for hospitalization, intensive patient monitoring, labo-ratory testing, and fluid administration during IV ther-apy, the cost of amphotericin B treatment is similar tothat of the newer, more expensive azole derivatives.Dose regimens of amphotericin B to treat specific dis-eases in companion animals have been reviewed, andthis information should be consulted before veterinari-ans attempt treatment using amphotericin B.
4,9
Administration and Dose
Amphotericin B is usually administered IV, and rapidand slow IV infusion techniques for amphotericin Bhave been described.
9,10
The rapid IV infusion tech-nique involves administration of boluses of 0.25 to 0.5mg/kg amphotericin B diluted in 30 to 120 ml of 5%dextrose over 10 to 15 minutes. Although these tech-niques have been widely used, the risk for renal toxicity is higher with this method than with slower infusiontechniques.
10
The slower technique requires an in-dwelling catheter and 0.25 to 0.5 mg/kg amphotericinB diluted in 250 to 1000 ml of 5% dextrose adminis-tered slowly for 4 to 6 hours. Before beginning eachtreatment, the packed cell volume, total protein, creati-nine, blood urea nitrogen, and potassium should bemeasured and urinalysis performed. Regardless of theIV infusion technique used, amphotericin B shouldonly be administered every other day to minimize ad-verse effects. Amphotericin B has also been used orally for local-ized treatment of gastrointestinal candidiasis.
11,12
Morerecently, subcutaneous infusion of 0.5 to 0.8 mg/kgamphotericin B diluted in 400 or 500 ml of 0.45%saline containing 2.5% dextrose (for dogs and cats, re-spectively) has been successful in treating cryptococco-sis. Two dogs and three cats received infusions two tothree times a week for several months, and local irrita-tion was only observed when concentrations of ampho-tericin B exceeded 20 mg/L.
13
Adverse Effects
The most common and serious side effect of ampho-tericin B administration is both acute and chronic nephro-toxicosis. Although clinical signs of early and acute re-versible nephrotoxicosis can occur with each daily dose,permanent renal dysfunction is related to the total cu-mulative dose of amphotericin B. A maximum total cu-mulative dose of 4 to 8 mg/kg is commonly described;but the total cumulative dose, and ultimately the treat-ment duration, is always limited by nephrotoxicosis.
4
Cats are more sensitive to this disorder than are dogs,and the maximum cumulative dose recommended incats is 4 mg/kg.
14
Several treatments have been used toprevent or delay nephrotoxicosis associated with am-photericin B administration. Concomitant administra-tion of mannitol, sodium bicarbonate, furosemide,dopamine, and aminophylline has been tried empirical-ly or experimentally; some of these agents have shownempiric beneficial effects.
4
Pretreatment diuresis withsaline-containing fluids helps decrease nephrotoxici-ty.
4,14
The availability of new formulations of ampho-tericin B in a lipid or cholesterol complex allows ad-ministration of amphotericin B at higher doses withgreater safety.
15
Three formulations are now available:an amphotericin B–cholesteryl sulfate complex; a lipo-somal complex of amphotericin B; and an ampho-tericin B lipid complex, which is a suspension of am-photericin B combined with two phospholipids. Theamphotericin B lipid complex was shown to be safe andeffective for treating blastomycosis in dogs at a dose of 8 to 12 mg/kg.
16
The liposomal complex of ampho-tericin B was used in another study of 13 dogs for treat-ment of
Leishmania infantum
at a dose of 3 to 3.3mg/kg.
17
Although clinical improvement was rapid, thedogs remained positive for
Leishmania
.Lipid and cholesterol formulations (3 mg/kg ormore) can be administered at higher doses than can theconventional formulation (0.25 to 0.5 mg/kg) and thusproduce greater efficacy with less toxicity.
18,19
Decreasedtoxicity is attributed to selective transfer of the ampho-tericin B lipid complex, which releases the drug directly to the fungal cell membrane and spares mammalian cellmembranes. Reduced drug concentrations in the kid-neys as well as release of fewer inflammatory cytokinesfrom the amphotericin B lipid complex than with theconventional formulation may also prevent adverse re-actions. Administration of amphotericin B as a subcu-taneous infusion also allows higher cumulative doses tobe administered without producing marked azotemia.
13
Other adverse effects caused by IV administration of amphotericin B are hypotension, vomiting, tremors,pyrexia, hypokalemia, anemia, and anorexia. Becausephlebitis should be expected with IV administration,the catheter site should be alternated.
4
MISCELLANEOUS SYSTEMIC AGENTS
The miscellaneous class of antifungal agents includethe systemic compounds flucytosine, potassium andsodium iodide, and griseofulvin. Also included in thisclass are numerous topical agents, such as tolnaftate, which is commonly used in human dermatology.
Flucytosine
Flucytosine is a fluorinated pyrimidine that is convert-ed into 5-fluorouracil in the cytoplasm of fungi contain-ing the enzyme cytosine permease.
4
This inhibits RNA synthesis and leads to cell death. Flucytosine is well ab-
Compendium
May 2000Small Animal/Exotics
AZOLE DERIVATIVES
I
RENAL TOXICITY
I
LEISHMANIA INFANTUM
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