Value of Inhaled Treatment With Aztreonam Lysine in Bronchiectasis

Chronic neutrophilic inflammation is a feature of bronchiectasis and the levels of neutrophilic inflammation predict the risk of future exacerbations. Neutrophilic inflammation is highest in participants with P. aeruginosa and other Gram negative pathogens and inflammation can be suppressed by inhaled antibiotic treatment . There is therefore a strong rationale for the effectiveness of inhaled antibiotic treatment in bronchiectasis.

Studies of inhaled antibiotics in bronchiectasis have given mixed results to date. Several open label studies in the late 1980's, testing nebulised β-lactams, demonstrated reduced sputum purulence, sputum volume and improvements in inflammatory markers. In an early phase II double-blind placebo-controlled trial by Barker et al. nebulised tobramycin significantly reduced the primary outcome of P. aeruginosa bacterial load but was poorly tolerated by some participants. Subsequently a single centre randomised controlled trial of nebulised gentamicin for 12 months reported significant benefits but was limited by open label design and small sample size. Haworth et al recruited 144 participants with chronic P. aeruginosa infection and randomized participants to nebulised colistin or placebo. The trial narrowly failed to meet its primary end-point (colistin group 165 days versus placebo 111 days; p=0.11). In the secondary end-points, a large improvement in quality of life using the SGRQ was noted (mean difference -10.5 points; p=0.006).

Aztreonam is an inhaled antibiotic licensed for treatment in cystic fibrosis. Two recent phase III trials in bronchiectasis randomised 266 (AIR-BX1) and 274 (AIR-BX2) participants to Aztreonam 75mg three times daily or placebo over the course of two 28-day treatment cycles (with 28 days off treatment between cycles). The primary outcome was the newly developed Quality of Life Bronchiectasis (QoL-B) questionnaire. Unfortunately the trial failed to meet its primary end-point, with a significant change observed in the QOL-B respiratory symptom score in AIR-BX2 but not in AIR-BX1. Treatment related adverse effects were also increased in the Aztreonam treated participants.

Likely explanations for the difficulties encountered in this previous trial include that the trial population was quite heterogeneous, with many participants having no history of exacerbations and appearing to have relatively mild disease. Many patients did not have a history exacerbations in this trial whereas the ERS bronchiectasis guidelines suggest limiting inhaled antibiotic use to patients with a history of 3 or more exacerbations per year. The characteristics of the included participants included high rates of pulmonary non-tuberculous mycobacterial disease and COPD. Nadig and Flume compared the characteristics of included participants in this trial to their own population of participants with severe bronchiectasis treated with inhaled antibiotics and identified little correlation, suggesting that the trials included a skewed population that was not representative of real-life clinical practice (Nadig and Flume AJRCCM 2016).