Klem Jack F, Kaur Jan Naseer, Liu Yang, Boissonneault Katie Rose, Kapoor Shivali, Holden Patricia N, Chen Albert, Zhao Yanan, Chen Liang, Smith Nicholas M, Tsuji Brian T
Center for Infectious Diseases and Next-Generation Therapeutics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
Division of Clinical and Translational Therapeutics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
JAC Antimicrob Resist. 2025 Jul 22;7(4):dlaf132. doi: 10.1093/jacamr/dlaf132. eCollection 2025 Aug.
Therapeutic modalities for pan-drug-resistant Gram-negatives co-expressing mobile colistin resistance and metallo-β-lactamases have not been defined. Here, we devised novel strategies involving aztreonam and ceftazidime/avibactam together with polymyxin B to combat persisters of a pan-drug-resistant strain ( , and ).
A hollow fibre infection model was utilized to profile the clinical combination of aztreonam + ceftazidime/avibactam + polymyxin B against a pan-drug-resistant clinical isolate over 168 h with reversion experiments conducted until a 216 h endpoint. The evolutionary profiles of the total and resistant subpopulations were assessed using real-time population analysis profiles. Scanning electron microscopy imaging was utilized to visualize time courses of salient structural alterations.
The clinical combination of aztreonam + ceftazidime/avibactam demonstrated initial activity with a total count reduction of 2.69 log CFU/mL over 24 h. Reversion experiments demonstrated complete regrowth to 10.2 log CFU/mL by 216 h. In contrast, the addition of polymyxin B to the β-lactam/β-lactamase inhibitor combination resulted in marked bactericidal activity (4.19 log CFU/mL) within 24 h and eventually below the limit of detection by 174 h. SEM imaging revealed filamentous persister cells under aztreonam selective pressure. However, with polymyxin B combinations, there was an absence of viable cells with no evidence of long filamentous persister cells, despite polymyxin resistance.
Despite intrinsic and resistance mechanisms, the proposed novel combination holds vast promise to maximally suppress the development of persisters and amplification of resistance in 'nightmare' pan-drug-resistant Gram-negative urgent threats.
对于同时表达可移动的黏菌素耐药性和金属β-内酰胺酶的泛耐药革兰氏阴性菌，尚未明确其治疗方式。在此，我们设计了新策略，将氨曲南、头孢他啶/阿维巴坦与多黏菌素B联合使用，以对抗一株泛耐药菌株（ 、 和 ）的持留菌。
利用中空纤维感染模型，分析氨曲南+头孢他啶/阿维巴坦+多黏菌素B针对一株泛耐药临床分离株的临床联合用药情况，为期168小时，并进行回复实验直至216小时的终点。使用实时群体分析图谱评估总群体和耐药亚群体的进化图谱。利用扫描电子显微镜成像观察显著结构改变的时间进程。
氨曲南+头孢他啶/阿维巴坦的临床联合用药显示出初始活性，在24小时内细菌总数减少2.69 log CFU/mL。回复实验表明，到216小时细菌完全重新生长至10.2 log CFU/mL。相比之下，在β-内酰胺/β-内酰胺酶抑制剂组合中添加多黏菌素B，在24小时内产生显著的杀菌活性（4.19 log CFU/mL），并最终在174小时时降至检测限以下。扫描电子显微镜成像显示，在氨曲南选择压力下存在丝状持留菌细胞。然而，对于多黏菌素B联合用药，尽管存在多黏菌素耐药性，但没有存活细胞，也没有长丝状持留菌细胞的证据。
尽管存在内在的 和 耐药机制，但所提出的新联合用药极有希望最大程度地抑制“噩梦般”的泛耐药革兰氏阴性菌紧急威胁中持留菌的形成和耐药性的扩增。
