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ANTIFUNGALS LauraLe Dyner, MD Pediatric Infectious Disease Fellow October 2008. Fungi. Plant-like organisms that lack chlorophyll 1 of the 5 Kingdoms More than 100,000 species 400 known to cause disease in plants, animals, and humans Cell: Chitin cell wall Cell membranes have ergosterol.
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ANTIFUNGALSLauraLe Dyner, MDPediatric Infectious Disease FellowOctober 2008
Fungi • Plant-like organisms that lack chlorophyll • 1 of the 5 Kingdoms • More than 100,000 species • 400 known to cause disease in plants, animals, and humans • Cell: • Chitin cell wall • Cell membranes have ergosterol
Yeasts Molds Dimorphic Candida Aspergillus Coccidioides Cryptococcus Zygomycetes Histoplasma Rhodotorula Scedosporidium Blastomycosis Cladosporidium Paracoccidiodes Ulocladium Sporothrix Fusarium Paecilomyces
Yeasts • Unicellular • Although some species form pseudohyphae • Smooth in appearance • Asexual reproduction (budding/fission) is more common than sexual reproduction
Molds • Multicellular • “Fuzzy” in appearance • Hyphae: determines the type of mold • Mold spores can survive harsh environments
Dimorphic Fungi • Capable of growing in mold or yeast form • Differs based on environmental condition • Temperature • CO2 • Nutrients • Coccidiomycosis:
Fungal Disease • Superficial/Subcutaneous • Dermatophytes • Candiadiasis • Sporotrichosis • Systemic • Exogenous • Blastomycosis, Histoplasmosis, Coccidiomycosis, Sporotrichosis • Opportunistic • Aspergillosis, Candidiasis, Cryptococcus, Zygomycosis
Immunocompromised Hosts • Neonates • Oncology patients • Bone Marrow Transplant patients • Solid Organ Transplant patients • Patients with primary immunodeficiencies • Patients with HIV
Invasive Fungal Infections • Neutropenic patients are particularly at risk for fungal infections • Percent of patients with neutropenia developing invasive fungal infections: • By day 20 of neutropenia, 20% of patients • By day 35 of neutropenia, 60% of patients • Most infections due to Candida and Aspergillus Wingard, CID 2004;39:S38-43
Classes of Antifungals • Polyenes: Amphotericin B (1958) Abelcet (1995) Ambisome (1997) • Nucleosides: Flucytosine (1972) • Allyamines: Terbinafine (1996) • Azoles: Miconazole (1978) Ketoconazole (1981) Fluconazole (1990) Itraconazole (1992) Voriconazole (2002) Posaconzole (2006) • Echinocandins: Caspofungin (2001) Micafungin (2005) Anidulafungin (2006)
Classes of Antifungals • Polyenes: Amphotericin B (1958) Abelcet (1995) Ambisome (1997) • Nucleosides: Flucytosine (1972) • Allyamines: Terbinafine (1996) • Azoles: Miconazole (1978) Ketoconazole (1981) Fluconazole (1990) Itraconazole (1992) Voriconazole (2002) Posaconzole (2006) • Echinocandins: Caspofungin (2001) Micafungin (2005) Anidulafungin (2006)
Polyenes • Amphotericin B, Ambisome, Abelcet • Nystatin
Polyenes • Mechanism: • Binds to ergosterol in the fungal cell membrane leakage of the intracellular cations and cell death • Selectivity is based on the difference in fungal vs. mammalian cell membrane (ergosterol vs. cholesterol) • Resistance is rare and mediated by changes in ergosterol content in fungal cell membrane
Amphotericin: Antifungal activity • Most Candida & Aspergillus • Does not have activity against: • Candida lusitaniae & guilliermondii • Aspergillus terreus & some flavus • Fusarium • Scedosporidium
Amphotericin: Toxicity • Can also bind to cholesterol • Its oxidation causes free radicals • **Nephrotoxicity • Dose-dependent • Increases with other nephrotoxic medications • Electrolyte abnormalities • Infusion reactions • Fever, rigors, headache, nausea, vomiting • Anemia • Thrombophlebitis
Amphotericin: Drug Interactions • Synergistic (increasing uptake) • Rifampin • Flucytosine • Tetracyclines • Antagonistic • Imidazoles (Ketoconazole, Clotrimazole)
Amphotericin Lipid Formulations • AmBisome • Abelcet • Amphotec
Amphotericin Lipid Formulations • Major advantage is that they have less nephrotoxicity • Require higher doses • 3 mg/kg/day for candidiasis • 4-6 mg/kg/day for invasive fungal infections • Decreased severity and frequency of acute infusion reactions
