Topical ophthalmic solution also shows properties comparable to prednisolone

By Nancy Groves

Reviewed by Zahra Sadrai, MD, and Reza Dana, MD, MPH, MSc

Boston—A broad-spectrum macrolide antibiotic also may have anti-inflammatory properties. In a recent study conducted in an animal model, topical azithromycin ophthalmic solution 1% (Azasite, Inspire Pharmaceuticals) reduced leukocyte infiltration to levels comparable to those seen with prednisolone and displayed an associated increase in the anti-inflammatory cytokine IL-10, according to Zahra Sadrai, MD, who presented findings from the study at the annual meeting of the American Society of Cataract and Refractive Surgery.

Dr. Sadrai, a research fellow at Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, and her colleagues are among the investigators who are seeking new strategies to suppress corneal inflammation. Corticosteroids currently are the primary therapy. However, their long-term use has the potential for serious complications.

The Schepens researchers in the laboratory of senior scientist Reza Dana, MD, MPH, MSc, evaluated azithromycin because it has been shown to have antiinflammatory and immunomodulatory properties, although this has not been demonstrated on the ocular surface. Previous studies have demonstrated that macrolides such as azithromycin suppress the NF KB pathway as well as the release of proinflammatory cytokines in vitro.

The new study was performed in a mouse model. The corneas of 6- to 8-week BALB/c mice underwent thermal cautery to induce inflammation and leukocyte influx. Fifteen corneas were randomly assigned to groups treated topically with azithromycin, vehicle, or prednisolone acetate 1% twice daily. Corneas were harvested at days 1, 3, 7, 10, and 14 for evaluation of leukocyte infiltration via FACS analysis and cytokine mRNA expression using real time polymerase chain reaction.

Looking at total infiltration of CD4S, a pan-leukocyte marker, the team observed a significant decrease in inflammation, demonstrated by a 39% reduction relative to control, at day 7 in the corneas treated with azithromycin, Dr. Sadrai said.

A similar reduction was observed in the prednisolone group.

They then analyzed leukocyte subsets important in innate immunity, such as neutrophils, microphages, and dendritic cells. These cells migrate from the cornea to the regional lymph node, where they contact T cells and induce inflammation; the T cells then migrate to the cornea and increase the amount of inflammation.

“Our aim is to suppress this leukocyte mobilization in the cornea to prevent subsequent inflammation,” Dr. Sadrai said.

The team found that dendritic cells demonstrated reduced infiltration (35%) at day 7 in the group treated with azithromycin and 40% in the prednisolone-treated group.

To learn what was causing the suppression observed in the mouse corneas, the researchers looked at intercellular adhesion molecule 1 (ICAM-I), which facilitates cell migration to the cornea.

ICAM-1 expression

The Dana laboratory has shown that ICAM-1 expression by normal limbal area of the cornea is undetectable; however, following an inflammatory insult, ICAM-1 expression is significantly upregulated. In their study, the researchers found high expression of 1CAM-1 in the limbal area in the vehicle treated group after cauterization, while expression was decreased in the limbal area of corneas treated with azithromycin.

in other results, the study showed that the expression levels of the anti-inflammatory cytokine IL-10 increased at all time paints in eyes treated with azithromycin, compared with vehicle-treated group. The expression of IL-6 varied at different time points.

“These preliminary results were very impressive, and we are continuing this project,” Dr. Sadrai said.

“At least in mice, we may use azithromycin as an antibiotic with ahti-inflammatory effects in ocular surface inflammation,” Dr. Sadrai concluded. “However, some investigations are required lo confirm these findings in the clinical population and to define which patient subgroups are most likely to [have a response] to topical azithromycin, in addition to determining the optimal dosage and dura tion of therapy.