Editors' ChoiceCystic Fibrosis

Digesting the Unexpected Side Effects of Chronic Antibiotic Use

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Science Translational Medicine  28 Sep 2011:
Vol. 3, Issue 102, pp. 102ec160
DOI: 10.1126/scitranslmed.3003239

Clinicians caring for patients with lung disorders such as cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD) are increasingly using macrolide antibiotics such as azithromycin as an adjunct to standard therapy. The benefit of these drugs is thought to result not necessarily from their antimicrobial properties but rather from their anti-inflammatory effects on macrophages and neutrophils. Indeed, several studies have demonstrated improved clinical outcomes of patients with a wide range of lung disorders characterized by airway inflammation and obstruction.

Cystic fibrosis is a multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator, a regulated chloride channel found in all exocrine tissue, including the lung. Patients with CF develop thick viscous mucus that leads to bacterial colonization of the airways and chronic inflammation. Recently, several studies have shown that CF patients on chronic azithromycin therapy have a higher incidence of mycobacterial infections, including the difficult-to-treat Mycobacterium abscessus. To identify the mechanism behind this phenomenon, Renna et al. examined the role that azithromycin has on autophagy, a key mediator of mycobacterial clearance.

The authors demonstrated a strong correlation in their hospital between the incidence of mycobacterial infections in CF patients and the long-term use of azithromycin. Azithromycin impaired autophagy-mediated degradation in both macrophages taken from healthy controls and those from CF patients. Using reporter constructs and fluorescent substrates that enable visualization of lysosomes and phagosomes by confocal microscopy, Renna et al. found that azithromycin blocked the clearance of autophagy substrates at concentrations observed clinically. Although autophagosome-lysozome fusion remained intact, the drug blocked the acidification of autophagosomes by impairing lysosomal function. This effect occurred even in the presence of the inflammatory cytokine IFN-γ, a potent activator of mycobacterial killing by macrophages, and led to a reduction in the intracellular killing of mycobacteria in primary human macrophages. Moreover, mice treated with azithromycin were more susceptible to mycobacterial infection, demonstrating that despite the bactericidal properties of the drug, the effects on autophagy may dominate. In this elegant translational study, the authors provide evidence that suggests a potential mechanism for an emerging, unexpected side effect of chronic azithromycin use. These important findings support close monitoring for patients on long-term macrolide antibiotics, particularly as the use of these drugs is expanded to patients with more prevalent diseases such as COPD and asthma.

M. Renna et al., Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J. Clin. Invest. 121, 3554–3563 (2011). [Full Text]

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