Inhaled Antibiotics to Treat Ventilator-Associated Pneumonia: A Systematic Review and Meta-Analysis

Objectives: To assess the effects of adjunctive inhaled antibiotics in treating ventilator-associated pneumonia (VAP). Data Sources: We searched PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov through May 31, 2025. Study Selection: We included randomized controlled trials (RCTs) and nonrandomized studies comparing adjunctive inhaled antibiotics with placebo/blank or IV antibiotics for VAP treatment. Data Extraction: Two groups independently screened studies, extracted data, and assessed risk of bias. Analyses used random effects models. Subgroup analyses, meta-regression, trial sequential analysis, and the Grading of Recommendations Assessment, Development, and Evaluation were performed. Data Synthesis: We included 32 RCTs in the primary analysis and 41 non-RCTs in sensitivity analysis. Compared with placebo/blank, inhaled antibiotics significantly improved clinical cure (16 RCTs; n = 1425; risk ratio 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), with consistent findings in sensitivity analyses including non-RCTs. These benefits were significant in VAP-only patients (clinical cure: 11 RCTs; n = 775; RR, 1.29; 95% CI, 1.10–1.52 and all-cause mortality: 15 RCTs; n = 1152; RR, 0.77; 95% CI, 0.65–0.90), but not in studies including mixed pneumonia populations. Meta-regression confirmed VAP-only population as a significant effect modifier. Inhaled antibiotics also improved microbiological eradication (20 RCTs; n = 1805; RR, 1.42; 95% CI, 1.27–1.58) and reduced emergence of new drug resistance (four RCTs; n = 182; RR, 0.20; 95% CI, 0.06–0.64). No differences were found in ICU length of stay, ventilator duration, or other adverse events. Compared with IV antibiotics, inhaled antibiotics shortened ventilator duration (three RCTs; n = 322; mean difference, –2.11 d; 95% CI, –3.73 to –0.49 d), and reduced nephrotoxicity (three RCTs; n = 292; RR, 0.42; 95% CI, 0.26–0.68). Conclusions: Compared with placebo/blank, adjunctive inhaled antibiotics improve clinical cure and microbiological eradication, and may reduce mortality, particularly in VAP-only patients. Exploratory analyses based on limited data suggest potential advantages over IV therapy, including shorter ventilator duration and lower nephrotoxicity, warranting further high-quality trials.