Pharmacokinetic-Pharmacodynamic Target Attainment Analyses as Support for Meropenem-Vaborbactam Dosing Regimens and Susceptibility Breakpoints.
Pharmacokinetic-Pharmacodynamic Target Attainment Analyses as Support for Meropenem-Vaborbactam Dosing Regimens and Susceptibility Breakpoints.
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DOI：
10.1128/aac.02130-21
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发表时间：
2022-12-20
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
作者：
美罗培南-戊硼巴坦是一种固定剂量的β-内酰胺/β-内酰胺酶抑制剂，对产肺炎克雷伯菌碳青霉烯酶（KPC）的肠球菌具有强效体外和体内活性。使用群体药代动力学模型、疗效的非临床PK-PD目标、体外监测数据和模拟进行药代动力学-药效学（PK-PD）目标达成分析，以支持每8小时（q8 h）2 g美罗培南-2 g伐硼巴坦作为3 h静脉（i. v.）输注，并针对肾损害患者调整给药方案。生成了不同肾功能指标（估计肾小球滤过率[eGFR]，mL/min/1.73 m2和绝对eGFR，mL/min）的模拟患者，这些患者与临床试验人群（复杂性尿路感染，包括急性肾盂肾炎）相似。计算美罗培南的PK-PD目标，即第1天游离药物血浆浓度高于MIC的时间百分比（%T>MIC），以及vaborbactam的PK-PD目标，即第1天浓度-时间曲线下游离药物血浆面积（AUC）与MIC的比值（AUC：MIC比值）。评估了达到美罗培南游离药物血浆%T>MIC和伐硼巴坦游离药物血浆AUC：MIC比率目标的概率百分比。肠球菌、产KPC肠球菌和铜绿假单胞菌的MIC分布被视为评估PK-PD目标实现的算法的一部分。对于评估与较基线减少1-log 10 CFU相关的游离药物血浆PK-PD目标，在模拟患者中，美罗培南-瓦硼巴坦MIC值为4或8 μg/mL时，PK-PD目标实现的百分比概率范围为81.3%至100%。这些PK-PD目标达成分析的结果为2 g美罗培南-2 g瓦硼巴坦q8 h 3 h i. v.输注给药方案提供了支持，根据这些给药方案，针对肾损害患者和肠球菌和铜绿假单胞菌的美罗培南-瓦硼巴坦敏感性折点≤8 μg/mL（使用8 μg/mL的固定瓦硼巴坦浓度进行检测）调整了给药方案。
Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 μg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 μg/mL (tested with a fixed vaborbactam concentration of 8 μg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.
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在产生KPC的Klebsiella肺炎中，MeropeNem/Vaborbactam耐药性的流行病学，导致意大利北部的血液感染，2018年。
DOI：
10.3390/antibiotics10050536
发表时间：
2021-05-06
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
--
作者：
Gaibani P;Lombardo D;Bussini L;Bovo F;Munari B;Giannella M;Bartoletti M;Viale P;Lazzarotto T;Ambretti S
通讯作者：
Ambretti S
影响因子：
4.9
作者：
Griffith, David C.;Sabet, Mojgan;Dudley, Michael N.
通讯作者：
Dudley, Michael N.
影响因子：
4
作者：
Trang, Michael;Dudley, Michael N.;Bhavnani, Sujata M.
通讯作者：
Bhavnani, Sujata M.
影响因子：
5.4
作者：
Wunderink RG;Giamarellos-Bourboulis EJ;Rahav G;Mathers AJ;Bassetti M;Vazquez J;Cornely OA;Solomkin J;Bhowmick T;Bishara J;Daikos GL;Felton T;Furst MJL;Kwak EJ;Menichetti F;Oren I;Alexander EL;Griffith D;Lomovskaya O;Loutit J;Zhang S;Dudley MN;Kaye KS
通讯作者：
Kaye KS
影响因子：
4.9
作者：
Rubino, Christopher M.;Bhavnani, Sujata M.;Griffith, David C.
通讯作者：
Griffith, David C.