V Vol. 22, No.

6 June 2000

CE Refereed Peer Review

Antifungal
FOCAL POINT Dermatologic Agents:
★New antifungal drugs have had a
great impact on the treatment of
cutaneous mycoses.
Azoles and Allylamines*
Centre Vétérinaire DMV, Ville St-Laurent, Quebec
KEY FACTS Caroline de Jaham, DMV, MSc
■ Ketoconazole, which is Université de Montréal
commonly used in veterinary Manon Paradis, DMV, MScV
dermatology to treat canine
Malassezia dermatitis, has North Carolina State University
broad-spectrum antifungal Mark G. Papich, DVM, MS
activity.

■ Ketoconazole has been known ABSTRACT: A companion article discussed the pharmacology and clinical uses of the more
to cause significant drug traditional antifungal therapies: polyenes, griseofulvin, and iodides. The availability of newer
interactions that affect its antifungal drugs, which are often more efficacious with fewer side effects, has led to many
bioavailability and toxicity. 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 (terbi-
■ Oral itraconazole solution is
nafine) classes for treating cutaneous fungal diseases in small animals. Clinical experience
an effective alternative treatment gained with the newer antifungals will aid practitioners in choosing appropriate drugs from an
for cats with dermatophytosis. expanded armamentarium.

■ Enilconazole is a topical broad-

spectrum imidazole derivative

A
lthough benzimidazole was the first azole to be discovered (in 1944),1 it
with excellent antimycotic activity was not until the introduction of clotrimazole and miconazole (in 1969)2
against many pathogenic fungi, that the therapeutic advantage of this class of antifungal drugs was recog-
including dermatophytes and nized. Ketoconazole became available in 1977 and rapidly became the most
Malassezia pachydermatis. widely used antifungal agent in humans. Reports of the drug’s success in veteri-
nary medicine were published in the early 1980s.3 In the mid-1980s, two potent
■ Although terbinafine is an broad-spectrum azole derivatives, itraconazole and fluconazole, were introduced
allylamine antifungal agent with and are currently used by veterinarians to treat deep and superficial mycoses.4–9
potent topical and oral fungicidal
activity against dermatophytes in AZOLES
humans, it also has potential for The azoles are subdivided into the imidazoles (i.e., ketoconazole, miconazole, enil-
treatment in small animals. conazole, clotrimazole, thiabendazole) and the triazoles (i.e., itraconazole, flucona-
zole). 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 Small Animal/Exotics

ties, and clinical uses. The list is administered with a meal.12

of azoles used in human TABLE I Ketoconazole is distributed
medicine is exhaustive, and Classification of Antifungal Agents well throughout the body
new products are continually and is highly protein bound
Class Agents Site of Action
being added. Only the azole in plasma. It does not easily
derivatives most relevant to Azoles penetrate into the cerebro-
veterinary dermatology are Imidazoles Ketoconazole, Inhibit spinal fluid (CSF) and is,
reviewed here. miconazole, the enzyme therefore, not usually recom-
enilconazole, lanosterol mended for fungal menin-
Ketoconazole clotrimazole, 14-demethylase, gitis. Oral ketoconazole is
thiabendazole thereby interfering
Ketoconazole is used in delivered to the stratum cor-
with ergosterol
both dermatologic and non- synthesis neum by excretion through
dermatologic pathologies in sebum and eccrine glands.13
small animal medicine. Triazoles Itraconazole, Hinder ergosterol Because it is metabolized ex-
fluconazole synthesis by tensively by the liver, keto-
Mechanism of Action inhibiting the conazole should be avoided
enzyme lanosterol
Ketoconazole, as well as in patients with liver dysfunc-
14-demethylase
the other azoles, inhibits the tion. Its half-life generally
conversion of lanosterol to Allylamines Terbinafine, Inhibit squalene permits once-daily dosing.14
ergosterol by the cytochrome naftidine epoxidase
P-450 enzyme lanosterol enzyme, thereby Clinical Use
14-demethylase. By inhibit- hindering Like the other azoles, ke-
ergosterol
ing the synthesis of ergoste- toconazole has broad-spec-
synthesis
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 en- sole therapeutic agent at a range of doses (10 to 30
zyme systems as the oxidative and peroxidative mecha- mg/kg/day) in the treatment of a variety of fungal in-
nisms may also be altered by ketoconazole. Ketocona- fections, including dermatophytosis,15 blastomycosis,16
zole is similar to other azoles in that it is primarily histoplasmosis,17 coccidioidomycosis,18 and cryptococco-
fungistatic. 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, keto-
Azole 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 se- Malassezia 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 lanos-
terol to cholesterol and for synthesis of cortisol and re- Adverse Effects
productive steroid hormones. Therefore, according to Anorexia, nausea, and vomiting are the most common
their degree of affinity and selectivity, azoles may de- side 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 decreas-
safer than are the imidazoles. ing the dose, dividing the total dose for twice-daily ad-
ministration, or administering each dose with food. Ele-
Pharmacokinetics vated serum liver enzyme activity and hepatotoxicosis
Ketoconazole is well absorbed from the gastrointesti- have 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 Compendium June 2000

