1. 10-27-b: Antifungal agents: Targets
    • Cell wall: Marinoptorein, beta glucan, chitin, mannoprotein
    • Cell membrane: ergosterol* - azoles inhibit synthesis of ergosterol
    • Cytoplasm: protein synthesis
    • Nucleus: DNA
  2. Amphotericin B
    • Very broad spectrum of activity
    • Binds to the primary fungal cell membrane sterol – ergosterol
    • Binding disrupts osmotic integrity of fungal membrane
  3. Lipid formulations of amphotericin B
    • Better distribution, so have reduced infusional and renal toxicity
    • Efficacy of lipid formulation is at least similar to conventional amphotericin B
    • BUT: expensive
    • Sterol 14 alpha-demethylase is the single cytochrome P450 required for sterol byosynthesis in different phyla
    • It is the most widely distributed P450 gene family being found in all biological kingdoms
    • In fungi, this enzyme conferts lanosterol to ergosterol, the key constituent of the cell membrane
    • All azoles act by inhibition of this enzyme
    • Cross inhibition of mammalian CYP 450 isoenzymes, leading to reduced clearance of drugs metabolized by the liver through these pathways!!:
    • Be aware of potential drug-drug interactions and need to modify drug dowing:
    • Cholestasis observed with all azoles
  5. Drug-drug interactions with azoles
    • Azoles increase the blood levels of many drugs metabolized through this pathways:
    • Cyclophosphamide, warfarin, astemizole, terfenidine, protease inhibitors, vinca alkaloids, benzodiazepines, calcium channel blockers, statin drugs, cisapride, cyclosporine, tacrolimus, sirolimus, methylprednisolone, digoxin, quinidine
    • Itraconazole and voriconazole are themselves metabolized by cytochrome p450 isoenzymes:
    • Certain drugs increase the metabolism of itraconaole and voriconazole beause they prime the hepatic cytochrome P-450 system (rifampin, phenytoin)
    • Drug-drug interactions are manageable by being aware of them, making dose adjustments, and monitoring drug levels:
    • Fluconazole: mainly renal clearance
  6. Fluconazole
    • IV and oral:
    • Oral bioavailability > 90%:
    • 19-hour half-life:
    • Mostly renally cleared: dose reduction required with significant renal damage
  7. Fluconazole: uses
    • Candidiasis: blood stream, oral “thrush”, systemic infections cause by Candida sp. , vaginal candidiasis – single 150 mg dose
    • Cryptococcal meningitis:
    • Dimorphic fungi (e.g. coccidioidomycosis):
    • Prophylaxis in patients at high risk for fungal infection:
    • Active against yeasts, not molds:
  8. Candida species
    • Candida albicans: ~50% of Candida blood stream isolates
    • Non-albicans Candida species:
    • Candida parapsilosis: almost always catheter-related, better prognosis
    • Candida glabrata: broad range of MICs to fluconazole
    • Candida krusei: always fluconazole-resistant
  9. Fluconazole-resistant Candida species:
    • Increased production of target enzyme: sometimes overcome by increasing fluconazole dosage
    • Increased efflux of drug:
    • Mutation of target enzyme: probably most common
    • Candida species that are resistant to fluconazole are commonly cross-resistant to broader spectrum azoles, including itraconazole, voriconazole and posaconazole
  10. Ketoconazole
    • Most common use probably topical
    • Oral tablet, cream, and dandruff shampoo formulations
    • Second-line drug as a systemic agent due to safer agents, itraconazole and fluconazole
  11. Ketoconazole side-effects
    • Liver enzyme abnormalities
    • Anti-thyroid function by impairing thyroglobulin iodination
    • May decrease testosterone and cortisol levels, resulting in gynecomastia and oligospermia in men and menstrual irregularities in women: can be exploited therapeutically, e.g. to suppress androgen production in prostrate cancer
  12. Azoles active against aspergillus and other molds
    • Itraconazole:
    • Voriconazole:
    • Posaconazole:
  13. Itraconazole
    • Unpredictable oral bioavailability: monitor serum levels
    • Reduces cardiac systolic function: contraindicated in patients with reduced ejection fraction or prior history of heart failure
    • Edema:
    • Hypokalemia:
  14. Voriconazole: toxicity
    • Potential for drug-drug interactions: most common
    • Liver enzyme abnormalities: second most important
    • Visual:
    • Potential for nephrotoxicity with IV administration of cyclodextrin vehicle in patients with pre-existing renal impairment:
    • Skin changes (long-term use):
  15. Posaconazole
    • Broad-spectrum azole, active against the major pathogenic yeasts and molds, including zygomycetes
    • Currently, only available as an oral formulation
  16. Posaconazole prophylaxis in high-risk patients
    • Neutropenia: prophylaxis with posaconazole led to
    • Fewer invasive fungal infections (IFI) and less orverall mortality compated to fluconazole or itraconazole in neutropenic patients with ACUTE LEUKEMIA or MYELODYSPLASTIC SYNDROME
    • Graft-versus-host disease (GVHD)
    • Prophylaxis with posaconazole led to a reduction in the incidence of IA, in the total number of IFIs while on treatment, and in the number of deaths attributed to fungal infection
  17. Terbinafine (lamisil)
    • Inhibits squalene epoxidase, an enzyme infolved in ergosterol synthesis:
    • Oral and topical formulation:
    • Mainly used for treatment of dermatophyte infection, including onychomycosis:
    • Side effects: Generally well-tolerated:
    • Liver toxicity is uncommon, but can be serious or fatal (FDA warning)
  18. Flucytosine
    • Inhibits fungal protein synthesis by replacing uracil with 5-fluorouracil in fungal RNA:
    • Also interferes with fungal DNA synthesis:
    • Major use is in combination with amphotericin B for cryptococcal meningitis: modest benefit in clearance of infection compared to amphotericin B alone
    • Oral formulation only:
  19. Flucytosine: side effects & toxicities
    • Major toxicities are bone marrow suppression and GI toxicity
    • Toxicity is dose and duration dependent
    • Toxicity likely due to 5-fluorouracil which is produced from flucytosine by bacteria in gut lumen!!:
    • Flucytosine is renally cleared and must be dose-adjusted in azotemic patients!!:
    • Since flucytosine is commonly combined with amphotericin B, renal impairment caused by amphotericin B may increase flucytosine levels and worsen toxicity
    • Monitoring flucytosine levels is helpful:
  20. Antifungal peptides
    • Echinocandins: inhibition of fungal beta(1,3)-glucan synthase – depletion of glucan, which is a fungal cell wall constituent
    • Target growing tips of Aspergillus fumigatus hyphae; candidiasis
  21. Echinocandins three names
    • Caspofungin
    • Micafungin
    • Anidulafungin
  22. Echinocandins: administration and toxic effects
    • Excellent toxicity profile:
    • Low incidence of infusion-related events: single case of anaphylaxis with caspofungin
    • IV formulations only
    • No known nephrotoxicity
    • Liver enzyme changes are rare
    • Echinocandins used with cyclosporin A can cause reversible liver enzyme abnormalities!:
  23. Echinocandins: candidiasis
    • Potentially cidal in vitro
    • Excellent activity against clinical isolates – including azole-resistant: cases of echinocandin-resistant candida species have been reported
    • Effective in mucosal candidiasis and candidemia
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