Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA.
Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0052722. doi: 10.1128/aac.00527-22. Epub 2022 Aug 4.
Metallo-β-lactamase (MBL)-producing Gram-negative bacteria cause infections associated with high rates of morbidity and mortality. Currently, a leading regimen to treat infections caused by MBL-producing bacteria is aztreonam combined with ceftazidime-avibactam. The purpose of the present study was to evaluate and rationally optimize the combination of aztreonam and ceftazidime-avibactam with and without polymyxin B against a clinical Klebsiella pneumoniae isolate producing NDM-1 and CTX-M by use of the hollow fiber infection model (HFIM). A novel de-escalation approach to polymyxin B dosing was also explored, whereby a standard 0-h loading dose was followed by maintenance doses that were 50% of the typical clinical regimen. In the HFIM, the addition of polymyxin B to aztreonam plus ceftazidime-avibactam significantly improved bacterial killing, leading to eradication, including for the novel de-escalation dosing strategy. Serial samples from the growth control and monotherapies were explored in a Galleria mellonella virulence model to assess virulence changes. Weibull regression showed that low-level ceftazidime resistance and treatment with monotherapy resulted in increased G. mellonella mortality ( < 0.05). A neutropenic rabbit pneumonia model demonstrated that aztreonam plus ceftazidime-avibactam with or without polymyxin B resulted in similar bacterial killing, and these combination therapies were statistically significantly better than monotherapies ( < 0.05). However, only the polymyxin B-containing combination therapy produced a statistically significant decrease in lung weights ( < 0.05), indicating a decreased inflammatory process. Altogether, adding polymyxin B to the combination of aztreonam plus ceftazidime-avibactam for NDM- and CTX-M-producing K. pneumoniae improved bacterial killing effects, reduced lung inflammation, suppressed resistance amplification, and limited virulence changes.
产金属β-内酰胺酶（MBL）的革兰氏阴性菌引起的感染与高发病率和死亡率相关。目前，治疗产 MBL 细菌感染的主要方案是使用氨曲南联合头孢他啶-阿维巴坦。本研究的目的是通过中空纤维感染模型（HFIM）评估和合理优化氨曲南与头孢他啶-阿维巴坦联合与不联合多黏菌素 B 治疗产 NDM-1 和 CTX-M 的临床肺炎克雷伯菌的方案，并探索多黏菌素 B 剂量的新降级方法，即标准 0 小时负荷剂量后给予 50%的典型临床方案维持剂量。在 HFIM 中，多黏菌素 B 联合氨曲南与头孢他啶-阿维巴坦显著提高了细菌清除率，包括新的降级剂量方案。在金蝇幼虫毒力模型中，探索了生长对照和单药治疗的连续样本，以评估毒力变化。威布尔回归显示，低水平头孢他啶耐药和单药治疗导致金蝇幼虫死亡率增加（ < 0.05）。中性粒细胞减少兔肺炎模型表明，氨曲南与头孢他啶-阿维巴坦联合与不联合多黏菌素 B 治疗的细菌清除率相似，这些联合治疗方案显著优于单药治疗（ < 0.05）。然而，只有包含多黏菌素 B 的联合治疗方案在统计学上显著降低了肺重（ < 0.05），表明炎症过程减少。总的来说，在氨曲南与头孢他啶-阿维巴坦联合治疗产 NDM 和 CTX-M 的肺炎克雷伯菌时，添加多黏菌素 B 可提高杀菌效果，减少肺部炎症，抑制耐药性扩增，并限制毒力变化。
