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
Candida
Cryptococcus
Rhodotorula
Molds
Aspergillus
Zygomycetes
Scedosporidium
Cladosporidium
Ulocladium
Fusarium
Paecilomyces
Dimorphic
Coccidioides
Histoplasma
Blastomycosis
Paracoccidiodes
Sporothrix
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




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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
Abelcet
Ambisome
(1958)
(1995)
(1997)


Nucleosides:
Allyamines:
Flucytosine
Terbinafine
(1972)
(1996)

Azoles:
Miconazole
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Posaconzole
(1978)
(1981)
(1990)
(1992)
(2002)
(2006)

Echinocandins:
Caspofungin
Micafungin
Anidulafungin
(2001)
(2005)
(2006)
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
Abelcet
Ambisome
(1958)
(1995)
(1997)


Nucleosides:
Allyamines:
Flucytosine
Terbinafine
(1972)
(1996)

Azoles:
Miconazole
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Posaconzole
(1978)
(1981)
(1990)
(1992)
(2002)
(2006)

Echinocandins:
Caspofungin
Micafungin
Anidulafungin
(2001)
(2005)
(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




Electrolyte abnormalities
Infusion reactions



Dose-dependent
Increases with other nephrotoxic medications
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
Abelcet
Ambisome
(1958)
(1995)
(1997)


Nucleosides:
Allyamines:
Flucytosine
Terbinafine
(1972)
(1996)

Azoles:
Miconazole
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Posaconzole
(1978)
(1981)
(1990)
(1992)
(2002)
(2006)

Echinocandins:
Caspofungin
Micafungin
Anidulafungin
(2001)
(2005)
(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
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
Abelcet
Ambisome
(1958)
(1995)
(1997)


Nucleosides:
Allyamines:
Flucytosine
Terbinafine
(1972)
(1996)

Azoles:
Miconazole
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Posaconzole
(1978)
(1981)
(1990)
(1992)
(2002)
(2006)

Echinocandins:
Caspofungin
Micafungin
Anidulafungin
(2001)
(2005)
(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
Abelcet
Ambisome
(1958)
(1995)
(1997)


Nucleosides:
Allyamines:
Flucytosine
Terbinafine
(1972)
(1996)

Azoles:
Miconazole
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Posaconzole
(1978)
(1981)
(1990)
(1992)
(2002)
(2006)

Echinocandins:
Caspofungin
Micafungin
Anidulafungin
(2001)
(2005)
(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 P450
Increased serum
concentration of coadministered drug or
metabolite
Oral hypoglycemics
S-warfarin
R-Wafarin
Cyclosporin
Tacrolimus
Sirolimus
Phenytoin
Carbamezepine
Triazolam, alprazolam,
midazolam
Diltiazem
Lovastatin
Isoniazid
Rifabutin
Quinidine
Protease inhibitors
(saquinavir,
ritonavir)
Busulfan
Vincristine
Cyclophosphamide
Digoxin
Loratidine
and others…
Azole Drug Interactions


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
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
Abelcet
Ambisome
(1958)
(1995)
(1997)


Nucleosides:
Allyamines:
Flucytosine
Terbinafine
(1972)
(1996)

Azoles:
Miconazole
Ketoconazole
Fluconazole
Itraconazole
Voriconazole
Posaconzole
(1978)
(1981)
(1990)
(1992)
(2002)
(2006)

Echinocandins:
Caspofungin
Micafungin
Anidulafungin
(2001)
(2005)
(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