L13 Antifungals Flashcards
How do most antifungals work in a general sense?
All except for Griseofulvin and Flucytosine target the cell membrane or wall
What are the major drug classes that are used for systemic fungal infections?
Amphotericin B is DOC for all systemic mycoses
Flucytosine
Azoles
Echinocandins
MOA of Amphotericin B
Binds to ergosterol in the cell membrane and creates a pore. Does not inhibit synthesis of ergosterol. Fungicidal
Spectrum of Amphotericin B
Broad
Some protozoa and Entamoeba also covered
Amphotericin B
Administration, Tissue penetration, Excretion
IV only, 6 weeks to 3-4 months
Poor CNS and Aqueous Humor
Slow excretion by the kidney–can cause nephrotoxicity
Renal/Hepatic impairment and hemodialysis have little effect in drug concentration
Amphotericin B Toxicities
Because it binds to Ergosterol can also bind weakly to cholesterol in human cell membranes–thought to be cause of toxicities.
Can occur:
1) With infusion: chills, fever, muscle spasms, vomiting, headache; prevented with slower infusion
2) Over time: Nephrotoxicity leading to azotemia (elevated BUN and Creatinine in almost all patients) (don’t combine with other nephrotoxic agents like Aminoglycosides),
MOA of Flucytosine
Converted to 5-FU (Fluorouracil) by cytosine deaminase which interferes with fungal DNA and RNA synthhesis
Only Fungi and Bac have the necessary enzyme
What is the DOC for Cryptococcus?
Flucytosine
Flucytosine
Administration, tissue penetration, elimination
Oral admin.
Differs from Amphotericin B in that it penetrates the CNS and Aqueous humors quite well
Renal elimination–impairment can lead to toxicity
Which anti-fungal agent can cause a depression of bone marrow causing anemia, leukopenia, thrombocytopenia?
Flucytosine
What are the toxicities of Flucytosine?
Bone marrow depression
GI disturbances (because Bac have the enzyme to convert to 5-FU)
Elevated liver enzymes
Are Azoles static or cidal?
Static
MOA of Azoles
Inhibit the synthesis of ergosterol and thereby force production of toxic metabolites
Spectrum of Ketoconazole
Broad
Think of it like Amphotericin B
Ketoconazole
Admin., tissue penetration, elimination
Oral
CNS penetration low, largely bound to albumin
Extensively metabolized by the liver prior to elimination
Serious hepatotoxicity
Shows up in urine, saliva, milk
Ketoconazole toxicity
Serious hepatotoxicity
Inhibits P450 enzymes (CYP3A4)
Inhibits adrenal and testicular function
Other azoles often preferred due to decreased drug interactions.
MOA of Fluconazole (Diflucan)
Inhibits P450 of fungus blocking ergosterol synthesis
Has a lower affinity for human P450 than Ketoconazole but can still increase levels of phenytoin, cyclosporine, warfarin, etc.
Use for Fluconazole
Cryptococcal meningitis–penetrates well into CSF
Candidiasis
Prophylaxis in HIV for the above diseases
Fluconazole
Admin., tissue distribution
Oral or IV
Penetrates well into CSF compared to Ketoconazole
Fluconazole toxicity
Less toxic than amphotericin B or flucytosine and better tolerated than ketoconazole
Many less drug interactions than other azoles
No inhibition of adrenal or testicular steroidogenesis
Itraconazole
Admin., use, metabolism
Oral admin. in capsule or solution
Same coverage as other azoles but especially good against aspergillus (though voriconazole is the DOC)
Hepatically metabolized
Voriconazole characteristics
Similar to Fluconazole Oral and IV Hepatic elimination Many drug interactions Visual impairment in 50% DOC for aspergillus Unlike Fluconazole good against molds
Isavuconazole
New antifungal
Treatment of mucormycosis and invasive aspergillosis
IV and oral
Decreases QT interval and is therefore contraindicated in patients with familial short QT
Which drug category inhibits the synthesis of fungal cell walls by inhibiting Beta(1,3)-D-glucan synthase?
Echinocandins
These include:
Caspofungin, Micafungin, Anidulafungin
Used for esophageal candidiasis and others
What drug would be given for invasive aspergillosis in refractory patients and how would it be administered?
Caspofungin
IV–slow infusion
also good for esophageal candidiasis
What drug is used for prophylaxis of candida in patients undergoing hematopoietic stem cell transplantation?
Micafungin
IV admin
What are the topical fungal treatments?
Griseofulvin (oral admin)
Terbinafine (oral or topical)
Nystatin (oral or topical)
What is the DOC for onychomytosis? MOA?
Griseofulvin
Binds to the microtubules of fungi and destroys the mitotic spindle structure
What makes Griseofulvin unique?
Binds to keratin and prevents infection in new skin structures
Requires 6 months to work
Griseofulvin contraindications
acute intermittent porphyria, hepatocellular failure, pregnancy (teratogenic coming from mother or father)
Terbinafine (Lamisil) admin and MOA and use
Oral or topical
Interferes with sterol biosynthesis
Effective against onychomycosis–superior to Griseofulvin and itraconazole
Fungicidal against dermatophytes but much less active against candida
What is Nystatin primarily used for? MOA?
Candida infections
Alters permeability of the cell leading to death–forms pores in the membrane like ampho B
Efinaconazole (Jublia)
Newest topical fungal drug
Used for onychomytosis of toenails caused by trichophyton sp.
Miconazole nitrate (Monistat)
Use: trichophyton, epidermophyton, microsporum, candida, cryptococcus, aspergillus
Clotrimazole (Lotrimin)
Use: dermatophytes, yeasts, Malassezia furfur
What is the causative agent of Tinea versicolor?
Malassezia furfur
Tolnaftate (Tinactin)
Tinea versicolor
Not effective for onychomycoses
Which drugs inhibit ergosterol production?
Terbinafine
Azoles
Which drugs form pores in the walls of fungi?
Amphotericin B
Nystatin
Which drugs act like the penicillins of antifungals and prevent synthesis of the molecules needed to make the cell wall?
Echinocandins
