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Drug Family 1: Griseofulvin

•1st modern antifungal (1939)

• Binds Microtubules, inhibits mitosis

• Dermatophytes only

• Oral, 1000mg/d, 4 wks hair skin, 6 mo. nails

• Largely replaced by azoles

microtubules

Penicillium griseofulvum

taxol, vinblastine, nocodazole,

BEFORE

Drug Family 1: Griseofulvin, good for fungal skin infections only

1939

Penicillium griseofulvum

Dermatophyte infections

taxol, vinblastine, nocodazole,

AFTER

Drug Family 1: GriseofulvinGood only for fungal skin infections

1939

Penicillium griseofulvum

Dermatophyte infections

taxol, vinblastine, nocodazole,

AFTER 2

Drug Family 1: GriseofulvinGood only for fungal skin infections

1939

Penicillium griseofulvum

Dermatophyte infections

taxol, vinblastine, nocodazole,

AFTER 3

Nystatin• Topical only

• Candida (mucocutaneous) ,Dermatophytes

•Liposomal form in testing

• Spoilage protection

BEFORE

Nystatin: for external use only…Candida (mucocutaneous)

Dermatophytes

Spoilage protectionAFTER

Amphotericin Bsummary

• Fungal resistance rare

• Chills, fever, dyspnea, nausea, hypotension phlebitis, anemia, nephrotoxic, hepatotoxic

• Fungicidal, broad spectrum

• AMB-DOC, systemic infections, IV 0.5-1 mg/kg 6-10 wks

• Long half life

Bad stuff…

Good stuff

BEFORE

Amphotericin B: Very effective but toxic…

AMB-DOC intravenous

The Bad stuff…

Chills, fever, dyspnea, nausea, hypotension phlebitis, anemia, nephrotoxic, hepatotoxic

AFTER (A)

The Good stuff

• Long half life

Fungicidal

Very wide kill spectrum

Amphotericin B

AFTER (B)

Flucytosine

Drug Family 3: Flucytosine

• Incorporated into RNA as FUTP. Translation blocked

• Incorporated into DNA (FdUMP). DNA synthesis blocked

5-Flucytosine

Cytosinedeaminase

5-Fluorouracil

Bacteria, fungi

• Side effects, leucopenia

• Narrow effectivity: Candida and Cryptococcus. Resistance.

• IV. Oral. •50-150mg/d, in 4 doses

• Usually given in combination with AMB

BEFORE

Flucytosine

Drug Family 3: Flucytosine, the only antifungal prodrug

5-Flucytosine

Cytosinedeaminase

5-Fluorouracil

Bacteria, fungi

IV/ Oral.

DNA RNA Protein

Leucopenia

How does it work?AFTER (A)

Flucytosine, no good on its own…

Narrow range… Rapid resistance…

Solution?AMB+ 5FC combo

AFTER (B)

The Older 1st- generation Imidazoles

Miconazole

Clotrimazole

Ketoconazole

• Mostly topical (Candida, Dermatophytes)

• Ketoconazole, oral

• Side effects• Fungistatic. Drug resistance.

econazole

BEFORE

The Older 1st- generation Imidazoles For external use only

Miconazole

Ketoconazole

Almost for systemic use…

AFTERClotrimazole

The newer 2nd generation triazoles

ItraconazoleFluconazole

• Pills, IV, Oral Suspension. •100-400mg/d• Long Half life• Well tolerated• Maintenance therapy• Not effective for Aspergillosis, Zygomycosis, • Drug resistance

• More potent• Effective for Aspergillosis•Poor solubility

FluconazoleItraconazole

BEFORE

The newer 2nd generation triazoles:Systemic at last!

Fluconazole

Fluconazole

Itraconazole

Itraconazole

No good for molds Poor solubility

AFTER

Voriconazole: 3rd generation

Derivative of fluconazole

Wide antifungal spectrum: but NOT Zygomycetes

Oral syrup, tablets and IV Better than AMB for Aspergillosis. As good as fluconazole for Candidiasis

Side effects few. 30% visual disturbances, 5% hallucinations. Drug drug interactions for all azoles: warfarin, cyclosporin, tacrolimus, statins, tranquilizers and many others

BEFORE

Voriconazole: 3rd generationSystemic and a mold killer

Derivative of fluconazole

Wide antifungal spectrum: but NOT Zygomycetes

Oral syrup, tablets and IV

Side effects few. 30% visual disturbances, 5% hallucinations.

AFTER (A)

Voriconazole is better than AMB in treating IPA

Herbrecht et al. NEJM 347:408 2002

102/144 (71%)

77/133 (58%)

Severe side effects: 13.4% vori vs. 24.3% AMB

AFTER (B)

Posaconazole: Generation 3.5

•Wide antifungal spectrum

including Zygomycetes

•Few side effects

•Proven prophylactic activity

•Oral syrup, tablets

BEFORE

Posaconazole: Generation 3.5Kills all molds (and yeast)

Derivative of itraconazole

Wide antifungal spectrum: INCLUDING Zygomycetes

Syrup, tablets but no IV…

AFTER

Systemic Azoles have side effects that need to be monitored

Hepatotoxicity

POINTSNOT STRESSED BEFORE

Systemic Azoles interact with MANY drugs…

Oral hypoglycemics

Tacrolimus

Ca+2 channel blockers

POINTSNOT STRESSED BEFORE

Allylamines: Terbinafine

• Primarily for Dermatophytes: lypophilic

• Well tolerated

• Also: Cutaneous Candidiasis

• Oral: 250mg/day. 2-4wks. Nails- 3-6 months

BEFORE

Terbinafine, great but only for fungal skin infections

lipophylic

AFTER

Cancidas™ (Caspofungin) fact sheet

• First clinically approved Candin

• Systemic (IV). 70mg/d1, 50mg/kg. 1h infusion

• As effective as AMB, less side effects

• Combination therapy?

• Not effective for zygomycetes, fusarium, cryptococcus

BEFORE

No good for crypto, zygo’s, fusarium

Only IV

Cancidas™ (Caspofungin) fact sheet

Fungal specific

AFTER

Control +Caspofungin

Candins: How do they work?

UDP glucose 1,3 b-D-glucan

Glucan synthase

Candins (e.g caspofungin)Rho

Cell wall stress sensors (Mid1p, Slg1p/wsc1)

Rom1p

BEFORE

Control

+Caspofungin

Candins: How do they work?

Glucan synthase

Rho1

Mid1 sensor

GEF

G6PCAS

AFTER