Eye care practitioners are creatures of habit. We are systematically trained to connect the dots and prescribe the magic potion to solve our patients’ dilemmas. Sometimes, however, the obvious isn’t always the answer, or even a possibility because of our patients’ unique circumstances. It is in those moments that we have to be creative.

A variety of highly effective, though non-traditional options exist for treating ocular diseases. While it is not our intent with this article to promote these new, more cutting-edge treatments, we wish to bring them to the attention of our colleagues, so they will recognize their benefit if the need arises in their own clinical practice. Almost without exception, all the products we will discuss need to be specially formulated by a compounding pharmacy. This speaks to the uniqueness of the patient issues and the products, but also to how well readily available products typically treat our most commonly encountered ocular disease states.

Compounding pharmacies can produce products quite quickly and, in many instances, less expensively than commercial pharmacies. Also, the dose units for children sometimes prove to be too strong and need weight adjusting.¹ But, there is an important catch that you must discuss with your patients—insurance companies may not reimburse for specialty products. And you thought this article was going to be all about good news.

Doxycycline
Doxycycline is an effective antibiotic from the tetracycline class; it has long been touted for its benefits in treating diseases of the eye, particularly in individuals with chronic posterior blepharitis. The drug works by inhibiting protein synthesis in the bacterial ribosome, thus rendering translation of the bacterial protein mute.² But, oral doxycycline can cause gastrointestinal upset—including diarrhea, gas and cramping—as well as profound photosensitivity.
There are other ways, however, to get doxycycline into the battle without causing GI upset. While very little attention has been paid to the topical formulation of doxycycline and its use, there are some distinct advantages. First, there is less of the drug absorbed systemically, which could be very helpful for those who are prone to gastrointestinal distress. Second, because the drug is applied topically, the concentration doesn’t need to be as high.^3,4 It has been noted in dermatologic applications that subantimicrobial doses of doxycyline has therapeutic benefits for skin conditions, such as rosacea or acne vulgaris or even in dental applications.⁵

Furthermore, lower doses might also be indicated to reduce the trends toward developed resistance.⁶ In instances of chronic inflammation—including
posterior blepharitis and dry eye—it is fascinating to wonder about topical doxycycline’s role in diminishing the impact of proinflammatory cytokines on the ocular surface.⁷

Indeed, this very concept was studied by Beardsley and associates in a mouse model. In a series of experiments, mice were induced with dry eye for a period of five days, while concurrently being treated randomly with 0.025% or 0.0025% strength doxycycline drops, or a vehicle four times daily. At the conclusion of the experiment, the animals were sacrificed and compared against the other stimulus conditions. Dry eye inducement was positively associated with corneal apical dessication, but the use of doxycycline significantly reduced the associated corneal stress and expression of cytokine activity.⁸

Lekhanont and colleagues also looked at mouse model eyes and studied the effect of topical steroids, non steroidals, doxycycline and artificial tears on induced dry eye. They found that topical steroids or doxycyline had the best therapeutic value in preventing punctate changes. Non-steroidals helped some, but artificial tears, interestingly, helped the least.⁹

Current offerings for human prescribing of the medication include 0.025% or 0.1% strength doses to be used t.i.d. The medication is minimally used for 10 days, but can be continuously used thereafter.

Acyclovir
Acyclovir is a mainstay therapy for patients with herpes zoster and chronic intermittent forms of herpes simplex. Available in generic form, it is also suggested as treatment for patients with chronic recurrent herpetic keratitis. Of course, these patients are also at risk for kidney function changes, so it is critical to monitor creatin levels for those forced to endure the drug for long periods of time.

But, what does the clinician do for those patients who are unable to utilize or tolerate oral acyclovir? In these instances, the option of using acyclovir in solution format (200/5ML) oral suspension is available. This can be especially helpful for children who cannot swallow a large pill.

Cyclosporin A
Cyclosporin A is routinely prescribed for treatment of inflammation-related dry eye. Currently, 0.05% strength is available as Restasis (cyclosporine, Allergan) and used b.i.d. But, there are instances where stronger concentrations of cyclosporine might be warranted, particularly in cases of recalcitrant anterior segment inflammation, vernal conjunctivitis and in the prevention and treatment of corneal graft rejection.

