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Fungi and Antifungals PPS 913 Fall 2012

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Craig Martin

on 13 May 2015

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Transcript of Fungi and Antifungals PPS 913 Fall 2012

Fungi and Antifungal Agents
Craig Martin, PharmD
PPS 913

Caspofungin
1950 1980 1990 1995 2000 2005 2006
Anidulafungin
Posaconazole
Micafungin
Terbinafine
Lipid
Amphotericin B
Formulations (1995-1997)
Voriconazole
Itraconazole
Fluconazole
Ketoconazole
Nystatin (1955)
Amphotericin B (1958)
Griseofulvin (1959)
Flucytosine (1973)
Miconazole (1979)
Development of Antifungal Drugs
Caspofungin
1950 1980 1990 1995 2000 2005 2006
Anidulafungin
Posaconazole
Micafungin
Terbinafine
Lipid
Amphotericin B
Formulations (1995-1997)
Voriconazole
Itraconazole
Fluconazole
Ketoconazole
Nystatin (1955)
Amphotericin B (1958)
Griseofulvin (1959)
Flucytosine (1973)
Miconazole (1979)
Development of Antifungal Drugs
Mycology
Kingdoms of Life
-Monera
-Protista
-Fungi
-Plantae
-Animalia
-Larger in size than bacteria or viruses
-May produce multicellular structures (e.g. hyphae)
-Nonmotile
-Aerobic
-Saprophytic
Fungi
Moulds
Dimorphic
Yeasts
Spores (conidia)
-Asexual reproductive elements
-Produced by filamentous fungi
Hyphae
Vegetative (non-reproductive)
Septate vs aseptate
Hyaline vs dematiaceous (pigmented)
Fungal Habitats
There's Candida in there...
and on there.
Yeasts
Cryptococcus neoformans
Candida spp.
Moulds
Septate hyphae
Nonseptate hyphae
Primary representative: Aspergillus spp.
Zygomycetes
Mucor
Rhizopus
etc
Dimorphic Fungi
Histoplasma
Blastomyces
Coccidoides
"Endemic"
Risk Factors for Fungal Infections
Immunosuppression
Chemotherapy
Steroids
Transplant
HIV/AIDS
Hospitalization and antibiotic therapy (mostly Candida)
Burns
Diabetes
Saccharomyces
Amphotericin B
MOA: Binds to ergosterol in cell membrane to form pores
Critical electrolytes leak from cell
Toxicities
Infusion-related
Nephrotoxicity
IV-only
Fever, chills, rigors
Extremely common
Ambisome
Toxicities led to development of lipid formulations
Azoles
MOA: Bind to 14-alpha-demethylase
(prevents conversion of lanosterol to ergosterol)
Broad spectrum
Candida
Aspergillus
Dimorphics
Zygomycetes
Fluconazole
IV and oral
Important for
Candida infections (most species)
Cryptococcal infections
Itraconazole
Oral capsule and solution
Broad spectrum, but only DOC for dimorphics
PK difficulties
Oral solution requires empty stomach
Capsules require high fat, acidic environment
Solution up to 30% better absorbed
Voriconazole
Expanded mould coverage
Drug of choice for Aspergillus
Very safe
Uncommon hepatotoxicity
More GI toxicity than fluconazole
Lots of drug interactions
Some hepatotoxicity
Unique AE: visual disturbances
Some cases of skin cancers
Posaconazole
Expands coverage to Zygomycetes
Oral suspension only
Lots of drug interactions
Requires hig fat meal
IV, tablets, oral suspension
Echinocandins
Micafungin
Anidulafungin
Caspofungin
Spectrum
Candida (almost all)
Aspergillus
Tip for remembering spectrum...
C for "Candida"
Asp for "Aspergillus"
IV only
Very safe
MOA: Inhibit formation of glucan in cell wall by binding Beta-glucan synthase
Flucytosine
Pyrimidine analog
Oral only
Causes renal toxicity
Not used alone due to rapid resistance developmen
Important in combo for cryptococcal meningitis
Full transcript