ANTIFUNGALS LauraLe Dyner, MD Pediatric Infectious Disease Fellow October 2008

1. ANTIFUNGALSLauraLe Dyner, MDPediatric Infectious Disease FellowOctober 2008

2. 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

3. Fungal Cell Structure

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

5. Yeasts • Unicellular • Although some species form pseudohyphae • Smooth in appearance • Asexual reproduction (budding/fission) is more common than sexual reproduction

6. Molds • Multicellular • “Fuzzy” in appearance • Hyphae: determines the type of mold • Mold spores can survive harsh environments

7. Dimorphic Fungi • Capable of growing in mold or yeast form • Differs based on environmental condition • Temperature • CO2 • Nutrients • Coccidiomycosis:

8. Fungal Disease • Superficial/Subcutaneous • Dermatophytes • Candiadiasis • Sporotrichosis • Systemic • Exogenous • Blastomycosis, Histoplasmosis, Coccidiomycosis, Sporotrichosis • Opportunistic • Aspergillosis, Candidiasis, Cryptococcus, Zygomycosis

9. Immunocompromised Hosts • Neonates • Oncology patients • Bone Marrow Transplant patients • Solid Organ Transplant patients • Patients with primary immunodeficiencies • Patients with HIV

10. 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

11. 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)

15. 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)

16. Polyenes • Amphotericin B, Ambisome, Abelcet • Nystatin

17. 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

18. Amphotericin

19. Amphotericin: Antifungal activity • Most Candida & Aspergillus • Does not have activity against: • Candida lusitaniae & guilliermondii • Aspergillus terreus & some flavus • Fusarium • Scedosporidium

20. 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

21. Amphotericin: Drug Interactions • Synergistic (increasing uptake) • Rifampin • Flucytosine • Tetracyclines • Antagonistic • Imidazoles (Ketoconazole, Clotrimazole)

22. Amphotericin Lipid Formulations • AmBisome • Abelcet • Amphotec

23. 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

24. 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)

25. Nucleoside Analogs • Flucytosine

26. 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

27. Nucleoside Analogs

28. Nucleoside Analogs: Antifungal activity • Candida & Cryptococcus • Does not have activity against: • Molds • *Well distributed in the CNS*

29. Nucleosides: Toxicity • Bone Marrow suppression • Abdominal pain • Loose stools

30. 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)

31. Allyamines • Terbinafine

32. Allyamines • Mechanism: • Reduced ergosterol biosynthesis • Terbinafine specifically inhibits squalene epoxidase • Highly lipophilic; accumulates in skin, nails, and fatty tissue • Treats dermatophytes

33. Terbinafine

34. 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)

35. Azoles • 5-membered organic ring with either 2 or 3 nitrogen molecules • 2 = Imidazoles • 3 = Triazoles

36. Imidazoles • Clotrimazole • Miconazole • Ketoconazole

37. Triazoles • Fluconazole • Itraconazole • Voriconazole • Posaconazole

38. 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

39. Triazoles

40. Azole Drug Interactions

41. Azole Drug Interactions • Rifampin • Sirolimus • Tacrolimus • Cyclosporine • Corticosteroids

42. Fluconazole: Antifungal activity • Most Candida species, Cryptococcus, Coccidioides • Does not have activity against: • Candida krusei (intrinsically resistant) • Candida glabrata (dose-dependent resistance) • Aspergillus

43. Fluconazole • Excellent bioavailability • Metabolized by the liver (cytochrome P450) • Cleared by the kidney • Required renal dosing • Few side effects • Can see transaminitis

44. Itraconazole: Antifungal activity • Candida, Cryptococcus, Histoplasma, Coccidioides, Aspergillus

45. Itraconazole • Absorption is not reliable • 55% for the solution • Less with the capsule • Metabolized by cytochrome P450 • Cleared by the kidney • Requires renal dosing

46. Voriconazole: Antifungal activity • Candida, Aspergillus, Fusarium, Scedosporidium • Has coverage for fluconazole resistant species of Candida and Aspergillus • Does not have activity against: • Zygomycetes

47. 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

48. Voriconazole: Drug Interactions • Sirolimus levels can be dramatically increased • Not advised while on Voriconazole • May need to decrease: • Tacrolimus • Cyclosporine • Coumadin • Omeprazole

49. Posaconazole: Antifungal activity • Similar to Voriconazole • Candida, Aspergillus, Fusarium, Scedosporidium • Includes Zygomycetes

50. 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)