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.

4. Ergosterol in fungi

5. cholesterol
ergosterol
mammalian
fungal

7. 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

8. 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

9. 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

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

11. 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

12. Pharmacokinetics

13. Mechanism of flucytosine action

14. 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

15. 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