Anti Fungal Logic Agents-azoles And Ally La Mines

V CE

Vol. 22, No. 6 June 2000

Refereed Peer Review

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

KEY FACTS ■ Ketoconazole, which is commonly used in veterinary dermatology to treat canine Malassezia dermatitis, has broad-spectrum antifungal activity. ■ Ketoconazole has been known to cause significant drug interactions that affect its bioavailability and toxicity. ■ Oral itraconazole solution is an effective alternative treatment for cats with dermatophytosis. ■ Enilconazole is a topical broadspectrum imidazole derivative with excellent antimycotic activity against many pathogenic fungi, including dermatophytes and Malassezia pachydermatis. ■ 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.

A

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” appeared in the May 2000 (Vol. 22 No. 5) issue 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 Azoles Imidazoles

Triazoles

Agents

Site of Action

Ketoconazole, miconazole, enilconazole, clotrimazole, thiabendazole

Inhibit the enzyme lanosterol 14-demethylase, thereby 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. Its half-life generally permits once-daily dosing.14

Mechanism of Action Ketoconazole, as well as the other azoles, inhibits the Terbinafine, Inhibit squalene 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. Oral fungal membranes, ketoconazole alters cell membrane ketoconazole (200-mg tablets) has been effective as a permeability and 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 10 topical application, these drugs may also be fungicidal. and sporotrichosis.20,21 In veterinary dermatology, ketoAzole potency is related to each 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, pathways.11 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 on a monthly basis during therapy. AZOLE DERIVATIVES ■ ERGOSTEROL ■ SERUM ALANINE AMINOTRANSFERASE

Small Animal/Exotics

Therapeutic doses of ketoconazole higher than 10 mg/ kg/day can variably and reversibly affect testosterone and cortisol synthesis in dogs11 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, drugs 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’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.

Compendium June 2000

Figure 1A

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.

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. Figure 1—(A) Microsporum canis dermatophytosis in an 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 In cats, oral bution in dogs. weeks of therapy with oral itraconazole. The cat did not 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 ■ TRIAZOLES ■ MECHANISM OF ACTION ■ LIPOPHILIC TISSUES

Compendium June 2000

to keratin that results in drug concentrations in the skin detectable 2 to 4 weeks after cessation of therapy.30 Itraconazole reaches the stratum corneum mainly by excretion in sebum in which drug levels are 5 to 10 times higher 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 histoplasmosis38 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 blastomyco-

Small Animal/Exotics

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,25 although dosages of 10 mg/kg/day or less have been re-

CANINE BLASTOMYCOSIS ■ DERMATOPHYTOSIS ■ PHARMACOKINETIC PROPERTIES

Small Animal/Exotics

Compendium June 2000

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. 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 infusion. Although its mechanism of action is similar to other compounds of the same 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, 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, Cryptococcus, Histoplasma, Malassezia, Microsporum, and Trichophyton.28 There are several reports of the use of fluconazole in animals. Various doses have been successful in treating dogs with nasal aspergillosis50 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) 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 Aspergillus organisms in poultry facilities and equipment by making a 1:100 dilution and spraying or fogging the

Compendium June 2000

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 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 pathogenic fungi, including Microsporum canis, Microsporum gypseum, Trichophyton mentagrophytes, 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 ease of application. 55–57 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 diluted 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-

LINEAR ABSORPTION KINETICS ■ CRYPTOCOCCOSIS ■ FUNGICIDAL ACTIVITY

Compendium June 2000

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 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, terbinafine has had a great impact on the treatment of superficial dermatophytosis and

Small Animal/Exotics

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, 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. 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) 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

