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How to Navigate Topical Antifungal Ophthalmic Products
C. Monk
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1. Introduction
Keratomycosis is a common and dangerous disease of the equine eye. Case presentation and disease course is variable. Cytology gives the best stallside identification of etiologic organism. A sample with good yield enables the practitioner to determine bacteria from fungi and additionally should provide fungal differentiation of multicellular hyphae from unicellular yeast. However, occasionally cytology cannot be performed due to the nature of the lesion (intact epithelium, deep lesion). Furthermore, culture or polymerase chain reaction (PCR) is required to obtain actual species identification. Since fungi are typically slower growing than other organisms, it may be weeks into treatment before a culture result is produced. Once a positive culture has been obtained, additional testing must be requested if sensitivities are desired. Therefore, instead of therapeutic treatment to target an organism, antifungal treatment is often empirical.
Empiric antifungal therapy can vary based on region. Retrospective studies collecting data on fungal species involved in keratomycosis have been performed in multiple regions within the United States.1–4 Regional isolates associated with fungal keratitis vary. Fungi appear in three main forms— yeast (single cell, budding), mold (hyphae, branching), and dimorphic populations. Regardless of the region, Aspergillus, the filamentous multicellular hyphae, appears to be the most common organism implicated in the disease. In the southeastern U.S., most studies point to primarily Aspergillus and another filamentous organism Fusarium.1,5 Conversely, in the northeast, the yeast Candida is more frequently isolated.2 Finally, a recent study originating from the west, specifically California, confirmed Aspergillus in almost all of the keratomycosis cases that cultured positive.3
Because of their structural commonalities with mammalian cells, specific pharmacologic targeting is more difficult. Most antifungals act on the fungal cell wall. Topical antifungal therapy offers increased concentrations at the site of disease, decreased systemic side effects, improved economics, and improved ease of administration. However, topical antifungal medications are fairly new, with only one producta gaining FDA approval. They vary substantially in cost, formulation, and availability. The purpose of this paper is to illustrate the antifungal options currently available and provide a basis behind choosing them to treat keratomycosis in the horse.
2. Materials and Methods
Formulation for Topical Medications
Topical medications are formulated as a solution, a suspension, or an ointment. These medications are deposited into the precorneal tear film where they follow one of three routes. The two nontherapeutic routes are nasolacrimal drainage and into the systemic circulation via the conjunctiva and nasopharynx. Ocular absorption is the third desired route for therapy. This is through both the cornea and conjunctiva/sclera. Corneal absorption is limited by the hydrophilic or phobic affinity of the drug and the integrity of the cornea. The epithelium is the rate-limiting barrier for absorption of hydrophilic drugs, while the stroma is the rate-limiting barrier for lipophilic drugs. Therefore, drug penetration can improve in the presence of a corneal ulcer. For example, it has been demonstrated that when 25% to 50% of the corneal epithelium is removed drug penetration into the cornea and anterior chamber can be increased over ninefold.6 Other considerations that can significantly impact concentration of drug in the ocular tissues include lacrimation, blink rate, and protein content of tears—all of which can be substantially altered in horses with keratomycosis.
Indications for Topical Antifungal
Indications for use of a topical antifungal can be either empiric or therapeutic. A positive cytology or culture necessitates the use of a topical antifungal as a therapeutic. However, indications for empiric therapy are less well defined. Specific factors such as appearance of the lesion, geographic location, season, and clinician preference can all guide empiric use.
Appearance
Fungal keratitis can vary widely in presentation. Superficial keratomycosis can manifest as a gritty or dull lesion with minimal vascular response. Midstromal lesions may form central plaques or areas of malacia surrounded by a deeper furrow. Deep lesions may be epithelialized in the form of a deep stromal abscess.

Geographic Location
Horses everywhere are at risk. However, while fungal keratitis has been reported to occur all across the United States, the most frequent reports emerge from the southeastern U.S. The clinical manifestations may vary by region.
Season
Similarly to the increased prevalence in the south-east, hot and humid summer months are thought to yield a higher prevalence of keratomycosis in horses.
Categories of Antifungals
The following is not an exhaustive list of antifungal therapies available. Instead they are the most common antifungals for ophthalmic topical use. Please refer to Table 1 for a quick comparison of their benefits and drawbacks.
Polyenes
Polyenes target ergosterol in the cell membrane of fungi. Amphotericin B has been validated for use topically.7 However, its penetration is limited when the corneal epithelium is intact (e.g., deep stromal abscess). Natamycin is another polyene. This is the only FDA-approved topical antifungal agent and is formulated as a 5% suspension. However, this formulation is irritating to healthy corneal cells, and therefore it is often compounded to a 3.33% suspension. It has better coverage of filamentous organisms than amphotericin, often making it a better choice in equine keratomycosis.
Azoles
Azoles also target ergosterol, but instead they inhibit its synthesis through the cytochrome P450 system. A concurrent action is inhibition of mitochondrial oxidative and peroxidative enzymes.
The first sub-group within the azoles is the imidazoles (named based on parent ring structure). [...]
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Affiliation of the authors at the time of publication
University of Florida, College of Veterinary Medicine, 2089 SW 16th Avenue, Gainesville, FL 32610
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