Liu Xiaofen, Qu Xingyi, Zhang Ruohao, Zhang Yuxin, Bian Xingchen, Lin Yu-Wei, Zhang Jing
Institute of Antibiotics, Huashan Hospital Affiliated to Fudan University, Key Laboratory of Clinical Pharmacology of the National Health Commission, National Clinical Research Center for Aging and Diseases, Shanghai, USA.
Clinical Pharmacology Center, Huashan Hospital Affiliated to Fudan University, Shanghai, USA.
Antimicrob Agents Chemother. 2025 Jul 2;69(7):e0191224. doi: 10.1128/aac.01912-24. Epub 2025 May 27.
MRX-8 is a new next-generation polymyxin with potent antibacterial activity against carbapenem-resistant (CRAB). This study evaluated the MRX-8 and meropenem combination and their dosing regimens against CRAB in clinics. Seven CRAB strains isolated from Huashan Hospital were tested. Two strains of AB21-3881 and AB21-3759 were selected for static time-kill and the Hollow Fiber Infection Model (HFIM). Adaptive resistance to MRX-8 was assessed via population analysis profiling (PAP) at 2 mg/L of MRX-8. Multilocus sequence typing identified all seven strains as ST2. Minimum inhibitory concentration values for MRX-8 ranged from 0.5 to 1 mg/L. Synergy was observed in six out of seven (85.7%) strains. The combination of 1 mg/L MRX-8 with 1 mg/L meropenem completely inhibited bacterial growth within 24 h for both selected strains. In HFIM, the combination of MRX-8 (0.75 mg/kg q8h continuous infusion) and meropenem (1 g q6h continuous infusion) achieved synergistic killing over 72 h for AB21-3759, while single treatment of MRX-8 (0.75 mg/kg q8h continuous infusion) achieved bactericidal effect (lower than the detect limitation) over 72 h. PAP analysis demonstrated that the combinational therapy could delay the emergence of adaptive resistance sub-populations by 12-24 h. The combination of MRX-8 and meropenem demonstrated synergistic bactericidal activity by checkerboard and static time-kill curves. Additionally, in HFIM, MRX-8 at 1 mg/kg q12h combined with meropenem at 2 g q12h, as well as MRX-8 at 0.75 mg/kg q8h continuous infusion combined with meropenem at 1 g q6h continuous infusion, achieved bacteriostatic killing at 72 h compared to the initial inoculum.
MRX-8是一种新型的下一代多粘菌素，对耐碳青霉烯类鲍曼不动杆菌（CRAB）具有强大的抗菌活性。本研究评估了MRX-8与美罗培南联合用药及其给药方案在临床上针对CRAB的效果。对从华山医院分离出的7株CRAB菌株进行了检测。选择AB21-3881和AB21-3759这两株菌株进行静态时间杀菌试验和中空纤维感染模型（HFIM）试验。通过在2 mg/L的MRX-8浓度下进行群体分析谱（PAP）评估对MRX-8的适应性耐药性。多位点序列分型将所有7株菌株鉴定为ST2型。MRX-8的最低抑菌浓度值范围为0.5至1 mg/L。7株菌株中有6株（85.7%）观察到协同作用。对于所选的两株菌株，1 mg/L的MRX-8与1 mg/L的美罗培南联合用药在24小时内完全抑制了细菌生长。在HFIM中，MRX-8（0.75 mg/kg每8小时持续输注）与美罗培南（1 g每6小时持续输注）联合用药在72小时内对AB21-3759实现了协同杀菌，而单独使用MRX-8（0.75 mg/kg每8小时持续输注）在72小时内达到了杀菌效果（低于检测限）。PAP分析表明，联合治疗可将适应性耐药亚群的出现延迟12至24小时。MRX-8与美罗培南联合用药通过棋盘法和静态时间杀菌曲线显示出协同杀菌活性。此外，在HFIM中，1 mg/kg每12小时的MRX-8与2 g每12小时的美罗培南联合用药，以及0.75 mg/kg每8小时持续输注的MRX-8与1 g每6小时持续输注的美罗培南联合用药，与初始接种物相比，在72小时时实现了抑菌作用。