Therapeutic doses of keto- azoles contain two nitrogen

conazole higher than 10 mg/ atoms in the azole ring; tri-
kg/day can variably and re- azoles contain three nitrogen
versibly affect testosterone and atoms. It has been theorized
cortisol synthesis in dogs11 but that the triazole ring may be
not in cats.24 Ketoconazole ther- responsible for increased po-
apy is contraindicated in preg- tency, decreased toxicity, and
nant animals; it is embryotox- a wider spectrum of action.25
ic and teratogenic in rats,25 and The mechanism of action of
mummified fetuses as well as itraconazole is similar to that
stillbirths have been reported Figure 1A
of the other azoles. Like other
in bitches.18 Other reported ad- azoles, itraconazole is primar-
verse effects include reversible ily fungistatic.
lightening of the haircoat, pru-
ritus,18 and, more recently, de- Pharmacokinetics
velopment of cataracts in dogs Itraconazole is keratino-
after long-term therapy.26 philic, lipophilic, and water
Significant multiple-drug insoluble. In North America,
interactions occur with keto- the drug is available in an oral
conazole therapy. Because of 100-mg beaded compound
the inhibition of P-450 me- enclosed in a capsule; in the
tabolizing enzymes, drugs such United States, a 10-mg/ml
as rifampin, cisapride, terfena- cherry-flavored solution is
dine, insulin, cyclosporine, also marketed for humans.
glucocorticoids, and most an- Figure 1B For optimal bioavailability,
ticonvulsants will have an al- the capsules should be taken
tered metabolism when ad- with a meal containing lipids,
ministered concomitantly with although the solution has an
ketoconazole.12 Ketoconazole optimal absorption if admin-
may increase the oral bioavail- istered in fasting conditions.
ability of such drugs as cy- To maximize absorption of
closporine by decreasing the itraconazole, concurrent ad-
activity of P-450 enzymes ministration of drugs that de-
that metabolize drugs in the crease stomach acidity, such as
intestinal wall. In humans, H2 receptor antogonists (cime-
ketoconazole will decrease the tidine, ranitidine) or proton
transformation of prednis- pump blocker (omeprazole),
Figure 1C
olone into inactive products, should be avoided.
thereby increasing the pa- Figure 1—(A) Microsporum canis dermatophytosis in an Itraconazole is rapidly ab-
tient’s exposure to active cor- otherwise healthy 2-year-old Persian cat. Note the partial sorbed and extensively dis-
hair loss over the dorsum. (B) Same cat after it had been
ticosteroids, but it does not shaved. Note the extensive truncal areas of hyperpigmen-
tributed in lipophilic tissue,
interfere with conversion of tation caused by the dermatophyte. (C) Same cat after 4 with a high volume of distri-
28
prednisone to the active drug weeks of therapy with oral itraconazole. The cat did not bution in dogs. In cats, oral
prednisolone. 27 Therefore, tolerate oral griseofulvin (30 mg/kg twice a day), which itraconazole solution is well
caution is advised and more caused vomiting and anorexia. The cat was also given absorbed and preferred to
detailed information should twice-weekly whole-body enilconazole dips. Note the hair capsules; a 24-hour dosing
be obtained before using ke- regrowth and the fading of the lesions. interval is sufficient. Disposi-
toconazole simultaneously tion of the drug is similar to
with other drugs. 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). Imid- higher in the skin than in plasma, with strong binding

