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THERAPY

Because they are eukaryotic, fungi are biochemically similar to the human host. Therefore it is difficult to develop chemotherapeutic agents that will destroy the invading fungus without harming the patient.

Mechanism of action IN FUNGAL THERAPY

We attempt to induce cell injury by causing the cell membrane of the fungus to become permeable.

PROBLEM

Finding an agent that will selectively injure fungal cell walls without damaging the host cell.

•Mammalian cells – cholesterol

•Fungal cells - ergosterol

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Acetyl-CoA

Acetoacetyl-CoA

HMG-CoA

Mevalonic Acid

Squalene

Squalene-2,3-Epoxide

Lanosterol

ErgosterolPolyenes

Azoles

Morpholines

Allylamines

JB 5/00

Ergosterol Synthesis

PRIMARY ANTI-FUNGAL AGENTS1. Polyene derivatives

Amphotericin B

Nystatin

2. Azoles

Ketoconazole

Fluconazole

Itraconazole

Voriconazole

PRIMARY ANTI-FUNGAL AGENTS3. Griseofulvin

4. 5-fluorocytosine (5-FC)

5. Allylamines

-Terbinafine (Lamasil)

6. Echinocandins

- Caspofungin

AMPHOTERICIN BMechanism of Action Amphotericin B binds to sterols

Ergosterol is a constituent of the fungal cell wall

AMB has a greater avidity for ergosterol than for the cholesterol in the human cell wall

Binding to the fungal cell wall alters the permeability and the intracellular contents leak

Adverse effects Infusion related toxicity- Fever, chills, muscle rigor,

hypotension due to histamine release (a test dose is advisable) and can be alleviated partly by pretreatment with NSAIDs, antihistamines, meperidine, and steroids.

Thrombophlebitis

Nephrotoxic, Anemia

Uses Amp B has a wide fungicidal spectrum and remains the DOC (or co-DOC) for

severe and rapidly progressive infections of mucormycosis, histoplasmosis, blastomycosis, coccidiodomycosis

Amp B is synergistic with flucytosine in candidiasis and cryptococcal meningitis

Infections not responding to azoles or when CNS is involved- invasive aspergillosis, sporotrichosis etc

To prevent relapse in AIDS patients

Nystatin (too toxic for systemic use) is used topically for localized infections (e.g., candidiasis).

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Formulations Amphotericin B is complexed with deoxycholate (C-AMB)

Three lipid formulations of amphotericin B

Amphotericin B colloidal dispersion (ABCD, AMPHOTEC, AMPHOCIL)

AMBISOME is a small, unilamellar vesicle formulation.

Amphotericin B lipid complex (ABLC, ABELCET)

Azoles Imidazole and triazole The imidazole and triazole groups of antifungal drugs inhibit

the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell membrane synthesis. These drugs also block steroid synthesis in humans, inhibit liver enzymes.

Imidazoles: Miconazole Ketoconazole Clotrimazole Econazole

Antifungal AgentsThe triazoles are newer, and are less

toxic and more effective: Fluconazole

Itraconazole

Voriconazole

Adverse effects Decreased synthesis of steroids, including cortisol and androgens →

decreased libido, gynecomastia, menstrual irregularities (ketoconazole)

Rash

Fluid retention, increase in BP

Rare hepatotoxicity

Inhibition of hepatic P450s and metabolism of cyclosporine, phenytoin, warfarin, etc. (ketoconazole)

Disulfiram-like reactions with ethanol

Uses Ketoconazole

Co-DOC for Paracoccidioides and backup for Blastomyces and Histoplasma.

Oral use in mucocutaneous candidiasis or dermatophytoses. Fluconazole-

DOC for esophageal and invasive candidiasis and coccidioidomycoses.

Prophylaxis and suppression in cryptococcal meningitis Itraconazole

DOC in blastomycoses, histoplasmosis, paracoccidiodosis, pseudolescheriasis and sporotrichoses; backup for several other mycoses and candidiasis

Clotrimazole and Miconazole Used topically for candidial and dermatophytic infections.

Interferes With RNA Synthesis

Inhibits DNA synthesis

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Mechanism of action Uses and Adverse effects Used in combination with amp B in severe candidial,

cryptococcal and chromoblastomycosis infections-especially when meninges involved as it enters CSF or in AIDS patients

Used alone- resistance develops

Adverse effects

Bone marrow supression

Enterocolitis

Azotemia when combined with amp B

Rash, hepatic dysfunction

Griseofulvin binds to polymerized microtubules, inhibits fungal mitosis

Active only against dermatophytes (orally, not topically) by depositing in newly formed keratin. Tinea capitis, cruris, corporis infections.

Adverse effects: headache, peripheral neuritis, phototoxicity, potentiates ethanol

Enzyme inducer, avoid with history of porphyria

Antifungal Agents Allylamines

Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis:

Terbinafine

Possibly superior to griseofulvin in onychomycoses.

Adverse effects: GI distress, rash, headache, possible hepatotoxicity.

Antifungal Agents Echinocandin

Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase:

Caspofungin

Invasive aspergillosis and esophageal candidiasis not responsive to amp B

Topical use Clotrimazole, econazole, miconazole etc

Nystatin, amp B

Indications for topical use include ringworm, tinea versicolor, and mucocutaneous candidiasis.

Formulations available for cutaneous, vaginal and oral application