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Vol. 22, No.

5 May 2000 V

CE Refereed Peer Review

Traditional Antifungal
FOCAL POINT Dermatologic Agents
★Several traditional antifungal
compounds are still widely used Centre Vétérinaire DMV, Ville St-Laurent, Quebec
and recommended for many Caroline de Jaham, DMV, MSc
cutaneous fungal disorders.
Université de Montréal
Manon Paradis, DMV, MVSc
KEY FACTS
North Carolina State University

■ Amphotericin B continues to be a Mark G. Papich, DMV, MS


recommended treatment option for
several invasive fungal infections ABSTRACT: In the past two decades, remarkable advances have occurred in the treatment of
despite the need for intravenous cutaneous fungal diseases. New generations of antifungal drugs have altered the therapeutic
administration and the possibility approaches to both systemic and superficial mycoses of companion animals. To understand
of nephrotoxicity. these advances and their impact in veterinary dermatology, traditional therapies and their clini-
cal applications are reviewed. The pharmacokinetics, methods of action, principal adverse ef-
■ Interest in the antifungal drug fects, and dermatologic uses of polyenes, iodides, and griseofulvin are summarized.
amphotericin B has been

A
renewed because encapsulated ntifungal agents target the cytoplasmic membrane and nucleus of cells
formulations, have a higher (Figure 1). Older antifungal agents, including ampheroticin B, remain
margin of safety than does the the mainstay of treatment of certain fungal infections despite the advent
traditional formulation. of newer agents (Table I). The antifungal agents discussed in this article include
the polyenes, flucytosine, iodides, and griseofulvin.
■ Potassium iodide remains an
economical, efficient initial POLYENES
treatment of choice for canine The two clinical polyene macrolide antibiotics used in veterinary dermatology
sporotrichosis. are nystatin and amphotericin B. Approximately 87 polyene antibiotics have
been developed since the discovery of nystatin in 1950.1
■ Although ineffective against
yeast, griseofulvin is highly Nystatin
effective against dermatophytes Because systemic administration of nystatin is associated with a high risk for
and remains the treatment of toxicity, only the topical preparation is used in veterinary medicine. Nystatin, a
choice. common ingredient in over-the-counter products, is active against the yeast
Malassezia pachydermatis, a frequent complicating organism of otitis externa.
■ Cats are apparently susceptible to Topical ear preparation of nystatin has been incriminated as an occasional cause
the adverse effects of griseofulvin of allergic contact dermatitis in the topical treatment of canine otitis externa.2
therapy.
Amphotericin B
Discovered in 1956,3 amphotericin B was the first effective systemic antifungal
agent and rapidly became the treatment of choice for systemic mycoses. The
drug is still recommended for invasive fungal infections despite its renal toxicity
Small Animal/Exotics Compendium May 2000

and the need for intravenous The metabolism of ampho-


TABLE I
(IV) administration. Interest tericin B is not clearly under-
in this drug has been re- Class and Site of Action of Antifungal Agents stood. It is incorporated into
newed because encapsulated Class Agents Site of Action cholesterol cell membranes
formulations, such as am- at various times, resulting in
Polyenes Amphotericin B, Bind to
photericin B lipid complex, complicated elimination and
nystatin, natamycin ergosterol and
have a higher margin of disrupt cell distribution of the drug dur-
safety than does the tradi- membranes ing cellular metabolism.5
tional formulation (ampho-
tericin B deoxycholate). Miscellaneous Flucytosine Inhibits RNA
Clinical Use
synthesis Amphotericin B is active
Griseofulvin Interferes with
Mechanism of Action against Blastomyces dermati-
spindle
Amphotericin B binds ir- tidis, Histoplasma capsulatum,
microtubules
reversibly to ergosterol, the Iodides Unknown Cryptococcus neoformans,
principal sterol in the cell Tolnaftate Inhibits Coccidioides immitis, Muco-
membrane of fungi. This qualene rales, Candida species, As-
binding results in cell death epoxidase pergillus species, Sporothrix
caused by altered cellular schenckii, and Fusarium
permeability and leakage of intracellular constituents. species. The minimum inhibitory concentration of am-
Amphotericin B binds to a lesser extent to other sterols photericin B varies for each group of fungi. The drug is
(e.g., cholesterol) in mammalian cells. This interaction most commonly used to treat blastomycosis, histoplas-
accounts for most of the toxicity and side effects in mosis, and coccidioidomycosis, all of which can have
mammals. Amphotericin B is fungicidal in sufficiently cutaneous manifestations as markers of systemic infec-
high concentrations but is considered fungistatic at tion. Despite the availability of newer agents, ampho-
lower concentrations.1 tericin B combined with flucytosine has remained the
treatment of choice for humans with cryptococcosis.6
Pharmacokinetics Fungal resistance rarely develops during treatment
Amphotericin B is poorly absorbed from the gas- with amphotericin B; however, relapse may occur when
trointestinal tract, thereby necessitating IV infusion. therapy is discontinued.4 Concurrent use of other drugs
The drug binds primarily to protein, resulting in poor (e.g., flucytosine, the azole derivatives) improves the
penetration of body fluids (e.g., cerebrospinal fluid), overall efficacy of therapy and has been shown to re-
but intrathecal administration of amphotericin B has duce the number of relapses.7,8 Amphotericin B remains
4
been described. a mainstay of initial therapy; but because of the need

