Cefiderocol and Sulbactam-Durlobactam against Carbapenem-Resistant Acinetobacter baumannii

Abstract

Infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) remain a clinical challenge due to limited treatment options. Recently, cefiderocol, a novel siderophore cephalosporin, and sulbactam-durlobactam, a bactericidal β-lactam–β-lactamase inhibitor combination, have been approved by the Food and Drug Administration for the treatment of A. baumannii infections. In this review, we discuss the mechanisms of action of and resistance to cefiderocol and sulbactam-durlobactam, the antimicrobial susceptibility of A. baumannii isolates to these drugs, as well as the clinical effectiveness of cefiderocol and sulbactam/durlobactam-based regimens against CRAB. Overall, cefiderocol and sulbactam-durlobactam show an excellent antimicrobial activity against CRAB. The review of clinical studies evaluating the efficacy of cefiderocol therapy against CRAB indicates it is non-inferior to colistin/other treatments for CRAB infections, with a better safety profile. Combination treatment is not associated with improved outcomes compared to monotherapy. Higher mortality rates are often associated with prior patient comorbidities and the severity of the underlying infection. Regarding sulbactam-durlobactam, current data from the pivotal clinical trial and case reports suggest this antibiotic combination could be a valuable option in critically ill patients affected by CRAB infections, in particular where no other antibiotic appears to be effective.

Treatment of infections caused by carbapenem-resistant Acinetobacter baumannii

“…Therefore, cefiderocol may be a valuable alternative for treating serious CRAB infections ( Falcone et al., 2022 ). Several reports have confirmed the effectiveness of cefiderocol combined with fosfomycin, tigecycline, and colistin as rescue treatments for serious CRAB infections, and the side effects of cefiderocol are rare ( Bavaro et al., 2021 ; Mabayoje et al., 2021 ; Tan et al., 2022 ; Karruli et al., 2023 ).…”

“…Therefore, SUL/DUR may be used against A. baumannii , which produces class A, C, and D β-lactamases. The frequency of spontaneous in vitro resistance to SUL/DUR is low, and the most common mutation found in stable mutants is in the ftsI gene (the target gene encoding SUL PBP3) ( Karruli et al., 2023 ). Current data show that mice treated with SUL/DUR can resist CRAB both in vitro and in vivo ( Findlay et al., 2022 ).…”

“…Additionally, the primary mechanism underlying drug resistance in carbapenem pathogens is the production of serine β-lactamases, and cefiderocol exhibits resistance against both serine β-lactamase and metallo-β-lactamase hydrolysis. Cefiderocol can sustain resistance to PER-1-producing A. baumannii , as demonstrated using in vitro models ( Yamano et al., 2020 ), and the resistance to cefiderocol is correlated with reduced expressions of pirA and piuA ( Karruli et al., 2023 ).…”

“…As a drug that belongs to a new class of catechol-substituted siderophore cephalosporins, cefiderocol has zwitterionic properties and can rapidly penetrate the outer cell membrane of Gram-negative bacteria ( Karruli et al., 2023 ). Cefiderocol is FDA approved for the treatment of CRAB, carbapenem-resistant Pseudomonas aeruginosa , and carbapenem-resistant Enterobacteriales (CRE), and it was the first siderophore cephalosporin to be approved ( ) ( US Food and Drug Administration, 2019 ).…”