Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistant Acinetobacter spp.

The emergence of Gram-negative bacteria resistant to multiple antibiotics, particularly carbapenem-resistant (CR) Acinetobacter strains, poses a significant threat globally. Despite efforts to develop new antimicrobial therapies, limited progress has been made, with only two drugs—cefiderocol and sulbactam-durlobactam—showing promise for CR-Acinetobacter infections. Cefiderocol, a siderophore cephalosporin, demonstrates promising efficacy in the treatment of Gram-negative infections. However, resistance to cefiderocol has been reported in A. baumannii. Combination therapies, such as cefiderocol with avibactam or sulbactam, show reduced MICs against cefiderocol-non-susceptible strains with in vivo efficacy, although the outcomes can be complex and species-specific. In the present work, the molecular characterization of spontaneous cefiderocol-resistant variants, a CRAB strain displaying antagonism with sulbactam and an A. lwoffii strain showing antagonism with avibactam, were studied. The results reveal intriguing insights into the underlying mechanisms, including mutations affecting efflux pumps, transcriptional regulators, and iron homeostasis genes. Moreover, gene expression analysis reveals significant alterations in outer membrane proteins, iron homeostasis, and β-lactamases, suggesting adaptive responses to selective pressure. Understanding these mechanisms is crucial for optimizing treatment strategies and preventing adverse clinical outcomes. This study highlights the importance of preemptively assessing drug synergies to navigate the challenges posed by antimicrobial resistance in CR-Acinetobacter infections.多重耐药革兰氏阴性菌的出现，尤其是碳青霉烯类耐药（carbapenem-resistant, CR）不动杆菌菌株，在全球范围内构成了重大公共卫生威胁。尽管科研人员已全力开发新型抗菌治疗手段，但进展寥寥，目前仅头孢地尔（cefiderocol）与舒巴坦-度洛巴坦（sulbactam-durlobactam）两款药物对碳青霉烯类耐药不动杆菌（CR-Acinetobacter）感染展现出治疗前景。头孢地尔作为一类铁载体头孢菌素，在革兰氏阴性菌感染的临床治疗中表现出可观的疗效。不过，已有研究报道鲍曼不动杆菌（A. baumannii）对头孢地尔产生了耐药性。诸如头孢地尔联合阿维巴坦（avibactam）或舒巴坦的联合治疗方案，可降低头孢地尔非敏感菌株的最低抑菌浓度（MICs），并在体内验证出抗菌活性，但治疗结局往往复杂多变，且存在菌种特异性差异。本研究对三类目标菌株进行了分子特征解析：自发头孢地尔耐药变异株、对舒巴坦呈现拮抗作用的碳青霉烯类耐药鲍曼不动杆菌（CRAB）菌株，以及对阿维巴坦呈现拮抗作用的洛菲不动杆菌（A. lwoffii）菌株。研究结果揭示了多项耐药机制的有趣发现，包括影响外排泵、转录调控因子与铁稳态基因的突变。此外，基因表达分析显示，外膜蛋白、铁稳态系统与β-内酰胺酶的表达水平均发生显著改变，提示菌株在药物选择压力下产生了适应性应答。阐明上述耐药机制，对于优化临床治疗策略、规避不良临床结局至关重要。本研究同时强调了提前评估药物协同作用的重要性，以应对碳青霉烯类耐药不动杆菌感染所带来的抗菌药物耐药挑战。