Introduction: Ventilator-associated pneumonia (VAP) is a serious complication of mechanical ventilation, associated with high morbidity, mortality, and cost. Adjunctive inhaled antibiotics allow targeted lung delivery but have uncertain efficacy and safety, leading to conflicting guideline recommendations. Recent randomized controlled trials (RCTs) necessitate an updated synthesis. Methods: This study followed PRISMA guidelines and registered with PROSPERO (CRD42024592304). We searched PubMed, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov through May 31, 2025 for RCTs and non-randomized studies comparing inhaled antibiotics with control (placebo/blank or intravenous antibiotics) in VAP treatment. Primary outcome was clinical cure, secondary outcomes included all-cause mortality, microbiological eradication, ventilator duration, length of stay, and adverse events. Treatment effects were estimated using fixed and random effects models. Subgroup analyses, meta-regression, trial sequential analysis (TSA), and GRADE assessment were performed. Results: We included 73 studies (32 RCTs, 41 non-RCTs). Compared to placebo/blank, inhaled antibiotics significantly improved clinical cure (16 RCTs, n=1425, RR 1.24, 95%CI 1.07-1.43) and reduced all-cause mortality (21 RCTs, n=1855, RR 0.84, 95%CI 0.71-0.98). Benefits were more prominent in VAP-only patients (clinical cure: RR 1.29, 95%CI 1.10-1.52; all-cause mortality: RR 0.77, 95%CI 0.65-0.90), confirmed by meta-regression adjusting for antibiotic types. Inhaled antibiotics also improved microbiological eradication (RR 1.42, 95%CI 1.27-1.58) and reduced new drug resistance (RR 0.20, 95%CI 0.06-0.64). No differences were found in ICU length of stay, ventilator duration, and adverse events. Compared to intravenous antibiotics, inhaled antibiotics improved clinical cure (3 RCTs, n=183, RR 1.32, 95%CI 1.11-1.58), shortened ventilator duration (3 RCTs, n=322, MD -2.11 days, 95%CI -3.73 to -0.49), and reduced renal impairment (3 RCTs, n=292, RR 0.42, 95%CI 0.26-0.68). Conclusions: Compared to placebo/blank, adjunctive inhaled antibiotics improve clinical cure, survival, and microbiological eradication, particularly in VAP-only patients. Compared to intravenous therapy, they may improve clinical cure, reduce ventilator duration, and lower nephrotoxicity risk.
Li et al. (Sun,) studied this question.