A Macrolide for Pseudomonas? The Wonders of Azithromycin

Abstract & Commentary

Synopsis: Azithromycin administration to patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection was associated with a reduction in number of exacerbations, improvement in airflow, and weight gain.

Source: Saiman L, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa. JAMA. 2003;290:1749-1756.

The Macrolide study group noted the apparent beneficial effects of azithromycin in the therapy of patients with panbronchiolitis, a condition seen mostly in Japan with similarities to cystic fibrosis. Both diseases are thought to have progressive lung damage due, in part, to the release of destructive factors released by neutrophils. Their network of centers in the United States studied 185 cystic fibrosis patients with an average age of about 20 years. Treatment was randomized, double blind, and placebo controlled and consisted of 24 weeks of oral azithromycin given at a dose of 250 or 500 mg 3 times each week for 24 weeks.

They found a clear improvement in the FEV 1 (mean, 0.097-L [SD, 0.26]) in the azithromycin treatment, which was statistically significantly better than the placebo group (P = .009). The treatment group also had fewer exacerbations (P = .03) and gained more weight (P = .02) than the placebo group. There were some side effects noted with the azithromycin treatment group, which consisted of nausea (17%), diarrhea (15%), and wheezing (13%). Saiman and colleagues felt the wheezing may well have been a good thing and attributed it to a better ability to clear secretions.

The microbiology of the respiratory tract samples was also studied. The recovery of Pseudomonas and its density were not affected. Staphylococcus aureus was not eradicated in the repeat samples when it was initially recovered (52%). Chlamydia and Mycoplasma were not looked for.

Measurement of elastase and IL-8 levels failed to show a difference. A review of the literature for a possible role of known inflammatory mediators failed to reveal any relevant information other than a decline in C-reactive protein levels, which correlate closely with baseline lung function in the groups studied.

Comment by Alan D. Tice, MD, FACP

These findings make one wonder about azithromycin and what it actually does aside from what can be demonstrated in the bacteriology lab. It has some activity against staphylococci and a little against Pseudomonas, but there was not a clear effect in eliminating the organisms in this study and not even an effect on the amount of Pseudomonas recovered. A role for other organisms, such as Chlamydia and Mycoplasma, could reasonably be postulated but was not studied. Nontuberculous mycobacteria were recovered in 3% of patients and probably played little role.

Inflammatory markers that have been studied with azithromycin provide little insight into how and why azithromycin had such a positive effect in these patients, although excess local neutrophil activity and cytokines are probably at the base of the mechanisms, as they are with alpha-1 antitrypsin deficiency lung disease. Recent studies have indicated macrolides can inhibit GM-CSF production as well as the oxidative burst of phagocytic cells.1,2

Looking further into some of the studies about the non-bacterial activities of azithromycin makes one wonder even more about this unusual macrolide. Its clinical activity does not correlate well with serum concentrations, which has been explained by its ability to concentrate in white blood cells, almost in a smart bomb fashion. Its terminal half-life of 30 or more hours also presents a dilemma in dosing. The initial double dose with oral administration made a lot of sense but seems to have been abandoned in the recent marketing of a 3-day 500-mg regimen instead of the 5-day 250-mg one (at a local cash price of $53.75) for respiratory infections.3 How often it really has to be dosed is also unknown, but it seems best for marketing to leave it at once a day to not go beyond the limits of the imagination of health care providers and payers.

Azithromycin has also been explored for benefits in preventing the progression of coronary artery disease. However, a large recent study could not find a benefit in more than 7000 postinfarction patients after they were given 600 mg per week for 12 weeks, even with a positive serology for Chlamydia pneumoniae.4

Other clinical studies have found this drug lacking in the treatment of acute bronchitis, even though it is commonly used for that infection.5 The placebo control of vitamin C appeared to be as effective as azithromycin at Cook County Hospital. While this discrepancy might be explained by the nonbacterial etiology of most cases of acute bronchitis, it makes one wonder. It was also interesting that there were more adverse effects reported with ascorbic acid than with the antimicrobial in that study.

Delving further into PubMed, one can also find other possible benefits of this drug. It is good for trachoma, has been found comparable to levofloxacin for travelers’ diarrhea,6 can inhibit biofilm formation,7 and even alter the production of Alzheimer’s amyloid precursor protein of Alzheimer’s disease.8

All this information makes me wonder just what to do with this drug. It is clearly beneficial in a number of clinical diseases, although probably overused in common respiratory infections, which are largely viral and/or reactive in etiology. Whether it should be used for long-term administration for chronic inflammatory diseases of the lungs for its anti-inflammatory effects is uncertain, as it will certainly bring antimicrobial resistance to the local pathogens. The potential benefits for a number of diseases that are not of obvious infectious etiology are particularly intriguing.

Dr. Tice is FACP Infections Limited, PS Tacoma, WA; Infectious Disease Consultant, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI  Section Editor, Managed Care

References

1. Yamasawa H, et al. Macrolides inhibit epithelial cell-mediated neutrophil survival by modulating GM-CSF release. Am J Respir Cell Mol Biol. 2003;e-pub.

2. Abdelghaffar H, et al. Interaction of macrolides and ketolides with the phagocytic cell line PLB-985. J Chemother. 2003;4:350-356.

3. Dunne MW, et al. Randomized double-blind study of the clinical efficacy of 3 days of azithromycin compared with co-amoxiclav for the treatment of acute otitis media. J Antimicrob Chemother. 2003;52:469-472.

4. O’Connor CM, et al. Azithromycin for the secondary prevention of coronary heart disease: The WIZARD study: A randomized controlled trial. JAMA. 2003;290: 1459-1466.

5. Evans AT, et al. Azithromycin for acute bronchitis: A randomized, double-blind, controlled trial. Lancet. 2002;359:1648-1654.

6. Adachi JA, et al. Azithromycin found to be comparable to levofloxacin for the treatment of US travelers with acute diarrhea acquired in Mexico. Clin Infect Dis. 2003;37:1165-1171.

7. Favre-Bonte S, et al. Biofilm formation by Pseudomonas aeruginosa: Role of the C4-HSL cell-to-cell signal and inhibition by azithromycin. J Antimicrob Chemother. 2003;52:598-604.

8. Payton S, et al. Drug discovery targeted to the Alzheimer’s APP mRNA 5’-untranslatede region: The action of paroxetine and dimercatopropanol. J Mol Neursci. 2003;20:267-275.