Gill Christian M, Abdelraouf Kamilia, Oota Merime, Nakamura Rio, Kuroiwa Miho, Ishioka Yoshino, Takemura Miki, Yamano Yoshinori, Nicolau David P
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
Shionogi TechnoAdvance Research & Co. Ltd, Osaka, Japan.
JAC Antimicrob Resist. 2022 May 3;4(3):dlac047. doi: 10.1093/jacamr/dlac047. eCollection 2022 Jun.
This study evaluated the sustained kill and potential for resistance development of exposed to human-simulated exposure of cefiderocol over 72 h in and infection models.
Seven isolates with cefiderocol MICs of 0.12-2 mg/L were tested. The sustained bactericidal activity compared with the initial inoculum and the resistance appearance over 72 h treatment were evaluated in both an chemostat and an murine thigh infection model under the human-simulated exposure of cefiderocol (2 g every 8 h as 3 h infusion).
In the model, regrowth was observed against all seven tested isolates and resistance emergence (>2 dilution MIC increase) was observed in five test isolates. Conversely, sustained killing over 72 h and no resistance emergence were observed in six of seven tested isolates . The mechanism of one resistant isolate that appeared only in the chemostat studies was a mutation in the region, which contributes to the energy transduction on the iron transporters. The resistance acquisition mechanisms of other isolates have not been identified.
The discrepancy in the sustained efficacy and resistance emergence between and models was observed for . Although the resistance mechanisms have not been fully identified, sustained efficacy without resistance emergence was observed for six of seven isolates. These studies reveal the bactericidal activity and the low potential for development of resistance among evaluated under human-simulated exposures.
本研究评估了在人体模拟暴露条件下，头孢地尔在72小时内对肺炎克雷伯菌和大肠埃希菌感染模型的持续杀菌作用及耐药性发展潜力。
对7株头孢地尔最低抑菌浓度（MIC）为0.12 - 2mg/L的菌株进行测试。在人体模拟暴露的头孢地尔（每8小时2g，输注3小时）条件下，在肺炎克雷伯菌恒化器和大肠埃希菌小鼠大腿感染模型中，评估与初始接种物相比的持续杀菌活性以及72小时治疗期间的耐药性出现情况。
在肺炎克雷伯菌模型中，对所有7株测试菌株均观察到再生长，并且在5株测试菌株中观察到耐药性出现（MIC增加>2倍稀释）。相反，在7株测试菌株中的6株中观察到72小时内的持续杀菌作用且未出现耐药性。仅在肺炎克雷伯菌恒化器研究中出现的1株耐药菌株的机制是铁转运蛋白区域的能量转导相关基因突变。其他菌株的耐药性获得机制尚未确定。
观察到肺炎克雷伯菌和大肠埃希菌模型在头孢地尔的持续疗效和耐药性出现方面存在差异。尽管耐药机制尚未完全明确，但在7株菌株中的6株中观察到持续疗效且未出现耐药性。这些研究揭示了在人体模拟暴露评估下，头孢地尔的杀菌活性以及耐药性发展的低潜力。
