Anti-fungal agentsAnti-fungal agents

The incidence of fungal sepsis has increased 3 fold between 1979 The incidence of fungal sepsis has increased 3 fold between 1979 and 2000and 2000

Candida 70-90%Candida 70-90%Aspergillus 10-20%Aspergillus 10-20%

Candida is the 4th most common bloodstream infection in US at Candida is the 4th most common bloodstream infection in US at 9.5% 9.5%

Mortality is higher in systemic fungal infections compared to Mortality is higher in systemic fungal infections compared to bacteriabacteria

Problem: Fungi are eukaryotesProblem: Fungi are eukaryotestherefore, fewer good drug targetstherefore, fewer good drug targets

Anti-fungal TargetsAnti-fungal Targets1. Cell wall/ cell membrane1. Cell wall/ cell membrane

-amphotericin B--binds ergosterol >>cholesterol-amphotericin B--binds ergosterol >>cholesterol-ketoconazole-ketoconazole-fluconazole-fluconazole --inhibits ergosterol synthesis --inhibits ergosterol synthesis-itraconazole-itraconazole-voriconazole-voriconazole

2. DNA synthesis2. DNA synthesis-flucytosine-->converted to fluorouracil in sensitive fungi-flucytosine-->converted to fluorouracil in sensitive fungi

3. Mitotic apparatus3. Mitotic apparatus-griseofulvin-->systemic treatment of mycotic disease of-griseofulvin-->systemic treatment of mycotic disease of

skin, hair, nails.skin, hair, nails.

-echinocandins (Caspofungin)blocks synthesis of -1,3, D-glucans, a structural component of fungal cell wall by inhibiting glucan synthase.

Ergosterol in fungiErgosterol in fungi

cholesterolcholesterol ergosterolergosterol

mammalianmammalian fungalfungal

Therapeutic considerationsTherapeutic considerations

Amphotericin B was gold standard but newer Amphotericin B was gold standard but newer triazoles (voriconazole) are now primary therapy triazoles (voriconazole) are now primary therapy for invasive aspergillosis--better success and for invasive aspergillosis--better success and less toxicityless toxicity

Combinations continue to be investigated:Combinations continue to be investigated: Ampho B + flucytosine usually synergisticAmpho B + flucytosine usually synergistic Ampho B + triazole expected to be antagonisticAmpho B + triazole expected to be antagonistic

Amphotericin Toxicity and ResistanceAmphotericin Toxicity and Resistance

low therapeutic indexlow therapeutic index acute toxicity (fever, chills, vomiting, headache) when first acute toxicity (fever, chills, vomiting, headache) when first

injectedinjected chronic use (6-12 wks) leads to nephrotoxicity in 40-80% of ptschronic use (6-12 wks) leads to nephrotoxicity in 40-80% of pts

• disrupts K+/H+ exchange leading to hypokalemia and acidosisdisrupts K+/H+ exchange leading to hypokalemia and acidosis• usually reversible unless total dosage too highusually reversible unless total dosage too high• consider alternative day therapyconsider alternative day therapy

lipid formulations less toxic but more expensivelipid formulations less toxic but more expensive drug interactions: synergistic with flucytosine, antagonistic with drug interactions: synergistic with flucytosine, antagonistic with

fluconazolefluconazole resistance: unusual, caused by reduced ergosterol in resistance: unusual, caused by reduced ergosterol in

membranesmembranes

Pharmacokinetics of Ampho BPharmacokinetics of Ampho B

must be given by i.v. infusionmust be given by i.v. infusion lipid formulations are available and appear to lipid formulations are available and appear to

have less nephrotoxicity but are some are more have less nephrotoxicity but are some are more likely to induce chills and hypoxialikely to induce chills and hypoxia cost of the lipid formulations is 20-50X higher and cost of the lipid formulations is 20-50X higher and

efficacy is not clearly improvedefficacy is not clearly improved excretion of drug? half life is in weeks. Binds to excretion of drug? half life is in weeks. Binds to

tissues and is only slowly eliminated. tissues and is only slowly eliminated. Metabolism by liver is not importantMetabolism by liver is not important

Triazole anti-fungal agentsselective toxicity:selective toxicity:inhibit fungal inhibit fungal cytochrome P450 enzyme cytochrome P450 enzyme required for ergosterol required for ergosterol biosynthesis (14-biosynthesis (14--demethylase)-demethylase)

newer one approved by FDA

Triazole antifungalsTriazole antifungals

Toxicity: Toxicity: anorexia, nausea, vomiting most commonanorexia, nausea, vomiting most common gynecomastia (only with ketoconazole due to suppression of gynecomastia (only with ketoconazole due to suppression of

testosterone synthesis) testosterone synthesis) hepatic toxicity (ketoconazole 5-10%)hepatic toxicity (ketoconazole 5-10%) transient visual disturbances (voriconazole)transient visual disturbances (voriconazole) drug interactions: by inhibiting P450 enzymes (CYP3A4), levels drug interactions: by inhibiting P450 enzymes (CYP3A4), levels

of many other drugs are increased: (e.g. oral anticoagulants, of many other drugs are increased: (e.g. oral anticoagulants, hypoglycemics, benzodiazepines, HMG-CoA reductase hypoglycemics, benzodiazepines, HMG-CoA reductase inhibitors)inhibitors)

Resistance: due to decreased uptake of drug or Resistance: due to decreased uptake of drug or mutations/overproduction of 14-mutations/overproduction of 14--demethylase-demethylase

PharmacokineticsPharmacokinetics

Drug Oral CSF metab/excretion

ketoconazole + - liver metab t1/2=3hr

fluconazole ++ + excreted by kidney

t1/2=22hr

voriconazole +++ + Liver metabolism

Drug Oral CSF metab/excretion

ketoconazole + - liver metab t1/2=3hr

fluconazole ++ + excreted by kidney

t1/2=22hr

voriconazole +++ + Liver metabolism

Mechanism of flucytosine actionMechanism of flucytosine action

FlucytosineFlucytosine

Toxicity: bone marrow depression due to conversion to Toxicity: bone marrow depression due to conversion to 5-fluorouracil5-fluorouracil

Resistance: common due to mutation in:Resistance: common due to mutation in: permease permease deaminase deaminase pyrophosphorylasepyrophosphorylase

Orally active, penetrates CSF, t1/2 about 4hr by renal Orally active, penetrates CSF, t1/2 about 4hr by renal excretionexcretion

CaspofunginCaspofungin

inhibits inhibits -glucan synthase-glucan synthase FDA approved in 2001 for FDA approved in 2001 for

aspergillosis salvage aspergillosis salvage therapytherapy

Recent (2006) studies Recent (2006) studies indicate that low doses may indicate that low doses may increase the exposure of increase the exposure of glucan on the surface of glucan on the surface of fungi stimulating elimination fungi stimulating elimination by the immune systemby the immune system