BIOAVAILABILITY ■ TRIAZOLES ■ MECHANISM OF ACTION ■ LIPOPHILIC TISSUES

Compendium June 2000 Small Animal/Exotics

to keratin that results in drug concentrations in the sis.33 Long-term treatments (6 months minimum) have
skin detectable 2 to 4 weeks after cessation of therapy.30 also been reported.32,43 Because of the pharmacokinetic
Itraconazole reaches the stratum corneum mainly by properties of itraconazole and its persistence in the
excretion in sebum in which drug levels are 5 to 10 skin, nails, and hair follicles, pulse therapy has been ad-
times higher than those in plasma. In plasma, 99% of vocated in human dermatology for a variety of superfi-
the drug is protein bound, which explains why aqueous cial fungal infections. Pulse therapy involves adminis-
fluids (saliva, CSF) with low protein content contain a tering oral itraconazole daily for 1 to 2 consecutive
negligible amount of the drug.31 Although itraconazole weeks per month for 3 months. This therapy has been
concentrations in CSF may be low, concentrations in successful in the treatment of onychomycosis in chil-
tissues of the central nervous system may still be high dren.44 In veterinary medicine, 15 cats with dermato-
enough for therapeutic success. phytosis were pulse-treated with oral itraconazole once
daily for 15 days, followed by a 2-week period during
Clinical Use which antifungal medication was not given. Six cats re-
Itraconazole has been found to be effective in vitro covered completely with a single 15-day course of treat-
and in vivo against medically important fungi. Several ment, but two cats required two and three rounds of
veterinary reports establish how useful and extensively pulse therapy, respectively.41
used itraconazole has become against superficial and
systemic mycoses in small animals. Conditions such as Adverse Effects
dermatophytosis, dermatophytic pseudomycetomas,23,32 Itraconazole may have fewer side effects, especially in
blastomycosis,33 cryptococcosis,7 sporotrichosis,34 as- cats, than does ketoconazole. However, a recent study
pergillosis, 35 cutaneous Alternaria, 36 pheohypho- reported that 5 of 15 cats with dermatophytosis experi-
mycosis,37 and histoplasmosis38 have all been successful- enced vomiting and anorexia at doses as low as 3
ly treated with itraconazole (Figure 1). Itraconazole has mg/kg/day of oral itraconazole.41 Other studies have re-
also been used successfully to treat cats with cryptococ- ported anorexia only occasionally in treated cats; gas-
cal meningitis39 and dogs with ocular blastomycosis.40 trointestinal signs such as vomiting and diarrhea were
generally uncommon and apparently dose related.43 An
Administration and Dosing asymptomatic increase in serum ALT and alkaline
Doses varying from 10 to 20 mg/kg/day have been phosphatase activities are observed in some animals,
suggested for the treatment of most fungal infections in but itraconazole-induced hepatotoxicosis is rare in dogs
dogs and cats. However, doses of itraconazole at 5 and cats.7,33 Ideally, serum ALT activity should be mon-
mg/kg/day have been demonstrated to be as effective as itored monthly during itraconazole therapy. One study
10 mg/kg/day in treating canine blastomycosis.33 Doses in dogs reported more side effects with itraconazole at a
of 5 to 10 mg/kg/day may be sufficient for treatment dose of 10 mg/kg/day than with a dose of 5 mg/
with less toxicity for most cutaneous mycoses in small kg/day.33 The most common side effects noted in this
animals even in the face of organisms with relatively study were anorexia and idiopathic cutaneous vasculitis
high minimum inhibitory concentrations (MICs) be- with skin ulceration that improved rapidly on cessation
cause skin concentrations of itraconazole seem high of therapy.33 A cutaneous drug eruption more compati-
enough to exceed elevated MIC. More recently, a small ble with erythema multiforme and associated with itra-
uncontrolled clinical trial reported complete recovery conazole administration has also been recently reported
in 8 of 15 cats with dermatophytosis treated with oral in one dog.45 Ketoconazole was subsequently prescribed
itraconazole at doses as low as 1.5 to 3.0 mg/kg/day.41 to the dog without a cross-reaction.
A 40-mg/ml itraconazole suspension, which can be In contrast to ketoconazole, itraconazole is more spe-
useful for doses less than 100 mg, has recently been de- cific for fungal than for mammalian cytochrome P-450
scribed in a short pharmaceutical profile review.42 The enzymes28; therefore, at therapeutic doses it has no sig-
suspension preparation requires grinding the capsule nificant effect on androgen or cortisol metabolism.31
content with alcohol and syrup and can be compound- Furthermore, itraconazole does not have an inhibitory
ed by pharmacists. The suspension was stable for 35 or inducing effect on hepatic microsomal enzymes to
days when kept refrigerated. the same degree as does ketoconazole; thus the risk for
As with the other azole derivatives, the length of drug interaction is minimized.30 Itraconazole may in-
therapy with itraconazole varies greatly. In general, 4 to hibit the metabolism of cyclosporine, cisapride, and
6 weeks is probably a strict minimum treatment dura- terfenadine. Itraconazole exhibits dose-dependent em-
tion for most diseases, although 2 months or more of bryotoxicity and should be avoided during pregnancy,25
therapy is required for most patients with blastomyco- although dosages of 10 mg/kg/day or less have been re-

CANINE BLASTOMYCOSIS ■ DERMATOPHYTOSIS ■ PHARMACOKINETIC PROPERTIES

Small Animal/Exotics Compendium June 2000 BY PRACTICING DERMATOLOGY
SPECIALISTS FOR THE BUSY
portedly administered to pregnant animals without ter- GENERAL PRACTITIONER
atogenic effect.22

