Download Introduction to Anti-Fungals

Introduction to Anti-Fungals
Selective toxicity = the ability to harm the parasite/virus while minimally affecting your patient
1. Example mechanism: fungi have cell walls and people have cell membranes, so target
components of cell walls
 Classification of anti fungal drugs
1. Polyenes (e.g. amphotericin B)
2. Flucytosine
3. Azoles
4. Echinocandins
5. Topical drugs for mucocutaneous infections (see handout)
1) Ergosterol is a good opportunity to express selective toxicity
2) Drugs that attack the mitotic spindles keep the fungi/viral infections from
reproducing
 Agents for systemic fungal infections
○ Amphotericin B
○ Azoles (Triazoles are now favorites)
○ Flucytosine
○ Echinocandins
 Oral Mucocutaneous Agent
○ Griseofulvin
○ Terbinafine
 Topical Mucocutaneous Agents
○ Nystatin
○ Topical Azoles
○ Topical Allylamines
1. Amphotericin B
o Mode of Action:
- Binds ergosterol and forms leaky pores (channels) on cell membranes
o Antifungal Activity:
- Candida spp, Cryptococcus neoformans, Blastomyces dermatitis, Histoplasma
capsulatum, Sporothrix schenkii, Coccidioides immitis, Paracoccidioides
braziliensis, Aspergillus spp, Penicillium marneffei and Mucormyces
2. Flucytosine
o Mechanism of action:
- Flucytosine undergoes several steps of metabolism within the fungal cells to the
active metabolites 5-fluorodeoxyuridine monophosphate (inhibits DNA
synthesis) and fluorouridine triphosphate, an inhibitor of RNA synthesis
o Clinical uses:
- Cryptococcus neoformans, some Candida species and dermatiaceous molds that
cause chromoblastomycosis
o Adverse Effects:
- Intestinal flora converts flucytosine to its metabolite fluorouracil (an anti
neoplastic drug)  bone marrow toxicity, anemia, leukopenia and
thrombocytopenia
Systemic Antifungal Drugs
1. Azoles
o Classification of azoles:
1) Imidazoles
- Ketoconazole, miconazole and clotrimazole (mic and clo- are now used
only as topical agents)
2) Triazoles
- Itraconazole, fluconazole and voriconazole
o Mechanism of action:
- azoles inhibit fungal cytochrome p450 enzymes and reduce ergosterol synthesis.
triazoles are more selective for fungal p450 than imidazoles
Fluconazole:
- highly water soluble and good body fluid distribution (e.g. CSF)
- Unlike ketoconazole and itraconazole, fluconazole has high bioavailability
and has the least effects of all azoles on cytochrome P450 enzymes
- It is the agent most used in treatment of mucocutaneous candidiasis.
Voriconazole:
- new, good absorption, high bioavailability and less plasma protein binding
than itraconazole. Oral and i.v. formulations are available
- Undergoes hepatic metabolism, less human P450 enzyme induction.
2. Echinocandins
o Mechanism of action:
destroys fungal cell wall by inhibiting  -glycan synthesis
o Clinical uses:
1) Caspofungin:
o disseminated and mucocutaneous candida infections, empiric antifungal
therapy during febrile neutropenia.
o Recommended for invasive aspergillosis only as salvage therapy in
patients not responding to amphotericin B
2) Micafungin:
o is used only for mucocutaneous candidiasis and prophylaxis of candida
infection in bone marrow transplant patients
3) Anidulafungin:
o esophageal candidiasis, invasive candidiasis septicemia
Drugs for Mucocutaneous Infection
1. Griseofulvin
○ Used only for systemic treatment of dermatophytosis
○ Griseofulvin binds to microtubules and disrupts mitosis. It binds to keratin in the skin
and protects from new fungal infections
○ Requires 2-6 weeks for the drug to take effect with skin treatment and months for nail
treatment
2. Terbinafine
o Available in oral formulations
o Used for treating dermatophytes esp. onychomycosis
o Interferes with ergosterol biosynthesis (like azoles), no action on P450, inhibits
fungal squalene epoxidase  accumulation of sterol squalene which is toxic to
fungi