ANTIFUNGALSLauraLe Dyner, MD

Pediatric 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

Fungal Cell Structure

Fungal cell

Mannoproteins

-(1,6)-glucan-(1,3)-glucan

Chitin

Phospholipid bilayerof cell membrane

Cell membrane and cell wall

Ergosterol-(1,3)-glucan synthase

Squalene

ErgosterolSynthesisPathway

DNA/ RNA Synthesi s

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, Wingard, CIDCID 2004;39:S38- 2004;39:S38-4343

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)

M e d ic a l M y c o lo g y :T h e L a s t 5 0 Y e a r s

0

2

4

6

8

1 0

1 2

1 4

1 9 5 0 1 9 6 0 1 9 7 0 1 9 8 0 1 9 9 0 2 0 0 0

5 - F CM i c o n a z o l e

K e t o c o n a z o l eF l u c o n a z o l e

I t r a c o n a z o l e

L - A m BA B C DA B L C

T e r b i n a f i n e

# o f d ru g s

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

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:

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

5-FC

5-FC

5-FU

Cytosine permeaseCytosine permease

Cytosine deaminaseCytosine deaminase

PhosphorylationPhosphorylation

Inhibition of thymidylate synthaseInhibition of thymidylate synthase

FdUMP

Conversion todeoxynucleosidesConversion todeoxynucleosides

dUMP

dTMP

Inhibition of DNA synthesisInhibition of DNA synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

FdUMP

FUTP

Substitution for uracilSubstitution for uracil

5-FC, 5-fluorocytosine; 5-FU, 5-fluorouracil; FdUMP, 5-fluorodeoxyuridine;FUMP, 5-fluorouridine monophosphate; FUDP, 5-fluorouridine diphosphate;FUTP, 5-fluorouridine triphosphate; dUMP, deoxyuridine monophosphate;dTMP, deoxythymidine monophosphate

5-FC

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 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 Inhibition of CYP P450I ncr eased ser um concent r at i on of co-admi ni st er ed dr ug or met abol i t e

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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)

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