Evaluating a novel macrolide based early intervention in the clinical management of chronic infections and inflammation in Cystic Fibrosis

Chronic persistent respiratory disease is a leading cause of death worldwide. Despite years of global research, the clinical management of respiratory disease, including the life-limiting genetic disease cystic fibrosis (CF), remains a significant challenge. Treatment options are extremely limited, due in part to the increased pathogen resistance to conventional antibiotics and the lack of development of effective alternatives. Lung scarring (known as bronchiectasis, a key factor in mortality of patients with CF) develops most rapidly in the first three years of life. Up to 70% of children with CF already have bronchiectasis before they enter school. Therefore, treatments aimed at preventing bronchiectasis must begin in early life, preferably as soon as possible following diagnosis. Lower respiratory infections are known to be a major underlying factor in bronchiectasis and the acquisition of respiratory pathogens is known to occur early in life. The collaborative group involved in this proposal have shown over the last 5 years that the accumulation of bile acids in the lungs of paediatric patients with CF correlates strongly with pathogen acquisition, chronicity, and the onset of inflammation. Using a combination of cross-sectional and longitudinal studies, the link between bile acids and persistent antibiotic tolerant microbiomes and inflammation has been established. Therefore, innovative strategies that intercept the accumulation of bile acids in the lungs could potentially arrest the onset of lung decline until an age at which existing therapies can be implemented. The macrolide antibiotic azithromycin possesses pro-kinetic properties that limits the transition of bile acids into the respiratory tract and lungs. This proposal integrates samples, data, knowledge, and expertise from the CUH paediatric CF cohort in Ireland and the COMBAT CF clinical trial in Australia and is designed to establish the effectiveness of azithromycin in reducing chronic pathogen microbiomes and inflammation in paediatric patients with CF.

Award Date
28 June 2018
Award Value
Principal Investigator
Professor Fergal O'Gara
Host Institution
University College Cork
MRCG-HRB Joint Funding Scheme