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

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.

Ergosterol in fungi

cholesterol ergosterol mammalian fungal

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

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

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

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

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

Pharmacokinetics

Mechanism of flucytosine action

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

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