Anti Fungal logic Agents-Azoles and Ally La Mines

Vol. Vo l. 22, 22, No. No. 6 Jun June e 2000 2000

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Refereed Peer Review

FOCAL POINT 5New antifungal drugs have had a great impact on the treatment of cutaneous mycoses.

KEY FACTS s

Ketoconazole, which is commonly used in veterinary dermatology to treat canine Malassezia dermatitis, has broad-spectrum antifungal activity.

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Ketoconazole has been known to cause significant drug interactions that affect its bioavailability and toxicity.

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Oral itraconazole solution is an effective alternative treatment for cats with dermatophytosis.

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Enilconazole is a topical broadspectrum imidazole derivative with excellent antimycotic activity against many pathogenic fungi, including dermatophytes and Malassezia pachydermatis .

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Although terbinafine is an allylamine antifungal agent with potent topical and oral fungicidal activity against dermatophytes in humans, it also has potential for treatment in small animals.

Antifungal Dermatologic Agents: Azoles and Allylamines* Centre Vétérinaire DMV, Ville St-Laurent, Quebec

Caroline de Jaham, DMV, MSc Université de Montréal

Manon Paradis, DMV, MScV North Carolina State University

Mark G. Papich, DVM, MS ABSTRACT: A companion article discussed the pharmacology and clinical uses of the more traditional antifungal therapies: polyenes, griseofulvin, and iodides. The availability of newer antifungal drugs, which are often more efficacious with fewer side effects, has led to many safe and effective applications in the management of small animal cutaneous fungal infections. This article describes the pharmacokinetics, modes of action, principal adverse effects, and clinical uses of antifungal agents of the azole (triazoles, imidazoles) and allylamine (terbinafine) classes for treating cutaneous fungal diseases in small animals. Clinical experience gained with the newer antifungals will aid practitioners in choosing appropriate drugs from an expanded armamentarium.

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lthough benzimidazole was the first azole to be discovered (in 1944), 1 it was not until the introduction of clotrimazole and miconazole (in 1969) 2 that the therapeutic advantage of this class of antifungal drugs was recognized. Ketoconazole became available in 1977 and rapidly became the most widely used antifungal agent in humans. Reports of the drug ’s success in veterinary medicine were published in the early 1980s. 3 In the mid-1980s, two potent broad-spectrum azole derivatives, itraconazole and fluconazole, were introduced and are currently used by veterinarians to treat deep and superficial mycoses. 4–9

AZOLES The azoles are subdivided into the imidazoles (i.e., ketoconazole, miconazole, enilconazole, clotrimazole, thiabendazole) and the triazoles (i.e., itraconazole, fluconazole). The azoles are structurally related, broad-spectrum antifungal compounds with similar mechanisms of action (Table I). They vary in their pharmacokinetics, toxici*A companion article entitled “Traditional Antifungal Dermatologic Agents” Agents” appeared in the May 2000 (Vol. 22 No. 5) issue of Compendium of Compendium .

Compendium June 2000

ties, and clinical uses. The list of azoles used in human medicine is exhaustive, and new products are continually being added. Only the azole derivatives most relevant to veterinary dermatology are reviewed here.

Ketoconazole Ketoconazole is used in both dermatologic and nondermatologic pathologies in small animal medicine.

Small Animal/Exotics

TABLE I Classification of Antifungal Agents

Class

Agents

Azoles Imidazoles

Triazoles

Site of Action

Ketoconazole, miconazole, enilconazole, clotrimazole, thia thiab benda endazzole

In Inhibit the enzyme lanosterol 14-demethylase, thereby in interfering with ergosterol synthesis

Itraconazole, fluconazole

Hinder ergosterol synthesis by inhibiting the enzyme lanosterol 14-demethylase

is administered with a meal.12 Ketoconazole is distributed well throughout the body and is highly protein bound in plasma. It does not easily penetrate into the cerebrospinal fluid (CSF) and is, therefore, not usually recommended for fungal meningitis. Oral ketoconazole is delivered to the stratum corneum by excretion through sebum and eccrine glands. 13 Because it is metabolized extensively by the liver, ketoconazole should be avoided in patients with liver dysfunction. tion. Its half-life half-life generall generally y 14 permits once-daily dosing.

