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Before and after slides:-Less text and bullets-more pictures
-Make pictures the center and not the text
-Use nice large high-definition pictures
-No more than 4 points per slide
-Good idea to break down complex slides into 2-3 easierand less dense ones
-Good idea to provide graphs/hard data to prove a point
-The header should be a declaration
-When a text is longer than 1 line – you decide where to break(use control+enter)-Font: arial calibri, century gotic, helvetika (Mac)--do not annoy with animations: use appear, wipe, box in/out, fade
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)
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)
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
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