Fluconazole
The triazole fluconazole was discovered in 1982 and
Canine & Feline
licensed in 1990 for use in human cryptococcal and
candidial infections. Fluconazole is water soluble and Dermatology
can be administered orally and intravenously. It is avail-
able in 50- and 100-mg tablets, a 150-mg capsule, 10- D i a g n o s i s a n d Tr e a t m e n t
and 40-mg/ml orange-flavored oral suspensions, and a
2-mg/ml intravenous infusion. Although its mechanism Gene H. Nesbitt • Lowell J. Ackerman
of action is similar to other compounds of the same
family, fluconazole is not approved for use in veterinary
medicine.

Pharmacokinetics
Canine
The low molecular weight and high water solubility & Feline
of fluconazole contribute to its rapid dissolution and
high bioavailability. Fluconazole is readily absorbed
from the gastrointestinal tract independently of the for-
Dermatology off!
%
Nesbitt • Ackerman

mulation, gastric acidity, or concomitant food intake.46 10

The drug is not extensively bound to tissue protein or
D i a g n o s i s a n d Tr e a t m e n t
fat, and its apparent volume of distribution is approxi-
mately that of total body water.47 Fluconazole is not ex-
tensively metabolized, and its primary route of excre-
89 $

$99
tion is renal. Therefore, the dose of fluconazole should
be decreased in patients with impaired renal function.47
After 50 mg of fluconazole was administered intra-
venously or orally to every cat in one study,48 the ob-
served 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 com- Replete with handy streamlined tables, highlighted
plete and high concentrations were achieved for CSF,
aqueous humor, and lung fluids.48 Urine has 10 times clinical profiles for each condition, and photos of
the fluconazole concentration of plasma and it pene- lesions and other pertinent characteristics.
trates the CSF well, making it a drug of choice for cen-
tral nervous system (cryptococcal meningitis) and uri- ■ Separate canine and feline sections
nary tract fungal infections. Fluconazole also penetrates ■ Nearly 250 color and black-and-white photos
the skin well; thus high concentrations can be found in
the stratum corneum, and its elimination from the skin ■ Step-by-step descriptions of all phases of care
is slower than that from plasma.49
■ Comprehensive coverage of 500 pages, coated
Clinical Use allergic, bacterial, fungal, soft cover, color and
The spectrum of action of fluconazole is similar to parasitic, endocrine, black & white,
that of itraconazole and includes fungi responsible for neoplastic, and various spring 1998
both superficial and deep mycoses. In animal models miscellaneous diseases
and in humans, fluconazole has been effective against
Aspergillus, Blastomyces, Candida, Coccidioides, Crypto- ■ Superb case studies
coccus, Histoplasma, Malassezia, Microsporum, and Tri- ■ Color type to highlight and organize
chophyton.28 There are several reports of the use of flu-
conazole in animals. Various doses have been successful
in treating dogs with nasal aspergillosis50 and blastomy- CALL OR FAX TODAY TO ORDER
cosis43 and cats with cryptococcosis.4 800-426-9119 • Fax: 800-556-3288
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STRATUM CORNEUM ■ NASAL ASPERGILLOSIS

