Eyeworld

EW NEWS & OPINION 20 I n ophthalmology, azithromycin is indicated for treating bacter- ial conjunctivitis, but a growing mound of evidence suggests it could be useful in a more wide- spread manner for corneal inflamma- tion. According to Inspire Pharma- ceuticals (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 pneu- monia to sexually transmitted dis- eases, and now it has ophthalmic indications. Azithromycin may also be grow- ing in importance as an anti-inflam- matory drug. Harvard Medical School researchers recently investigated it as an anti-inflammatory agent. "The currently available phar- maceutical armamentarium to ame- liorate corneal inflammation is principally comprised of corticos- teroids," 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 seri- ous side effects such as cataract formation, elevated intraocular pres- sure (glaucoma), opportunistic infec- tions, and corneal thinning. Azithromycin has been reported to possess non-ocular anti-inflamma- tory and immunomodulatory activi- ties. Given these, we hypothesized that AZM [azithromycin] could be used as a therapeutic agent for ame- liorating corneal inflammation." The results, published online in February in Investigative Ophthalmol- ogy & 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 useful—although off-label—treat- ment for blepharitis, an inflamma- tory disease affecting the eyelid. In July 2010 in Clinical Ophthal- mology, Jodi Luchs, M.D., Depart- ment 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 topi- cal 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 an- tibiotics such as azithromycin ex- hibit anti-inflammatory properties," Dr. Luchs wrote. The Harvard research more ac- curately 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 pred- nisolone acetate 1%. "We found that within 24 hours of cauterization, leukocytic infiltra- tion 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% reduc- tion in leukocyte infiltration at day 1 and 39% reduction at day 7." AzaSite also regulated inflamma- tory cytokine expression in the cornea better than the vehicle alone. Prednisolone acetate was work- ing, too, decreasing CD45+ infiltra- tion 36% at day 3, 50% at day 7, and 30% at day 10. Neutrophil infiltra- tion, CD11c+ cell infiltration, and macrophage infilitration were also significantly decreased. "In our current study, treatment with AZM reduced dendritic cell in- filtration to the cornea to the levels comparable with prednisolone," Dr. Sadrai reported. "Importantly, how- ever, the effect of treatment with prednisolone starts earlier and stays longer than topical treatment with AZM." AzaSite had no suppression ef- fect on corneal neovascularization, a marker of severe, chronic corneal in- flammation. Other problems with AzaSite as an anti-inflammatory agent also sur- faced. "Corneal angiogenesis, a com- mon 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-inflam- matory and therapeutic benefit of AZM is rather limited for the more severe inflammatory insults to the cornea, which may require treat- ment with corticosteroids or other anti-angiogenic therapies, such as topical anti-VEGF agents." Still, in a world where cataracts, glaucoma, and opportunistic infec- tions remain serious concerns, the demonstrated anti-inflammatory benefits of azithromycin may begin playing a more important role in ophthalmology. John D. Sheppard, M.D., pro- fessor of ophthalmology, microbiol- ogy, and immunology, Eastern Virginia Medical School, Norfolk, considers AzaSite to be a "great ther- apeutic option" for chronic blephar- itis 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 com- bat 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-inflamma- tory properties of azithromycin have been thoroughly analyzed and pub- lished in the pulmonary literature. Topically, there are no real safety is- sues other than extremely rare med- ication or preservative allergies. This is clearly understood by physicians who keep track of medications and their beneficial properties." EW Editors' note: Drs. Luchs and Sheppard have financial interests with Inspire Pharmaceuticals. Dr. Sadrai has no financial interests related to the Inves- tigative Ophthalmology study, but re- search 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 September 2011 by Matt Young EyeWorld Contributing Editor Azithromycin—not steroids— for inflammation? Cataract continued from page 19 Editors' note: Neil Bressler, M.D., Wilmer Eye Institute, Johns Hopkins Baltimore, was also a contributing author. Drs. Bressler, Pan, and Stark have no financial interests related to this article. Contact information Bressler: nbressler@jhmi.edu Pan: panqing@hotmail.com Stark: wstark@jhmi.edu vest Ophthalmol Vis Sci. 2008;49(3):1079-83. 20. Lak D, Lubinski W, Sylwestrzak Z, Szych Z, Karczewicz D. Comparative assessment of the course of age-related macular degeneration in patients after phacoemulsification cataract surgery with implantation of AcrySof Natural SN 60 AT and AcrySof SA 60 AT lenses. Ann Acad Med Stetin. 2007;53 Suppl 1:43-7; dis- cussion 7-8.

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