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Compendium June 2000

CONCLUSION Clinicians at all levels of patient care are faced with the management of a growing variety of fungal infections. Consequently, systemic administration of antifungal agents has increased in recent years in many fields of veterinary medicine, including dermatology. Fungal infections range from the benign (but tenacious and irritating) dermatophytosis to aggressive life-threatening systemic mycoses. The cornerstone of the treatment strategies involved in managing these fungal infections are systemic and topical antifungal agents. Treatments for fungal infections are often difficult, costly, and frustrating; furthermore, many of these antifungal agents either have not been labeled for animal use or have not been labeled for the different clinical applications discussed. Therefore, an understanding of the pharmacology and potential complications of the continually expanding antifungal armamentarium is essential. REFERENCES 1. Woolley DW: Some biological effects produced by benzimidazole and their reversal by purines. J Biol Chem 152:225– 232, 1944. 2. Godefroi EF, Heeres J, Van Custem J, et al: The preparation and antimycotic properties of derivative of 1-phenylethylimidazole. J Med Chem 12:784–791, 1969. 3. Legendre AM, Gompf R, Bone D: Treatment of feline cryptococcosis with ketoconazole. JAVMA 181:1541–1542, 1982. 4. Malik R, Wigney DI, Muir DB, et al: Cryptococcosis in cats: Clinical and mycological assessment of 29 cases and evaluation of treatment using orally administered fluconazole. J Med Vet Mycol 30:133–144, 1992. 5. Moriello KM, DeBoer DJ: Efficacy of griseofulvin and itraconazole in the treatment of experimentally induced dermatophytosis in cats. JAVMA 207:439–444, 1995. 6. Heit MC, Riviere JE: Antifungal therapy: Ketoconazole and other azole derivatives. Compend Contin Educ Pract Vet 17(1):21–31, 1995. 7. Medleau L, Gilbert JJ, Marks MA: Itraconazole for the treatment of cryptococcosis in cats. J Vet Intern Med 9:39–42, 1995.

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ry blood chemist nation. All

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for PT determi PT at recheck hours later limits. The because corwithin normal d for 48 hours ted finding values were tion was schedule , an unexpec confirm K deficiency A recheck examina vitamin K regimen to was 65.9 seconds al PT due to vitamin initiating an ion of the owners reportrection of abnorm 48 hours of after complet Although his within 24 to and Mugsy coagulopathy. should resolve K1 as directed resolution of K1. of dose of vitamin persistent prolongation had given vitamin re to rat poison, clotting appropriate ed that they y the cause of al vitamin nity for reexposu was markedl To determine whether addition for more had no opportu time (PT) assay finding in the PT and prothrombin was sent : 9.5-12.5). This clotting time time in the sample a (normal prewas drawn was needed, 57 seconds that his early K therapy . Whole blood prolonged at it appeared ion analyses 3.8 percent prevented ted because detailed coagulat anticoagulant (one part was unexpec vomiting had ive howproduct citrate ged, and the Contrac, and centrifu directly into sentation with of rodenticide. to a vetpoison. parts blood) a toxic dose on cold packs a long-acting citrate to nine absorption of shipped iolone, K was 1 Coagulation vitamin s bromad plasma at the same supernatant (Comparative ever, contain e laboratory University, therefore resumed ory, Cornell erinary referenc Treatment was tic Laborat two weeks. completion Section, Diagnos dosage for another recheck, 48 hours after d ed and York). d of activate At Mugsy’s next was still markedly prolong Ithaca, New ion panel consiste thrombin sample. A , the PT The initial coagulattime (aPTT), PT, and of vitamin K1 g from the previous vitaplastin TCT screenin unchanged d, parenteral partial thrombo aPTT and essentially submitte The was were (TCT). ry profile owners clotting time blood chemist SC, and the 48 given 50 mg and recheck min K1 was vitamin K1 2000 oral August resume instructed to

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THERAPEUTIC CHALLENGE

THERAPEUTIC CHALLENGE

While the course of therapy is often clear-cut, some patients present true challenges to medical skills. In 1000-1500 words, these cases describe the steps that eventually lead to case resolution.

KAREN WILSON

Adverse Effects Adverse effects are not reported in companion animals because of lack of experience. Terbinafine does not cause drug interactions. In humans, very few adverse effects have been observed with terbinafine therapy; and most of these effects are related to the gastrointestinal system. Idiosyncratic acute hepatotoxicoses have been reported occasionally.68 No embryonic or fetal toxicity or teratogenicity has been reported with the use of terbinafine in rats and rabbits, even at high doses.28 In humans, there are no reported effects on pregnancy and the drug is not contraindicated in pregnant women.

