Although griseofulvin is the only antifungal approved for systemic administration by the Food and Drug Administration (FDA) for veterinary use, a variety of systemic antifungals are available for use in veterinary medicine. With the introduction of generic formulations, prescribing many of them is no longer cost-prohibitive. The development of newer antifungals such as itraconazole, fluconazole, voriconazole, and posaconazole has been spurred on by the occurrence of resistance in fungal organisms, as seen in bacteria.

A scanning electron photomicrograph of Cryptococcus neoformans (magnification X1,200). Image copyright Dennis Kunkel Microscopy, Inc.

This review addresses the mechanisms of action, potential indications, pharmacokinetics, adverse effects, and recommendations for the use of several azole antifungal drugs—ketoconazole, itraconazole, fluconazole, voriconazole, and posaconazole—as well as terbinafine in veterinary patients. The azole antifungal drugs were first discovered in the early 1970s, with ketoconazole being the first orally active azole antifungal.¹ The azoles have a broad spectrum of antifungal activity, but important differences exist. Terbinafine is not an azole antifungal drug, but it has a broad spectrum of activity against many yeast and fungal organisms. See Table 1 for the recommended dosages for these antifungals.

MECHANISM OF ACTION

The azole antifungal drugs have a similar mechanism of action, which is inhibiting the cytochrome P (CYP)-450-dependent enzyme, lanosterol-14alpha-demethylase. This enzyme is responsible for forming ergosterol. Ergosterol depletion results in disruption of cell wall function. Lanosterol-14alpha-demethylase is present in most species of yeasts and molds with the exception of Pythium species.² Lanosterol-14alpha-demethylase is also present in Leishmania species, which explains the variable activity of the azoles in leishmaniasis.^3-5 The azoles have a higher affinity for fungal CYP than they do for mammalian CYP; however, adverse effects in mammals are due in part to inhibiting mammalian CYP. Decreased synthesis of testosterone, cortisol, cholesterol, and androgens may occur during azole administration.¹

Terbinafine's mechanism of action differs from that of the azoles. It inhibits the enzyme squalene epoxidase with a net effect of decreasing ergosterol formation.¹ The different mechanism of action results in a different adverse effects profile (i.e. terbinafine does not inhibit mammalian CYP and has fewer drug-drug interactions) and may be efficacious in organisms resistant to the azoles.

KETOCONAZOLE

Table 1: Recommended Dosages of Antifungals in Dogs and Cats*

Ketoconazole is still used regularly in veterinary medicine, but its use is being supplanted by some of the newer antifungal agents. Ketoconazole, which is available as 200-mg tablets, is an affordable alternative when itraconazole or voriconazole are cost-prohibitive. However, ketoconazole has a lower efficacy against many fungal organisms compared with itraconazole and voriconazole, and ketoconazole may have a greater potential for adverse effects. The typical cost of ketoconazole treatment for a 44-lb (20-kg) dog (10 mg/kg orally twice a day) is about 50¢/day.

Potential indications

Ketoconazole is typically effective for the systemic treatment of otitis and dermatitis caused by Malassezia species as well as of infections caused by Candida species and dermatophytosis caused by Microsporum canis.^1,6 Ketoconazole has also been used to treat blastomycosis, histoplasmosis, cryptococcosis, coccidioidomycosis, and aspergillosis, but itraconazole is considered more efficacious in treating these infections.¹

Pharmacokinetics

Ketoconazole is variably absorbed when administered orally in dogs.⁷ In people, ketoconazole absorption is increased with increased gastric acidity.⁸ No studies in dogs have examined the effect of a fed or fasted state on ketoconazole absorption, but as in people, it is recommended to be given with food. In people, gastric acid suppression therapy—such as antacids, H₂-receptor antagonists (cimetidine, famotidine), or proton pump inhibitors (omeprazole)—decreases ketoconazole absorption. So concurrent administration of these drugs in animals receiving ketoconazole is also not recommended.

ESSENTIAL ELEMENTS

No data are available on the pharmacokinetics of ketoconazole in cats.

Drug interactions and adverse effects

Since ketoconazole inhibits the metabolizing enzyme CYP3A12 in dogs, adverse effects can occur if it is given concurrently with drugs metabolized by CYP3A12.⁹ The metabolism of the concomitant drugs is decreased, so toxicosis can occur because of drug accumulation.

