Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
Umm Al-Qura University, Makkah, Saudi Arabia.
Antimicrob Agents Chemother. 2018 Jun 26;62(7). doi: 10.1128/AAC.00113-18. Print 2018 Jul.
The role of inhalational combination therapy when treating carbapenem-resistant and with newer beta-lactam/beta-lactamase inhibitors has not been established. Using a 72-h pharmacodynamic chemostat model, we simulated the human exposures achieved in epithelial lining fluid (ELF) following intravenous treatment with ceftazidime-avibactam (CZA) 2.5 g every 8 h (q8h) alone and in combination with inhaled amikacin (AMK-I) 400 mg q12h, a reformulated aminoglycoside designed for inhalational administration, against three isolates (CZA [ceftazidime/avibactam] MICs, 4/4 to 8/4 μg/ml; AMK-I MICs, 8 to 64 μg/ml) and three isolates (CZA MICs, 1/4 to 8/4 μg/ml; AMK-I MICs, 32 to 64 μg/ml). Combination therapy resulted in a significant reduction in 72-h CFU compared with that of CZA monotherapy against two of three isolates (-4.14 log CFU/ml, = 0.027; -1.42 log CFU/ml, = 0.020; and -0.4 log CFU/ml, = 0.298) and two of three isolates (0.04 log CFU/ml, = 0.963; -4.34 log CFU/ml, < 0.001; and -2.34 log CFU/ml, = 0.021). When measured by the area under the bacterial growth curve (AUBC) over 72 h, significant reductions were observed in favor of the combination regimen against all six isolates tested. AMK-I combination therapy successfully suppressed CZA resistance development in one isolate harboring that was observed during CZA monotherapy. These studies suggest a beneficial role for combination therapy with intravenous CZA and inhaled AMK when treating pneumonia caused by carbapenem-resistant Gram-negative bacteria.
在治疗耐碳青霉烯肠杆菌科细菌和铜绿假单胞菌时，吸入性联合治疗的作用尚未确定。我们使用 72 小时药效动力学恒化器模型，模拟了静脉注射头孢他啶-阿维巴坦（CZA）2.5 g 每 8 小时（q8h）单药治疗和与吸入性阿米卡星（AMK-I）400 mg 每 12 小时（q12h）联合治疗时在肺上皮衬液（ELF）中达到的人体暴露量，阿米卡星是一种为吸入给药而重新配制的氨基糖苷类药物，针对三种 分离株（CZA [头孢他啶/阿维巴坦] MICs，4/4 至 8/4μg/ml；AMK-I MICs，8 至 64μg/ml）和三种 分离株（CZA MICs，1/4 至 8/4μg/ml；AMK-I MICs，32 至 64μg/ml）。与 CZA 单药治疗相比，联合治疗在 72 小时 CFU 中显著降低了两株 分离株（-4.14 log CFU/ml， = 0.027；-1.42 log CFU/ml， = 0.020；-0.4 log CFU/ml， = 0.298）和两株 分离株（0.04 log CFU/ml， = 0.963；-4.34 log CFU/ml， < 0.001；-2.34 log CFU/ml， = 0.021）。通过 72 小时细菌生长曲线下面积（AUBC）测量，联合治疗方案对所有 6 株受试分离株均有显著降低。在 CZA 单药治疗中观察到携带 的一株 分离株中，AMK-I 联合治疗成功抑制了 CZA 耐药性的发展。这些研究表明，在治疗耐碳青霉烯革兰氏阴性菌引起的肺炎时，静脉注射 CZA 和吸入性 AMK 的联合治疗具有有益作用。