Mechanism of Action Ketoconazole, as well as the other azoles, inhibits the Terbinafine, Inhibit sq s qualene conversion of lanosterol to Allylamines naftidine epoxidase ergosterol by the cytochrome enzyme, thereby P-450 enzyme lanosterol Clinical Use hindering 14-demethylase. By inhibitLike the other azoles, keergosterol ing the synthesis of ergostetoconazole has broad-specsynthesis rol, the primary sterol of trum antifungal activity ac tivity.. Oral fungal membranes, ketoconazole alters cell membrane ketoconazole (200-mg tablets) has been effective as a permeability and fluidity. fluidity. The activity of such other ensole therapeutic agent at a range of doses (10 to 30 zyme systems as the oxidative and peroxidative mechamg/kg/day) in the treatment of a variety of fungal innisms may also be altered by ketoconazole. Ketoconafections, including dermatophytosis, 15 blastomycosis, 16 zole is similar to other azoles in that it is primarily histoplasmosis, 17 coccidioidomycosis, 18 and cryptococcofungistatic. At high concentrations, generally through sis.19 It seems to be less effective in treating aspergillosis topical application, these drugs may also be fungicidal. 10 and sporotrichosis. 20,21 In veterinary dermatology, keto Azole potency is related to each drug’ drug’s affinity for conazole administered at reduced doses ranging from binding the fungal cytochrome P-450. However, the 10 to as low as 5 mg/kg/day is commonly used to treat toxicity of each compound depends directly on its seMalassezia dermatitis in dogs. 22 Ketoconazole is also lectivity for binding of fungal rather than mammalian available in topical formulations that can be used to cytochrome P-450 enzymes. 6 Mammalian cytochrome treat dermatologic conditions in small animals. P-450 enzymes are responsible for conversion of lanosterol to cholesterol and for synthesis of cortisol and reAdverse Effects productive steroid hormones. Therefore, according to Anorexia, nausea, and vomiting are the most common their degree of affinity and selectivity, azoles may deside effects from oral administration of ketoconazole. crease cholesterol, cortisol, androgen, and testosterone Cats are more likely to experience the adverse effects, biosynthesis as well as interfere with liver metabolic with up to 25% of cats having some degree of anorexia, 11 pathways. The triazoles, which have greater affinity vomiting, depression, and weight loss. 23 Side effects are for fungal than for mammalian enzymes, are usually usually dose related and may be diminished by decreassafer than are the imidazoles. ing the dose, dividing the total dose for twice-daily administration, or administering each dose with food. ElePharmacokinetics vated serum liver enzyme activity and hepatotoxicosis Ketoconazole is well absorbed from the gastrointestihave developed from ketoconazole therapy. However, nal tract, but its bioavailability depends on an acidic the incidence of hepatotoxicosis is relatively low; and in environment. Therefore, concomitant administration humans, it appears to be an idiosyncratic reaction not of antacids, H2 blockers (cimetidine, ranitidine), and related to the daily or cumulative dose. 12 However, the other gastric alkalinizing agents decreases absorption of serum alanine aminotransferase (ALT) activity should be the drug. Ketoconazole is also better absorbed when it monitored monitored on a monthly basis during therapy. therapy. AZOLE DERIVATIVES

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ERGOSTEROL

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SERUM ALANINE AMINOTRANSFERASE