Small Animal/Exotics Compendium June 2000

Administration and Dosing area to be treated. Although there are no published tox-
In a study by Malik and colleagues,4 cats with crypto- icology studies on this particular solution in animals, it
coccosis were treated with doses ranging from 25 to 100 has been used by one of us (M.G.P.) in a 50:1 dilution
mg every 12 hours, with 50 mg per cat every 12 hours applied topically to dogs and cats at North Carolina
as the recommended dose based on the clinical results.4 State University without adverse effects. The topical ap-
These doses are much higher than the routinely recom- plication of the diluted product is used in the same way
mended dose of 2.5 to 5 mg/kg/day given either orally as the approved Canadian formulation.
or intravenously for other types of fungal infections.43 Enilconazole acts on fungi in the same way as do the
One recent pharmacokinetic study of fluconazole in cats other azoles with the only difference being that enil-
confirmed that 50 mg/day may be appropriate for most conazole also has shown fungicidal activity when ap-
fungal infections.48 Because fluconazole has linear ab- plied topically. Higher concentrations of antifungal
sorption kinetics and high bioavailability, oral and intra- agents can usually be achieved with topical applica-
venous dosages are identical.48 The skin and nails have tions; therefore, fungicidal doses of enilconazole can be
high levels of fluconazole, and intermittent therapy at 3 obtained.
to 6 mg/kg once weekly has been described in hu-
mans.44 Although the duration of therapy is variable, a Pharmacokinetics
minimum of 6 to 8 weeks of treatment is necessary for Enilconazole is a light-yellow solid substance that is
most fungal infections and periods of 4 to 6 months only slightly soluble in water. At room temperature and
have been necessary for some cats with cryptococcosis.4 protected from light, it remains stable for up to 5 years.
Following oral absorption, concentration of the active
Adverse Effects compound in tissue has been shown to be negligible,
In humans, the most common side effects noted with limiting its use to topical applications.52 Enilconazole
fluconazole were related to the gastrointestinal system.51 mainly acts superficially, with the dermal absorption be-
Compared with the other azoles, fluconazole inhibits ing very low. The small amounts absorbed by the skin
the fungal lanosterol 14-demethylase to a much greater are the same for intact as for scarified epidermis. One
extent than the corresponding mammalian enzyme.28 explanation for its topical efficacy is that after applica-
In fact, fluconazole demonstrates a 10,000-fold selec- tion of enilconazole, a vapor phase activity develops on
tivity for the fungal enzyme. In a study in which cats the treated surface and a residual effect remains.53
received fluconazole at 50 mg/kg every 12 hours, no
side effects were reported.4 Similarly, no adverse effects Clinical Use
were noted in dogs undergoing fluconazole therapy for The antimycotic activity of enilconazole in vitro and
blastomycosis.43 The major disadvantage of fluconazole in vivo is excellent against many pathogenic fungi, in-
therapy is its high cost. cluding Microsporum canis, Microsporum gypseum, Tri-
chophyton mentagrophytes, Trichophyton verrucosum,
Enilconazole Malassezia pachydermatis, and Aspergillus species.52 The
Enilconazole, also known as imazalil, is a topical, label on the Canadian formulation indicates enilcona-
broad-spectrum imidazole derivative labeled for veteri- zole as a treatment for dermatophytosis in dogs and
nary use only. In Canada, enilconazole is available as a horses. Described off-label uses of enilconazole, includ-
10% (100 mg/ml) concentrated solution approved for ing use in cats, have been multiple and varied. Enil-
use in dogs and horses. In the United States, enilcona- conazole is believed to be one of the most effective
zole (Clinafarm® EC, American Scientific Laboratory, treatments against nasal aspergillosis, and protocols im-
Union, New Jersey) is labeled only for use as a disinfec- plying direct infusion of the drug in the nasal passages
tant in cleaned poultry hatcheries. Clinafarm® EC is through fenestrated tubes have been well described.54
available in a 750-ml bottle containing 13.8% (138 Enilconazole emulsion is also used successfully in the
mg/ml) enilconazole. The other ingredients listed on topical treatment of feline dermatophytosis, in which
the material safety data sheet are benzyl alcohol and the emulsion provides the advantages of efficacy and
dioctyl sodium sulfosuccinate; it also contains ethoxy- ease of application. 55–57 Enilconazole is also recom-
lated castor oil. The Canadian formulation contains mended in the topical therapy of canine yeast dermati-
polysorbate 20 and sorbitan monolaurate as its inert in- tis caused by M. pachydermatis or Candida species.58,59
gredients, with 10% enilconazole as the active drug. The 10% enilconazole concentrated solution is dilut-
Clinafarm® EC is registered for controlling Aspergil- ed 50:1 with water to yield a 0.2% white emulsion
lus organisms in poultry facilities and equipment by with low viscosity. The emulsion is traditionally applied
making a 1:100 dilution and spraying or fogging the as a whole-body immersion; sponge application fol-