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Intussuscep tio In a Yearlin n g By Linnea Lentz, D.V.M.

B

eau, a 15-mont h-old colt, had been colicky for about when the owners four hours called the referring and no other veterinarian. The abnormalidescribed as mild, colic was ties. An initial and Beau was treated IV injection with 10 cc Banamin ® nixine) administe of xylazine appeared e (flured intravenously to (IV), 10 cc of control the pain approximately 1 dipyrone IV, and for only 20 ⁄2 gallon of mineral minutes before oil administered a second tube. Within the via nasogastric dose was necessary. hour, Beau was again colicky and Rectal University of Minneso was referred to the palpation revealed ta. many distended loops of small testine. After placemen inInitial Treatme t of a nasogastric nt on Referra l Clinical signs reflux were obtained. tube, 6-7 L of on presentation Abdominocenincluded profuse tesis results were sweating, numerous normal. attempts to lie Because of the down, and a distended severity of the abdomen. Physical colic, the small examination reintestinal distention vealed a pulse , and nasogastr of 84 beats per ic reflux, we minute, recomdecreased gastrointe mended explorato stinal motility ry laparotomy in all four quadrants to diagnose the cause , slightly toxic of the colt’s colic. mucous membran The owners quickly es, a capillary agreed, and prerefill time of 2.5 seconds operative antibiotic (normal: 1-2), and a normal potassium penicillin s, including temperature. 22,000 units/kg Blood work revealed IV and Gentocin a packed cell (gentamicin) 6.6 volume of 48 percent mg/kg IV, (normal: 32-48), were administe red before total protein of 7.2 g/dL preparing the colt (normal: 5.7-7.9), for surgery. During surgery, a jejunocec al intussuscep-➔

August 2000

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73

MONTH CASE OF THE

CASE OF THE MONTH

Some case presentations are so confounding that both diagnosis and therapy are perplexing. Often, a patient may return again and again with continuously changing signs. Word count: 1000-2000.

is Canine Hemipares

, D.V.M. By Donivan Hudgins

had been normal, activity levels old, 29were current asmine, a four-yearand vaccinations Retrievhepatitis, lepkg, spayed Golden for distemper, nza, parto the clinic er, was presented tosporosis, parainflue irus, Lyme of lameness. for sudden onset vovirus, coronoav found a stray The owner had disease, and rabies. and susgiven Solu The patient was goat in the backyard ® (prednisolone) goat may have pected that the Delta Cortef presentaOn usly (IV) and butted Jasmine. 100 mg intraveno ry 2.5 cc inwas ambulato tion, the dog amoxicillin injectable nated, uncoordi The owner was but obviously tramuscularly. n revealed the provide cage rest and observatio instructed to and return deficit was in primary walking over the weekend dog’s condition the right rear leg. Monday if the ion re. Physical examinat had not improved week, Jasre of 101.6˚F, The following vealed a temperatu capiles, to improve, and pink mucous membran (normal: mine appeared she did have of 1 sec lary refill time whatever problems heart and Over the next 1-2 sec), normal seemed subtle. sign of pain. The weeks, her problungs, and no two to three but not as prodid knuckle over, right rear foot lems recurred the propriobefore, and indicating decreased indicatnounced as that the dog pinch ception, but toe owner reported were intact. to her deficits. ed sensory nerves seemed to adjust next few weeks, of the affected Temperatures Then, over the no different of coördination foot and leg were Jasmine’s lack other three feet than that of the seemed to worsen. and flexion 21, Jasmine On October and legs. Extension were examinajoints for hip of the stifle and was re-presented reflex on on a leash normal, but patellar tion. When followed appeared exaggerated, the right was in the lawn, Jasmine ated, with upper motor which suggested to be very uncoördin Appetite and neuron disease.

