RX Perspective

New Drop Aimed at Lid Margin Disease

Nine-drop treatment employs vehicle that favors rapid symptom relief, resolution of blepharitis.

By Kerry D. Solomon, M.D.

Lid margin disease is a common, chronic disease that may be the most under-diagnosed and under-treated disease in ophthalmology. Usually, we differentiate lid margin disease or blepharitis into three categories: anterior blepharitis, posterior blepharitis and seborrheic blepharitis. Of these, posterior blepharitis is the most common and is often misdiagnosed as aqueous deficient dry eye disease. Clinical features include inspissantion meibomian glands, thickened eyelid margin, conjunctival injection, telangiectatic vessels on the lids and often a burning sensation. In this article, we will examine the effectiveness of one new macrolide in combating acute blepharitis.

Treating Blepharitis

Azithromycin ophthalmic 1% (AzaSite, Inspire Pharmaceuticals) is an attractive empiric treatment for blepharitis, which is both associated with and confused with conjunctivitis. Immunosuppressants to control the inflammatory process followed by artificial tears to provide lubrication do not treat bacteria that may contribute to the pathophysiology, particularly on the anterior lid. With the exception of macrolides, previously available antibiotics did not directly address the inflammation.

The advantage of azithromycin in blepharitis is that it does exert antiinflammatory activity along with antibacterial activity. Again, the antibacterial effect is enhanced by good penetration of the eyelids. In addition, the viscous vehicle provides lubrication for immediate relief of the dry eye sensation.

Treatment algorithms for blepharitis should be adjusted to accommodate a topical antibiotic with an anti-inflammatory effect. Warm compresses and lid scrubs to be used twice daily for 2 days, then once a day for one month.

For persistent or frequently recurring blepharitis, patients should consider dietary fish oil supplements and a course of oral tetracycline (20 mg of doxycycline t.i.d. or 50 mg of minocycline once daily) with topical cyclosporine. Topical steroids such as loteprednol can be reserved for breakthrough episodes.

Unique Characteristics

In 2007, the FDA granted approval to 1% azithromycin in a DuraSite vehicle (AzaSite, Inspire Pharmaceuticals) for treatment of bacterial conjunctivitis caused by Haemophilus influenzae, Streptococcus mitis group, Streptococcus pneumoniae, Staphylococcus aureus and CDC coryneform group G. (Note: Most antibiotics receive approval from the FDA for bacterial conjunctivitis, but are used in various areas by specialists.) This therapy has several characteristics not common to other options. The most conspicuous is a reduced frequency of dosing. Unlike current topical antibiotics, which require four drops per day for a treatment course of 7 days, AzaSite requires two drops per day during the first two days and then one drop per day for the remaining 5 days of the 7-day course. This dosing regimen will last a significant amount of time longer when treating posterior blepharitis.

The efficacy of AzaSite at treatment intervals of up to once per day is credited both to the long half life of the antibiotic and to the characteristics of the vehicle, a combination of polycarbophil, edentate disodium and sodium chloride. On application, the vehicle yields gel-forming particles that enlarge in the aqueous environment of the eye. The increased viscosity extends exposure of ocular tissues to the antibiotic and is resistant to washout, a substantial advantage in those with a high degree of tear formation in response to topical drug administration, as well as in crying children.

In addition to good coverage of common pathogens, particularly gram-positive organisms, it has demonstrated a high degree of penetration of ocular tissue, such as the cornea.¹ Moreover, azithromycin, like other macrolides, has an anti-inflammatory effect that can speed resolution of redness and swelling.² The effect of this anti-inflammatory activity is likely to be additive to the symptom relief provided by the vehicle alone, which is also an effective lubricant that relieves the dry eye characteristic of conjunctivitis.

Examining the Data

In pivotal clinical trials leading to regulatory approval of azithromycin, the active therapy was more effective for bacteriologic eradication than its vehicle (88.5% vs. 66.4%; P<0.001) in a double-blind, multicenter study involving 279 patients in the per protocol population.³ When compared with 0.3% topical tobramycin in 743 children and adults at 47 participating centers, the bacteriologic eradication rates for azithromycin and the active control (88.1% vs. 94.3%) did not differ significantly.⁴

The similarity in efficacy was also observed when eradication rates were compared for the most common pathogens, such as S. aureus or H. influenzae. The most common side effects on topical azithromycin, occurring in less than 2% of patients, were eye irritation and conjunctival hyperemia.

In the comparison of AzaSite to topical tobramycin, both arms took four drops per day, but those in the AzaSite group only received active therapy according to the currently recommended regimen (t.i.d. for 2 days followed by once daily for the remainder of the course). While this was necessary to maintain the study blind, it obscures the ability of AzaSite to achieve similar efficacy on half as many active drops. Relative to four-times-daily dosing, the compliance advantage of a drug that only requires one drop in the morning and one at night at its peak dosing frequency can be expected to be substantial outside of a clinical trial.

More Benefits

Much of the attention devoted to release of AzaSite has been on the reduction in dosing frequency relative to other options. The characteristics of the vehicle also deserve attention. On application, the lubrication delivered by the vehicle soothes the dry eye symptoms. The comfort conferred by the vehicle may contribute substantially to improved rates of compliance. In patients with blepharitis, for example, the vehicle may provide more symptomatic relief than the artificial tears commonly administered to control dry eye.

Due to the lubrication provided in the treatment of conjunctivitis, it may be appropriate to supplement rather than replace azithromycin with an aminoglycoside or fourth-generation fluoroquinolone in patients with Pseudomonas aeruginosa or another gram negative infection unresponsive to azithromycin.

Azithromycin was introduced for the control of bacterial conjunctivitis, but the unique properties of this agent may be at least as important to the empiric treatment of blepharitis, whether or not it is associated with conjunctivitis. In either case, the agent combines an effective antibiotic with a viscous vehicle to address bacterial load, inflammation and lubrication, which are typically the key features of both conditions. OM

References

1. Kuehne JJ, Yu ALT, Holland GN, et al. Corneal pharmacokinetics of topically applied azithromycin and clarithromycin. Am J Ophthalmol 2004;138:547-553.
2. Ianaro A, Ialenti A, Maffia P, et al. Anti-inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther 2000;292:156-163.
3. Abelson MB, Shapiro AM, Heller W, The AzaSite Clinical Study Group. Efficacy of azithromycin 1% eye drops vs vehicle as first-line therapy for bacterial conjunctivitis. Annual meeting of the American Academy of Ophthalmology. 2006. Abstract 74.
4. Protzko E, Bowman L, Abelson M, et al. Phase 3 safety comparisons for 1.0% azithromycin in polymeric mucoadhesive eye drops versus 0.3% tobramycin eye drops for bacterial conjunctivitis. Invest Ophthalmol Vis Sci 2007;48:3425-3429.