Cytoplasmic Membrane Nucleus


Contains ergosterol as Contains nucleic acid
the major sterol • Site of griseofulvin activity:
• Site of amphotericin B activity: interferes with spindle
binds to ergosterol and disrupts microtubules, thereby inhibiting
the cell membrane nucleic acid synthesis
• Site of azole activity: inhibits the • Site of flucytosine activity:
enzyme lanosterol 14-demethylase, converts to 5-fluorouracil in
thereby inhibiting ergosterol cytoplasm of fungi, thereby
synthesis inhibiting RNA synthesis
• Site of allylamine activity: inhibits
squalene epoxidase enzyme,
thereby inhibiting ergosterol
synthesis
Cell Wall
Contains chitin

Figure 1—Schematic representation of a fungal cell and target sites of action of antifungal agents.

ERGOSTEROL ■ CELLULAR METABOLISM ■ FLUCYTOSINE ■ FUNGAL RESISTANCE


Compendium May 2000 Small Animal/Exotics

for hospitalization, intensive patient monitoring, labo- photericin B administration. Concomitant administra-
ratory testing, and fluid administration during IV ther- tion of mannitol, sodium bicarbonate, furosemide,
apy, the cost of amphotericin B treatment is similar to dopamine, and aminophylline has been tried empirical-
that of the newer, more expensive azole derivatives. ly or experimentally; some of these agents have shown
Dose regimens of amphotericin B to treat specific dis- empiric beneficial effects.4 Pretreatment diuresis with
eases in companion animals have been reviewed, and saline-containing fluids helps decrease nephrotoxici-
this information should be consulted before veterinari- ty.4,14 The availability of new formulations of ampho-
ans attempt treatment using amphotericin B.4,9 tericin B in a lipid or cholesterol complex allows ad-
ministration of amphotericin B at higher doses with
Administration and Dose greater safety.15 Three formulations are now available:
Amphotericin B is usually administered IV, and rapid an amphotericin B–cholesteryl sulfate complex; a lipo-
and slow IV infusion techniques for amphotericin B somal complex of amphotericin B; and an ampho-
have been described.9,10 The rapid IV infusion tech- tericin B lipid complex, which is a suspension of am-
nique involves administration of boluses of 0.25 to 0.5 photericin B combined with two phospholipids. The
mg/kg amphotericin B diluted in 30 to 120 ml of 5% amphotericin B lipid complex was shown to be safe and
dextrose over 10 to 15 minutes. Although these tech- effective for treating blastomycosis in dogs at a dose of
niques have been widely used, the risk for renal toxicity 8 to 12 mg/kg.16 The liposomal complex of ampho-
is higher with this method than with slower infusion tericin B was used in another study of 13 dogs for treat-
techniques. 10 The slower technique requires an in- ment of Leishmania infantum at a dose of 3 to 3.3
dwelling catheter and 0.25 to 0.5 mg/kg amphotericin mg/kg.17 Although clinical improvement was rapid, the
B diluted in 250 to 1000 ml of 5% dextrose adminis- dogs remained positive for Leishmania.
tered slowly for 4 to 6 hours. Before beginning each Lipid and cholesterol formulations (3 mg/kg or
