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5 May 2000 V
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
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
Figure 1—Schematic representation of a fungal cell and target sites of action of antifungal agents.
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-