Ketoconazole also inhibits the p-glycoprotein (Pgp) efflux pump present in numerous anatomical locations, including, but not limited to, the gastrointestinal tract, liver, and blood-brain barrier.¹⁰ Pgp actively secretes absorbed substrates back into the lumen of the intestines (decreasing drug absorption), back into the lumen of the brain capillary (an active component of the blood-brain barrier), and into the bile canaliculus (active biliary secretion). The consequences of inhibiting the Pgp efflux pump include increased oral bioavailability of Pgp substrates, increased penetration of Pgp substrates into the CNS, and decreased biliary secretion of Pgp substrates. A thorough review of Pgp substrates and inhibitors has been previously published.¹¹

Ketoconazole's inhibition of CYP3A12 and Pgp has been used therapeutically to decrease the dose of cyclosporine needed to achieve targeted concentrations in both dogs and cats.^12,13 Ketoconazole may decrease the elimination of cisapride, vincristine, diltiazem, lidocaine, buspirone, quinidine, some benzodiazepines, and fentanyl, resulting in toxicity of the concurrently administered drug if dosages are not adjusted. Long-term phenobarbital administration increases ketoconazole metabolism and may require increased ketoconazole dosages to maintain similar efficacy.

Other adverse effects associated with ketoconazole include nausea, anorexia, and vomiting; they occur more frequently at higher dosages.¹ Pruritus, alopecia, lightening of the coat, and weight loss can occur with long-term therapy.¹

Slight to moderate increases in serum hepatic enzyme activities can also occur with long-term therapy, which may not be accompanied by hepatic injury. However, large increases in serum hepatic enzyme activities accompanied by elevated serum bilirubin concentrations may be indicative of hepatic injury. So routine monitoring of serum hepatic enzyme activities during long-term therapy is warranted. Cats may be more sensitive to hepatotoxicosis,¹ but with the lack of pharmacokinetic studies in cats, it is unclear whether this is truly an increased sensitivity or whether the toxicosis is due to inappropriate dose recommendations. Idiosyncratic (non-dose-dependent) hepatotoxicosis has also been reported in animals.¹

Ketoconazole is teratogenic and not recommended for use in pregnant or lactating animals.¹⁴ Inhibition of testosterone has resulted in gynecomastia, impotence, and azoospermia in people. Cortisol production is also inhibited by ketoconazole, more so in dogs than in cats.^1,15 Cataract formation has also occurred in dogs with long-term administration of ketoconazole (average duration of therapy 15 months).¹

ITRACONAZOLE

Itraconazole is preferred to ketoconazole for most fungal infections in people because of its increased activity and decreased adverse effects.¹⁶ It is available as 100-mg capsules and as a suspension (10 mg/ml). The capsules contain beads coated with itraconazole, which facilitates drug absorption from the intestines. The use of compounded itraconazole from bulk chemical is not recommended because of its low solubility and poor stability. The commercially available formulations of itraconazole are incorporated into a hydroxypropyl-beta-cyclodextrin carrier, so the bulk compounded formulations are not equivalent. Reformulating the capsules into smaller doses has been successful, but the beads must remain intact. The cost of itraconazole for a 44-lb dog (5 mg/kg orally once a day) is about $8/day.

Potential indications

Clinical uses for itraconazole include treating all of the fungal infections listed for ketoconazole, but itraconazole is preferred to ketoconazole because of its increased activity and decreased adverse effects.¹ Aspergillus species is more sensitive to itraconazole than to ketoconazole, but resistance does occur.¹ Itraconazole may be less active against Leishmania species compared with the other azoles.¹⁷

Itraconazole's activity against Sporothrix schenckii is variable but itraconazole is considered the treatment of choice. In comparison to itraconazole, terbinafine, which is discussed in more detail later, has greater in vitro potency as well as demonstrated successful treatment of clinical cases in people.^18,19

Pharmacokinetics

Itraconazole is highly protein-bound (> 99%) but is well-distributed throughout the body. It accumulates in skin, liver, fat, and the adrenal medulla. Itraconazole does not reach minimum inhibitory concentrations in the cerebrospinal fluid, but it has been effective in experimental models of CNS disease and in cats with Cryptococcus species CNS infections.¹ In dogs, itraconazole is metabolized in part to hydroxyitraconazole, which has antifungal activity similar to that of the parent compound.