Kiliç and Gürler studied the use of preservative-free 2% cyclosporin A in 20 patients with vernal conjunctivitis. They found considerable improvement in the appearance and comfort for all the patients.¹⁰ Doan and colleagues treated 11 children with chronic corneal surface inflammation with topical Cyclosporin A in 2% strength q.i.d., and found complete elimination of the inflammatory process during treatment.¹¹ Cyclosporin A compounded to 2% strength is also recommended for cases of graft failure following penetrating keratoplasty.

Nejabat and associates divided 40 patients experiencing graft failure into two groups—patients in group one received topical and oral steroids, while those in group two received topical steroids and 2% cyclosporine. At the conclusion of the study, the patients receiving the cyclosporine drops had a 90% recovery rate from graft failure, while the patients receiving steroids alone experienced only a 70% recovery rate.¹²

Know Your Options
Awareness of these less conventional, but highly useful offshoots of some of our most commonly used drugs allows us to customize treatment for some of our most complex and unique cases. Use the information we provided cautiously and always have thorough discussion with patients and their insurance company representatives. Don’t let an insurance company denial come as a surprise at the pharmacy window. Discuss discuss this possibility with them ahead of time, as well as the logic behind the choice of medications.

We can only imagine how much easier this process will be in the near future. It is critical for us as clinicians to make certain that sterility issues and stability have been discussed with patients and that a very reputable formulation pharmacy is used.
Lastly, while we attempted to highlight three more commonly used medications, we don’t want to appear to slight other compounded medications that can be produced preservative-free, including agents for anti-infectives, glaucoma and steroids. 

1. Gray C. Systemic toxicity with topical ophthalmic medications in children. Pediatr Perinat Drug Ther. 2006;7(1):23-9.
2. Wikipedia. Tetracycline antibiotics. Available at: http://en.wikipedia.org/wiki/Tetracycline_antibiotics. (Accessed August 2010).
3. De Paiva CS, Corrales RM, Villarreal AL, et al. Apical corneal barrier disruption in experimental murine dry eye is abrogated by methylprednisolone and doxycycline. Invest Ophthalmol Vis Sci. 2006 Jul;47(7):2847-56.
4. Correlation of the controlled adverse environment methodology with a murine model of experimental dry eye in assessing the ability of topical doxycycline to prevent corneal barrier disruption. Available at: www.alhttp://en.wikipedia.org/wiki/Tetracycline_antibioticsacritybio.com/pdf/ARVO_Abstract.pdf. (Accessed August 2010)
5. Bikowski JB. Subantimicrobial dose doxycycline for acne and rosacea. Skinmed. 2003 Jul-Aug;2(4):234-45.
6. Alikhan A, Kurek L, Feldman SR. The role of tetracyclines in rosacea. Am J Clin Dermatol. 2010;11(2):79-87.
7. Stechmiller J, Cowan L, Schultz G. The role of doxycycline as a matrix metalloproteinase inhibitor for the treatment of chronic wounds. Biol Res Nurs. 2010 Apr;11(4):336-44.
8. Beardsley RM. De Paiva C, Power DF, Pflugfelder SC. Desiccating stress decreases apical corneal epithelial cell size-modulation by the metalloproteinase inhibitor doxycycline. Cornea. 2008; 27(8): 935-940.
9. Lekhanont K, Park CY, Smith JA, et al. Effects of topical anti-inflammatory agents in a botulinum toxin B-induced mouse model of keratoconjunctivitis sicca. J Ocul Pharmacol Ther. 2007 Feb;23(1):27-34.
10. Kiliç A, Gürler B. Topical 2% cyclosporine A in preservative-free artificial tears for the treatment of vernal keratoconjunctivitis. Can J Ophthalmol. 2006 Dec;41(6):693-8.
11. Doan S, Gabison E, Gatinel D, et al. Topical cyclosporine A in severe steroid-dependent childhood phlyctenular keratoconjunctivitis. Am J Ophthalmol. 2006 Jan;141(1):62-66.
12. Nejabat M, Khoshghadam J, Eghtedari M, Hosseini H. Topical Cyclosporine A in corneal graft rejection. Am J Immunology. 2006;2(2):29-34