treatment, the packed cell volume, total protein, creati- more) can be administered at higher doses than can the
nine, blood urea nitrogen, and potassium should be conventional formulation (0.25 to 0.5 mg/kg) and thus
measured and urinalysis performed. Regardless of the produce greater efficacy with less toxicity.18,19 Decreased
IV infusion technique used, amphotericin B should toxicity is attributed to selective transfer of the ampho-
only be administered every other day to minimize ad- tericin B lipid complex, which releases the drug directly
verse effects. to the fungal cell membrane and spares mammalian cell
Amphotericin B has also been used orally for local- membranes. Reduced drug concentrations in the kid-
ized treatment of gastrointestinal candidiasis.11,12 More neys as well as release of fewer inflammatory cytokines
recently, subcutaneous infusion of 0.5 to 0.8 mg/kg from the amphotericin B lipid complex than with the
amphotericin B diluted in 400 or 500 ml of 0.45% conventional formulation may also prevent adverse re-
saline containing 2.5% dextrose (for dogs and cats, re- actions. Administration of amphotericin B as a subcu-
spectively) has been successful in treating cryptococco- taneous infusion also allows higher cumulative doses to
sis. Two dogs and three cats received infusions two to be administered without producing marked azotemia.13
three times a week for several months, and local irrita- Other adverse effects caused by IV administration of
tion was only observed when concentrations of ampho- amphotericin B are hypotension, vomiting, tremors,
tericin B exceeded 20 mg/L.13 pyrexia, hypokalemia, anemia, and anorexia. Because
phlebitis should be expected with IV administration,
Adverse Effects the catheter site should be alternated.4
The most common and serious side effect of ampho-
tericin B administration is both acute and chronic nephro- MISCELLANEOUS SYSTEMIC AGENTS
toxicosis. Although clinical signs of early and acute re- The miscellaneous class of antifungal agents include
versible nephrotoxicosis can occur with each daily dose, the systemic compounds flucytosine, potassium and
permanent renal dysfunction is related to the total cu- sodium iodide, and griseofulvin. Also included in this
mulative dose of amphotericin B. A maximum total cu- class are numerous topical agents, such as tolnaftate,
mulative dose of 4 to 8 mg/kg is commonly described; which is commonly used in human dermatology.
but the total cumulative dose, and ultimately the treat-
ment duration, is always limited by nephrotoxicosis.4 Flucytosine
Cats are more sensitive to this disorder than are dogs, Flucytosine is a fluorinated pyrimidine that is convert-
and the maximum cumulative dose recommended in ed into 5-fluorouracil in the cytoplasm of fungi contain-
cats is 4 mg/kg.14 Several treatments have been used to ing the enzyme cytosine permease.4 This inhibits RNA
prevent or delay nephrotoxicosis associated with am- synthesis and leads to cell death. Flucytosine is well ab-

