Transcript Nir`s Before and After powerpoint slides

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 easier
and 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
BEFORE
Drug Family 1:
Griseofulvin
•1st modern antifungal (1939)
• Binds Microtubules, inhibits mitosis
• Dermatophytes only
Penicillium griseofulvum
• Oral, 1000mg/d, 4 wks hair skin,
6 mo. nails
• Largely replaced by azoles
microtubules
taxol, vinblastine, nocodazole,
Drug Family 1: Griseofulvin, good for
fungal skin infections only
AFTER
1939
taxol, vinblastine, nocodazole,
Penicillium
griseofulvum
Dermatophyte infections
Drug Family 1: Griseofulvin
Good only for fungal skin infections
AFTER 2
1939
taxol, vinblastine, nocodazole,
Penicillium
griseofulvum
Dermatophyte infections
Drug Family 1: Griseofulvin
Good only for fungal skin infections
AFTER 3
1939
taxol, vinblastine, nocodazole,
Penicillium
griseofulvum
Dermatophyte infections
BEFORE
Nystatin
Topical only
• Candida (mucocutaneous) ,Dermatophytes
•
• Spoilage protection
•Liposomal form
in testing
Nystatin: for external use only…
AFTER
Candida (mucocutaneous)
Dermatophytes
Spoilage protection
Amphotericin B
BEFORE summary
Bad stuff…
• AMB-DOC, systemic infections, IV 0.5-1 mg/kg 6-10 wks
• Chills, fever, dyspnea, nausea, hypotension
phlebitis, anemia, nephrotoxic, hepatotoxic
Good stuff
• Long half life
• Fungicidal, broad spectrum
• Fungal resistance rare
Amphotericin B: Very effective but toxic…
AFTER (A)
The Bad stuff…
AMB-DOC
intravenous
Chills, fever,
dyspnea, nausea,
hypotension phlebitis,
anemia, nephrotoxic,
hepatotoxic
Amphotericin B
AFTER (B)
The Good stuff
• Long half life
Fungicidal
Very wide
kill spectrum
Drug Family 3: Flucytosine
BEFORE
5-Flucytosine
Bacteria, fungi
• IV. Oral.
•50-150mg/d, in 4 doses
Flucytosine
Cytosine
deaminase
5-Fluorouracil
• Incorporated into RNA as FUTP. Translation blocked
• Incorporated into DNA (FdUMP). DNA synthesis blocked
• Side effects, leucopenia
• Narrow effectivity: Candida and Cryptococcus. Resistance.
• Usually given in combination with AMB
Drug Family 3: Flucytosine, the only antifungal prodrug
AFTER (A)
How does it work?
5-Flucytosine
Bacteria, fungi
Cytosine
deaminase
Flucytosine
IV/ Oral.
5-Fluorouracil
DNA
RNA
Leucopenia
Protein
Flucytosine, no good on its own…
AFTER (B)
Narrow range…
Solution?
Rapid resistance…
AMB+ 5FC combo
The Older 1st- generation Imidazoles
BEFORE
• Mostly topical (Candida, Dermatophytes)
•
Clotrimazole
Ketoconazole, oral
• Side
effects
• Fungistatic. Drug resistance.
Miconazole
Ketoconazole
econazole
The Older 1st- generation Imidazoles
For external use only
AFTER
Clotrimazole
Almost for
systemic use…
Miconazole
Ketoconazole
The newer 2nd generation triazoles
BEFORE
Fluconazole
Fluconazole
• Pills,
IV, Oral Suspension.
•100-400mg/d
• Long Half life
• Well tolerated
• Maintenance therapy
• Not effective for Aspergillosis,
Zygomycosis,
• Drug resistance
Itraconazole
Itraconazole
• More potent
• Effective for
Aspergillosis
•Poor solubility
The newer 2nd generation triazoles:
Systemic at last!
AFTER
Fluconazole
Fluconazole
No good for molds
Itraconazole
Itraconazole
Poor solubility
Voriconazole: 3rd generation
BEFORE
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
Voriconazole: 3rd generation
Systemic and a mold killer
AFTER (A)
Derivative of fluconazole
Wide antifungal spectrum:
but NOT Zygomycetes
Side effects few. 30% visual
disturbances, 5% hallucinations.
Oral syrup, tablets and IV
Voriconazole is better than AMB in treating IPA
AFTER (B)
102/144 (71%)
77/133 (58%)
Herbrecht et al. NEJM 347:408 2002
Severe side effects: 13.4% vori vs. 24.3% AMB
Posaconazole: Generation 3.5
BEFORE
•Wide antifungal spectrum
including Zygomycetes
•Few side effects
•Proven prophylactic activity
•Oral syrup, tablets
Posaconazole: Generation 3.5
Kills all molds (and yeast)
AFTER
Derivative of itraconazole
Wide antifungal spectrum:
INCLUDING Zygomycetes
Syrup, tablets but no IV…
Systemic Azoles have side effects
that need to be monitored
POINTS
NOT
STRESSED
BEFORE
Hepatotoxicity
Systemic Azoles interact with MANY drugs…
POINTS
NOT
STRESSED
BEFORE
Oral hypoglycemics
Ca+2 channel blockers
Tacrolimus
BEFORE
Allylamines: Terbinafine
• Primarily for Dermatophytes: lypophilic
• Also: Cutaneous Candidiasis
• Oral: 250mg/day. 2-4wks.
Nails- 3-6 months
• Well tolerated
AFTER
lipophylic
Terbinafine, great but only for
fungal skin infections
Cancidas™ (Caspofungin) fact sheet
BEFORE
• First clinically approved Candin
• Systemic (IV). 70mg/d1,
50mg/kg. 1h infusion
• As effective as AMB, less side effects
• Not effective for zygomycetes, fusarium,
cryptococcus
• Combination therapy?
Cancidas™ (Caspofungin) fact sheet
AFTER
Fungal specific
Only IV
No good for crypto, zygo’s, fusarium
Candins: How do they work?
Cell wall stress sensors
(Mid1p, Slg1p/wsc1)
BEFORE
Rom1p
Candins (e.g caspofungin)
Rho
UDP glucose
Control
1,3 b-D-glucan
Glucan synthase
+Caspofungin
Candins: How do they work?
AFTER
Mid1 sensor
Control
GEF
Rho1
Glucan
synthase
G6P
CAS
+Caspofungin