1. Treatment of Aspergillosis John R. Perfect Duke University Medical Center

2. Practice Guidelines for Aspergillosis* Therapy Invasive Aspergillosis Amphotericin B deoxycholate (1-1.5 mg/kg/d) BIII Lipid formulations of amphotericin B AII Itraconazole BII Aspergilloma Surgery CIII Allergic Bronchopulmonary Aspergillosis Steroids BIII Itraconazole BI t * Clin. Infect. Dis. 30:696-709, 2000 t N. Engl. J. Med. 342:756-762, 2000

3. Aspergillosis Outcome Heme-Onc Pts a All patients b 19981995 3 month survival44/130 (36%)56/148 (38%)* _______________________ *Death Rate of 62% in 3 months Death due to Aspergillosis40% Death due to underlying disease10% Other causes/unknown 8% a Denning, et al, J. Infect. 37:173-180, 1998 b MSG Retrospective Study, 1995

4. Strategies To Overcome Drug Resistance (1) Accurate and rapid diagnosis (2) Immune modulation (3) Drug prescription (4) Prophylaxis/Empiric strategies (5) Surgery (6) Drug combination (7) New drugs

5. Accurate and Rapid Diagnosis Aspergillosisgalactomannan; glucan Candidiasisarabinitol, mannan, enolase, glucan PCR (Awaits its day) Except for Cryptococcosis/Histoplasmosis accurate and rapid diagnosis for invasive mycoses not available.

6. Immunomodulation in Mycoses Cytokines well-studied at basic science level Theoretically, important in this immunocompromised population Clinically, not optimized for treatment (successes, failures, or no impact)

7. An EORTC Multicentre Prospective Survey of Invasive Aspergillosis in Hematological Patients: Diagnosis and Therapeutic Outcome.* 130 cases 20 hospitals8 countries Use of growth factors did not appear to influence outcome * Denning, et al, J. Infect. 37:173-180, 1998

8. Aspergillus Treatment (G-CSF)* During Neutropenia 0  4500 WBCDeaths Rapid < 5 days4/8 (50%) Slow > 5 days2/12 (17%) *Todeschini, EMM Meetings, Barcelona, 2000

9. Dosing We still do not optimize triazole pharmacokinetics What is optimal daily dose for lipid products of amphotericin B What about administering drugs at specific site? (i.e., aerosols)

10. Ambisome Aspergillosis % (No.)CR/PR 1 mg/kg 41 64 t 4 mg/kg 46 48 5 mg/kg 17 77  5 mg/kg 52 52 vs 29 (AmB)  _______________________________________________________ tEllis et al. Clin. Infect. Dis. 27:1406-1412, 1998  Chopra et al. Brit. J. Haem. 86:754-760, 1994 Leenders et al. Brit. J. Haem. 103:205-212, 1998

11. Aerosolized ABLC for Fungal Prophylaxis in Lung Transplants* Safe (> 100 pts)< 3% toxicity No pulmonary infections; occ. fungemia 50 mg (Respigard II) 100 mg (for vent) Randomized study ABLC vs AmB Palmer et al *Transplantation, 2000

12. Prophylaxis Primary focus for success 10% rule Aspergillus ?

13. Empirical Antifungal Therapy in Neutropenia (AmB vs Ambisome)* Breakthrough Fungal Infections Ambisome Aspergillosis 5 Candidiasis 3 Other 2 10 Ambisome < AmB Ambisome < Amb Walsh et al, NEJM, 1999 AmB 11 12 3 26 P >0.01 (Infusion-related Rxn) (Nephrotoxicity)

14. Empirical Antifungal Therapy in Neutropenia (Vori vs Ambisome) Breakthrough Fungal Infections VorI Aspergillosis 4 Candidiasis 2 Dimorphic Moulds 0 Zygomytcosis 2 8(1%) Vori < Ambisome * Walsh et al - ICAAC, 2000 Ambisome 13 6 2 0 21 (9%) P = 0.03 (Infusion-related Rxn) (Nephrotoxicity)

