1. ANTIFUNGALS LauraLe Dyner, MD Pediatric Infectious Disease Fellow October 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 Smooth in appearance
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 Systemic Exogenous
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)

14. 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

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: 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

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 Resistance
Inhibits the fungal cytochrome P 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 Metabolized by cytochrome P450
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)

51. Echinocandins
Caspofungin
Micafungin
Anidulafungin

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

53. Echinocandins

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

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

59. 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.

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

61. 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

62. Questions and Comments

63. 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