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Anti-fungal agents

Anti-fungal agents. Problem: Fungi are eukaryotes therefore, fewer good drug targets. The incidence of fungal sepsis has increased 3 fold between 1979 and 2000 Candida 70-90% Aspergillus 10-20% Candida is the 4th most common bloodstream infection in US at 9.5%

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Anti-fungal agents

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  1. Anti-fungal agents Problem: Fungi are eukaryotes therefore, fewer good drug targets The incidence of fungal sepsis has increased 3 fold between 1979 and 2000 Candida 70-90% Aspergillus 10-20% Candida is the 4th most common bloodstream infection in US at 9.5% Mortality is higher in systemic fungal infections compared to bacteria

  2. Anti-fungal Targets 1. Cell wall/ cell membrane -amphotericin B--binds ergosterol >>cholesterol -ketoconazole -fluconazole --inhibits ergosterol synthesis -itraconazole -voriconazole -echinocandins (Caspofungin) blocks synthesis of -1,3, D-glucans, a structural component of fungal cell wall by inhibiting glucan synthase. 2. DNA synthesis -flucytosine-->converted to fluorouracil in sensitive fungi 3. Mitotic apparatus -griseofulvin-->systemic treatment of mycotic disease of skin, hair, nails.

  3. Ergosterol in fungi

  4. ergosterol cholesterol fungal mammalian

  5. Therapeutic considerations • Amphotericin B was gold standard but newer triazoles (voriconazole) are now primary therapy for invasive aspergillosis--better success and less toxicity • Combinations continue to be investigated: • Ampho B + flucytosine usually synergistic • Ampho B + triazole expected to be antagonistic

  6. Amphotericin Toxicity and Resistance • low therapeutic index • acute toxicity (fever, chills, vomiting, headache) when first injected • chronic use (6-12 wks) leads to nephrotoxicity in 40-80% of pts • disrupts K+/H+ exchange leading to hypokalemia and acidosis • usually reversible unless total dosage too high • consider alternative day therapy • lipid formulations less toxic but more expensive • drug interactions: synergistic with flucytosine, antagonistic with fluconazole • resistance: unusual, caused by reduced ergosterol in membranes

  7. Pharmacokinetics of Ampho B • must be given by i.v. infusion • lipid formulations are available and appear to have less nephrotoxicity but are some are more likely to induce chills and hypoxia • cost of the lipid formulations is 20-50X higher and efficacy is not clearly improved • excretion of drug? half life is in weeks. Binds to tissues and is only slowly eliminated. Metabolism by liver is not important

  8. Triazole anti-fungal agents selective toxicity:inhibit fungal cytochrome P450 enzyme required for ergosterol biosynthesis (14-a-demethylase) newer one approved by FDA

  9. Triazole antifungals • Toxicity: • anorexia, nausea, vomiting most common • gynecomastia (only with ketoconazole due to suppression of testosterone synthesis) • hepatic toxicity (ketoconazole 5-10%) • transient visual disturbances (voriconazole) • drug interactions: by inhibiting P450 enzymes (CYP3A4), levels of many other drugs are increased: (e.g. oral anticoagulants, hypoglycemics, benzodiazepines, HMG-CoA reductase inhibitors) • Resistance: due to decreased uptake of drug or mutations/overproduction of 14-a-demethylase

  10. Pharmacokinetics

  11. Mechanism of flucytosine action

  12. Flucytosine • Toxicity: bone marrow depression due to conversion to 5-fluorouracil • Resistance: common due to mutation in: • permease • deaminase • pyrophosphorylase • Orally active, penetrates CSF, t1/2 about 4hr by renal excretion

  13. Caspofungin • inhibits -glucan synthase • FDA approved in 2001 for aspergillosis salvage therapy • Recent (2006) studies indicate that low doses may increase the exposure of glucan on the surface of fungi stimulating elimination by the immune system

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