Abstract
BACKGROUND: Acinetobacter baumannii is a major global health threat due to its rapid acquisition of multidrug resistance, particularly to carbapenems. Combination antibiotic therapy has been proposed to enhance antimicrobial activity and suppress resistance; however, evidence from randomized trials remains inconclusive. METHODS: A systematic review of randomized controlled trials (RCTs) was conducted following PRISMA guidelines to evaluate the efficacy and safety of antibiotic combination therapy versus monotherapy for drug-resistant A. baumannii infections. Searches across MEDLINE, Embase, Global Health, and Cochrane Central (January 2010-June 2025) identified eligible RCTs reporting clinical outcomes. Data on clinical cure, mortality, microbiological eradication, adverse events, and resistance emergence are described narratively. RESULTS: Eight RCTs enrolling 324 participants were included. Most trials investigated colistin-based combinations (e.g., colistin plus rifampicin, meropenem, fosfomycin, or sitafloxacin); one assessed tigecycline plus cefoperazone-sulbactam. No regimen demonstrated a significant mortality or clinical cure benefit over monotherapy, despite some combinations showing earlier or higher microbiological clearance, most notably colistin-fosfomycin and colistin-rifampicin, without corresponding improvement in clinical outcomes. Adverse events, predominantly nephrotoxicity, were common but comparable across groups. Heterogeneity in trial size, infection severity, and resistance mechanisms limited cross-study comparability. CONCLUSIONS: Current RCT evidence does not support routine use of combination therapy over monotherapy for drug-resistant A. baumannii infections, particularly in septic ICU populations where host factors dominate outcomes. Future trials should focus on early-stage or non-sepsis infections, incorporate molecular resistance profiling, and evaluate emerging agents such as sulbactam-durlobactam to guide precision therapy.