Classes of Antifungals • Polyenes: Amphotericin B (1958) Abelcet (1995) Ambisome (1997) • Nucleosides: Flucytosine (1972) • Allyamines: Terbinafine (1996) • Azoles: Miconazole (1978) Ketoconazole (1981) Fluconazole (1990) Itraconazole (1992) Voriconazole (2002) Posaconzole (2006) • Echinocandins: Caspofungin (2001) Micafungin (2005) Anidulafungin (2006)
Nucleoside Analogs • Flucytosine
Nucleoside Analogs • Mechanism: • DNA substrate analog that leads to incorrect DNA synthesis • Only given PO • Often used in combination with Amphotericin • Should not be used as monotherapy • Resistance develops rapidly through alteration of cytosine permease or altered metabolism
Nucleoside Analogs: Antifungal activity • Candida & Cryptococcus • Does not have activity against: • Molds • *Well distributed in the CNS*
Nucleosides: Toxicity • Bone Marrow suppression • Abdominal pain • Loose stools
Classes of Antifungals • Polyenes: Amphotericin B (1958) Abelcet (1995) Ambisome (1997) • Nucleosides: Flucytosine (1972) • Allyamines: Terbinafine (1996) • Azoles: Miconazole (1978) Ketoconazole (1981) Fluconazole (1990) Itraconazole (1992) Voriconazole (2002) Posaconzole (2006) • Echinocandins: Caspofungin (2001) Micafungin (2005) Anidulafungin (2006)
Allyamines • Terbinafine
Allyamines • Mechanism: • Reduced ergosterol biosynthesis • Terbinafine specifically inhibits squalene epoxidase • Highly lipophilic; accumulates in skin, nails, and fatty tissue • Treats dermatophytes
Classes of Antifungals • Polyenes: Amphotericin B (1958) Abelcet (1995) Ambisome (1997) • Nucleosides: Flucytosine (1972) • Allyamines: Terbinafine (1996) • Azoles: Miconazole (1978) Ketoconazole (1981) Fluconazole (1990) Itraconazole (1992) Voriconazole (2002) Posaconzole (2006) • Echinocandins: Caspofungin (2001) Micafungin (2005) Anidulafungin (2006)
Azoles • 5-membered organic ring with either 2 or 3 nitrogen molecules • 2 = Imidazoles • 3 = Triazoles
Imidazoles • Clotrimazole • Miconazole • Ketoconazole
Triazoles • Fluconazole • Itraconazole • Voriconazole • Posaconazole
Triazoles • Mechanism • Inhibits the fungal cytochrome P450 14-alpha dexamethylase; an enzyme that acts in ergosterol biosynthesis • Resistance • Mutations in the target enzymes • Upregulation of efflux transporters
Azole Drug Interactions • Rifampin • Sirolimus • Tacrolimus • Cyclosporine • Corticosteroids
Fluconazole: Antifungal activity • Most Candida species, Cryptococcus, Coccidioides • Does not have activity against: • Candida krusei (intrinsically resistant) • Candida glabrata (dose-dependent resistance) • Aspergillus
Fluconazole • Excellent bioavailability • Metabolized by the liver (cytochrome P450) • Cleared by the kidney • Required renal dosing • Few side effects • Can see transaminitis
Itraconazole: Antifungal activity • Candida, Cryptococcus, Histoplasma, Coccidioides, Aspergillus
Itraconazole • Absorption is not reliable • 55% for the solution • Less with the capsule • Metabolized by cytochrome P450 • Cleared by the kidney • Requires renal dosing
Voriconazole: Antifungal activity • Candida, Aspergillus, Fusarium, Scedosporidium • Has coverage for fluconazole resistant species of Candida and Aspergillus • Does not have activity against: • Zygomycetes
Voriconazole • Bioavailability > 95% • Metabolized by CYP2C19 • Requires renal dosing for the IV formulation • PO voriconazole does not require renal dosing • Side effects • Visual disturbances • Photosensitivity
Voriconazole: Drug Interactions • Sirolimus levels can be dramatically increased • Not advised while on Voriconazole • May need to decrease: • Tacrolimus • Cyclosporine • Coumadin • Omeprazole
Posaconazole: Antifungal activity • Similar to Voriconazole • Candida, Aspergillus, Fusarium, Scedosporidium • Includes Zygomycetes
Classes of Antifungals • Polyenes: Amphotericin B (1958) Abelcet (1995) Ambisome (1997) • Nucleosides: Flucytosine (1972) • Allyamines: Terbinafine (1996) • Azoles: Miconazole (1978) Ketoconazole (1981) Fluconazole (1990) Itraconazole (1992) Voriconazole (2002) Posaconzole (2006) • Echinocandins: Caspofungin (2001) Micafungin (2005) Anidulafungin (2006)