Antifungal Agents Flashcards
Why are fungal infections more difficult to treat than bacterial infections?
Fungal infections grow more slowly and are difficult to culture, often occur in tissues that are poorly penetrated
Mechanism of action for amphotericin
Binds to ergosterol and creates pores in membrane, hydrophilic regions bind with water on one side and hydrophobic regions bind with cell lipids on other side, cause loss of Mg and Ca.
Differences between fungal and mammalian cells
Fungal cells have ergosterol, mammalian have cholesterol.
Fungal cell enzymes used for intracellular transport and metabolism - targeted by flucytosine
Fungal cells have cell walls (targeted by echinocandins), mammalian have membranes.
Fungal cells have specific CYP450 enzymes (targeted by azoles)
Mechanism of resistance for amphotericin
If ergosterol binding is impaired via reduced membrane concentrations or altered binding site. Inherent resistance to amphotericin by Pseudallescheria boydii and candida lusitaniae.
Use-limiting toxicity of amphotericin
Nephrotoxicity: severity is variable, has reversible (decreased renal perfusion) and irreversible (renal tubular injury) components.
FDA Pregnancy category B
Mechanism of action for flucytosine
Transported into cell by fungal cell specific cytosine permease, then metabolized to 5-FU by cytosine deaminase. Various conversions inhibit RNA and DNA synthesis, and synthase involved in DNA synthesis and nuclear division.
OVERALL: Interferes with pyrimidine metabolism, RNA, DNA, and protein synthesis in fungal cell.
Mechanism of resistance for flucytosine
Permeaseless/decreased fungal cell membrane permeability, defective deaminase, low UMP proliferase. Cannot use as monotherapy.
Mechanism of action for azoles
Reduce ergosterol synthesis by inhibiting fungal CYP450 system
Ketoconazole characteristics
Seldom used now. Requires acidic gastric pH for absorption.
M: Most effects on metabolic enzymes.
E: hepatically eliminated.
-Narrow therapeutic range
-7-10 hour half-life, adverse effects of infertility, menstrual irregularities (via hormone synth blocking), anorexia, hepatic toxicity.
-Useful for mucocutaneous candidiasis and non-meningeal coccidioidomycosis
Mechanisms of resistance for azoles
1) Mutations in demethylase that alter drug binding
2) Mutations in delta 5(6) desaturase, result in precursor accumulation instead of ergosterol
3) Overexpression of specific drug efflux pumps
4) Increased copies of target enzyme
Itraconazole characteristics
Requires acidic gastric pH for absorption. Hepatically eliminated. Do not use in patients with CHF or ventricular dysfunction. Strong inhibtor of CYP3A4 and P-gp.
Uses: Broader spectrum than fluconazole, use for dermatophytosis and onchomycosis. Use also for aspergillus, histoplama, blastomyces, lymphocutaneous sporotrichosis.
Fluconazole characteristics
Has least effects on metabolic enzymes, best CSF penetration. Renal elimination. Use for candida, cryptococci, coccidiodal meningitis.
DO NOT USE FOR ASPERGILLLUS OR FILAMENTOUS FUNGI.
Widest therapeutic index of azoles.
Posaconazole characteristics
Activity against zygomycetes. Inhibits CYP3A4. Adverse effects of QT prolongation and hepatic abnormalities.
Approved for prophylaxis of invasive aspergillus and candida.
Voriconazole characteristics
Hepatically eliminated, use for invasive aspergillosis (as effective as amphotericin for invasive aspergillosis). Broad spectrum, similar to itraconazole.
Ketoconazole drug interaction issues
Ketoconazole is the least selective azole for P450 inhibition, so the most interactions can be expected. Also has many adverse effects on steroid hormones, and hepatic toxicity.