LINEAR ABSORPTION KINETICS ■ CRYPTOCOCCOSIS ■ FUNGICIDAL ACTIVITY

Compendium June 2000 Small Animal/Exotics

lowed by a brushing of the entire haircoat has also been onychomycosis in humans. Terbinafine is available in
described in cats.55 Clipping of long-coated animals will 125- and 250-mg tablets for oral treatment and is also
facilitate the recommended twice-weekly application. available in a topical form.
Length of therapy varies with the condition treated; a
minimum of 3 weeks for Malassezia dermatitis and 4 to Mechanism of Action
6 weeks for dermatophytosis has been advocated. Once Like the azoles, the allylamines are potent inhibitors
the solution is diluted, it remains stable for 4 to 6 of ergosterol synthesis. Ergosterol is an essential com-
weeks if protected from light. However, the manufac- ponent of fungal cell membranes. However, the mecha-
turer advises fresh dilution of the concentrated solution nism by which terbinafine interferes with the sterol
prior to each application. biosynthetic pathway differs. Terbinafine inhibits the
enzyme squalene epoxidase and blocks the conversion
Adverse Effects of squalene to lanosterol, thereby depleting ergosterol
Accidental ingestion of diluted enilconazole or lick- within the fungal cell membrane.62 Inhibition of the
ing after the washing involves minimal risk. The safety enzyme also causes the accumulation of squalene,
of oral enilconazole has been demonstrated in acute which may be the cause of fungicidal activity. The inhi-
and chronic toxicity studies in which beagles were given bition of squalene epoxidase is not mediated through
5 mg/kg/day for 24 months, with only a slight and cytochrome P-450, further differentiating allylamines
transient decrease in appetite noted.52 The acute oral from azoles. Unlike the azoles, terbinafine would not
LD50 in dogs was 640 mg/kg. Although there have been affect cortisol or testosterone levels even at high doses.
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 Pharmacokinetics
cats with dermatophytosis failed to reveal any adverse When given orally, terbinafine is well absorbed; and
or toxic reactions.60 The diluted emulsion does not irri- although the bioavailability is higher when the drug is
tate the skin or eyes.52 taken with a meal high in lipids, it can be given on an
empty stomach. After absorption, most of the drug is
Thiabendazole, Miconazole, and Clotrimazole metabolized by the liver; therefore, dosage adjustment
The azole drugs thiabendazole, miconazole, and is necessary in patients with liver dysfunction. The half-
clotrimazole are broad-spectrum antifungal agents that life and lipophilicity of the drug enable once-daily dos-
show some activity against gram-positive bacteria. ing in humans.63 High concentrations of terbinafine are
These drugs are widely used in topical otic preparations found in the stratum corneum, sebum, and hair. Se-
in combination with other drugs, classically an antibi- bum is the major route of drug delivery to the stratum
otic and a corticosteroid. The primary reason for their corneum, and high levels are found within the first 2
incorporation into triple-action ear medications is be- days of therapy.63
cause of their activity against yeasts such as M. pachy-
dermatis, a common complicating organism of external Clinical Use
otitis. An antibiotic combined with a broad-spectrum Terbinafine is primarily fungicidal against dermato-
antifungal of the azole family can have a synergistic ef- phytes (e.g., Sporothrix schenckii, Aspergillus species) but
fect, such as that seen with miconazole and polymyxin is only fungistatic and clinically somewhat less effica-
B.61 The broad-spectrum activity of these antifungals cious against yeasts.64 In humans, terbinafine is used
contained in otic preparations has also led to off-label successfully to treat dermatophytosis, sporotrichosis,
use as topical agents against such superficial mycoses as and onychomycosis, even in children.44 The adult dose
dermatophytosis. is 125 mg twice daily; the pediatric dose ranges from 4
to 8 mg/kg/day.65 Little data on the use of terbinafine
ALLYLAMINES in veterinary medicine are available. A preliminary
The allylamine derivatives are a new class of synthetic study on the pharmacokinetics of terbinafine in cats
antifungal agents of relatively recent discovery. Their showed that a dose of 20 to 40 mg/kg/day induced ade-
mechanism of action is fungicidal, which distinguishes quate concentrations of the drug in the skin and ap-
them from most other antifungal agents. pendages, with no observed side effects or toxicities.66
Based on these preliminary results, terbinafine adminis-
Terbinafine tered at 20 mg/kg every 24 to 48 hours would be the
Since its discovery, terbinafine has had a great impact experimental recommended dosage for treating feline
on the treatment of superficial dermatophytosis and dermatophytosis.67

ENILCONAZOLE ■ BROAD-SPECTRUM ANTIFUNGAL AGENTS ■ SQUALENE

Small Animal/Exotics Compendium June 2000

Adverse Effects
Share Your
Adverse effects are not reported in companion ani-
mals because of lack of experience. Terbinafine does
Knowledge
not cause drug interactions. In humans, very few ad-
verse effects have been observed with terbinafine thera- We invite you to impart your clinical knowledge
py; and most of these effects are related to the gastroin- by discussing your interesting cases, unusual
testinal system. Idiosyncratic acute hepatotoxicoses
have been reported occasionally.68 No embryonic or fe- presentations, or procedures for clinical solutions
tal toxicity or teratogenicity has been reported with the
use of terbinafine in rats and rabbits, even at high dos- for the following features:
es.28 In humans, there are no reported effects on preg- E
IC CHALLENG

nancy and the drug is not contraindicated in pregnant DIAGNOST

rn on a Rat Po
isoning
Unexpected Tu
women. DIAGNOSTIC CHALLENGE By Marjory
Brooks, D.V.M
and Jeff Jacobs
on, D.V.M
.
., Dipl. A.C.V.
I.M.,

was exam-
d male Beagle,
r-old, neutere Con-
ugsy, a four-yea n of the rat poison
M ined within one
hour of ingestio l placement

A detailed account of a clini- trac® . Initial

of apomorphine
treatment consiste
and 30 mL of
d of subconjunctiva
oral hydrogen
peroxide to induce
, Mugsy vomited
a large

CONCLUSION
this therapy
response to the rat bait.
Addi-
vomiting. In identified as
of green-b lue material d charcoa l by gas-
amount mL of activate
nt included 200 neously (SC).
tional treatme 2.5 mg/kg subcuta

cal dilemma takes readers from

and vitamin K1 supply of
tric intubation with a 10-day
ed to his owners
Mugsy was discharg hours orally.

