The potential anti-microbial use of azithromycin against multi-drug resistant Burkholderia cepacia complex in cystic fibrosis patients
Cystic Fibrosis (CF) is an autosomal recessive disease that affects thousands of individuals worldwide. The disease is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in the dysregulation of apical ion channels. This disruption in ion transport leads to the production of the characteristic thick mucus seen in patients with CF. Although many organ systems are affected, the hallmark of the disease is viscous mucous plugs in the respiratory tracts leading to the disruption of mucociliary clearance and chronic bacterial colonization of the airways. Infections by organisms of the Burkholderia cepacia complex (BCC), a group of about 17 closely related species of Gram-negative bacteria, are associated with fulminant necrotizing pneumonia and severe decline in CF lung function. Acute exacerbations of CF are treated rapidly with antibiotics to halt further destruction of the lung. This repeating antibiotic exposure, however, has naturally led to the emergence of multidrug-resistant (MDR) organisms. Azithromycin, a macrolide antibiotic with anti-inflammatory properties is considered one of the standard-of-care therapies for patients colonized with Pseudomonas aeruginosa, and is commonly administered three times a week. Azithromycin treatment has been shown to decrease the frequency of exacerbations, and has largely been attributed to azithromycin's anti-inflammatory properties, since the drug does not show direct bacterial killing of the pathogen in standard minimum inhibitory concentration (MIC) tests in bacteriologic media. However, recent data from Lin and Nizet et al suggests that azithromycin may indeed have direct antimicrobial effects on P. aeruginosa and other Gram-negative bacteria, which are appreciated only under more physiological conditions (e.g. tissue culture media) and in synergy with cationic antimicrobial peptides of the host innate immune system. However, the effectiveness of azithromycin in patients with BCC is largely unknown. In this project, we investigate the effects of azithromycin against BCC in CF patients, with special attention to functional interactions with host defense factors. This research can lead to a better understanding of the future use of Azithromycin to reduce the development of MDR infections as well as its use as an anti-microbial agent against these infections.