Itraconazole is variably absorbed after oral administration in dogs and cats.^20,21 In dogs, itraconazole absorption is above 90% when capsules are administered with food compared with about 40% absorption in fasted patients. In fasted cats, itraconazole solution is about 70% absorbed.²¹

Itraconazole is primarily eliminated by hepatic metabolism and biliary secretion, with less than 1% of the drug eliminated by renal mechanisms.²⁰ The half-life in dogs and cats is 28 to 30 hours after a single dose. The half-life increases with multiple doses. Itraconazole is highly lipophilic, so concentrations in tissues persist longer than plasma concentrations. As a result of itraconazole accumulation in tissue such as the stratum corneum, pulse dosing has been effective in treating Malassezia dermatitis in dogs (5 mg/kg orally once a day for two days, repeated weekly for three weeks) and dermatophyte infections in cats (5 to 10 mg/kg orally once a day for seven days, then alternating one week on, one week off until a cure is achieved).²² However, systemic treatment with itraconazole as a sole treatment for Malassezia otitis has resulted in poor responses, and adjunctive treatments, such as topical medications, are suggested.²²

Drug interactions and adverse effects

Itraconazole appears to be better tolerated than ketoconazole in dogs and cats. Itraconazole can result in nausea, vomiting, and anorexia, but these signs may occur less frequently and appear to be dose-dependent.²³ Hepatotoxicosis may occur in as many as 10% of dogs receiving long-term treatment with itraconazole.²³ As with ketoconazole, slight increases in liver enzyme activities can occur with itraconazole administration but are not indicative of hepatotoxicosis. The increases in liver enzyme activities appear to be correlated with increasing itraconazole plasma concentrations and dosages.^1,23 In contrast to ketoconazole, itraconazole has minimal effects on cortisol and testosterone concentrations.²⁴

Itraconazole inhibits CYP-mediated drug metabolism similar to ketoconazole but to less of an extent.²⁵ However drug-drug interactions with itraconazole may include those listed for ketoconazole. Itraconazole, similar to ketoconazole, is also a Pgp efflux pump inhibitor.¹¹ Itraconazole absorption is decreased when the drug is administered with gastric acid suppression treatment, so it should not be administered concurrently. Itraconazole has a negative inotropic effect, which may lead to congestive heart failure in patients with impaired ventricular function.¹⁶ Long-term administration of phenobarbital increases itraconazole metabolism and may require increased dosages to maintain similar efficacy.

FLUCONAZOLE

Fluconazole is available as tablets (50, 100, 150, and 200 mg) and as a 10-mg/ml suspension. The typical cost of fluconazole for a 44-lb dog (10 mg/kg orally once a day) is about 50¢/day.

Potential indications

Fluconazole has similar antifungal activity to itraconazole with a few notable exceptions. Typically, Aspergillus and Microsporum species are resistant to fluconazole.²⁶ Malassezia species are less sensitive to fluconazole than to other azoles.²⁷ Leishmania species may be more sensitive to fluconazole than to itraconazole, although extensive efficacy studies are lacking.¹⁷ Fluconazole is the treatment of choice for Cryptococcus species CNS infections because of the high drug concentrations achieved in the CNS.¹⁶

Pharmacokinetics

In contrast to the other antifungals, fluconazole exhibits low plasma protein binding (about 11%) in all species evaluated.²⁸ Limited studies have been done on the pharmacokinetics of fluconazole in dogs. In a study evaluating two dogs, fluconazole was completely absorbed after oral administration with a 15-hour half-life. The maximum plasma concentration (C_MAX) achieved in dogs was about 10 μg/ml at about four hours (T_MAX; the time to maximum plasma concentration) after 10 mg/kg was administered orally. In contrast to itraconazole and ketoconazole, fluconazole is well-absorbed in the fasted state.¹⁶ Greater than 70% of the dose was eliminated in the urine of dogs as unchanged drug.²⁸

The pharmacokinetics of fluconazole in cats is similar to that in dogs: a C_MAX of 12.9 μg/ml at a T_MAX of 1.3 hours with complete absorption after oral administration (10.8 mg/kg) and a terminal half-life of about 24 hours.²⁹ Fluconazole penetrates the cerebrospinal fluid, aqueous humor, and bronchial epithelial fluid well.²⁹

Drug interactions and adverse effects

Fluconazole is generally well-tolerated, but adverse effects similar to those of the other azoles can occur,¹ including nausea, anorexia, and vomiting. Severe hepatic reactions have been reported in people, so serum hepatic enzyme activities should be routinely monitored before and during long-term therapy.¹⁶ Rare hematologic adverse effects including anemia, thrombocytopenia, leukopenia, and neutropenia have been reported in people.

