title: Inhaled aztreonam lysine for the treatment of acute pulmonary exacerbations of cystic fibrosis
Creators: name: Frost, Frederick
Publisher: name: University of Liverpool Repository
Year: 2021

description: Introduction Pulmonary exacerbations cause significant morbidity in people with cystic fibrosis, but their treatment with extended courses of intravenous antibiotics may result in important systemic side-effects, adverse reactions and complications. Treatment through the inhaled route, where the lungs are targeted directly with less systemic exposure may be more appropriate, however little is known about the clinical and microbiological utility of using inhaled antibiotics in the acute setting. A recent expansion in available inhaled antibiotics licensed for the chronic suppression of P. aeruginosa means some may now also be repurposed in the acute setting. This thesis examined the clinical and microbiological outcomes of using inhaled aztreonam lysine (AZLI) in the treatment of acute pulmonary exacerbations of cystic fibrosis. Methods Adults with CF were recruited to an open-label pilot randomised crossover study at a regional adult centre in the UK (AZTEC-CF Study, ClinicalTrials.gov: NCT02894684). Inclusion criteria included age &gt; 16 years, P. aeruginosa infection and no prior use of AZLI. Exclusion criteria included Burkholderia cepacia complex infection and solid organ transplant. During two consecutive exacerbations requiring hospitalisation for intravenous antibiotics, subjects received 14 days AZLI plus intravenous colistimethate (AZLI+IV) or standard dual intravenous antibiotics (IV+IV). Primary outcome was change in % predicted FEV1 (ppFEV1) at 14 days. Key secondary outcomes included health-related quality of life outcomes, sputum bacterial load and 16S rRNA sequenced microbiome dynamics associated with each treatment. Results Sixteen people with CF were consented and randomised, and 28/32 (87.5%) exacerbations were completed. At 14 days, improvement in ppFEV1 was greater in the AZLI +IV compared to the IV+IV arm (mean 13.5% versus 8.8%; paired differences [95% CI] +4.6% [2.1 to 7.2], p=0.002). The minimum clinically important difference in CFQ-R Respiratory Domain was achieved more frequently in exacerbations treated with AZLI+IV (83.3% vs. 43.8%, p=0.04). No significant differences were found between treatments for changes in sputum bacterial load, systemic inflammation, antimicrobial resistance or adverse events. IV+IV and AZLI+IV exerted different effects on the lung microbiome, where IV+IV reduced the abundance of the anaerobes Prevotella melaninogenica and Veillonella dispar. Comparatively, AZLI+IV was associated with little change in either structure or composition of the microbiome. Neither treatment consistently reduced the abundance of P. aeruginosa but where reductions were seen they were associated with improved quality of life. Conclusion: AZLI is effective and well tolerated in the treatment of acute pulmonary exacerbations of CF. Superior improvements in lung function and quality of life outcomes alongside a potentially advantageous microbiological profile suggest AZLI may represent a new treatment approach for acute pulmonary exacerbations and larger studies are warranted.