An In Vitro Study to Rationalise Combination Therapies for Cystic Fibrosis Treatment
Zara Sheikh1, Hui Xin Ong1, Michele Pozzoli1, Paul Young1, Daniela Traini1
1Woolcock Institute of Medical Research and Faculty of Medicine and Health, University of Sydney,
431 Glebe Point Road, Glebe NSW 2037, Australia
Chronic inflammation associated with recurrent infections that leads to pulmonary failure is the principal cause of morbidity and mortality in cystic fibrosis (CF) patients. Therefore current CF therapy is focused on inhaled antibiotics (e.g. tobramycin) in combination with oral anti-inflammatory drugs (e.g. high dose ibuprofen) and other oral/intravenous antibiotics (e.g. azithromycin). However, there is a gap in the understanding of potential interactions between these drugs in terms of their efficacy and mechanism of action, resulting in variable treatment outcomes, as stated in the current CF consensus treatment guidelines. For instance, a recent clinical trial of 263 CF subjects has shown that oral azithromycin antagonises the antimicrobial efficacy of inhaled tobramycin. Based on this recent evidence, this study aims to investigate other potential interactions between tobramycin and other anti-inflammatory drugs used in CF treatment, specifically, ibuprofen and azithromycin. To achieve this aim, an in vitro inflammation study of two combinations of tobramycin with either ibuprofen or azithromycin on IL-8 expression was performed using CuFi-1 and BEAS-2B pulmonary epithelial cell lines. Both combinations demonstrated a significant increase in IL-8 concentration in the two cell lines compared to the control using lipopolysaccharide (LPS) in CuFi-1 cells, suggesting an enhanced inflammatory effect. This study was a preliminary step in elucidating these drug-drug interactions with the aim to rationalize combination therapies for CF treatment that could potentially change future current clinical practice and overall, reduce treatment burden of CF patients.