dermatophytes

• Class: cutaneous mycoses 
• Location: dead layer of skin, hair, nail
• Disease: dermatophytosis

Sporothrix

• class:  subcutaneous mycoses

• location: subcutis, lymphatics

• disease: sporotrichosis

Histoplasma, blastomyces, coccidioides

• class: systemic mycoses

• location: deep organs, & skin

• disease: histoplasmosis, blastomycosis, coccidioido-mycosis

Amphotericin B: MOA

• polyenes bind avidly to ergosterol in the fungal membranes.

• resistant strains are deficient in ergosterol

• binding leads to leakage of ions & other molecules across cell membrane (thru channels)

• fungicidal

Amphotericin B: uses

• wide spectrum of activity

• remains DOC for initial therapy of several complicated, systemic infections:

  • cryptococcal meningitis, severe histoplasmosis

Amphotericin B: toxicity

• major drawback is inherent toxicity due in part to deoxycholate

• therapeutic index is low

imidazoles

• ketoconazole

• miconazole

• clotrimazole

triazoles

• fluconazole

• itraconazole

• voriconazole

Azoles: MOA

• inhibit lanosterol 14 alpha-demethylase, leading to depletion of erogesterol & altered membrane permeability

• fungistatic

• toxicity not as bad as ampho B

Fluconazole

• narrow spectrum

  • candidiasis, disseminated

  • cryptococcal meningitis

  • coccidioidal meningitis

Itraconazole

• broad spectrum

• all fungal infections (uncomplicated) except CCC

Voriconazole

• In complicated infections, when ampho B doesn't work

  • aspergillosis in cancer pts

  • very narrow spectrum (more than flucanozole)

Flucytosine: MOA

• fungal specific deamination to 5-fluorouracil

• incorporation & DNA chain termination

• selective toxicity in fungi

• combo w/AmphoB (crytococcal meningitis)

Echinocandins: caspofungin

• new class of anti-fungals

• inhibit synthesis of beta (1,3)-D-glucan in fungal cw

• beta (1,3)-D-glucan is not present in mammalian cells

• fungicidal

Echinocandins: caspofungi USES

• narrow spectrum beta (1,3)-D-glucan is important part of cw of candida & aspergillus

• candidiasis, refractory infections b/c aspergillus

• not metabolized by cyt P450~NO TOXICITY

Griseofulvin

• taken orally for treatment of dermatophytes--chronic scalp & nail infections

• deposited keratin precursor cells

• when drug-coated cells reach skin surface, they are resistant to infection

• inhibit disassembly of fungal microtubules--cells become multinucleated

Nystatin

• polyene antibiotic that is too toxic for systemic use

• used mainly for candida albicans infections of skin & mucous membranes--applied topically

Ketoconazole

• topical azole 

• 1st oral azole

• broad spectrum, but poorly tolerated 

Miconazole

• toxicity of IV form

• topical use (2% organic base) for superficial & cutaneous infections

Allylamines: terbinafine, naftifine

MOA

• inhibits squalene epoxidase in ergosterol biosyn pathway, depleting ergosterol

• drug extensively metabolized by cyt P450 enzymes in liver & toxic systemic use