Combination of Cefiderocol and Sulbactam Against Carbapenem-Resistant Enterobacterales: Mechanisms of Synergy and Prospects for Clinical Application

Background . The spread of carbapenem-resistant Enterobacterales (CRE) is associated with high mortality rates, limited therapeutic options, as well as the risk of ineffective empirical antibacterial therapy. Cefiderocol retains activity against many producers of serine carbapenemases and metallo-β-lactamases through its utilization of bacterial iron transport systems. However, hyperproduction of β-lactamases, alterations in siderophore receptors and PBP3, as well as heteroresistance, may compromise its efficacy. One potential strategy to enhance the activity of this agent is its combination with sulbactam. The aim of the study was to summarize and critically appraise the data on the mechanisms of synergy between cefiderocol and sulbactam against carbapenem-resistant Enterobacterales, the available experimental and clinical evidence base, limitations, and prospects for the clinical use of this combination. Material and Methods . The review was prepared in accordance with the SANRA criteria and PRISMA-S guidelines. A literature search was conducted in PubMed/MEDLINE, SpringerLink, ScienceDirect, eLIBRARY.ru, CyberLeninka, and Google Scholar for the period 2007–2026. Studies on mechanisms of resistance to cefiderocol, inhibitory and PBP-mediated activity of sulbactam, microbiological synergy, heteroresistance, PK/PD characteristics, preclinical efficacy, and clinical use of the agents were analyzed. The final analysis included a total of 92 publications. Results. Potential synergy may be mediated through reduced hydrolysis of cefiderocol by inhibited serine β-lactamases, increased periplasmic exposure of the drug, possible additional action on PBPs, and suppression of certain resistant subpopulations. However, sulbactam does not inhibit metallo-β-lactamases and has limited activity against KPC and OXA-48-like enzymes. It does not compensate for impairments in iron transport, PBP3 alterations, or other non-enzymatic resistance mechanisms. Direct investigation of the combination against CRE included only two isolates of K. pneumoniae. Representative studies on Enterobacterales collections, dynamic PK/PD models, direct in vivo studies, and clinical trials are lacking. Optimal sulbactam exposure, predictors of response, and standardized criteria for laboratory confirmation of synergy have not been established. Conclusion. The cefiderocol–sulbactam combination has an experimental mechanistic rationale; however, the available evidence is insufficient for its routine use in infections caused by carbapenem-resistant Enterobacterales. The evidence is insufficient to define the therapeutic niche of this combination, including its use as salvage therapy. Until reproducible microbiological, PK/PD, preclinical, and clinical data are obtained, the combination should be considered solely as an object of further research. Mechanistically stratified microbiological, PK/PD, preclinical, and clinical studies are required for clinical translation.