Clinicians at all levels of patient care are faced with ILLUSTRATIO

NS BY LES
SEALING
vitamin K1 50
mg every 24

for PT determi
nation. All
blood chemist
PT at recheck
ry

specific patient presentation

hours later limits. The
d for 48 hours within normal because cor-
tion was schedule values were ted finding

the management of a growing variety of fungal infec- A recheck examina vitamin K regimen to
confirm , an unexpec K deficiency
was 65.9 seconds al PT due to vitamin
ion of the owners report- initiating an
after complet Although his rection of abnorm 48 hours of
coagulopathy. and Mugsy within 24 to
resolution of K1 as directed should resolve K1. of
had given vitamin re to rat poison, clotting appropriate
dose of vitamin persistent prolongation
ed that they y the cause of
nity for reexposu was markedl To determine al vitamin
had no opportu time (PT) assay whether addition for more
prothrombin finding in the PT and
time in the : 9.5-12.5). This clotting time was sent

through the steps leading to the

a sample

tions. Consequently, systemic administration of anti-

(normal pre- was needed, was drawn
prolonged at
57 seconds that his early . Whole blood
it appeared prevented
K therapy
ion analyses 3.8 percent
ted because detailed coagulat anticoagulant (one part
was unexpec ive vomiting had
product Contrac, how- citrate ged, and the
sentation with of rodenticide. directly into and centrifu
a toxic dose poison. parts blood) to a vet-
absorption of iolone, a long-acting K citrate to nine shipped on cold packs
s bromad vitamin 1 plasma was Coagulation
ever, contain at the same supernatant (Comparative
therefore resumed e laboratory University,
Treatment was two weeks.
erinary referenc
tic Laborat
ory, Cornell

fungal agents has increased in recent years in many

completion
dosage for another recheck, 48 hours after Section, Diagnos

ultimate diagnosis in 1000-1500

ed and d
At Mugsy’s next was still markedly prolong York). d of activate
Ithaca, New ion panel consiste
, the PT sample. A thrombin
of vitamin K1 from the previous The initial coagulattime (aPTT), PT, and g
unchanged vita-
essentially submitte d, parenteral partial thrombo
plastin
aPTT and
TCT screenin
ry profile was were (TCT). The
owners clotting time
blood chemist SC, and the
given 50 mg and recheck
48
min K1 was oral vitamin K1 2000

fields of veterinary medicine, including dermatology.

resume August
instructed to
ed
Peer Review

words. 76 Veterinary
Forum

Fungal infections range from the benign (but tenacious THERAPEUTIC

CHALLENGE

and irritating) dermatophytosis to aggressive life-threat-

THERAPEUTIC CHALLENGE

KAREN WILSON
ening systemic mycoses.
Intussuscep
tio
The cornerstone of the treatment strategies involved While the course of therapy is of- In a Yearlin n
g
in managing these fungal infections are systemic and ten clear-cut, some patients pre-
By Linnea Lentz,
D.V.M.

B
topical antifungal agents. Treatments for fungal infec- sent true challenges to medical
eau, a 15-mont
when the owners
described as mild,
nixine) administe
h-old colt, had been
called the referring
and Beau was treated
red intravenously
colicky for about
veterinarian. The
four hours

with 10 cc Banamin ®
colic was
e (flu-
and no other
ties. An initial
abnormali-
IV injection
of xylazine appeared
to

tions are often difficult, costly, and frustrating; further-

approximately 1 (IV), 10 cc of control the pain
⁄2 gallon of mineral dipyrone IV, and for only 20
oil administered minutes before
tube. Within the via nasogastric a second
hour, Beau was dose was necessary.
University of Minneso again colicky and Rectal
was referred to the palpation revealed

skills. In 1000-1500 words, these

ta. many
distended loops
of small
testine. After placemen in-
Initial Treatme t of

more, many of these antifungal agents either have not

nt on Referra a nasogastric
Clinical signs l reflux were obtained. tube, 6-7 L of
on presentation Abdominocen-
included 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 re- intestinal distention

cases describe the steps that

vealed a pulse and nasogastr ,
of 84 beats per ic reflux, we
decreased gastrointe minute, mended explorato recom-

