Background: Carbapenemase-producing Klebsiella pneumoniae (CRKP) presents a serious global health threat, particularly in critical care settings where it significantly contributes to mortality in patients with severe sepsis. Carbapenem-based regimens, once the mainstay for Gram-negative infections, have shown declining efficacy due to growing resistance. In response, cephalosporin–beta-lactamase inhibitor (C-BLI) combinations such as ceftazidime–avibactam and cefiderocol have emerged as potential alternatives, though their clinical superiority remains uncertain.Objective: This systematic review aims to compare the efficacy of carbapenem-based regimens versus C-BLI combinations in the treatment of severe sepsis caused by CRKP, following PRISMA guidelines.Methods: A comprehensive search was conducted across PubMed, Embase, Scopus, and Web of Science for randomized controlled trials and cohort studies published between 2010 and 2024. Primary outcomes included 30-day mortality, microbiological clearance, and nephrotoxicity.Results: Carbapenem-based combinations particularly those including colistin or tigecycline, were associated with reduced mortality but increased nephrotoxicity. In contrast, C-BLI regimens demonstrated better microbiological clearance and a more favorable toxicity profile. However, their efficacy against certain resistance mechanisms—especially metallo-beta-lactamases—remains limited. Agents like ceftazidime–avibactam show promise but are challenged by emerging resistance.Conclusion: Therapeutic decisions should be individualized, considering local resistance patterns, patient comorbidities, and drug toxicities. There is an urgent need for further large-scale randomized trials to identify optimal treatment strategies for CRKP-induced severe sepsis and mitigate antibiotic resistance
