Nebulized Antibiotics for Preventing and Treating Gram-Negative Respiratory Infections in Critically Ill Patients: An Overview of Reviews

Background. Ventilator-associated tracheobronchitis (VAT) and pneumonia (VAP) are the most frequent nosocomial infections in the critical care setting and are associated with increased morbidity. At the same time, VAP is also associated with attributable mortality, especially when caused by difficult-to-treat (DTR) Gram-negative bacteria (GNB) that have limited treatment options. Studies have assessed the impact of nebulized aminoglycosides or colistin to improve VAT and VAP outcomes or as an adjunct to intravenous antimicrobial treatment or as a preventive approach. Objective. This overview aimed to assess systematic reviews that examine the efficacy and safety of antimicrobial nebulization for preventing and treating ventilator-associated infections in the critically ill. Methods. Systematic reviews, meta-analyses, and original randomized controlled trials and prospective observational studies were included. Searches were conducted in MEDLINE (via PubMed), the Cochrane, Epistemonikos, and PROSPERO. The methodological quality assessment was performed using standardized tools. Results. Regarding VAP treatment, the included systematic reviews presented critically low quality. The clinical response effect size to amikacin and colistin nebulization were RR 1.23 (95% CI 1.13–1.34), I2 = 47% and OR 1.39 (0.87–2.20), I2 = 56%. The main safety concern was bronchospasm with RR 2.55 (1.40–4.66), I2 = 0% and OR 5.19 (1.05–25.52), I2 = 0%. The certainty of evidence was usually very low. For VAT treatment, limited evidence showed a better clinical response and less emergence of resistant bacteria. Regarding VAP prevention, data are limited to two trials; however, only the larger one presented a low risk of bias and resulted in a reduced VAP rate. Conclusions. Delivery via nebulization might be considered in addition to IV antimicrobial treatment of GNB ventilator-associated infections. The available evidence is weak, and more studies focused on infections due to DTR-GNBs should be prioritized.