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

Fungal Cell Structure

Yeasts Molds Dimorphic Candida Aspergillus Coccidioides Cryptococcus Zygomycetes Histoplasma Rhodotorula Scedosporidium Blastomycosis Cladosporidium Paracoccidiodes Ulocladium Sporothrix Fusarium Paecilomyces

Yeasts Unicellular Smooth in appearance 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 Systemic Exogenous 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)

Amphotericin B Fluconazole Voriconazole/ Itraconazole Posaconazole Active against most fungal pathogens, but certain species; Resistant to A. terreus, Scedosporidium, C. lusitaniae, some zygomyces. Fluconazole Active against yeasts, but not molds. Voriconazole/ Itraconazole Very broad-spectrum activity against yeasts, molds, endemic fungi, but no activity against zygomyces. Posaconazole Very broad-spectrum activity against yeast, molds (e.g. Aspergillus spp., Fusarium spp., Scedosporium spp., some zygomyces) Echinocandins Active against yeasts and Aspergillus; not very active against other molds

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

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: Only given PO 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

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

Terbinafine

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 Resistance 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

Triazoles

Azole Drug Interactions

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 Metabolized by cytochrome P450 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)

Echinocandins Caspofungin Micafungin Anidulafungin

Echinocandins Only given IV Mechanism of Action Block fungal wall synthesis by inhibiting the enzyme 1,3 beta glucan synthase

Echinocandins

Echinocandins: Antifungal activity Most Candida & Aspergillus Does not have activity against: Cryptococcus

Treatment of Fever and Neutropenia Consider adding antifungal coverage for fever lasting > 4-5 days. Empiric therapy Amphotericin (Gold Standard) Ambisome Itraconazole Caspofungin Voriconazole

Treatment of Candidiasis Removal of the affected central line Treatment with Amphotericin, Ambisome, or Fluconazole Fluconazole would not be appropriate if the organism is resistant.

Treatment of Aspergillus Voriconazole Amphotericin/Ambisome Surgical excision may be required in some cases

Conclusion Important to consider first if you are treating a mold or yeast, then direct therapy if the organism is known Different antifungals have different spectrums of antifungal coverage

Questions and Comments

Resources IDSA (Infectious Disease Society of America) Centers for Disease Control Doctor Fungus UpToDate 2007 The 2006 American Academy of Pediatrics Redbook PREP American Academy of Pediatrics Questions 1999-2006