Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA
Institute of Infectious Disease and Pathogenic Microbiology, Prienai, Lithuania.
Antimicrob Agents Chemother. 2020 Mar 24;64(4). doi: 10.1128/AAC.02157-19.
carbapenemase-producing (KPC-) is an emerging global public health threat that causes life-threatening pneumonia and bacteremia. Ceftazidime-avibactam (CZA) represents a promising advance for the treatment of serious infections caused by KPC- We investigated the pharmacokinetics and efficacy of ceftazidime-avibactam in the treatment of experimental KPC- pneumonia in persistently neutropenic rabbits. For single-dose and multidose (administration every 8 h) pharmacokinetics, rabbits received ceftazidime-avibactam intravenous infusions at 60/15, 90/22.5, and 120/30 mg/kg of body weight. Ceftazidime mean area under the concentration-time curves (AUCs) ranged from 287 to 608 μg·h/ml for a single dose and from 300 to 781 μg·h/ml for multiple doses. Avibactam AUCs ranged from 21 to 48 μg·h/ml for a single dose and from 26 to 48 μg·h/ml for multiple doses. KPC- pneumonia was established by direct endotracheal inoculation. Treatments consisted of ceftazidime-avibactam at 120/30 mg/kg every 6 h, a polymyxin B (PMB) loading dose of 2.5 mg/kg followed by 1.5 mg/kg every 12 h q12h, or no treatment (untreated controls [UC]). There were significant reductions in the residual bacterial burden, lung weights, and pulmonary hemorrhage scores in CZA- and PMB-treated rabbits for a 7-day or a 14-day ( ≤ 0.01) course in comparison with those in the UC. These results corresponded to significant decreases in the bacterial burden in bronchoalveolar lavage fluid after a 7-day or a 14-day treatment ( ≤ 0.01). The outcomes demonstrated an improved response at 14 days versus that at 7 days. There was significantly prolonged survival in rabbits treated with CZA for 14 days in comparison with that in the PMB-treated or UC rabbits ( ≤ 0.05). This study demonstrates that ceftazidime-avibactam displays linear dose-proportional exposures simulating those seen from human plasma pharmacokinetic profiles, is active for the treatment of experimental KPC- pneumonia in persistently neutropenic rabbits, and provides an experimental foundation for the treatment of severely immunocompromised patients with this life-threatening infection.
产碳青霉烯酶（KPC）是一种新出现的全球公共卫生威胁，可导致危及生命的肺炎和菌血症。头孢他啶-阿维巴坦（CZA）是治疗由 KPC 引起的严重感染的有希望的进展。我们研究了头孢他啶-阿维巴坦治疗持续中性粒细胞减少兔实验性 KPC 肺炎的药代动力学和疗效。对于单剂量和多剂量（每 8 小时给药一次）药代动力学，兔子接受了 60/15、90/22.5 和 120/30 mg/kg 体重的头孢他啶-阿维巴坦静脉输注。头孢他啶的平均浓度-时间曲线下面积（AUC）范围为单剂量 287 至 608μg·h/ml，多剂量 300 至 781μg·h/ml。阿维巴坦的 AUC 范围为单剂量 21 至 48μg·h/ml，多剂量 26 至 48μg·h/ml。通过直接气管内接种建立 KPC 肺炎。治疗包括每 6 小时 120/30 mg/kg 的头孢他啶-阿维巴坦、2.5 mg/kg 的多粘菌素 B（PMB）负荷剂量，然后每 12 小时 1.5 mg/kg q12h，或不治疗（未治疗对照[UC]）。与 UC 相比，CZA 和 PMB 治疗的兔子的残留细菌负荷、肺重和肺出血评分在 7 天或 14 天（≤0.01）疗程中有显著降低。这些结果对应于支气管肺泡灌洗液中细菌负荷在 7 天或 14 天治疗后显著降低（≤0.01）。与 7 天相比，14 天的治疗效果有显著改善。与 PMB 治疗或 UC 兔子相比，头孢他啶-阿维巴坦治疗 14 天的兔子的存活时间显著延长（≤0.05）。这项研究表明，头孢他啶-阿维巴坦显示出线性剂量比例暴露，模拟了从人血浆药代动力学曲线观察到的暴露，对持续中性粒细胞减少兔实验性 KPC 肺炎具有治疗作用，并为治疗这种危及生命的感染的严重免疫功能低下患者提供了实验基础。
