EXAM #4: ANTIFUNGALS Flashcards
List the systemic fungi.
- Histoplasma capsulatum
- Blastomyces dermatiditis
- Coccidioides immitis
- Sporothrix schenckii
List the opportunistic fungi.
- Candida
- Aspergillus
- Cryptococcus neoformans
What are the common cutaneous and subcutaneous fungal infections?
Sporothrix schenckii Dermatophytes - Ringworm - Athlete's Foot - Onychomycosis
What are the unique targets used in antifungal therapy?
- Fungal cell membrane i.e. ERGOSTEROL
- Fungal cell wall i.e. GLUCANS
List the drugs that inhibit Ergosterol synthesis.
Azoles
Naftidfine
Terbnafine
What drug inhibits fungal membrane function?
Amphotericin B
What drug inhibits fungal cell wall synthesis?
Caspofungin
What drug inhibits fungal nuclei acid synthesis?
5-fluorocytosine
What drugs can be used to treat systemic fungal infections?
1) Polyenes- amphotericin B
2) Azoles
3) Flucytosine
4) Echinocandins
What drug has the broadest spectrum of all the antifungals?
Amphotericin B
Why has Amphotericin B been replaced for newer compounds?
High degree of toxicity
What is the MOA of Amphotericin B
- Binds ergosterol in fungal cell membrane
- Forms Amp B pores in fungal membrane
Why is there high toxicity associated with Amphotericin B?
Not only binds ergosterol, but can also bind cholesterol
What is Amphotericin B the treatment of choice for?
1) Disseminated candidasis
2) Cryptococcal (neoformans) meningitis
Note that it is a second line treatment for systemic disease caused by molds
What is the mechanism of resistance of Amphotericin B?
Decreased membrane ergosterol concentration
How is Amphotericin B administered?
- Note that it is INSOLUBLE in water*
- Complex-ed to a bile salt
- Given IV
How is Amphotericin B administered for Cryptococcal meningitis?
Intrathecal
What are the adverse reactions seen with Amphotericin B?
1) Infusion reaction seen in nearly all patients
2) NEPHROTOXICITY
How is the toxicity of Amphotericin B being combated?
Packaging the drug in lipid micelle i.e. “liposomal packaging”
What are the two groups of Azoles?
1) Imidazoles (2x nitrogens)
2) Triazoles (3x nitrogens)
List the imidazoles.
Ketoconazole
Miconazole
Clotrimazole
List the triazoles.
Fluconazole
Itraconazole
Voriconazole
Posaconazole
What is the MOA of the azoles?
Inhibit the enzyme the produces ergosterol
- Makes the cell membrane leaky
What are the mechanisms of resistance to the azoles?
1) Drug efflux pumps
2) Mutation in target enzyme
3) Decreased ergosterol synthesis
Why is Ketoconazole rarely used clinically today?
Toxicity
What is the typical first line drug for systemic fungal infections?
Fluconazole
Why is Fluconazole highly utilized in the treatment of systemic fungal infections?
- Highest TI
- Distributed to the CNS
- Few drug-drug interactions
What is Fluconazole a first ling agent for?
1) Systemic Candidiasis
2) Cryptococcosis
3) Coccidiomycosis
How does Itraconazole compared to Fluconazole?
Broader spectrum of activity BUT lower TI
What does Itraconazole require for absorption?
Low GI pH
Can Itraconazole penetrate the CNS?
NO
What is Itraconazole the drug of choice for?
adf
What is Voriconazole?
Derivative of Fluconazole
What is Voriconazole commonly used to treat?
Aspergillosis
Note that it has replaced Amphotericin B as the first line drug b/c of lower toxicity.
What is the major adverse reaction associated with Voriconazole?
Visual disturbances
What drug has the broadest spectrum of all the azoles?
Posaconazole
What is Posaconazole used to treat?
Mucromycoses
Aspergillus
What is the MOA of Flucytosine?
This is a fluorinated pyrimidine analog that inhibits DNA synthesis
What is Flucytosine used to treat?
Used as a combination therapy for severe Cryptococcal infections
What are the adverse reactions seen with Flucytosine?
Bone marrow supression i.e.
- Anemia
- Leukopenia
- Thrombocytopenia
What is the MOA of the Echinocandins?
Inhibit the synthesis of Beta-glucan i.e. inhibit the CELL WALL
We don’t have Beta-glucan; thus, very low toxicity
List the Echinocandins.
Caspofungin
Micafungin
Andidulafungin
What are the Echinocandins primarily used to treat?
Aspergillus
Candida
Note that both have a high degree of Beta-glucan in their cell wall
What is Griseofulvin used to treat?
This is an oral agent used to treat Dermatophyte infections
What is unique about Griseofulvin?
Concentrates in Keratin precursor cells
- Skin
- Hair
- Nails
What are Allylamines?
Class of antifungal that inhibits ergosterol synthesis
What is the MOA of Allylamines?
Inhibit the enzyme squalene epoxidase
What is the hallmark Allylamine?
Terbinafine
What is Terbinafine used to treat?
First line for Onychomycosis i.e. nail infections
What are the topical antifungal agents?
Nystatin- polyene Clotrimazole- azole Miconazole- azole Terbinafine- Allylamine Naftifine- Allylamine
What is the MOA of Nystatin?
Polyene that binds ergosterol and forms pores
- Only used topically
What is Nystatin used to treat?
Candida
- Oral
- Vagial i.e. yeast infections
What are the topical azoles, Clotrimazole and Miconazole used to treat?
1) Vulvovaginal candidiasis
2) Dermatophyte infections
3) Oral thrush
What infections are the topical Allylamines used to treat?
Tinea curis (jock-itch) Tinea corporis (ringworm)
