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

To assess the effects of adjunctive inhaled antibiotics in treating ventilator-associated pneumonia (VAP).

We searched PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov through May 31, 2025.

We included randomized controlled trials (RCTs) and nonrandomized studies comparing adjunctive inhaled antibiotics with placebo/blank or IV antibiotics for VAP treatment.

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.

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).

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.