In vivo pharmacodynamics of new-generation β-lactamase inhibitor taniborbactam (formerly VNRX-5133) in combination with cefepime against serine-β-lactamase-producing Gram-negative bacteria
In vivo pharmacodynamics of new-generation β-lactamase inhibitor taniborbactam (formerly VNRX-5133) in combination with cefepime against serine-β-lactamase-producing Gram-negative bacteria
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DOI：
10.1093/jac/dkaa373
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发表时间：
2020-12-01
影响因子：
5.2
通讯作者：
Nicolau, David P.
中科院分区：
文献类型：
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作者：
Abdelraouf, Kamilia;Abuhussain, Safa Almarzoky;Nicolau, David P.
目的：头孢吡肟/taniborbactam是一种正在开发的头孢菌素/环硼酸β -内酰胺酶抑制剂组合，用于治疗耐多药肠杆菌和铜绿假单胞菌感染。使用中性粒细胞减少小鼠大腿感染模型，我们旨在确定与头孢吡肟/坦尼波巴坦联合用药的药效最密切相关的药代动力学/药效学指数，以及对产生丝氨酸-内酰胺酶的菌株有效所需的指数的大小。方法：对26种临床肠杆菌（表达ESBLs、质粒介导的AmpC和/或A类或D类碳青霉烯酶；头孢吡肟/塔尼波巴坦联合mic 0.06 ~ 16 mg/L）和11种临床铜绿假单胞菌（AmpC过量或表达KPC；头孢吡肟/塔尼波巴坦联合mic 1 ~ 16 mg/L）进行评价。头孢吡肟人体模拟方案（HSR）相当于2 g / 8h的临床剂量，作为2小时输注与塔尼波巴坦联合使用24小时。对于铜绿假单胞菌分离物的一个亚群，使用了亚治疗性头孢吡肟暴露。结果：剂量分级研究显示，给药频率对头孢吡肟的坦波巴坦增强作用没有影响。相对于初始细菌负荷，联合头孢吡肟对肠杆菌和铜绿假单胞菌的1 Log杀伤相关的中位taniborbactam fac (0-)(24)/MIC分别为2.62和0.46。与亚治疗性头孢吡肟联合使用时，相对于头孢吡肟治疗组的细菌负荷，坦波巴坦对过量产生ampc的fac (0-)(24)/MIC与1和2 Log杀伤相关的中位值分别为2.00和3.30。taniborbactam HSR（相当于0.5 g q8h输注2 h）足以使所有测试分离株的>= 1 Log降低。结论：我们的数据表明，头孢吡肟/他尼波巴坦组合（2 g/0.5 g q8h输注2 h）对头孢吡肟耐药菌株具有有效的体内活性，包括丝氨酸-碳青霉烯酶产生菌。
Objectives: Cefepime/taniborbactam is a cephalosporin/cyclic boronate beta-Lactamase inhibitor combination under development for the treatment of infections due to MDR Enterobacterales and Pseudomonas aeruginosa. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic index, relative to taniborbactam exposure, that correlated most closely with the efficacy of the cefepime/taniborbactam combination and the magnitude of index required for efficacy against serine-beta-Lactamaseproducing strains.Methods: Twenty-six clinical Enterobacterales (expressing ESBLs, plasmid-mediated AmpC and/or carbapenemases of classes A or D; cefepime/taniborbactam combination MICs 0.06-16 mg/L) and 11 clinical P. aeruginosa (AmpC overproducing or KPC expressing; cefepime/taniborbactam combination MICs 1-16 mg/L) were evaluated. A cefepime human-simulated regimen (HSR) equivalent to a clinical dose of 2 g q8h as a 2 h infusion was given in combination with taniborbactam for 24 h. For a subset of P. aeruginosa isolates, a sub-therapeutic cefepime exposure was utilized.Results: Dose-fractionation studies revealed that dosing frequency had no impact on taniborbactam potentiation of cefepime activity. Relative to the initial bacterial burden, the median taniborbactam fAUC(0-)(24)/MIC associated with 1 Log kill in combination with the cefepime HSR for Enterobacterales and P. aeruginosa isolates was 2.62 and 0.46, respectively. In combination with sub-therapeutic cefepime, the median taniborbactam fAUC(0-)(24)/MIC associated with 1 and 2 Log kill against AmpC-overproducing P. aeruginosa was 2.00 and 3.30, respectively, relative to the bacterial burden in the cefepime-treated groups. The taniborbactam HSR (equivalent to 0.5 g q8h as a 2 h infusion) was adequate to attain >= 1 Log reduction against all test isolates.Conclusions: Our data show that the cefepime/taniborbactam combination (2 g/0.5 g q8h as a 2 h infusion) exerts potent in vivo activity against cefepime-resistant isolates, including serine-carbapenemase producers.