Comparing Long Versus Shorter Antibiotic Regimens for Gram-Negative Bacteremia and Their Implications in Antimicrobial Resistance: A Systematic Review And Meta-Analysis

Abstract Background The optimal duration of antibiotic therapy for gram-negative bacteremia remains uncertain. We conducted a systematic review and meta-analysis to compare short (≤ 10 days) versus long (> 10 days) antibiotic duration for gram-negative bacteremia in hospitalized adults. Methods We searched MEDLINE, Embase, Cochrane Library, and trial registries from inception to June 2025. We included randomized controlled trials (RCTs) and observational studies comparing antibiotic durations for gram-negative bacteremia. Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2.0 for RCTs and Newcastle-Ottawa Scale for observational studies. Primary outcomes were 30-day mortality and relapse. Secondary outcomes included 90-day mortality, antibiotic-associated adverse events, and antimicrobial resistance (AMR). We calculated risk ratios (RR) with 95% confidence intervals (CI) using random-effects models and assessed certainty of evidence using GRADE. Results Seven studies (4 RCTs, 3 observational) including 4,520 patients met inclusion criteria. Short duration therapy showed no significant difference in 30-day mortality compared to long duration (87/1,185 [7.3%] vs 91/1,365 [6.7%]; RR 1.10, 95% CI 0.83–1.46; I²=5%; moderate certainty) or 30-day relapse (33/1,200 [2.8%] vs 53/1,378 [3.8%]; RR 0.85, 95% CI 0.55–1.32; I²=0%; moderate certainty). Four studies reporting 90-day mortality (including BALANCE trial gram-negative subgroup) showed no significant difference (328/2,272 [14.4%] vs 357/2,248 [15.9%]; RR 0.91, 95% CI 0.79–1.04; I²=40%; moderate certainty). Sensitivity analyses were consistent across study designs, study quality, and analytical approaches. Risk of bias was low for observational studies (Newcastle-Ottawa Score ≥ 8/9) and showed some concerns for RCTs due to open-label design. Conclusions Moderate certainty evidence suggests that short duration (≤ 10 days) antibiotic therapy is non-inferior to longer courses for gram-negative bacteremia, with no significant differences in mortality or relapse. These findings support shorter antibiotic courses to reduce antibiotic exposure while maintaining clinical effectiveness. Adverse events and AMR were infrequently reported. In light of recent fears of drug-resistant bacteria, future studies on the same are recommended.