Frustrating fungal diseases (Proceedings)

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Frustrating fungal diseases (Proceedings)

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Apr 01, 2008

Introduction


Key drugs, dosages and indications
In recent years, the use of antifungal drugs in human medicine has increased, especially with the advent of the AIDS epidemic. Efforts have focused on the development of new, less toxic and more efficacious antifungal drugs, and antifungal drugs with novel mechanisms of action. Many previously cost prohibitive antifungal drugs have become available in generic form, making them more accessible for treatment of small animal patients. The purpose of this presentation is to review the use of some of the major antifungal drugs, and introduce some new human antifungal drugs with potential applications in veterinary medicine.

Amphotericin B

Amphotericin B (AMB) is a polyene macrolide antibiotic. The drug irreversibly binds sterols in fungal cell membranes, forming pores with subsequent leakage of ions. Although generally considered fungistatic, at high doses it may be fungicidal. Amphotericin B also possesses immunomodulating effects; it activates macrophages and enhances macrophage-killing capacity.

Amphotericin B has antifungal activity against all important small animal fungal pathogens. It is virtually unabsorbed from the gastrointestinal tract, so it is formulated for IV infusion (Fungizone(, AMB-D) as a complex with the bile salt deoxycholate. The complex forms a colloid in water. Addition of electrolyte to the solution causes it to aggregate, so it is administered in D5W. In the bloodstream, AMB dissociates from deoxycholate and binds extensively to plasma proteins and cholesterol in membranes throughout tissues. Penetration of the CSF and vitreous humor is poor.

The major adverse effect of AMB-D is nephrotoxicity, which is dose-dependent and transient. Loading with IV NaCl for 1 hour before the infusion decreases nephrotoxicity. Slow administration in a large volume of fluid also decreases nephrotoxicity. In humans, AMB-D can also cause fever, chills, headache, nausea, vomiting, and rarely cytopenias and anaphylaxis. Fever, inappetence and vomiting also appear to occur in some dogs treated with AMB-D. Treatment with nonsteroidal anti-inflammatory drugs can be used to decrease pyrexia during therapy.

New Lipid Formulations of AMB

Currently, three lipid formulations of AMB are marketed in the US. These are associated with a considerable reduction in nephrotoxicity compared with AMB-D. This allows administration of a higher dose of the drug, sometimes with improved treatment efficacy.

Amphotericin B colloidal dispersion (ABCD, Amphotec() contains AMB and cholesterol sulfate, which form disk-shaped particles. It more commonly causes chills, fever and hypotension in humans than AMB-D (80% cf 12%), so it is given over 3-4 hours and with premedication.

Ambisome( ($215/50 mg) consists of AMB and a lipid mixture (phosphatidylcholine, cholesterol and distearoylphosphatidylglycerol), and is the most widely used formulation in humans. Blood levels equal those achieved with an equivalent dose of AMB-D. Nephrotoxicity and infusion-related reactions are much less common with Ambisome than with ABCD or AMB-D.

Amphotericin B lipid complex (ABLC, Abelcet) is a mixture of AMB, dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol that forms ribbon-like sheets. Blood levels are five times lower than with the same dose of AMB-D. Nephrotoxicity and infusion-related reactions are intermediate between AMB-D and Ambisome. Abelcet has been used in small animal patients to treat systemic aspergillosis, cryptococcal meningitis, disseminated coccidioidomycosis, blastomycosis, histoplasmosis, and pythiosis.

Flucytosine (5-fluorocytosine)

Flucytosine is a fluorinated pyrimidine related to fluorouracil. It has activity only against Cryptococcus neoformans and Candida spp. These fungi deaminate flucytosine to 5-fluorouracil, a potent antimetabolite. Mammalian cells cannot convert flucytosine into 5-fluorouracil. Drug resistance arising during therapy is very common, and so flucytosine is ALWAYS used in combination with other drugs.

Flucytosine is absorbed rapidly from the gastrointestinal tract. Penetration of the CSF is excellent. Because about 80% of the dose is excreted unchanged in the urine, high urinary concentrations can be achieved. The drug should be avoided in patients with renal failure. The most common adverse effects are myelosuppression and gastrointestinal upset. Administration of flucytosine should be avoided in dogs, as development of a severe (but reversible) drug eruption within 2-3 weeks of starting treatment is common.