Therapeutics in Practice

The Use of Antifungals

Column Editor
Debra Deem Morris, DVM, MS, DACVIM 190 State Route 10 East Hanover, NJ 07936 phone 973-599-1191 fax 973-599-1193 email stretchdeem@yahoo.com

Jennifer L. Davis, DVM, PhD, DACVIM, DACVCP*

North Carolina State University

Fungal diseases are relatively rare in horses, but they can be life-threatening and are often extremely difficult to treat because the few available drugs may have poor bioavailability, induce severe toxicity, or be cost prohibitive. This column is a summary of the drugs that can be used to treat fungal diseases in horses.

GRISEOFULVIN The use of griseofulvin is limited to treatment of ringworm caused by Trichophyton equinum or Microsporum gypseum. Two convenient dosing forms (a bolus and a powder to be used as a top dressing in feed) are currently available for horses. Each dose of each form contains 2.5 g of drug, and a single daily dose for an adult horse is 5 mg/kg. Smaller doses (1.25 g) should be used for foals or ponies. The available veterinary formulations contain microsize particles of griseofulvin. In contrast, human formulations may contain ultramicrosize particles, which increase the surface area of the drug available for dissolution, thereby increasing drug solubility and bioavailability. These formulations can be used in veterinary species; however, the dose should be decreased by 50% to avoid toxicity. Griseofulvin should not be used in pregnant mares during the early stages of gestation because teratogenic effects, including ocular and skeletal malformations, have been reported.1 This drug has been given, without adverse effects, to mares in the later stages of pregnancy.

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AZOLE ANTIFUNGALS The azole antifungals include the imidazole ketoconazole as well as the triazoles, which include fluconazole, itraconazole, and voriconazole. The pharmacokinetics of these drugs have been studied in horses. Unfortunately, ketoconazole, which is inexpensive and readily available, is not absorbed following oral administration (30 mg/kg) in horses unless it is administered in a highly acidic vehicle, such as hydrochloric acid.2 Even when ketoconazole is administered in this fashion, the bioavailability is still low (around 23%2), and use of this drug is not recommended in horses. Of the antifungals studied in horses, fluconazole is among the most convenient to Therapeutics in Practice administer; affordable generic formulations are now available. A study of the pharmafeatures current medical cokinetics of fluconazole in horses has shown that the bioavailability is approximately protocols used to treat a 100%, and no side effects have been reported, even with long-term administration.3 Fluconazole has been safely used in mares in the seventh and 10th months of pregnancy variety of conditions with no adverse effects on the fetus.4 The recommended dosing regimen involves a in horses. loading dose of 14 mg/kg PO followed by 5 mg/kg PO once daily.3 This regimen produces plasma and tissue concentrations greater than 8 g/ml, which is sufficient to kill Send comments/questions via email editor@CompendiumEquine.com susceptible fungi, including the dermatophytes as well as Blastomyces, Candida, Coccidioides, Cryptococcus, Conidiobolus, and Histoplasma spp. However, fluconazole may be or fax 800-556-3288. ineffective against Aspergillus spp, which is often highly resistant to the drug.
*Dr. Davis discloses that she has received a grant and speaking honorarium from Bayer Animal Health for a study related to enrofloxacin in cattle. This study is unrelated to antifungals.

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The pharmacokinetics of itraconazole have been studied in horses,5 and the drug has been used to successfully treat equine fungal diseases. Two oral formulations of itraconazole are currently available in the United States: one is a capsule containing small, drugcoated spheres, and the other is an oral solution in which the drug has been complexed with cyclodextrins to improve solubility. The capsules have low and variable absorption (approximately 12%) in horses; the spheres must be delivered intact: crushing them decreases bioavailability. The solution has better oral absorption (approximately 65%), but at the recommended dose of 5 mg/kg once daily, the 250-ml volume required for a 500kg (1100-lb) horse would be difficult for owners to deliver. Both formulations of itraconazole are cost prohibitive in many cases. Generic capsules are available but still expensive. To make dosing more affordable, many practitioners have tried using compounded formulations. Unfortunately, testing of the formulations as well as plasma samples from horses that have received them indicates that the drug concentration varies considerably