Fluconazole use during pregnancy is generally not recommended, as there are conflicting data on its mutagenic or teratogenic potential.^16,30 Fluconazole is excreted in milk, so it is not recommended to be administered to lactating animals.¹⁶

Fluconazole absorption is not affected by decreased gastric acidity, so concurrent administration with gastric acid suppression treatment is not expected to affect absorption.¹⁶ Fluconazole exhibits a slightly different CYP inhibitory profile than ketoconazole and itraconazole, so some differences in drug-drug interactions are expected. In people, the metabolism of cyclosporine, buspirone, warfarin, quinidine, and some benzodiazepines has been decreased when they are concurrently administered with fluconazole.¹⁶

VORICONAZOLE

Voriconazole is a fluconazole derivative, but it has a higher intrinsic activity against many fungal organisms. Voriconazole is available as 50- and 200-mg tablets. The typical cost of voriconazole for a 44-lb dog (5 mg/kg orally twice a day) is about $40/day.

Potential indications

Voriconazole is the drug of choice for invasive Aspergillus species infections in people because of its fungicidal activity and its safety as compared with amphotericin B.¹⁶ Voriconazole also has activity against many organisms such as Aspergillus, Candida, Cryptococcus, and Fusarium species that develop resistance to other azoles.¹⁶

Pharmacokinetics

Voriconazole's plasma protein binding is intermediate (about 51%).³¹ Complete absorption occurs in dogs receiving oral voriconazole with a C_MAX of 6.5 μg/ml at three hours after a single 6 mg/kg dose.²⁰ Voriconazole penetrates the CNS and is effective against CNS fungal infections.¹⁶

Voriconazole primarily undergoes hepatic metabolism with the metabolites excreted in the urine and feces.³¹ About 5% of the total dose is eliminated in the urine of dogs as unchanged drug with an approximate 4.5-hour half-life after a single dose.

The plasma concentration of voriconazole remained above the minimum fungicidal concentration against Aspergillus species for 24 hours after a single 6-mg/kg oral dose in dogs.³¹ However, multiple doses resulted in increased metabolism of voriconazole and subsequently reduced drug exposure as measured by the area under the curve with 16 days of treatment. Increasing the dose of voriconazole from 3 mg/kg to 12 mg/kg, a fourfold increase, resulted in a disproportionate increase in area under the curve—a ninefold increase. Therefore, dose adjustments must be made cautiously.³¹

There are no reports of the pharmacokinetics of voriconazole in cats.

Adverse effects

The liver was the primary organ affected in toxicology studies, but the kidneys and adrenal glands may also be affected, and anemia may occur.³² Evidence of hepatotoxicosis occurred in acute (30 days at 24 mg/kg) and chronic (six to 12 months at 12 mg/kg) toxicology studies in dogs, including cell necrosis and increased alanine transaminase and alkaline phosphatase activities. Increased liver weight, centrilobular hypertrophy, proliferation of smooth endoplasmic reticulum, and induction of CYP occurred in a dose-dependent manner.³²

Administration of intravenous voriconazole (10 mg/kg) in dogs resulted in unspecified acute toxicosis.³² In rats, high intravenous doses (50 mg/kg) resulted in CNS signs such as mydriasis, titubation (loss of balance during movement), depression, prostration, extensor rigidity, ptosis, and dyspnea.³² In people, voriconazole produced unspecified changes in the retina at therapeutic drug concentrations, which resulted in blurred vision; the visual effects were reversible, and no histopathologic changes were observed.³²

Voriconazole can exhibit drug-drug interactions similar to fluconazole's. Additionally, concurrent administration of phenobarbital may increase the metabolism of voriconazole with subsequent decreased efficacy.¹⁶

POSACONAZOLE

Posaconazole is an itraconazole derivative recently approved by the FDA for use in people and is available as a 40-mg/ml suspension. The typical cost of posaconazole for a 44-lb dog (5 mg/kg orally once a day) is about $11/day.

Potential indications

Posaconazole has similar activity as the other azoles except that it has increased activity against resistant strains of Aspergillus and Candida species.³³

Pharmacokinetics

Similar to itraconazole, the oral absorption of posaconazole is increased when it is administered with food and decreased when it is administered with gastric acid suppression therapy. In dogs that received 10 mg/kg, the half-life was seven hours, the oral bioavailability was 27% in fed dogs, the C_MAX was 3.5 μg/ml, and the T_MAX was three hours.^34,35 Posaconazole is primarily metabolized and inactivated by glucuronide conjugate formation in most species. No pharmacokinetic or metabolism studies are available in cats.

