Why Long-Term Azithromycin Use Increases Infection With a Mycobacterium

ScienceDaily (Aug. 1, 2011) — The clinical outcome is improved if patients with chronic lung diseases such as cystic fibrosis are treated long-term with the antibiotic azithromycin. However, azithromycin treatment in patients with cystic fibrosis as recently associated with increased infection with nontuberculous mycobacteria. Now, researchers have confirmed that long-term use of azithromycin by adults with cystic fibrosis is associated with infection with nontuberculous mycobacteria and identified an underlying mechanism.

Azithromycin is an antibiotic that also has antiinflammatory properties. It is these antiinflammatory properties that are thought to account for the improvement in clinical outcome observed when patients with chronic lung diseases such as cystic fibrosis are treated long-term with azithromycin.

However, a recent study indicated that azithromycin treatment in patients with cystic fibrosis is associated with increased infection with nontuberculous mycobacteria, a serious complication in such individuals. Now, a team of researchers -- led by Andres Floto and David Rubinsztein, at the University of Cambridge, United Kingdom; and Diane Ordway, at Colorado State University, Fort Collins -- has confirmed that long-term use of azithromycin by adults with cystic fibrosis is associated with infection with nontuberculous mycobacteria and identified an underlying mechanism.

Specifically, the team found that in mice, azithromycin treatment inhibited the intracellular killing of nontuberculous mycobacteria within immune cells known as macrophages by impairing the cellular process autophagy. As azithromycin was not known to block autophagy prior to this work, these data highlight a clinical danger associated with inadvertent pharmacological blockade of this important cellular process.


http://www.sciencedaily.com/releases/2011/08/110801122952.htm

Azithromycin Treatment Alters Gene Expression in Inflammatory, Lipid Metabolism, and Cell Cycle Pathways in Well-Differentiated Human Airway Epithelia

Azithromycin Treatment Alters Gene Expression in Inflammatory, Lipid Metabolism, and Cell Cycle Pathways in Well-Differentiated Human Airway Epithelia


Carla Maria P. Ribeiro,^1,2* Harry Hurd,³ Yichao Wu,^3¤ Mary E. B. Martino,¹ Lisa Jones,¹ Brian Brighton,¹ Richard C. Boucher,^1,2 and Wanda K. O'Neal^1,2

Prolonged macrolide antibiotic therapy at low doses improves clinical outcome in patients affected with diffuse panbronchiolitis and cystic fibrosis. Consensus is building that the therapeutic effects are due to anti-inflammatory, rather than anti-microbial activities, but the mode of action is likely complex.

To gain insights into how the macrolide azithromycin (AZT) modulates inflammatory responses in airways, well-differentiated primary cultures of human airway epithelia were exposed to AZT alone, an inflammatory stimulus consisting of soluble factors from cystic fibrosis airways, or AZT followed by the inflammatory stimulus. RNA microarrays were conducted to identify global and specific gene expression changes.

Analysis of gene expression changes revealed that the AZT treatment alone altered the gene profile of the cells, primarily by significantly increasing the expression of lipid/cholesterol genes and decreasing the expression of cell cycle/mitosis genes. The increase in cholesterol biosynthetic genes was confirmed by increased filipin staining, an index of free cholesterol, after AZT treatment.

AZT also affected genes with inflammatory annotations, but the effect was variable (both up- and down-regulation) and gene specific. AZT pretreatment prevented the up-regulation of some genes, such as MUC5AC and MMP9, triggered by the inflammatory stimulus, but the up-regulation of other inflammatory genes, e.g., cytokines and chemokines, such as interleukin-8, was not affected.

On the other hand, HLA genes were increased by AZT. Notably, secreted IL-8 protein levels did not reflect mRNA levels, and were, in fact, higher after AZT pretreatment in cultures exposed to the inflammatory stimulus, suggesting that AZT can affect inflammatory pathways other than by altering gene expression.

These findings suggest that the specific effects of AZT on inflamed and non-inflamed airway epithelia are likely relevant to its clinical activity, and their apparent complexity may help explain the diverse immunomodulatory roles of macrolides. (edited to add by me: and why zithro used to work so well with me and now it doesn't really do all that much, or so it seems, for me)

Full article: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19503797

Azithromycin Maintains Airway Epithelial Integrity During Pseudomonas aeruginosa Infection.

Am J Respir Cell Mol Biol. 2009 Apr 16. [Epub ahead of print]

Azithromycin Maintains Airway Epithelial Integrity During Pseudomonas aeruginosa Infection.

Halldorsson S, Gudjonsson T, Gottfredsson M, Singh PK, Gudmundsson GH, Baldursson O.

University of Iceland, Institute of Biology, Reykjavik, Iceland; Biomedical Center, University of Iceland, Reykjavik, Iceland.

Tight junctions (TJs) play a key role in maintaining bronchial epithelial integrity, including apical-basolateral polarity and paracellular trafficking. Patients with chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) often suffer from chronic infections by the opportunistic Gram-negative bacterium Pseudomonas aeruginosa, which produces multiple virulence factors including rhamnolipids. The macrolide antibiotic azithromycin (AZM) has been shown to improve lung function in CF patients without reducing the bacterial count within the lung. However, the mechanism of this effect is still debated. It has previously been shown that AZM increased transepithelial electrical resistance (TER) in a bronchial epithelial cell line. In this study we used an air-liquid interface model of human airway epithelia and measured TER, changes in TJ expression and architecture following exposure to live P. aeruginosa PAO1, and PAO1-Deltarhl which is a PAO1 mutant lacking rhlA and rhlB, which encode key enzymes for rhamnolipid production. In addition, the cells were challenged with bacterial culture medium conditioned by these strains, purified rhamnolipids or synthetic 3O-C12-HSL. Virulence factors secreted by P. aeruginosa reduced TER and caused TJ rearrangement in the bronchial epithelium, exposing the epithelium to further bacterial infiltration. Pretreatment of the bronchial epithelium with AZM attenuated this effect and facilitated epithelial recovery. These data suggest that AZM protects the bronchial epithelium during P. aeruginosa infection independent of antimicrobial activity, and could explain in part the beneficial results seen in clinical trials of CF patients.

PMID: 19372247 [PubMed - as supplied by publisher]