Therapeutic doses of ketoconazole higher than 10 mg/ kg/day can variably and reversibly affect testosterone and cortisol synthesis in dogs 11 but not in cats.24 Ketoconazole therapy is contraindicated in pregnant animals; it is embryotoxic and teratogenic in rats, 25 and mummified fetuses as well as stillbirths have been reported in bitches.18 Other reported adverse effects include reversible lightening of the haircoat, pruritus,18 and, more recently, development of cataracts in dogs after long-term therapy. 26 Significant multiple-drug interactions occur with ketoconazole therapy. Because of the inhibition of P-450 metabolizing enzymes, enzymes, drugs drugs such such as rifampin, cisapride, terfenadine, insulin, cyclosporine, glucocorticoids, and most anticonvulsants will have an altered metabolism when administered concomitantly with ketoconazole. 12 Ketoconazole may increase the oral bioavailability of such drugs as cyclosporine by decreasing the activity of P-450 enzymes that metabolize drugs in the intestinal wall. In humans, ketoconazole will decrease the transformation of prednisolone into inactive products, thereby increasing the patient’ tient’s exposure to active corticosteroids, but it does not interfere with conversion of prednisone to the active drug prednisolone. 27 Therefore, caution is advised and more detailed information should be obtained before using ketoconazole simultaneously with other drugs.


azoles contain two nitrogen atoms in the azole ring; triazoles contain three nitrogen atoms. It has been theorized that the triazole ring may be responsible for increased potency, decreased toxicity, and a wider spectrum of action. 25 The mechanism of action of itraconazole is similar to that of the other azoles. Like other azoles, itraconazole is primarily fungistatic.

Figure 1A

Pharmacokinetics Itraconazole is keratinophilic, lipophilic, and water insoluble. In North America, the drug is available in an oral 100-mg beaded compound enclosed in a capsule; in the United States, a 10-mg/ml cherry-flavored solution is also marketed for humans. Figure 1B For optimal bioavailability, the capsules should be taken with a meal containing lipids, although the solution has an optimal absorption if administered in fasting conditions. To maximize absorption of itraconazole, concurrent administration of drugs that decrease stomach acidity, such as H2 receptor antogonists (cimetidine, ranitidine) or proton pump blocker (omeprazole), Figure 1C should be avoided. A ) Microsporum canis dermatophytosis in an Figure 1— ( A Itraconazole is rapidly abotherwise healthy 2-year-old Persian cat. Note the partial sorbed and extensively dishair loss over the dorsum. ( B) Same cat after it had been tributed in lipophilic tissue, shaved. Note the extensive truncal areas of hyperpigmenof distritation caused by the dermatophyte. ( C) Same cat after 4 with a high volume 28 weeks of therapy with oral itraconazole. The cat did not bution in dogs. In cats, oral tolerate oral griseofulvin (30 mg/kg twice a day), which itraconazole solution is well caused vomiting and anorexia. The cat was also given absorbed and preferred to twice-weekly whole-body enilconazole dips. Note the hair capsules; a 24-hour dosing regrowth and the fading of the lesions. interval is sufficient. Disposition of the drug is similar to that in dogs, with steady-state concentrations achieved in 3 weeks.29 Itraconazole is extensively metabolized by Itraconazole the liver and excreted mainly as inactive metabolites in The most recent additions to the azole family have urine and feces. 30 Drug levels may be 3 to 10 times been the triazoles (i.e., itraconazole, fluconazole). Imidhigher in the skin than in plasma, with strong binding BIOAVAILABILITY

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TRIAZOLES

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MECHANISM OF ACTION

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LIPOPHILIC TISSUES



to keratin that results in drug concentrations in the skin detectable 2 to 4 weeks after cessation of therapy. therapy. 30 Itraconazole reaches the stratum corneum corneum mainly by by excretion in sebum in which drug levels are 5 to 10 times higher than than those in plasma. In plasma, 99% of the drug is protein bound, which explains why aqueous fluids (saliva, CSF) with low protein content contain a negligible amount of the drug. 31 Although itraconazole concentrations in CSF may be low, concentrations in tissues of the central nervous system may still be high enough for therapeutic success.

