September 2011

 

NEWS & OPINION

 

Azithromycin not steroids for inflammation?


by Matt Young EyeWorld Contributing Editor

     

In ophthalmology, azithromycin is indicated for treating bacterial conjunctivitis, but a growing mound of evidence suggests it could be useful in a more widespread manner for corneal inflammation. According to Inspire Pharmaceuticals (Raleigh, N.C.), the company that makes AzaSite (azithromycin ophthalmic solution 1%), the drug has been found to eradicate more than 90% of most common pathogens found on the ocular surface. Azithromycin is an antibiotic a top-selling antibiotic, marketed as Zithromax (Pfizer, New York) in the United States. It's used to treat everything from bronchitis to pneumonia to sexually transmitted diseases, and now it has ophthalmic indications. Azithromycin may also be growing in importance as an anti-inflammatory drug. Harvard Medical School researchers recently investigated it as an anti-inflammatory agent.

"The currently available pharmaceutical armamentarium to ameliorate corneal inflammation is principally comprised of corticosteroids," wrote lead study author Zahra Sadrai, M.D., Department of Ophthalmology, Harvard Medical School, Boston. "Although topical corticosteroids continue to be the mainstay of treatment, their long-term use can be associated with serious side effects such as cataract formation, elevated intraocular pressure (glaucoma), opportunistic infections, and corneal thinning. Azithromycin has been reported to possess non-ocular anti-inflammatory and immunomodulatory activities. Given these, we hypothesized that AZM [azithromycin] could be used as a therapeutic agent for ameliorating corneal inflammation."

The results, published online in February in Investigative Ophthalmology & Visual Science, supported their hypothesis and also revealed some areas of concern for such use.

Adequate anti-inflammatory drug?

Already, solid research has been done suggesting that azithromycin can be a usefulalthough off-labeltreatment for blepharitis, an inflammatory disease affecting the eyelid. In July 2010 in Clinical Ophthalmology, Jodi Luchs, M.D., Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, N.Y., reviewed other published studies on azithromycin and found that topical azithromycin "is more successful in treating the signs and symptoms of blepharitis than just mechanical therapy (warm compresses) alone."

FDA clinical trials are underway to further investigate the use of topical azithromycin for blepharitis. Dr. Luchs reminded readers that anti-inflammatory research on azithromycin dates back some time. "Through almost 2 decades of study, while azithromycin was available for the treatment of systemic infections, it was discovered that macrolide antibiotics such as azithromycin exhibit anti-inflammatory properties," Dr. Luchs wrote.

The Harvard research more accurately pinpoints what those anti-inflammatory uses could be in ophthalmology. Researchers applied six light burns to the central corneas of mice as an experimental model for corneal inflammation. The mice were then divided into three groups: those that received AzaSite, those that received the DuraSite vehicle only, and those that received prednisolone acetate 1%. "We found that within 24 hours of cauterization, leukocytic infiltration into the vehicle-treated corneas was apparent and peaked by day 7," Dr. Sadrai wrote. "In contrast, corneas treated with AZM led to a 30% reduction in leukocyte infiltration at day 1 and 39% reduction at day 7."

AzaSite also regulated inflammatory cytokine expression in the cornea better than the vehicle alone. Prednisolone acetate was working, too, decreasing CD45+ infiltration 36% at day 3, 50% at day 7, and 30% at day 10. Neutrophil infiltration, CD11c+ cell infiltration, and macrophage infilitration were also significantly decreased.

"In our current study, treatment with AZM reduced dendritic cell infiltration to the cornea to the levels comparable with prednisolone," Dr. Sadrai reported. "Importantly, however, the effect of treatment with prednisolone starts earlier and stays longer than topical treatment with AZM."

AzaSite had no suppression effect on corneal neovascularization, a marker of severe, chronic corneal inflammation. Other problems with AzaSite as an anti-inflammatory agent also surfaced. "Corneal angiogenesis, a common morbidity seen in chronic inflammation, which itself amplifies immunoinflammatory responses and portends a poor prognosis for transplants, was not affected by AZM treatment," Dr. Sadrai noted. "This suggests that the anti-inflammatory and therapeutic benefit of AZM is rather limited for the more severe inflammatory insults to the cornea, which may require treatment with corticosteroids or other anti-angiogenic therapies, such as topical anti-VEGF agents."

Still, in a world where cataracts, glaucoma, and opportunistic infections remain serious concerns, the demonstrated anti-inflammatory benefits of azithromycin may begin playing a more important role in ophthalmology. John D. Sheppard, M.D., professor of ophthalmology, microbiology, and immunology, Eastern Virginia Medical School, Norfolk, considers AzaSite to be a "great therapeutic option" for chronic blepharitis patients. "You can put it in the eye and it lasts all night and all day," Dr. Sheppard said. "The mucoadhesive DuraSite vehicle keeps the drug, which is already incredibly soluble, on the surface of the eye."

AzaSite downregulates matrix metalloproteinases, which when triggered and upgraded due to infection, can be deleterious, Dr. Sheppard said. It also downregulates other cytokines and chemokines that are "master orchestrators of the inflammatory response," he said. "I don't think there's any doubt that the anti-inflammatory effect is extremely useful," Dr. Sheppard said. Dr. Sheppard maintains that steroids are powerful agents to combat inflammation but that treatment regimens involving azithromycin could be warranted in some cases. "Blast with steroids for a couple of days or weeks of induction therapy, and then maintain on azithromycin when an acute phase of inflammation is under control," Dr. Sheppard said. When asked if such an approach would be considered experimental, Dr. Sheppard responded, "I don't think so. I completely recognize [the anti-inflammatory properties of azithromycin] as a well-established phenomenon. The anti-inflammatory properties of azithromycin have been thoroughly analyzed and published in the pulmonary literature. Topically, there are no real safety issues other than extremely rare medication or preservative allergies. This is clearly understood by physicians who keep track of medications and their beneficial properties."

Editors' note: Drs. Luchs and Sheppard have financial interests with Inspire Pharmaceuticals. Dr. Sadrai has no financial interests related to the Investigative Ophthalmology study, but research support was given in part by Inspire Pharmaceuticals.

Contact information

Luchs: 516-785-3900, jluchs@aol.com
Sadrai: 617-912-0256, z.sadrai@schepens.harvard.edu
Sheppard: 757-622-2200, docshep@hotmail.com

Azithromycin not steroids for corneal inflammation? Azithromycin not steroids for corneal inflammation?
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