Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
Shionogi & Co., Ltd., Osaka, Japan.
Antimicrob Agents Chemother. 2017 Oct 24;61(11). doi: 10.1128/AAC.01022-17. Print 2017 Nov.
Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 μg/ml was noted in 77, 88, and 85% of , , and , respectively. For isolates with MICs of ≥8 μg/ml, bacterial stasis or ≥1 log reduction was observed in only 2 of 28 (8 , 19 , and 1 ) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 μg/ml, whereas isolates with MICs of ≥8 μg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.
头孢他啶（S-649266）是一种新型的铁载体头孢菌素，对临床遇到的多种耐药（MDR）革兰氏阴性菌具有强大的活性；然而，其对这些难以治疗的分离株的抗菌活性谱仍有待充分探索。在这里，我们评估了头孢他啶在中性粒细胞减少的鼠大腿模型中的人体暴露效果，以支持适当的 MIC 折点。此外，我们比较了头孢他啶与美罗培南和头孢吡肟的人体暴露效果，以对抗这些表型多样的分离株中的一部分。研究了 95 株革兰氏阴性菌。通过与 0 小时对照相比，在 24 小时时 CFU 的对数变化来确定疗效。在 MIC 值≤4μg/ml 的 67 株细菌中，有 77%、88%和 85%观察到细菌停滞或减少≥1 对数，分别为 、和 。对于 MIC 值≥8μg/ml 的分离株，仅在 28 株中的 2 株（8%、19%和 1%）中观察到细菌停滞或减少≥1 对数。对于高度耐药的美罗培南和头孢吡肟菌，头孢他啶仍保持其杀菌活性。总体而言，对于 MIC 值≤4μg/ml 的细菌，头孢他啶的人体暴露产生了类似的细菌密度降低，而对于 MIC 值≥8μg/ml 的分离株，在该化合物存在的情况下，细菌通常会生长。本研究获得的数据将有助于确定头孢他啶对这些重要的医院获得性革兰氏阴性病原体的 MIC 敏感性折点；然而，需要更多的临床数据来证实这些观察结果。
