Presentation is loading. Please wait.

Presentation is loading. Please wait.

ANTIFUNGALS LauraLe Dyner, MD Pediatric Infectious Disease Fellow October 2008.

Similar presentations


Presentation on theme: "ANTIFUNGALS LauraLe Dyner, MD Pediatric Infectious Disease Fellow October 2008."— Presentation transcript:

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 CandidaAspergillus Coccidioides CryptococcusZygomycetes Histoplasma RhodotorulaScedosporidium 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)

12

13

14 Amphotericin B 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:  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 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 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)

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

55

56

57

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


Download ppt "ANTIFUNGALS LauraLe Dyner, MD Pediatric Infectious Disease Fellow October 2008."

Similar presentations


Ads by Google