AZOLE DERIVATIVES ■ RENAL TOXICITY ■ LEISHMANIA INFANTUM


Small Animal/Exotics Compendium May 2000

sorbed orally and is excreted Pharmacokinetics


predominantly in urine in an Griseofulvin is weakly wa-
unchanged form. Flucytosine ter soluble and is erratically
has been used in conjunction absorbed from the gastroin-
with amphotericin B13 and ke- testinal tract. Enhanced ab-
toconazole20 to treat cryptococ- sorption depends on several
cosis in companion animals. factors,1 including concomi-
tant dietary fat intake, dose
Iodides regimen (twice daily instead
In 1903, the use of iodides of once daily), formulation
was first described to treat with polyethylene glycol, and
human sporotrichosis.21 Both particle size (microsized or ul-
sodium and potassium iodide Figure 2—Cutaneous sporotrichosis ulceration in a cat. tramicrosized). The half-life
have been successfully used to of griseofulvin is much short-
manage cutaneous and lym- er in animals than in humans,
phocutaneous forms of sporo- necessitating a higher dose
trichosis in dogs and cats22–25 rate in animals.31 Within 48
(Figure 2). Potassium iodide to 72 hours after discontinua-
remains an economical and tion of therapy, griseofulvin is
efficient initial treatment for no longer detected in the stra-
canine sporotrichosis.26 The tum corneum, suggesting that
precise mechanism of action nothing binds the drug with-
and pharmacokinetics of these in the skin.32 Griseofulvin is
drugs are unknown. The io- metabolized primarily by the
dides are administered orally liver to 6–desmethylgriseoful-
as a 20% solution. Dogs have vin and its glucuronide con-
been treated with 10 to 40 jugate.
Figure 3—Microsporum canis dermatophytosis in a Sphinx
mg/kg every 8 to 12 hours. cat. Note the crusted and mildly hyperpigmented annular
Because cats are more suscep- lesion on the digit. Clinical Use
tible to the effects of iodides, Although griseofulvin is high-
doses of 10 mg/kg every 12 ly effective against Microspo-
hours are sufficient.22,26 rum, Trichophyton, and Epidermophyton dermatophytes,
The most common adverse reactions to the iodides it is ineffective against yeasts.33 Griseofulvin is still rec-
are signs of iodism, which include oculonasal discharge, ommended as an efficient initial therapy for most cases
dry haircoat, excessive scaling, vomiting, anorexia, cen- of dermatophytosis in small animals because side effects
tral nervous system depression, and collapse. 24–26 If are predictable and the drug is cost-effective.34–36 Fungal
iodism is observed, medication should be stopped for 1 resistance is uncommon but may vary according to geo-
week and then started at lower doses. graphic locations. Recently in Europe, an in vitro study
reported more than 88% activity of griseofulvin against
Griseofulvin several strains of Microsporum canis.37
Griseofulvin was isolated as a metabolic product of
the mold Penicillium griseofulvum in 1939 but was ig- Administration and Dose
nored until 1958 when it cured experimentally induced Doses ranging from 22 to 60 mg/kg every 12 hours
dermatophytosis in guinea pigs. 27 Griseofulvin was for the microsized formulation and 2.5 to 15 mg/kg ev-
thereafter widely used to treat dermatophytosis in both ery 12 hours for the ultramicrosized formulation have
humans and animals28 (Figure 3). been recommended to treat dermatophytosis.34–36 Al-
though optimum dose regimens have not been estab-
Mechanism of Action lished, 25 mg/kg every 12 hours of the microsized for-
Griseofulvin inhibits nucleic acid synthesis and cell mulation and up to 50 or 60 mg/kg every 12 hours for
mitosis metaphase by interfering with the function of problematic cases are commonly accepted.34–36 Griseo-
29
spindle microtubules. Griseofulvin is a fungistatic an- fulvin should always be administered with a fatty meal.
tifungal that has antiinflammatory properties and may A teaspoon of corn or sunflower oil can be added to en-
modulate immune response.30 hance absorption.

SPOROTRICHOSIS ■ IODISM ■ DERMATOPHYTOSIS ■ SPINDLE MICROTUBULES


Compendium May 2000 Small Animal/Exotics

Adverse Effects phia, WB Saunders Co, 1995, pp 327–331.


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38. Helton KA, Nesbitt GH, Caciolo PL: Griseofulvin toxicities


in cats: Literature review and report of seven cases. JAAHA 22: About the Authors
453–458, 1986. Dr. de Jaham is affiliated with the DMV Veterinary Center,
39. Scott DW: Fungal disorders: Feline dermatology 1900– Dermatology Service, Ville St-Laurent, Québec, Canada.
1978: A monograph. JAAHA 16:349–356, 1980. Dr. Paradis is affiliated with the Department of Clinical
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with feline immunodeficiency virus infection. J Vet Intern and Paradis are Diplomates of the American College of
Med 4:317–319, 1990. Veterinary Dermatology. Dr. Papich, who is a Diplomate
41. Scott DW, De Lahunta AD, Schultz RD, et al: Teratogene- of the American College of Veterinary Clinical Pharmacol-
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11:79–86, 1975. logical Sciences, and Radiology, College of Veterinary
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Medicine, North Carolina State University, Raleigh, North
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1975.