The efficacy and safety of inhaled antibiotics for the treatment of bronchiectasis in adults: a systematic review and meta-analysis

Background Although use of inhaled antibiotics is the standard of care in cystic fibrosis, there is insufficient evidence to support use of inhaled antibiotics in patients with bronchiectasis not due to cystic fibrosis. We aimed to assess the efficacy and safety of inhaled antibiotics for the long-term treatment of adults with bronchiectasis and chronic respiratory tract infections. Methods We did a systematic review and meta-analysis of all randomised controlled trials of inhaled-antibiotic use in adult patients with bronchiectasis and chronic respiratory tract infections. Eligible publications were identified by searching MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov. Randomised controlled trials of inhaled antibiotics were included if the patients were adults with stable bronchiectasis diagnosed by CT or bronchography, the trials had treatment a duration of at least 4 weeks, and their outcomes met at least one of the endpoints of interest. Studies in cystic fibrosis were excluded. Efficacy endpoints assessed were bacterial load, bacterial eradication from sputum, frequency of exacerbations, time to first exacerbation, proportion of patients with at least one exacerbation, frequency of severe exacerbations, quality of life, change in FEV1, 6-min walk distance, mortality, adherence to treatment, and sputum volume; safety endpoints were adverse events and bacterial resistance in sputum. Each study was independently reviewed for methodological quality using the Cochrane risk of bias tool. Random-effects meta-analysis was used to pool individual studies. Heterogeneity was assessed using I2. The review is registered on PROSPERO, number CRD42019122892. Findings 16 trials (n=2597 patients) were included for analysis. The mean reduction of colony forming units per g of sputum with inhaled antibiotics was −2·32 log units (95% CI −3·20 to −1·45; p<0·0001). Bacterial eradication was increased with inhaled antibiotic therapy (odds ratio [OR] 3·36, 1·63 to 6·91; p=0·0010). Inhaled antibiotics significantly reduced exacerbation frequency (rate ratio 0·81, 0·67 to 0·97; p=0·020). Time to first exacerbation was significantly prolonged with inhaled antibiotics (hazard ratio 0·83, 0·69 to 0·99; p=0·028). The proportion of patients with at least one exacerbation decreased (risk ratio 0·85, 0·74 to 0·97; p=0·015). There was a significant reduction in the frequency of severe exacerbations (rate ratio 0·43, 0·24 to 0·78; p=0·0050). The scores for neither the Quality of Life Bronchiectasis questionnaire nor St George's Respiratory Questionnaire improved above the minimal clinically important difference. The relative change in FEV1 was a deterioration of 0·87% predicted value (−2·00 to 0·26%; p=0·13). Other efficacy endpoints were reported in only few studies or had few events. There was no difference in treatment-emergent adverse effects (OR 0·97, 0·67 to 1·40; p=0·85) or bronchospasm (0·99, 0·66 to 1·48; p=0·95). Emergence of bacterial resistance was evident at the end of the treatment period (risk ratio 1·91, 1·46 to 2·49; p<0·0001). Interpretation Inhaled antibiotics are well tolerated, reduce bacterial load, and achieve a small but statistically significant reduction in exacerbation frequency without clinically significant improvements in quality of life in patients with bronchiectasis and chronic respiratory tract infections. Funding British Lung Foundation through the GSK/British Lung Foundation Chair of Respiratory Research and European Respiratory Society through the EMBARC2 consortium. EMBARC2 is supported by project partners Chiesi, Grifols, Insmed, Novartis, and Zambon.