Exam 3: Antifungals Flashcards
What is the MOA of antifungals and what are the two exceptions to this?
They target the cell membrane or cell wall, except for Griseofulvin and Flucytosine
What is Amphotericin B produced by?
Streptomyces Nodosus
What is the MOA of amphotericin B?
Interaction with sterol of fungal membrane, ergosterol, that results in the loss of intracellular components through depolarization and pore formation
What is the spectrum of Amphotericin B. Is it fungicidal or static?
Broad spectrum.
Fungicidal
What is the DOC for most systemic fungal infections?
Amphotericin B
What is the likely cause of the toxicities of amphotericin?
It binds to human membrane sterols as well as fungal sterols.
Due to either
1) Infusion of drug
2) Reactions occurring over time
What are the infusion related toxicities of Amphotericin B?
Immediate.
Chills, fever, muscle spasms, headache, vomiting. May occur with each injection and can be lessened by slowing the infusion rate or decreasing daily dose
What are the toxicities that occur from reactions over time with Amphotericin B?
- Powerful nephrotoxicity agent (dose dependent and can cause irreversible kidney damage)
- Azotemia (BUN and creatinine elevated)
- Hepatic failure
- Hypersensitivity
What is the MOA of Flucytosine?
Flucytosine is converted to 5- fluorouracil which interferes with fungal DNA and RNA synthesis
What is the spectrum of Flucytosine?
Lower than amphotericin B, used for cryptococcus neoformans, some strains of candida, aspergillosis fumigatus, etc.
What is the DOC for crytococcus infections?
Flucytosine plus amphotericin B (significant synergistic effect)
Does Amphotericin B or Flucytosine have better CSF penetration?
Flucytosine
What are the toxicities of Flucytosine?
Depression of bone marrow, GI disturbace, elevated ALT/AST
What is the MOA of the “-azoles”?
Static or cidal?
Inhibits synthesis of ergosterol, leads to depletion of ergosterol and accumulation of toxic sterols causing increased permeability and inhibition of fungal growth.
Fungistatic
What is the spectrum of ketoconazole?
Broad spectrum antifungals
Poor CNS penetration
What are the toxicities associated with ketoconazole?
- Potent inhibitor of P450s, drug interactions
- Gynecomastia and impotence due to inhibition of adrenal and testicular function
- Prolonged QT
What are the contraindications of Ketoconazole?
Hepatic disease
Why is fluconazole used in Fungal meningitis?
It penetrates well into body fluids, particularly CSF where drug concentration reaches 50-90%
What are the toxicities associated with Fluconazole?
- Less toxic than amphotericin B or Flucytosine and better tolerated than Ketoconazole
- Less drug interactions, but potent inhibitor of CYP2C9
- Headache
What is used for suppressive therapy and/or prophylactic therapy in HIV+ patients?
Fluconazole
How is fluconazole administered?
Oral or IV
How is Ketoconazole administered?
Oral, or available in shampoos and creams
How is Voriconazole administed?
Oral or IV
What is the DOC for Aspergillus?
Voriconazole and amphotericin B
What are the toxicities associated with Voriconazole?
-Drug interactions (potent inhibitor of P450s)
-Genetic polymorphism of CYP2C19
Extensive metabolizer results in low drug concentration
Poor metabolizer results in high drug concentration
-Reversible visual impairment
What is the spectrum of Itraconazole?
Active against many of the same fungi as ketoconazole and fluconazole, but has greater activity against Apergillus (but not DOC!)
What are the toxicities associated with Itraconazole?
- Drug interactions (potent inhibitor of CYP34A)
- GI effects
How is itraconazole administered?
Oral or IM
How does Itraconazole bioavailability change when taken via capsule and oral solution?
- Capsules: 40-50% if administered on empty stomach, 90-100 when administered with meal
- Oral solution: 55% under fed conditions, increases to 72% under fasting
What is the spectrum for Isavuconazonium?
Indicated for the treatment of Mucormycosis and invasive aspergillosis
What are the toxicities associated with Isavuconazonium?
- Drug interactions (moderate inhibitor of CYP3A4)
- Nephrotoxicity
- Decrease in the QT interval
What are the contraindications of Isavuconazonium?
Patients with familial short QT syndrome
What is the spectrum for Posaconazole?
Indicated for the treatment of Apergillus and candida
What are the toxicites associated with Posaconazole?
- Drug interactions (potent inhibitor of CYP3A4)
- GI upset, stomatitis, vaginal bleeding, hypokalemia, and thrombocytopenia
What are the 3 drugs in the Echinocandins class?
Caspofungin, Micafungin, and Andulafungin
What makes Caspofungin a good treatment option for Apergillosis?
Lack of nephrotoxicity and few drug interactions
How is caspofungin administered?
IV slow infusion
What is the MOA of Griseofulvin? Is it cidal or static?
Binds to the microtubules of certain fungi. It binds specifically to keratin and prevents infection in new skin. Fungistatic
What is the DOC for onychomycosis?
Griseofulvin
What are the contraindications for griseofulvin?
- Acute intermittent porphyria
- Hepatocellular failure
- Pregnancy and men 6 months prior to fathering a child
What are the toxicites associated with griseofulvin?
GI upset, headache*, disulfiram like effects, hematological disturbances, rashes, photosensitivity, etc
What is the MOA of Terbinafine? Is it cidal or static?
Interferes with sterol biosynthesis, inhibits squalene monooxygenase, build up of squalene is toxic to fungi.
Fungicidal
What is terbinafine used to treat?
Less active against candida, but effective for onychomycosis (not DOC).
What is nystatin used for?
Potent antibiotic used for candidal infections.
How is nystatin administered?
Orally for GI candida infections and topically for other candida infections
What is efinaconazole used for? How it it administered?
Onychomycosis of the toenail caused by trichophyton rubrum and trichophyton mentagrophytes
Topical