J

CORBIS

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August 2000

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8. Greek JS: Update on dermatologic therapy. Vet Med (Nov): 1021–1024, 1996. 9. Papich MG: Antifungal drugs. Proc Annu Members Meet Am Acad Vet Dermatol Am Coll Vet Dermatol :4–9, 1997. 10. Sud IJ, Feingold DS: Mechanisms of action of the antimycotic imidazoles. J Invest Dermatol 76:438–441, 1982. 11. Willard MD, Nachreiner R, McDonald R, Roudebush P: Ketoconazole-induced changes in selected canine hormone concentrations. Am J Vet Res 47:2504–2509, 1986. 12. Gupta AK, Sauder DN, Shear NH: Antifungal agents: An overview. Part I. J Am Acad Dermatol 30:677–698, 1994. 13. Artis WM: Final pathway for delivery of oral antifungals to keratinized cornified skin, in Oral Therapy in Dermatoses: A Step Forward. Oxford, The Medicine Publishing Foundation, 1985, pp 61–70. 14. Moriello KA: Ketoconazole: Clinical pharmacology and therapeutic recommendations. JAVMA 188:303–306, 1986. 15. Medleau L, Chalmers SA: Ketoconazole for treatment of dermatophytosis in cats. JAVMA 200:77–78, 1992. 16. Dunbar M, Lee Pyle R, Boring JG, McCoy CP: Treatment of canine blastomycosis with ketoconazole. JAVMA 182: 156–157, 1983. 17. Noxon JO, Diglio K, Schmidt DA: Disseminated histoplasmosis in a cat: Successful treatment with ketoconazole. JAVMA 181:817–819, 1982. 18. Greene CE: Antifungal chemotherapy, in Greene CE (ed): Infectious Diseases of Dogs and Cats. Philadelphia, WB Saunders Co, 1989, pp 649–658. 19. Noxon JO, Monroe WE, Chinn DR: Ketoconazole therapy in canine and feline cryptococcosis. JAAHA 22:179–183, 1986. 20. Werner AH, Werner BE: Feline sporotrichosis. Compend Contin Educ Pract Vet 15(9):1189–1198, 1993. 21. Sharp NJH, Sullivan M: Use of ketoconazole in treatment of canine nasal aspergillosis. JAVMA 194:782–784, 1989. 22. Scott DW, Miller WH Jr, Griffin CE: Fungal skin diseases, in Scott DW, Miller WH Jr, Griffin CE (eds): Small Animal Dermatology, ed 5. Philadelphia, WB Saunders Co, 1995, pp 329–391. 23. DeBoer DJ, Moriello KM, Cairns R: Clinical update on feline dermatophytosis—Part II. Compend Contin Educ Pract Vet 17(12):1471–1480, 1995. 24. Willard MD, Nachreiner R, Howard VC: Effect of longterm administration of ketoconazole in cats. Am J Vet Res 47:2510–2513, 1986. 25. Van Cauteren H, Lampo A, Vanderberghe J, et al: Toxicological profile and safety evaluation of antifungal azole derivatives. Mycoses 32:60–66, 1989. 26. da Costa PD, Merideth RE, Sigler RL: Cataracts in dogs after long-term ketoconazole therapy. Vet Comp Ophthalmol 6:176–180, 1996. 27. Zürcher RM, Frey BM, Frey FJ: Impact of ketoconazole on the metabolism of prednisolone. Clin Pharmacol Ther 45: 366–372, 1989. 28. Gupta AK, Sauder DN, Shear NH: Antifungal agents: An overview. Part II. J Am Acad Dermatol 30: 911–933, 1994. 29. Boothe DM, Herring I, Calvin J, Way N, Dvorak J: Itraconazole disposition after single oral and intravenous and multiple oral dosing in healthy cats. Am J Vet Res 58:872– 877, 1997. 30. Heykants J, Michiel M, Meuldermans W, et al: The pharmacokinetics of itraconazole in animals and man: An overview, in Fromtling RA (ed): Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents.

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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.