15. Surgery Debulking may be helpful (Aspergillus/Zygomycetes) Must be individualized and many times not clinically possible

16. Drug Combinations Aspergillosis. AmB + 5FC. AmB + Rifampin Polyenes + Azoles (Antagonism vs Additive). AmB + ITZ (Sequential) AmB vs AmB/ITZ Death Rate 36.6% 8.3%. New drugs + old drugs (improve fungicidal activity) More data urgently needed! _______________________________________________________ * Mycoses Study Group, 1995

17. Aspergillosis* % Response Rates (CR/PR) AmB (187) ITZ (58) AmB/ITZ (93) Severe immunosuppression24 40 41 Less immunosuppression51 61 66 * Patterson et al. Medicine 79:250-260, 2000

18. New Antifungal Agents How can they help? (Better antifungal spectrum; reduced toxicity, less drug interactions; fungicidal activity; use in combination) Will they help? Yes (Here is why)

19. Almost New Antifungal Agents - Lipid products of Amphotericin B (ABLC, Ambisome) Effective in refractory cases of aspergillosis 40-45% cases Safety: nephrotoxicity matters (Wingard CID 29:1402-1407, 1999) Empirical use effective Cost Comparison of products (ABLC vs Ambisome) (Wingard, Clin. Infect. Dis. 31:1155-1163, 2000) - Intravenous Itraconazole Efficacy data Use during reduce renal function

20. Amphotericin B Lipid Complex * Aspergillosis % No. (Pts)CR/PR CR PR S F ALL 170 4217 25 13 45 Pulmonary 74 38 9 28 16 46 Disseminated 27 3015 15 11 59 Sinus 14 6436 29 7 29 Single organ 15 6740 27 0 33 extrapulmonary * Walsh et al. Clin. Infect. Dis. 26:1383-1396, 1998

21. New Agents Triazoles Posaconazole Ravuconazole Voriconazole Others R 120758, R 102557 KP 103, TAK 456, T 8581, UR 9825 Candins Capsofungin FK 463 V- Echinocandin (LY 303366) Polyene Liposomal Nystatin Others Nikkomycin Z Azasordarins Pradimicins Peptides

22. NYOTRAN (Liposomal Nystatin) IA Refractory or Intolerant to Polyenes 4 mg/kg/d is well tolerated in treatment of IA (27 days) 2/25 (8%) IRR; 3/25 (12%) nephrotoxicity Response (CR/PR) 6/19 (32%) 30 day survival (refractory pts) 7/16 (44%) Offner, et al, Abstr. 1102, 40th ICAAC, 2000

23. CASPOFUNGIN* IA Refractory or Intolerant to Polyenes 70 mg/50 mg/d is well tolerated in Rx of IA 3/54 (5.5% ) AE Pulmonary (40) Disseminated (10) Single Organ (4) CR/PR 18 (45%) 2 (20%) 2 (50%) Stable/ Failure 22 (55%)8 (80%) 2 (50%) Salvage therapy, favorable response 41% *Maertens, et al, Abstr. 1103, 40th ICAAC, 2000

24. POSACONAZOLE (SCH456592)* Oral preparation Oropharyngeal candidiasis (CR/PR >80%) Effective in coccidioidomycosis Open, non-comparative trial (800 mg/d) (Invasive fungal infections refractory to standard Rx) 1 Month (% CR/PR) Candidiasis (10)80% Aspergillus (22)50% Fusarium ( 5)80% Cryptococcus (12)58% Other (19)74% AEs 6-12% *Hachem RY, et al, Abstr. 1109, 40th ICAAC, 2000

25. Voriconazole Response Rates (CR/PR) in Refractory Aspergillosis

26. Summary In the next 5 years the single biggest advance for antifungal drug resistance will be new drugs. They will not cure every infection or prevent every infection as our immunocompromised population increases. But they will make a positive clinical impact if properly studied!!!