The Role of Combination Antibiotic Therapy in Combatting Drug-Resistant Acinetobacter baumannii Infections: A Systematic Review of Randomised Control Trials

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.