1. 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

2. Drug Family 1: Griseofulvin 1 st 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

3. Drug Family 1: Griseofulvin, good for fungal skin infections only 1939 Penicillium griseofulvum Dermatophyte infections taxol, vinblastine, nocodazole, AFTER

4. Drug Family 1: Griseofulvin Good only for fungal skin infections 1939 Penicillium griseofulvum Dermatophyte infections taxol, vinblastine, nocodazole, AFTER 2

5. Drug Family 1: Griseofulvin Good only for fungal skin infections 1939 Penicillium griseofulvum Dermatophyte infections taxol, vinblastine, nocodazole, AFTER 3

6. Nystatin Topical only Candida (mucocutaneous), Dermatophytes Liposomal form in testing Spoilage protection BEFORE

7. Nystatin: for external use only… Candida (mucocutaneous) Dermatophytes Spoilage protection AFTER

8. Amphotericin B summary 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

9. Amphotericin B: Very effective but toxic… AMB-DOC intravenous The Bad stuff… Chills, fever, dyspnea, nausea, hypotension phlebitis, anemia, nephrotoxic, hepatotoxic AFTER (A)

10. The Good stuff Long half life Fungicidal Very wide kill spectrum Amphotericin B AFTER (B)

11. Flucytosine Drug Family 3: Flucytosine Incorporated into RNA as FUTP. Translation blocked Incorporated into DNA (FdUMP). DNA synthesis blocked 5-Flucytosine Cytosine deaminase 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

12. Flucytosine Drug Family 3: Flucytosine, the only antifungal prodrug 5-Flucytosine Cytosine deaminase 5-Fluorouracil Bacteria, fungi IV/ Oral. DNARNAProtein Leucopenia How does it work? AFTER (A)

13. Flucytosine, no good on its own… Narrow range…Rapid resistance… Solution? AMB+ 5FC combo AFTER (B)

14. The Older 1 st - generation Imidazoles Miconazole Clotrimazole Ketoconazole Mostly topical (Candida, Dermatophytes) Ketoconazole, oral Side effects Fungistatic. Drug resistance. econazole BEFORE

15. The Older 1 st - generation Imidazoles For external use only Miconazole Ketoconazole Almost for systemic use… AFTER Clotrimazole

16. The newer 2nd generation triazoles Itraconazole Fluconazole 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 Fluconazole Itraconazole BEFORE

17. The newer 2nd generation triazoles: Systemic at last! Fluconazole Itraconazole No good for molds Poor solubility AFTER

18. Voriconazole: 3 rd 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

19. Voriconazole: 3 rd generation Systemic 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)

20. 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)

21. Posaconazole: Generation 3.5 Wide antifungal spectrum including Zygomycetes Few side effects Proven prophylactic activity Oral syrup, tablets BEFORE

22. Posaconazole: Generation 3.5 Kills all molds (and yeast) Derivative of itraconazole Wide antifungal spectrum: INCLUDING Zygomycetes Syrup, tablets but no IV… AFTER

23. Systemic Azoles have side effects that need to be monitored Hepatotoxicity POINTS NOT STRESSED BEFORE

24. Systemic Azoles interact with MANY drugs… Oral hypoglycemics Tacrolimus Ca +2 channel blockers POINTS NOT STRESSED BEFORE

25. Allylamines: Terbinafine Primarily for Dermatophytes: lypophilic Well tolerated Also: Cutaneous Candidiasis Oral: 250mg/day. 2-4wks. Nails- 3-6 months BEFORE

26. Terbinafine, great but only for fungal skin infections lipophylic AFTER

27. 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

28. No good for crypto, zygo’s, fusariumOnly IV Cancidas™ (Caspofungin) fact sheet Fungal specific AFTER

29. 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

30. Control +Caspofungin Candins: How do they work? Glucan synthase Rho1 Mid1 sensor GEF G6P CAS AFTER