Abstract
BACKGROUND: Acinetobacter baumannii is a bacterial pathogen frequently implicated in healthcare-associated infections, with limited effective treatment options due to widespread antibiotic resistance. Sulbactam/durlobactam is a novel β-lactam/β-lactamase inhibitor (βL/βLI) combination recently approved for the treatment of hospital-associated bacterial pneumonia and ventilator-associated bacterial pneumonia due to A. baumannii. METHODS: We evaluated the in vitro activity of sulbactam/durlobactam alone and in combination with 15 clinically relevant antibiotics against 22 A. baumannii clinical isolates, including 21 extensively or pandrug-resistant strains (M1-M22) and one metallo-β-lactamase (MBL)-producing strain (BAA-3302). Susceptibility testing, chequerboard synergy assays, and static time-kill assays were performed to assess antimicrobial interactions. RESULTS: All 21 XDR/PDR isolates were susceptible to sulbactam/durlobactam (MIC < 4/4 mg/L), while the MBL-harbouring strain BAA-3302 showed intermediate susceptibility (MIC = 8/4 mg/L). Chequerboard assays revealed consistent synergy between sulbactam/durlobactam and multiple β-lactams and βL/βLI agents, including cefepime, meropenem, cefiderocol, ceftazidime-avibactam, and piperacillin-tazobactam, with ≥95% of strains showing synergistic effects. Selected combinations demonstrated rapid and sustained bactericidal activity against select strains in time-kill assays. Combinations with tetracyclines also showed synergy in select strains, particularly against the MBL-carrying isolate. CONCLUSIONS: Sulbactam/durlobactam demonstrates strong activity against highly drug-resistant A. baumannii isolates and shows enhanced potency when combined with specific β-lactam and βL/βLI agents. Further investigation of sulbactam/durlobactam-based combination therapy is warranted as a therapeutic strategy for the treatment of carbapenem-resistant A. baumannii infections.