been labeled for animal use or have not been labeled for
stinal motility ry laparotomy
all four quadrants in diagnose the cause to
, slightly toxic of the colt’s colic.
cous membran mu- The owners quickly
es, a capillary agreed, and pre-
time of 2.5 seconds refill operative antibiotic
(normal: 1-2),
and a normal
temperature. potassium penicillin s, including
work revealed Blood 22,000 units/kg
a packed cell IV and Gentocin
volume (gentamicin) 6.6

eventually lead to case resolu-

of 48 percent mg/kg

the different clinical applications discussed. Therefore,

(normal: 32-48), IV, were administe
protein of 7.2 g/dL total preparing the colt red before
(normal: 5.7-7.9), for surgery. During
surgery, a jejunocec
August 2000 al intussuscep-➔
Peer Reviewed
Veterinary Forum
73

an understanding of the pharmacology and potential tion.

complications of the continually expanding antifungal CASE OF THE
MONTH

armamentarium is essential. Canine Hemipares

is , D.V.M.

CASE OF THE MONTH

By Donivan Hudgins

REFERENCES Some case presentations are so J asmine, a four-year-

kg, spayed Golden
old, 29-
Retriev-
activity levels
and vaccinations
for distemper,
had been normal,
were current
hepatitis, lep-

1. Woolley DW: Some biological effects produced by benzimid- er, was presented
for sudden onset
to the clinic
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tosporosis, parainflue
vovirus, coronoav
nza, par-
irus, Lyme

confounding that both diagnosis

found a stray
The owner had and sus- disease, and rabies.
given Solu
goat in the backyard The patient was
goat may have ® (prednisolone)
pected that the Delta Cortef

azole and their reversal by purines. J Biol Chem 152:225– butted Jasmine.
tion, the dog
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and observatio
On presenta-
was ambulato
uncoordi
ry
nated,
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100 mg intraveno

tramuscularly.
instructed to
usly (IV) and
amoxicillin injectable
2.5 cc in-
The owner was
provide cage rest

and therapy are perplexing. Often,

deficit was in and return
primary walking over the weekend

232, 1944. the right rear leg.

Physical examinat
vealed a temperatu
ion re-
re of 101.6˚F,
pink mucous membran (normal:
es, capil-
Monday if the
had not improved
dog’s condition

The following
.
week, Jas-
to improve, and
CORBIS

mine appeared
of 1 sec she did have
lary refill time whatever problems

2. Godefroi EF, Heeres J, Van Custem J, et al: The preparation a patient may return again and
1-2 sec), normal
lungs, and no
right rear foot
heart and
sign of pain. The
did knuckle over,
indicating decreased indicat-
pinch
proprio-
seemed subtle.
two to three
lems recurred
nounced as
Over the next
weeks, her prob-
but not as pro-
before, and
that the dog
the

ception, but toe owner reported

and antimycotic properties of derivative of 1-phenylethylim- ed sensory nerves

Temperatures
foot and leg were
were intact.
of the affected
no different
seemed to adjust
Then, over the
Jasmine’s lack
to her deficits.
next few weeks,
of coördination

again with continuously changing

other three feet
than that of the seemed to worsen.
and flexion 21, Jasmine
and legs. Extension On October

idazole. J Med Chem 12:784–791, 1969. hip joints were for examina-
of the stifle and reflex on was re-presented
on a leash
normal, but patellar tion. When followed appeared
exaggerated,
the right was in the lawn, Jasmine
upper motor ated, with
which suggested to be very uncoördin
Appetite and
neuron disease.

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SEND YOUR ARTICLES TO:
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matophytosis in cats. JAVMA 207:439–444, 1995.
6. Heit MC, Riviere JE: Antifungal therapy: Ketoconazole and 275 Phillips Blvd.
other azole derivatives. Compend Contin Educ Pract Vet Trenton, NJ 08618
17(1):21–31, 1995.
7. Medleau L, Gilbert JJ, Marks MA: Itraconazole for the treat- Fax: (609) 882-6357
ment of cryptococcosis in cats. J Vet Intern Med 9:39–42,
1995. E-mail: [email protected]

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62. Ryder NS: Terbinafine: Mode of action and properties of and Paradis are Diplomates of the American College of
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1992. Department of Anatomy, Physiological Sciences, and Ra-
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in serum, stratum corneum, dermis-epidermis (without stra-
erinary Medicine, Raleigh, NC. He is a Diplomate of the
tum corneum), hair, sebum and eccrine sweat during and af-
ter 250 mg terbinafine orally once per day in man. J Invest American College of Veterinary Clinical Pharmacology.
Dermatol 24:523–528, 1990.