Clinical Use Itraconazole has been found to be effective in vitro and in vivo against medically important fungi. Several veterinary reports establish how useful and extensively used itraconazole has become against superficial and systemic mycoses in small animals. Conditions such as dermatophytosis, dermatophytic pseudomycetomas, 23,32 blastomycosis, 33 cryptococcosis,7 sporotrichosis,34 aspergillosis, 35 cutaneous Alternaria,36 pheohyphomycosis,37 and histoplasmosis 38 have all been successfully treated with itraconazole (Figure 1). Itraconazole has also been used successfully to treat cats with cryptococcal meningitis39 and dogs with ocular blastomycosis. 40 Administration and Dosing Doses varying from 10 to 20 mg/kg/day have been suggested for the treatment of most fungal infections in dogs and cats. However, doses of itraconazole at 5 mg/kg/day have been demonstrated to be as effective as 10 mg/kg/day in treating canine blastomycosis. 33 Doses of 5 to 10 mg/kg/day may be sufficient for treatment with less toxicity for most cutaneous mycoses in small animals even in the face of organisms with relatively high minimum inhibitory concentrations (MICs) because skin concentrations of itraconazole seem high enough to exceed elevated MIC. More recently, a small uncontrolled clinical trial reported complete recovery in 8 of 15 cats with dermatophytosis treated with oral itraconazole at doses as low as 1.5 to 3.0 mg/kg/day. 41 A 40-mg/ml itraconazole suspension, which can be useful for doses less than 100 mg, has recently been described in a short pharmaceutical profile review. 42 The suspension preparation requires grinding the capsule content with alcohol and syrup and can be compounded by pharmacists. The suspension was stable for 35 days when kept refrigerated. As with the other azole derivatives, the length of therapy with itraconazole varies greatly. In general, 4 to 6 weeks is probably a strict minimum treatment duration for most diseases, although 2 months or more of therapy is required for most patients with blastomycoCANINE BLASTOMYCOSIS

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sis.33 Long-term treatments (6 months minimum) have also been reported. 32,43 Because of the pharmacokinetic properties of itraconazole and its persistence in the skin, nails, and hair follicles, pulse therapy has been advocated in human dermatology for a variety of superficial fungal infections. Pulse therapy involves administering oral itraconazole daily for 1 to 2 consecutive weeks per month for 3 months. This therapy has been successful in the treatment of onychomycosis in children.44 In veterinary medicine, 15 cats with dermatophytosis were pulse-treated with oral itraconazole once daily for 15 days, followed by a 2-week period during which antifungal medication was not given. Six cats recovered completely with a single 15-day course of treatment, but two cats required two and three rounds of pulse therapy, respectively. 41

Adverse Effects Itraconazole may have fewer side effects, especially in cats, than does ketoconazole. However, a recent study reported that 5 of 15 cats with dermatophytosis experienced vomiting and anorexia at doses as low as 3 mg/kg/day of oral itraconazole.41 Other studies have reported anorexia only occasionally in treated cats; gastrointestinal signs such as vomiting and diarrhea were generally uncommon and apparently dose related. 43 An asymptomatic increase in serum ALT and alkaline phosphatase activities are observed in some animals, but itraconazole-induced hepatotoxicosis is rare in dogs and cats.7,33 Ideally, serum ALT activity should be monitored monthly during itraconazole therapy. One study in dogs reported more side effects with itraconazole at a dose of 10 mg/kg/day than with a dose of 5 mg/ kg/day.33 The most common side effects noted in this study were anorexia and idiopathic cutaneous vasculitis with skin ulceration that improved rapidly on cessation of therapy.33 A cutaneous drug eruption more compatible with erythema multiforme and associated with itraconazole administration has also been recently reported in one dog. 45 Ketoconazole was subsequently prescribed to the dog without a cross-reaction. In contrast to ketoconazole, itraconazole is more specific for fungal than for mammalian cytochrome P-450 enzymes28; therefore, at therapeutic doses it has no significant effect on androgen or cortisol metabolism. 31 Furthermore, itraconazole does not have an inhibitory or inducing effect on hepatic microsomal enzymes to the same degree as does ketoconazole; thus the risk for drug interaction is minimized. 30 Itraconazole may inhibit the metabolism of cyclosporine, cisapride, and terfenadine. Itraconazole exhibits dose-dependent embryotoxicity and should be avoided during pregnancy, pregnancy, 25 although dosages of 10 mg/kg/day or less have been re-