Fungal diseases in horses are expensive and difficult to treat.

in the formulations and oral bioavailability is negligible. Therefore, compounded preparations of itraconazole should not be used in horses. The spectrum of activity of itraconazole is similar to that of fluconazole, with the exception that Aspergillus spp are typically susceptible to itraconazole, often with minimum inhibitory concentrations less than 0.06 g/ml. To date, based on susceptibility and clinical use in horses, itraconazole is the recommended drug for treating aspergillosis. No adverse effects have been reported following administration of itraconazole to horses. In other species, itraconazole has been shown to inhibit cytochrome P-450mediated drug metabolism in the liver, indicating potential drugdrug interactions in horses. In addition, in other species, concurrent administration of drugs that increase gastric pH (i.e., H2 antagonists [cimetidine, ranitidine], proton pump inhibitors [omeprazole, pantoprazole]) has been shown to decrease the bioavailability of itraconazole by inhibiting the pHdependent dissolution in the stomach; therefore, coadministration of these drugs in horses should be avoided.
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The newest azole antifungal to be studied in horses is voriconazole. The drug exhibits an oral bioavailability of approximately 100% and a long half-life, allowing once-daily dosing. 6 The spectrum of activity of voriconazole is broad, including Aspergillus and some Fusarium spp. Doses of 3 mg/kg PO q24h should be sufficient to treat aspergillosis, but higher doses (4 to 5 mg/kg) are probably necessary to treat infection with Fusarium spp. Voriconazole has excellent potential for

determined in this species. The use of this drug should be limited to severe systemic fungal diseases because of potential irreversible nephrotoxicity. It is impractical to use amphotericin B in a field setting because it must be diluted in 5% dextrose and administered intravenously over a 60-minute period and because fluid preloading is recommended to help prevent renal damage. The serum biochemistry panel should be monitored frequently during the course of drug administration, and urine sedi-

The only antifungal labeled for use in horses is griseofulvin, which is limited to the treatment of ringworm.
use as an antifungal in horses; however, clinical experience is lacking, and the drug is currently too expensive for practical use. ment tests should be conducted to monitor for early cast formation. Reported doses have ranged from 0.1 to 0.9 mg/kg IV q2448h. Liposomal encapsulated formulations are available and have decreased toxicity, allowing higher cumulative doses to be used. However, these formulations are cost prohibitive, and their use has not been reported in equine medicine.

AMPHOTERICIN B Amphotericin B has been used in a limited number of horses, even though the pharmacokinetics have not been

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OTHER ANTIFUNGALS Sodium or potassium iodide compounds have been used to treat fungal infections in horses and cattle for many years. The mechanism of action of these compounds against fungi and bacteria is unknown, and there is no in vitro evidence that these compounds are effective. In vivo, they are used to treat equine nasal fungal granulomas caused by Conidiobolus, Basidiobolus, and Pseudallescheria spp. It is recommended to begin therapy with intravenous 20% sodium iodide (125 ml q24h) for 3 days, followed by 30 g PO q24h for at least 30 days past resolution of clinical signs. Adverse effects (salivation, lacrimation, tachycardia, dry skin, anorexia, abortion, infertility) have been reported, particularly with intravenous dosing. Iodide compounds are not particularly effective as a monotherapy and should be combined with surgical excision, intralesional therapy, or other systemic antifungals. Lufenuron has also been studied as an antifungal in horses. It has been used successfully in an intrauterine lavage to treat fungal endometritis7; however, oral absorption is minimal, and systemic use of this drug is not recommended in horses.8 Terbinafine is an allylamine antifungal that has been used in humans and small animals to treat dermatophytosis and onychomycosis. Its spectrum of activity includes yeast and other systemic fungi, but its use in these infec-

Fluconazole has an excellent pharmacokinetic profile and good bioavailability and is currently affordable. Unfortunately, it has limited activity against filamentous fungi (i.e., Aspergillus and Fusarium spp), which can limit its efficacy in many situations.
tions has been limited. It has recently become generic and may be an affordable alternative treatment in horses, although the pharmacokinetics have not been studied in this species.

