"In vitro evaluation of sulbactam combination therapies for Acinetobacter baumannii"

Acinetobacter baumannii, a leading cause of hospital-acquired infections in critically ill patients, is increasingly resistant to carbapenems, leading WHO to designate carbapenem-resistant Acinetobacter baumannii (CRAB) as a critical priority pathogen. While the 2024 IDSA guidelines recommend sulbactam-based regimens as the cornerstone of therapy, high-dose sulbactam is effective only against isolates with MICs up to 16-32 μg/mL. This study aimed to describe the sulbactam MIC distribution and to evaluate MIC reduction and synergy when combined with β-lactam antibiotics against CRAB.

CRAB isolates from respiratory samples of ventilator-associated pneumonia patients were tested using E-tests to determine MICs of individual antibiotics. Combinations of sulbactam with ceftriaxone, cefepime, and meropenem were assessed using the E-test cross method. Synergy was evaluated by the FIC index: synergy (≤0.5), additive (>0.5-1), indifference (>1-<4), and antagonism (≥4).

Thirty-five non-duplicate CRAB isolates were tested. All isolates were resistant to ceftriaxone, cefepime, and meropenem when tested individually, with MICs exceeding E-test detection limits. Hence, although sulbactam combinations significantly reduced MICs, the resulting values often remained above CLSI-defined susceptibility breakpoints. Notably, sulbactam alone showed an MIC₅₀ of 12 μg/mL and an MIC₉₀ of 24 μg/mL. In combination, sulbactam MIC₅₀/MIC₉₀ values were reduced to 8/24 μg/mL with ceftriaxone, 6/16 μg/mL with cefepime, and 8/24 μg/mL with meropenem. Sulbactam-cefepime showed the highest synergy (11.43 %) and additive effects (34.29 %), followed by sulbactam-ceftriaxone (2.86 % synergy; 31.43 % additive). Sulbactam-meropenem showed no synergy but 31.43 % additive effects. No antagonism was observed with any combination.

Combining sulbactam with β-lactams, particularly cefepime, significantly reduced sulbactam MICs. However, the β-lactam MICs themselves remained largely within not-susceptible ranges, highlighting that the observed benefit was confined primarily to sulbactam rather than the companion β-lactams. These findings supported further clinical studies of high-dose sulbactam-β-lactam combinations to optimize the pharmacodynamic efficacy of sulbactam against CRAB strains with elevated MICs.