<i>In vitro</i> activity of sulbactam in combination with other antimicrobial agents against extensively drug-resistant <i>Acinetobacter baumannii</i>

Extensively drug-resistant (XDR) <i>Acinetobacter baumannii</i> infection has significant challenges due to limited treatment options. Although sulbactam (SUL) shows <i>in vitro</i> effectiveness against XDR <i>A. baumannii</i>, the efficacy of SUL-based combinations remains unclear. This investigation aimed to delineate the <i>in vitro</i> activity of SUL combined with various antimicrobial agents against XDR <i>A. baumannii</i>. Sixty-two clinical isolates of XDR <i>A. baumannii</i> were tested for minimal inhibitory concentrations (MICs) of SUL, amikacin (AMI), ciprofloxacin, colistin (COL), fosfomycin (FOS), gentamicin, meropenem (MER), rifampicin (RIF), sitafloxacin (SIT), and tigecycline (TIG) using broth microdilution. The checkerboard method, employing the fractional inhibitory concentration index, assessed <i>in vitro</i> synergy between the SUL-based combination. Time-kill analyses of selected isolates were conducted to measure log₁₀ colony-forming unit per milliliter growth changes over 24 hours between individual and combined agents. The SUL MICs ranged from <4 to 256 mg/L, with an MIC₅₀ of 64 mg/L. MIC ranges were lower for TIG (0.12-4.0 mg/L) and COL (0.5-2.0 mg/L), but higher for FOS (64->512 mg/L). Synergism was evident in the combinations of SUL/FOS (41.9%), SUL/AMI (19.3%), SUL/MER (17.7%), SUL/RIF (14.5%), SUL/TIG (12.9%), SUL/COL (6.5%), and SUL/SIT (4.8%). Only 1.6%-3.2% of the combinations exhibited antagonism. In the time-kill assays, a combination of SUL/FOS/AMI/MER exhibited sustained bactericidal activity at 24 hours against the two isolates, whereas two- and three-agent combinations showed varying degrees of synergism. Combining SUL with available antimicrobial agents had varying degrees of synergistic effect against XDR <i>A. baumannii</i>. Notably, the clinical utility of SUL-based combination therapy for XDR <i>A. baumannii</i> infections requires further exploration.IMPORTANCEThis study evaluated the <i>in vitro</i> effectiveness of SUL combined with other antibiotics against XDR <i>Acinetobacter baumannii</i>. Sixty-two clinical isolates were tested using broth microdilution and checkerboard methods. The SUL MIC₅₀ was 64 mg/L, with tigecycline and colistin showing lower MIC ranges and higher fosfomycin. Synergistic activity was most notable with SUL/fosfomycin (41.9%), followed by SUL/amikacin (19.3%) and SUL/meropenem (17.7%). Antagonism was rare (1.6%-3.2%). Time-kill assays showed that the four-drug combination of SUL/fosfomycin/amikacin/meropenem had sustained bactericidal activity over 24 hours. While SUL-based combinations showed variable synergy, further studies are needed to determine their clinical potential.