DERMATOPHYTOSIS

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PHARMACOKINETIC PROPERTIES



portedly administered to pregnant animals without teratogenic effect.22

Fluconazole The triazole fluconazole was discovered in 1982 and licensed in 1990 for use in human cryptococcal and candidial infections. Fluconazole is water soluble and can be administered orally and intravenously. intravenously. It is available in 50- and 100-mg tablets, a 150-mg capsule, 10and 40-mg/ml orange-flavored oral suspensions, and a 2-mg/ml intravenous intravenous infusion. Although its mechanism of action is similar to other compounds of the same family, family, fluconazole is not approved for use in veterinary medicine. Pharmacokinetics The low molecular weight and high water solubility of fluconazole contribute to its rapid dissolution and high bioavailability. Fluconazole is readily absorbed from the gastrointestinal tract independently of the formulation, gastric acidity, or concomitant food intake. 46 The drug is not extensively bound to tissue protein or fat, and its apparent volume of distribution is approximately that of total body water. 47 Fluconazole is not extensively metabolized, and its primary route of excretion is renal. Therefore, the dose of fluconazole should be decreased in patients with impaired renal function. 47 After 50 mg of fluconazole was administered intravenously or orally to every cat in one study, 48 the observed volume of distribution was high (1.14 L/kg) and the elimination half-life was 25 hours. Following oral administration in cats, absorption was rapid and complete and high concentrations were achieved for CSF, aqueous humor, and lung fluids. 48 Urine has 10 times the fluconazole concentration of plasma and it penetrates the CSF well, making it a drug of choice for central nervous system (cryptococcal meningitis) and urinary tract fungal infections. Fluconazole also penetrates the skin well; thus high concentrations can be found in the stratum corneum, corneum, and its elimination from the skin is slower than that from plasma. 49 Clinical Use The spectrum of action of fluconazole is similar to that of itraconazole and includes fungi responsible for both superficial and deep mycoses. In animal models and in humans, fluconazole has been effective against Aspergillus , Blastomyces, Candida, Coccidioides, Crypto- coccus, Histoplasma, Malassezia, Microsporum, and Tri- chophyton.28 There are several reports of the use of fluconazole in animals. Various doses have been successful in treating dogs with nasal aspergillosis 50 and blastomycosis43 and cats with cryptococcosis. 4

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Administration and Dosing In a study by Malik and colleagues, 4 cats with cryptococcosis were treated with doses ranging from 25 to 100 mg every 12 hours, with 50 mg per cat every 12 hours as the recommended dose based on the clinical results. 4 These doses are much higher than the routinely recommended dose of 2.5 to 5 mg/kg/day given either orally or intravenously for other types of fungal infections. 43 One recent pharmacokinetic study of fluconazole in cats confirmed that 50 mg/day may be appropriate for most fungal infections. 48 Because fluconazole has linear absorption kinetics and high bioavailability, oral and intravenous dosages are identical. 48 The skin and nails have high levels of fluconazole, and intermittent therapy at 3 to 6 mg/kg once weekly has been described in humans.44 Although the duration of therapy is variable, a minimum of 6 to 8 weeks of treatment is necessary for most fungal infections and periods of 4 to 6 months have been necessary for some cats with cryptococcosis. 4 Adverse Effects In humans, the most common side effects noted with fluconazole were related to the gastrointestinal system. 51 Compared with the other azoles, fluconazole inhibits the fungal lanosterol 14-demethylase to a much greater extent than the corresponding mammalian enzyme. 28 In fact, fluconazole demonstrates a 10,000-fold selectivity for the fungal enzyme. In a study in which cats received fluconazole at 50 mg/kg every 12 hours, no side effects were reported. 4 Similarly, no adverse effects were noted in dogs undergoing fluconazole therapy for blastomycosis.43 The major disadvantage of fluconazole therapy is its high cost. Enilconazole Enilconazole, also known as imazalil, is a topical, broad-spectrum imidazole derivative labeled for veterinary use only. In Canada, enilconazole is available as a 10% (100 mg/ml) concentrated solution approved for use in dogs and horses. In the United States, enilconazole (Clinafarm ® EC, American Scientific Laboratory, Union, New Jersey) Jersey) is labeled only for use as a disinfectant in cleaned poultry hatcheries. Clinafarm ® EC is available in a 750-ml bottle containing 13.8% (138 mg/ml) enilconazole. The other ingredients listed on the material safety data sheet are benzyl alcohol and dioctyl sodium sulfosuccinate; it also contains ethoxylated castor oil. The Canadian formulation contains polysorbate 20 and sorbitan monolaurate as its inert ingredients, with 10% enilconazole as the active drug. Clinafarm® EC is registered for controlling Aspergil- lus organisms in poultry facilities and equipment by making a 1:100 dilution and spraying or fogging the LINEAR ABSORPTION KINETICS