OCULAR ANTIFUNGALS One of the most common manifestations of fungal disease in horses is keratomycosis. Fungal infections of the cornea and the intraocular structures can be vision threatening and are often difficult to treat. Natamycin is commercially available as a 5% ophthalmic suspension and has excellent activity against fungi that commonly cause keratomycosis, including Aspergillus and Fusarium spp as well as yeasts. Natamycin is expensive, has a tendency to precipitate with other medicine, and may sometimes block subpalpebral lavage catheters. Ophthalmic formulations of miconazole are not commercially available, but the drug can be compounded as a 1% solution and used topically in the eyes. Miconazole creams have been used in equine eyes by some practitioners; however, these creams may impair vision and should not be used in cases in which perforation of the cornea is likely, as the vehicles used can be irritating to the intraocular structures.
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Itraconazole can also be compounded for ocular use. Combining the drug with 30% dimethyl sulfoxide increases the corneal drug concentration but does not increase penetration of the drug into the anterior chamber, making this drug suitable for corneal surface and corneal stromal infections, but not for fungal endophthalmitis.9 The intravenous formulation of voriconazole has been studied for topical use in equine eyes. It penetrates well through an intact cornea, and aqueous humor concentrations reach greater than 2 g/ml after topical application of 0.2 ml of 1% voriconazole every 4 hours. 10 Higher concentrations of the drug or more frequent administration may result in signs of ocular irritation. Voriconazole is stable for up to 30 days when kept refrigerated in a well-sealed container. In cases that do not respond to traditional topical therapies, subconjunctival injection of amphotericin B has been used. The deoxycholate salt is diluted to a concentration of 0.5 mg/ml in sterile water (not saline). The injection volume is approximately 0.25 ml every other day. Amphotericin can be irritating to tissue, and some conjunctival inflammation or sloughing can occur.

REFERENCES
1. Schutte JG, van den Ingh TS. Microphthalmia, brachygnathia superior, and palatocheiloschisis in a foal associated with griseofulvin administration to the mare during early pregnancy. Vet Q 1997;19(2):58-60. 2. Prades M, Brown MP, Gronwall R, Houston AE. Body fluid and endometrial concentrations of ketoconazole in mares after intravenous injection or repeated gavage. Equine Vet J 1989;21(3):211-214. 3. Latimer FG, Colitz CM, Campbell NB, Papich MG. Pharmacokinetics of fluconazole following intravenous and oral administration and body fluid concentrations of fluconazole following repeated oral dosing in horses. Am J Vet Res 2001;62(10):1606-1611. 4. Taintor J, Crowe C, Hancock S, et al. Treatment of conidiobolomycosis with fluconazole in two pregnant mares. J Vet Intern Med 2004;18(3): 363-364. 5. Davis JL, Salmon JH, Papich MG. Pharmacokinetics and tissue distribution of itraconazole after oral and intravenous administration to horses. Am J Vet Res 2005;66(10):1694-1701. 6. Davis JL, Salmon JH, Papich MG. Pharmacokinetics of voriconazole after oral and intravenous administration to horses. Am J Vet Res 2006;67(6): 1070-1075. 7. Hess MB, Parker NA, Purswell BJ, Dascanio JD. Use of lufenuron as a treatment for fungal endometritis in four mares. JAVMA 2002;221(2):240, 266-267. 8. Scotty NC, Evans TJ, Giuliano E, et al. In vitro efficacy of lufenuron against filamentous fungi and blood concentrations after PO administration in horses. J Vet Intern Med 2005;19(6):878-882. 9. Ball MA, Rebhun WC, Trepanier L, et al. Corneal concentrations and preliminary toxicological evaluation of an itraconazole/dimethyl sulphoxide ophthalmic ointment. J Vet Pharmacol Ther 1997;20(2):100-104. 10. Clode AB, Davis JL, Salmon J, et al. Evaluation of concentration of voriconazole in aqueous humor after topical and oral administration in horses. Am J Vet Res 2006;67(2):296-301.