Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-Lactamase Inhibitor, in Combination with Meropenem
Pharmacokinetics/Pharmacodynamics of Vaborbactam, a Novel Beta-Lactamase Inhibitor, in Combination with Meropenem
复制标题
DOI：
10.1128/aac.01659-18
复制
发表时间：
2019-01-01
影响因子：
4.9
通讯作者：
Dudley, Michael N.
中科院分区：
文献类型：
--
作者：
Griffith, David C.;Sabet, Mojgan;Dudley, Michael N.
Vaborbactam是一种新型β-内酰胺酶抑制剂，对重要的β-内酰胺酶具有活性，特别是丝氨酸碳青霉烯酶，目前已批准与美罗培南联合作为Vabomere用于治疗复杂性尿路感染，包括肾盂肾炎。该组合对革兰氏阴性病原体具有高度活性，尤其是产碳青霉烯酶（KPC）的肺炎克雷伯菌耐碳青霉烯肠杆菌科。这些研究的目的是评价使用含KPC的肠杆菌科菌株联合美罗培南固定暴露时，在血小板减少小鼠大腿感染模型以及体外中空纤维感染模型中与有效性相关的戊博巴坦药代动力学（PK）和药效学（PD）关系。对于这两种模型，美罗培南给药方案设计为模拟每8小时（q8 h）输注2 g剂量。在大腿感染模型中，设计了Vaborbactam给药方案，以产生广泛的24小时浓度-时间曲线下面积（AUC）。然而，对于中空纤维模型，AUC限于192、320或550 mg的值。h/L。在动物和体外模型中，当与美罗培南联合给药时，暴露量相当于2 g q8 h给药，3 h输注给药时，最能描述人体中vaborbactam抗菌活性的PK-PD参数是24 h游离vaborbactam AUC/美罗培南-vaborbactam（vaborbactam为8 mg/L）MIC比。该抑菌比率的量级为9至12，观察到1-log杀灭的量级为18至38。此外，大于24的幅度抑制了体外中空纤维模型中耐药性的发展。
Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gramnegative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae. The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model, as well as in an in vitro hollow-fiber infection model, in combination with a fixed exposure of meropenem using KPCcontaining strains of Enterobacteriaceae. For both models, the meropenem dosage regimen was designed to simulate a 2-g dose administered every eight hours (q8h) by 3-h infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24-h areas under the concentration-time curves (AUCs) in the thigh infection model. However, for the hollow-fiber model, the AUCs were limited to values of 192, 320, or 550mg . h/liter. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by 3-h infusion in humans, was the 24-h free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/liter) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 to 12 and the magnitude to observe a 1-log kill was 18 to 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow-fiber model.