维巴坦（CZA）对从CF患者中回收的分离株（包括耐药菌株）表现出优异的体外活性。在CF患者中报告了几种β内酰胺类抗生素的药代动力学（PK）改变。因此，本研究旨在描述CZA的PK特征，并进行目标实现分析，以确定最佳治疗方案。测定了12例成人CF患者接受3次静脉给药（2.5 g，每8 h输注一次，持续2 h）后CZA的PK。群体建模采用最大似然期望法。蒙特卡洛模拟确定的概率达到目标（PTA）。评价头孢他啶（CAZ）的暴露目标，包括稳态药代动力学条件下游离药物浓度超过MIC的24小时累积百分比（fT（>MIC）），以及暴露目标，其由游离药物浓度超过1 mg/L阈值浓度（fT（>1））的24小时期间的累积百分比组成，（mg/L））。纳入已发表的CAZ和CZA MIC分布，以评价累积应答概率。CAZ和AVI最好用一室模型描述。总体清除率（CL; CAZ CL，7.53 +/- 1.28升/小时; AVI CL，12.30 +/- 1.96升/小时）和分布容积（V; CAZ V，18.80 +/- 6.54升; AVI V，25.30 +/- 4.43升）的值与健康成人的已发表值大致相似。CZA实现了PTA（fT（>MIC），50%）>0.9，MIC为
Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several betalactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (fT(>MIC)) was evaluated for ceftazidime (CAZ), and an exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds a 1-mg/liter threshold concentration (fT(>1) (mg/liter)) was evaluated for avibactam (AVI). Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities. CAZ and AVI were best described by one-compartment models. The values of total body clearance (CL; CAZ CL, 7.53 +/- 1.28 liters/h; AVI CL, 12.30 +/- 1.96 liters/h) and volume of distribution (V; CAZ V, 18.80 +/- 6.54 liters; AVI V, 25.30 +/- 4.43 liters) were broadly similar to published values for healthy adults. CZA achieved a PTA (fT(>MIC), 50%) of >0.9 for MICs of