Frustrating fungal diseases (Proceedings)

Introduction

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.

Key drugs, dosages and indications

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.

Imidazoles and Triazoles

Imidazoles and triazoles inhibit sterol 14-alpha-demethylase, a fungal enzyme involved in synthesis of ergosterol from lanosterol. Examples of imidazoles are ketoconazole and clotrimazole. Itraconazole, fluconazole and newer azoles are triazoles. Imidazoles and triazoles have been widely used to treat candidiasis, cryptococcosis, blastomycosis, histoplasmosis, coccidioidomycosis, dermatophytosis, sporotrichosis, and aspergillosis. Unfortunately, resistance to these drugs has emerged with prolonged treatment. Resistance to one azole confers resistance to other azoles.

Use of ketoconazole has been replaced by itraconazole, except where cost is an issue, due to its greater propensity to cause hepatotoxicity and suppression of adrenal steroid synthesis. The absorption of ketoconazole is not affected by food, but is inhibited by concurrent use of antacids. The drug is metabolized extensively by the liver, with inactive products being excreted in the feces. Hepatic microsomal enzyme induction may accelerate its clearance.

Itraconazole is available in capsules, oral suspension and an IV solution. The capsules are best absorbed when given with food, whereas the suspension is best absorbed on fasting. The suspension provides peak plasma concentrations 150% that produced by administration of capsules. Itraconazole undergoes hepatic metabolism, and inhibits metabolism of other P450-dependent drugs. Itraconazole does not appear in urine or CSF. A loading dose is recommended for the first 3 days. Advanced liver disease increases itraconazole concentrations. If possible, itraconazole should be avoided during pregnancy. The most common adverse effects in dogs are vomiting and anorexia, increased serum ALT, and ulcerative skin lesions.

Fluconazole is almost completely absorbed after oral administration, and bioavailability is not altered by food or gastric acidity. Renal excretion accounts for > 90% of the elimination of fluconazole. It diffuses into saliva, body fluids, and CSF. The dosage interval must be increased in patients with renal failure. Fluconazole has poor efficacy against molds; Aspergillus has intrinsic resistance to fluconazole. The drug is available as tablets, an oral suspension and as an IV solution.

New Triazoles

Several new triazoles have been developed, which are currently undergoing trials in humans. Voriconazole (Vfend, Pfizer) has been approved for use in humans for treatment of invasive aspergillosis and refractory fungal infections caused by Pseudallescheria boydii and Fusarium spp. It is a fluconazole derivative that is excreted by the liver. Adverse effects in humans include reversible visual effects, as well as the same toxicities as other triazoles. It is more expensive than other triazoles. Posaconazole (Schering-Plough) is an itraconazole analog. It is undergoing phase III clinical trials in humans. Ravuconazole (Bristol-Meyers Squibb) is a fluconazole derivative with good bioavailability and a long half life (8.8 hr in dogs). It is in phase II clinical trials in humans.

Pneumocandins/Echinocandins

The echinocandins inhibit formation of beta(1,3)-D-glucans in the fungal cell wall. The prototype drug is caspofungin acetate (Cancidas(). Other drugs in this class are micafungin and anidulafungin. Caspofungin is given once daily as a slow IV infusion. It is metabolized slowly by the liver, with some renal excretion. Caspofungin is effective against resistant Candida albicans, and it also has efficacy against Aspergillus and Pneumocystis. It is relatively ineffective against Cryptococcus. Cost is slightly less than for lipid formulations of AMB. Side effects noted in humans include fever, phlebitis, and elevated ALT (< 20% of patients).

Terbinafine

Terbinafine (Lamasil() is a synthetic allylamine that inhibits fungal squalene epoxidase, blocking fungal ergosterol synthesis. Terbinafine is well absorbed, although there is a high hepatic first pass effect in humans. It accumulates in skin, nails and fat. Hepatic failure and azotemia increase plasma levels unpredictably. In humans, it is associated with a low incidence of gastrointestinal upset, headache and rash. In veterinary medicine, it has been most commonly used to treat dermatophytosis. Its efficacy for invasive fungal infections has not been well investigated,

although there are a few reports of its use to successfully treat pythiosis.

References

Available on request: jesykes@ucdavis.edu