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area to be treated. Although there are no published toxicology studies on this particular solution in animals, it has been used by one of us (M.G.P.) in a 50:1 dilution applied topically to dogs and cats at North Carolina State University without adverse effects. The topical application of the diluted product is used in i n the same way as the approved Canadian formulation. Enilconazole acts on fungi in the same way as do the other azoles with the only difference being that enilconazole also has shown fungicidal activity when applied topically. Higher concentrations of antifungal agents can usually be achieved with topical applications; therefore, fungicidal doses of enilconazole can be obtained.

Pharmacokinetics Enilconazole is a light-yellow solid substance that is only slightly soluble in water. At room temperature and protected from light, it remains stable for up to 5 years. Following oral absorption, concentration of the active compound in tissue has been shown to be negligible, limiting its use to topical applications. 52 Enilconazole mainly acts superficially, with the dermal absorption being very low. The small amounts absorbed by the skin are the same for intact as for scarified epidermis. One explanation for its topical efficacy is that after application of enilconazole, a vapor phase activity develops on the treated surface and a residual effect remains. 53 Clinical Use The antimycotic activity of enilconazole in vitro and in vivo is excellent against many many pathogenic fungi, including Microsporum canis, Microsporum gypseum, Tri- chophyton mentagrophytes, Trichophyton Trichophyton verrucosum, Malassezia pachydermatis, and Aspergillus species.52 The label on the Canadian formulation indicates enilconazole as a treatment for dermatophytosis in dogs and horses. Described off-label uses of enilconazole, including use in cats, have been multiple and varied. Enilconazole is believed to be one of the most effective treatments against nasal aspergillosis, and protocols implying direct infusion of the drug in the nasal passages through fenestrated tubes have been well described. 54 Enilconazole emulsion is also used successfully in the topical treatment of feline dermatophytosis, in which the emulsion provides the advantages of efficacy and 55 –57 ease of application. 55– Enilconazole is also recommended in the topical therapy of canine yeast dermatitis caused by M. pachydermatis or Candida species.58,59 The 10% enilconazole concentrated solution is dilutdi luted 50:1 with water to yield a 0.2% white emulsion with low viscosity. The emulsion is traditionally applied as a whole-body immersion; sponge application fol-

CRYPTOCOCCOSIS

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FUNGICIDAL ACTIVITY



lowed by a brushing of the entire haircoat has also been described in cats. 55 Clipping of long-coated animals will facilitate the recommended twice-weekly application. Length of therapy varies with the condition treated; a minimum of 3 weeks for Malassezia dermatitis and 4 to 6 weeks for dermatophytosis has been advocated. Once the solution is diluted, it remains stable for 4 to 6 weeks if protected from light. However, the manufacturer advises fresh dilution of the concentrated solution prior to each application.

