Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, New York, USA.
School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
Antimicrob Agents Chemother. 2024 Oct 8;68(10):e0077024. doi: 10.1128/aac.00770-24. Epub 2024 Sep 17.
Gram-negatives harboring metallo-β-lactamases (MBLs) and extended-spectrum β-lactamases (ESBLs) pose a substantial risk to the public health landscape. In ongoing efforts to combat these "superbugs," we explored the clinical combination of aztreonam and ceftazidime/avibactam together with varying dosages of polymyxin B and imipenem against ( CDC Nevada) in a 9-day hollow fiber infection model (HFIM). As previously reported by our group, although the base of aztreonam and ceftazidime/avibactam alone leads to 3.34 log fold reductions within 72 hours, addition of polymyxin B or imipenem to the base regimen caused maximal killing of 7.55 log and 7.4 log fold reduction, respectively, by the 72-hour time point. Although low-dose polymyxin B and imipenem enhanced the bactericidal activity as an adjuvant to aztreonam +ceftazidime/avibactam, regrowth to ~9 logCFU/mL by 216 hours rendered these combinations ineffective. When aztreonam +ceftazidime/avibactam was supplemented with high-dose polymyxin B and or low-dose polymyxin B + imipenem, it resulted in effective long-term clearance of the bacterial population. Time lapse microscopy profiled the emergence of long filamentous cells in response to PBP3 binding due to aztreonam and ceftazidime. The emergence of spheroplasts via imipenem and damage to the outer membrane via polymyxin B was visualized as a mechanism of persister killing. Despite intrinsic and resistance, polymyxin B and β-lactam combinations represent a promising strategy. Future studies using an integrated molecularly precise pharmacodynamic approach are warranted to unravel the mechanistic details to propose optimal antibiotic combinations to combat untreatable, pan-drug-resistant Gram-negatives.
产金属β-内酰胺酶（MBLs）和超广谱β-内酰胺酶（ESBLs）的革兰氏阴性菌对公共卫生领域构成了重大威胁。在对抗这些“超级细菌”的持续努力中，我们在为期 9 天的中空纤维感染模型（HFIM）中研究了不同剂量多黏菌素 B 和亚胺培南与氨曲南和头孢他啶/阿维巴坦联合应用对耐碳青霉烯类肠杆菌科（CDC 内华达州）的临床疗效。正如我们小组之前报道的那样，尽管单独使用氨曲南和头孢他啶/阿维巴坦的基础方案在 72 小时内导致 3.34 对数减少，但在基础方案中添加多黏菌素 B 或亚胺培南分别导致 7.55 对数和 7.4 对数减少，在 72 小时时达到最大杀伤效果。尽管低剂量多黏菌素 B 和亚胺培南作为氨曲南+头孢他啶/阿维巴坦的佐剂增强了杀菌活性，但到 216 小时时，细菌重新生长到~9 对数 CFU/mL，使这些组合无效。当氨曲南+头孢他啶/阿维巴坦与高剂量多黏菌素 B 或低剂量多黏菌素 B+亚胺培南联合使用时，可有效长期清除细菌群体。延时显微镜分析显示，由于氨曲南和头孢他啶，对 PBP3 结合的反应出现长丝状细胞。通过亚胺培南出现原生质球，通过多黏菌素 B 对细胞膜外膜造成损伤，作为持续杀伤的机制。尽管存在固有 和 耐药性，多黏菌素 B 和β-内酰胺联合用药代表了一种很有前途的策略。未来使用分子精确的药效学综合方法的研究是必要的，以揭示机制细节，提出对抗无法治疗的泛耐药革兰氏阴性菌的最佳抗生素联合用药方案。
