Abstract
Background
The use of inhaled antibiotics for treating pneumonia in invasively ventilated patients offers a direct approach, allowing for high local concentrations of the drug in the lower respiratory tract while simultaneously reducing systemic toxicity. However, the real efficacy and safety of nebulized antibiotics remain unclear. The aim of the present is to assess among critically adult patients with pneumonia and invasive ventilation, whether receiving adjuvant inhaled antibiotics improves the rate of microbiological eradication.
Methods
A comprehensive literature search of randomized clinical trials (RCTs) was conducted (from inception until September 20, 2024, PROSPERO-CRD592906) across Medline, Embase, and Scopus. Randomized controlled trials, enrolling intensive care units (ICU) patients with pneumonia and comparing nebulized antimicrobial therapy (inhaled group) with intravenous antimicrobial treatment or intravenous antimicrobial therapy plus inhaled placebo (control group), were included. The primary outcome was the rate of microbiological eradication after treatment. Secondary outcomes were the rate of clinical recovery, the incidence of drug-related adverse events, ICU and hospital mortality. A qualitative analysis was conducted according to the GRADE framework. Data were pooled using an odds-ratio analysis. The heterogeneity and reliability of our results were evaluated using the I2-statistic and trial sequential analysis (TSA), respectively.
Results
A total of 11 RCTs (1472 patients) met the inclusion criteria. Compared to controls, the use of adjuvant inhaled antibiotics determined a greater rate of microbiological eradication (OR 2.63, 95% CI 1.36–5.09; low certainty of evidence). The TSA confirmed the reliability of our primary outcome. Moreover, nebulized antibiotics increased the risk of bronchospasm (OR 3.15, 95% CI 1.33–7.47; high evidence), while nephrotoxicity, clinical recovery, ICU and hospital survival (either in the case of pneumonia caused by MDR bacteria or not) were not different between groups.
Conclusions
In conclusion, compared to the sole intravenous therapy, the use of adjuvant inhaled antibiotics for treatment of pneumonia in invasively ventilated critically ill patients was associated with a greater incidence of microbiological eradication (low GRADE and high risk of publication bias), but not with clinical recovery and survival.
Key Points
- Study Scope: Analysis included 11 randomized controlled trials (RCTs) with 1,472 critically ill patients comparing inhaled antibiotics to intravenous therapy.
- Primary Outcome: Inhaled antibiotics significantly increased microbiological eradication rates (OR 2.63; 95% CI 1.36–5.09) but with low certainty due to publication bias and heterogeneity.
- Secondary Outcomes: No significant differences were found in clinical recovery, ICU survival, or hospital survival between groups.
- Adverse Events: Bronchospasm risk was notably higher in patients receiving inhaled antibiotics (OR 3.15; 95% CI 1.33–7.47), while nephrotoxicity rates were comparable.
- Subgroup Analyses: Both aminoglycosides and polymyxins showed similar microbiological eradication efficacy, with no significant differences based on nebulizer device types.
- Trial Sequential Analysis: Demonstrated sufficient sample size for reliability of primary outcome findings, despite low overall evidence certainty.
- Clinical Implications: Adjuvant inhaled antibiotics may enhance microbiological outcomes but do not guarantee clinical or survival benefits, suggesting careful patient selection is necessary.
- Limitations: Limited number of trials, variability in microbiological eradication definitions, and exclusion of non-RCT studies may affect generalizability.
- Recommendations: Further studies should explore patient subgroups (e.g., organ transplant recipients) that might benefit from inhaled antibiotics and evaluate their role in reducing treatment duration.
- Guidelines Alignment: Findings align with existing recommendations for inhaled antibiotics as adjunctive therapy in resistant Gram-negative infections but emphasize tailored use.
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