Adverse Effects Accidental ingestion of diluted enilconazole or licking after the washing involves minimal risk. The safety of oral enilconazole has been demonstrated in acute and chronic toxicity studies in which beagles were given 5 mg/kg/day for 24 months, with only a slight and transient decrease in appetite noted. 52 The acute oral LD50 in dogs was 640 mg/kg. Although there have been anecdotal reports of adverse reactions in cats following topical enilconazole use, a recent study of that drug ’s whole-body application twice weekly for 8 weeks in cats with dermatophytosis failed to reveal any adverse or toxic reactions. 60 The diluted emulsion does not irritate the skin or eyes. 52 Thiabendazole, Miconazole, and Clotrimazole The azole drugs thiabendazole, miconazole, and clotrimazole are broad-spectrum antifungal agents that show some activity against gram-positive bacteria. These drugs are widely used in i n topical otic preparations in combination with other drugs, classically an antibiotic and a corticosteroid. The primary reason for their incorporation into triple-action ear medications is because of their activity against yeasts such as M. pachydermatis , a common complicating organism of external otitis. An antibiotic combined with a broad-spectrum antifungal of the azole family can have a synergistic effect, such as that seen with miconazole and polymyxin B.61 The broad-spectrum activity of these antifungals contained in otic preparations has also led to off-label use as topical agents against such superficial mycoses as dermatophytosis. ALLYLAMINES The allylamine derivatives are a new class of synthetic antifungal agents of relatively recent discovery. Their mechanism of action is fungicidal, which distinguishes them from most other antifungal agents. Terbinafine Since its discovery, discovery, terbinafine has had a great impact on the treatment of superficial dermatophytosis and ENILCONAZOLE

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onychomycosis in humans. Terbinafine is available in 125- and 250-mg tablets for oral treatment and is also available in a topical form.

Mechanism of Action Like the azoles, the allylamines are potent inhibitors of ergosterol synthesis. Ergosterol is an essential component of fungal cell membranes. However, However, the mechanism by which terbinafine interferes with the sterol biosynthetic pathway differs. Terbinafine inhibits the enzyme squalene epoxidase and blocks the conversion of squalene to lanosterol, thereby depleting ergosterol within the fungal cell membrane. 62 Inhibition of the enzyme also causes the accumulation of squalene, which may be the cause of fungicidal activity. activity. The inhibition of squalene epoxidase is not mediated through cytochrome P-450, further differentiating allylamines from azoles. Unlike the azoles, terbinafine would not affect cortisol or testosterone levels even at high doses. Pharmacokinetics When given orally, terbinafine is well absorbed; and although the bioavailability is higher when the drug is taken with a meal high in lipids, it can be given on an empty stomach. After absorption, most of the drug is metabolized by the liver; therefore, dosage adjustment is necessary in patients with liver dysfunction. The halflife and lipophilicity of the drug enable once-daily dosing in humans. 63 High concentrations of terbinafine are found in the stratum corneum, sebum, and hair. Sebum is the major route of drug delivery to the stratum corneum, and high levels are found within the first 2 days of therapy. 63 Clinical Use Terbinafine is primarily fungicidal against dermatophytes (e.g., Sporothrix schenckii, Aspergillus species species)) but is only fungistatic and clinically somewhat less efficacious against yeasts. 64 In humans, terbinafine is used successfully to treat dermatophytosis, sporotrichosis, and onychomycosis, even in children. 44 The adult dose is 125 mg twice daily; the pediatric dose ranges from 4 to 8 mg/kg/day. 65 Little data on the use of terbinafine in veterinary medicine are available. A preliminary study on the pharmacokinetics of terbinafine in cats showed that a dose of 20 to 40 mg/kg/day induced adequate concentrations of the drug in the skin and appendages, with no observed side effects or toxicities. 66 Based on these preliminary results, terbinafine administered at 20 mg/kg every 24 to 48 hours would be the experimental recommended dosage for treating feline dermatophytosis.67

BROAD-SPECTRUM ANTIFUNGAL AGENTS

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SQUALENE


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ABOUT THE AUTHORS Dr. de Jaham is affiliated with the DMV Veterinary Center, Dermatology Service, Ville St-Laurent, Québec, Canada. Dr. Paradis is affiliated with the Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, St-Hyacinthe, Quebec, Canada. Drs. de Jaham and Paradis are Diplomates of the American College of Veterinary Dermatology. Dr. Papich is affiliated with the Department of Anatomy, Physiological Sciences, and Radiology, North Carolina State University, College of Veterinary Medicine, Raleigh, NC. He is a Diplomate of the American College of Veterinary Clinical Pharmacology.

Anti Fungal logic Agents-Azoles and Ally La Mines

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