11 - Antifungals Flashcards
What predisposes someone to serious fungal infections?
Immunocompromised
Broad-spectrum antibacterial use
Indwelling catheters
What are classifications of mycosis?
Systemic (potentially life-threatening): in immunosuppressed, geographically organized
Superficial: mucous membranes and dermatophytic
What are current effective antifungal targets?
Membranes (ergosterol) Nucleic acids (limited) Cell wall (1 drug class)
What drugs are used for systemic fungal infections?
Amphotericin B Flucytosine Fluconazole Itraconazole Voriconazole Caspofungin
What antifungal is an effective broad-spectrum agent for most serious systemic mycoses, especially those that are immediately life-threatening?
Amphotericin B
Gold standard for antifungal effectiveness by which other drugs are judged
Why is Amphotericin B only used for proven or highly suspected systemic infections?
Side effects
Total cumulative dose is important for reasons of permanent renal toxicity (90% of people will show nonpermanent nephrotoxicity)
What is the mechanism of action of amphotericin B?
Very lipophilic; binds ergosterol in fungal membranes producing rapid membrane instability/leakage
What are the side effects of Amphotericin B?
Fever, nausea, vomiting, headache, chills.
Hypotension, hypokalemia, tachypnea.
90% nonpermanent nephrotoxicity
Reversible hypochromic, normocytic anemia.
What can Flucytosine (5-FC) be used to treat? How is it used?
To treat serious infections from candida and cryptococcus.
Used in conjunction (synergistic) with amphotericin B.
What drug gets converted by fungal cytosine deaminase to a new compound whose metabolites block nucleic acid synthesis?
Flucytosine (5-FC)
5-FC gets converted to 5-FU, and metabolites of 5FU then block nucleic acid synthesis
What are side effects of Flucytosine?
Nausea, vomiting, diarrhea, enterocolitis.
Leukopenia, thrombocytopenia: extreme caution in those with renal insufficiency or BM depression
Reversible elevated hepatic enzymes
What three triazoles are used to treat serious fungal infections?
Fluconazole
Voriconazole
Itraconazole
What is the mechanism of action of imidazoles and triazoles?
Inhibit 14-a-sterol demethylase, a fungal cytochrome P450 that converts lanosterol to ergosterol.
Net effect is inhibition of ergosterol synthesis while eventually causes membrane instability. Not a rapid onset because there’s no effect on existing ergosterol.
What types of fungal infections can fluconazole treat?
Cryptocossus,
Candidia (incl. CNS and urinary):
- most C. albicans
- some C. glabrata
- NOT C. krusei
What type of infections does itraconazole treat?
Blastomyces, histoplasma, candida (NOT CNS and urinary).
Candida spectrum: more albicans and glabrata.
What types of fungal infections does voriconazole treat?
Aspergillus, candida (NOT urinary) including glabrate and krusei.
Studies show ______ is superior to Amphotericin for invasive aspergillus?
Voriconazole
Out of fluconazole, itraconazole, and voriconazole, which drug has CNS penetration and is active in the urine?
Fluconazole
What are side effects common to fluconazole, itraconazole, and voriconazole?
Nausea, vomiting, rash, diarrhea, and headache.
Mild hepatotoxicity - discontinue with onset of liver dysfunction.
Inhibits metabolism of other drugs b/c they are potent inhibitors of CYP3A and 2C
What are contraindications for itraconazole?
Do not give with other drugs that are metabolized by CYP3A4.
Potential for serious cardiovascular events, including death.
Which -azole antifungal has the lowest incidence of hepatotoxicity?
Fluconazole
What are side effects associated with voriconazole?
Visual disturbances (30%)
Photosensitive component to rash.
What antifungal drug inhibits fungal cell wall synthesis by non-competitively blocking synthesis of B(1,3)-D-glucan? Does this have cross-resistance?
Caspofungin
No cross-resistance with imidazole and triazoles
What types of fungal infections can caspofungin treat?
Invasive aspergillus
Esophageal and systemic candida - broad species coverage includes glabrata and krusei
What are side effects of caspofungin?
Fever, nausea/vomoting, flushing
Phlebitis at injection site
What are the infection sites of superficial mycoses?
Oropharyngeal
Bladder
Vagina
What drugs can be used to treat superficial mycoses?
Nystatin Fluconazole Miconazole Clotrimazole Itraconazole Natamycin
What does fluconazole treat, and how is it given?
Candida infections:
Vaginal (single oral dose).
Urinary tract
Oropharynx
What is the mechanism of action and use of clotrimazole? What are side effects?
Mechanism similar to fluconazle.
Used for candida infections: can be via oral troches or vaginal creams
Side effects of oral troches: abnormal liver function tests
What type of candida infections does itraconazole treat? How is it given?
Oropharyngeal and esophageal candida
Given orally
What drug has a similar mechanism of action to amphotericin B and should be effective against -azole resistant strains? What is it used to treat?
Nystatin
Topic for candida or oral for GI tract candida.
Can cause GI distress.
Can amphotericin B be given in ways other than IV?
Yes, can be used topically for candida infections.
Not used for dermatophytes.
What drug is used to treat ophthalmic fungal infections? What is it especially useful for? How does it work?
Natamycin
Esp. useful for fusarium, cephalosporium, and aspergillus.
Same mechanism of action as amphotericin B.
What are side effects of natamycin?
Conjunctival chemosis (edema) and hyperemia (increased blood flow)
What antifungal drugs can be used topically to treat dermatophytes?
Miconazole Clotrimazole Tolnaftate Terbinafine Ciclopirox
What topical treatment is used to treat fungal nail infections?
Ciclopirox
FDA approved for topical use in mild-to-moderate fungal nail infections
What drug can be used to treat dermatophyte infections and is taken orally?
Terbinafine - 12 week oral therapy for fungal nail infections
What is the mechanism of action of terbinafine?
It blocks squalene epoxidase, which prevents ergosterol synthesis.
This causes squalene to build up and form lipid droplets that disrupt fungal cell membrane –> FUNGICIDAL
What is the mechanism of action of azoles?
Azoles block 14a-demethylase (a CYP P450) which results in ergosterol deficiency that interferes with membrane function and cell growth.
They are FUNGISTATIC
What are side effects of terbinafine?
Diarrhea, dyspepsia (indigestion), and abdominal pain.
Inhibits CYP2D6
What oral antifungal interferes with microtubule function/mitotic spindle/mitosis? What is this drug used to treat?
Griseofulvin
For recalcitrant (stubborn) dermatophytic infections of skin, hair, and nails. Good for tinea capitis infection.
What are side effects of griseofulvin? What are contraindications?
Contraindicated in those with porphyria (heme build up) and advanced liver disease.
Increased metabolism of other drugs (CYP inducer)
Use with caution in those with penicillin allergies (produced in penicillium)
What is a second use of itraconazole other than for systemic fungal infections? What are side effects and when should it be stopped?
Orally for fungal toenail infections (dermatophytes)
Nausea, vomiting, rash, diarrhea, headache, edema. Inhibits metabolism of many drugs.
Discontinue is signs of liver dysfunction appear.
What oral antifungals are given for dermatophytes?
Itraconazole
Griseofulvin
Terbinafine
