Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan
Antibacterial Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, Upper Providence, Pennsylvania, USA.
Antimicrob Agents Chemother. 2017 Aug 24;61(9). doi: 10.1128/AAC.00700-17. Print 2017 Sep.
Cefiderocol (S-649266), a novel siderophore cephalosporin, shows potent activity against carbapenem-resistant Gram-negative bacilli. In this study, we evaluated the efficacy of cefiderocol against carbapenem-resistant Gram-negative bacilli (, , and ) in immunocompetent-rat respiratory tract infection models recreating plasma pharmacokinetics (PK) profiles in healthy human subjects. A total of 6 clinical isolates (1 cephalosporin-susceptible isolate, 1 multidrug-resistant isolate, 2 multidrug-resistant isolates, and 2 carbapenem-resistant isolates) were evaluated. Four-day treatment with a human exposure of 1 g ceftazidime every 8 h as a 0.5-h infusion showed potent efficacy only against a ceftazidime-susceptible isolate, not against five ceftazidime-resistant isolates harboring carbapenemase. With cefiderocol, a human exposure of 2 g every 8 h as a 3-h infusion for 4 days produced a >3 log reduction in the number of viable cells of these carbapenem-resistant isolates in the lungs. When the infusion time was 1 h, bactericidal activity was also observed against all isolates tested, although for 2 of 5 carbapenem-resistant isolates, a 3 log reduction was not achieved. The difference in efficacy achieved by changing the infusion period from 1 h to 3 h was considered to be due to the higher percentage of the dosing interval during which free-drug concentrations were above the MIC (%), as observed for β-lactam antibiotics. These results suggest the potential utility of cefiderocol for the treatment of lung infections caused by carbapenem-resistant , , and strains.
头孢他啶侧链酸(S-649266)是一种新型的铁载体头孢菌素,对耐碳青霉烯类革兰氏阴性菌具有强大的活性。在这项研究中,我们评估了头孢他啶侧链酸对免疫功能正常的大鼠呼吸道感染模型中耐碳青霉烯类革兰氏阴性菌(、、和)的疗效,该模型重现了健康人体中的血浆药代动力学(PK)特征。共评估了 6 株临床分离株(1 株头孢菌素敏感株、1 株多药耐药株、2 株多药耐药株和 2 株耐碳青霉烯类株)。4 天的治疗方案为人暴露于 1 g 头孢他啶,每 8 h 静脉输注 0.5 小时,结果仅对 1 株头孢他啶敏感株有效,而对 5 株携带碳青霉烯酶的头孢他啶耐药株无效。用头孢他啶侧链酸,每 8 h 人暴露 2 g,静脉输注 3 小时,连续 4 天,可使肺部这些耐碳青霉烯类菌的活菌数减少>3 对数。当输注时间为 1 h 时,也观察到对所有测试的分离株均具有杀菌活性,尽管对于 5 株耐碳青霉烯类分离株中的 2 株,未达到 3 对数减少。通过将输注期从 1 h 改为 3 h 而实现的疗效差异,被认为是由于β-内酰胺类抗生素观察到的自由药物浓度高于 MIC(%)的给药间隔的比例更高所致。这些结果表明,头孢他啶侧链酸有可能用于治疗由耐碳青霉烯类、、和 引起的肺部感染。