Drug interactions and adverse effects

Posaconazole should be used cautiously in cats; dose extrapolation may not be appropriate because of decreased formation of glucuronide conjugates in cats. However, a single case report of posaconazole (5 mg/kg orally once a day for 16 weeks) administered to a cat with an itraconazole-resistant Aspergillus species infection demonstrated efficacy with minimal adverse effects, which included erythema and pruritus of the pinna and superficial excoriations of the temporal region.³⁶

Posaconazole's adverse effect profile and drug-drug interactions are expected to be similar to those of itraconazole.³⁴ Gastrointestinal adverse effects such as nausea, vomiting, and diarrhea are commonly reported in people. Complete blood counts and serum chemistry profiles should be evaluated routinely during long-term therapy as with the other antifungals. In dogs, posaconazole at doses as low as 3 mg/kg/day caused neuronal phospholipidosis in the peripheral nervous system.³⁴ Higher doses also affected the CNS, although no neurologic deficiencies were observed with either dose. In people receiving posaconazole, cardiovascular effects including hypertension and hypotension have also been reported.³⁴

TERBINAFINE

Terbinafine is not an azole antifungal but is classified as an allylamine. It is available as 250-mg tablets. Clinical reports of terbinafine use in dogs and cats are sparse and limited primarily to Malassezia species and dermatophyte infections.^37,38 The typical cost of terbinafine to treat a 44-lb dog (30 mg/kg orally once a day) is about $1/day.

Potential indications

Terbinafine has a broad spectrum of activity against yeast and fungi, including dermatophytes.³⁹ Terbinafine is typically active against Aspergillus species, Blastomyces dermatitidis, Cryptococcus neoformans, Histoplasma capsulatum, Microsporum canis, Malassezia pachydermatis, and Sporothrix schenckii; however, in vivo efficacy studies are lacking.⁴⁰ Candida species may be less sensitive to terbinafine, so other antifungals may be a better choice.⁴⁰

Pharmacokinetics

Minimal pharmacokinetic data are available for terbinafine use in dogs or cats. The oral bioavailability in dogs is approximately 46%.⁴¹ In dogs, terbinafine is primarily eliminated by hepatic metabolism with the metabolites eliminated in the urine. In people, terbinafine exhibits high plasma protein binding (> 99%).⁴¹

Terbinafine administered in cats at 10 to 20 mg/kg orally once a day resulted in median plasma concentrations of 1.38 μg/ml after nine days, increasing to 2.19 and 4.13 μg/ml 60 and 120 days after administration, respectively.³⁷ Cats given terbinafine at 30 to 40 mg/kg once a day had median plasma concentrations of 1.69, 1.89, and 5.48 μg/ml at days 9, 60, and 90, respectively.³⁷ Clinical trials in cats infected experimentally with Microsporum canis have indicated 30 to 40 mg/kg orally once daily was effective in clearing the infections.³⁷

Adverse effects

Terbinafine is typically well-tolerated, but adverse effects can occur. Nausea and vomiting have been reported in cats treated with terbinafine, but these effects decreased when the drug was administered with food.³⁸ Rare but serious adverse effects such as hepatotoxicosis, neutropenia, and toxic epidermal necrolysis have been reported in people.¹⁶

There have been minimal reports of drug-drug interactions with terbinafine, but phenobarbital may increase the metabolism of terbinafine, which would decrease terbinafine efficacy if the dosage is not increased.

CONCLUSION

Many different antifungal agents for dogs and cats are at your disposal. Adverse effects commonly observed with systemic antifungals include nausea, vomiting, anorexia, and diarrhea. Severe adverse effects such as hepatotoxicosis and blood dyscrasias can also occur but are less frequent. Routine monitoring of patients receiving antifungals should minimally include complete blood counts, serum chemistry profiles, and urinalyses. It is important to note that additional treatment options, such as systemic antimicrobials, topical therapy, and baths, are often beneficial and should be considered as a component of a treatment regimen for fungal dermatitis or otitis.

Ketoconazole and terbinafine are cost-effective treatment options for dermatophyte infections or yeast dermatitis and otitis in dogs and cats.

Itraconazole is also expected to be an effective treatment for dermatophyte infections and yeast dermatitis, but it may be cost-prohibitive in some cases.

Fluconazole exhibits poor activity against Malassezia species and dermatophytes, so is not routinely recommended for those indications.

Voriconazole and posaconazole are the newest azoles available in the United States with a primary indication of treating resistant fungal infections. However, their routine use is not recommended because of the limited information available for dogs and cats, their high cost, and the potential for inducing resistance. ?

ACKNOWLEDGMENT

I would like to thank Dr. Stuart Snyder for his help with this review.

Butch KuKanich, DVM, PhD, DACVCP
Department of Anatomy and Physiology
College of Veterinary Medicine
Kansas State University
Manhattan, KS 66506

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