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Treatment of Aspergillosis

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

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Treatment of Aspergillosis

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  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 BIt * Clin. Infect. Dis. 30:696-709, 2000 t N. Engl. J. Med. 342:756-762, 2000

  3. Aspergillosis Outcome Heme-Onc Ptsa All patientsb 19981995 3 month survival 44/130 (36%) 56/148 (38%)* ___________ ____________ *Death Rate of 62% in 3 months Death due to Aspergillosis 40% Death due to underlying disease 10% Other causes/unknown 8% aDenning, et al, J. Infect. 37:173-180, 1998 bMSG 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 Aspergillosis galactomannan; glucan Candidiasis arabinitol, 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 hospitals 8 countriesUse of growth factors did not appear to influenceoutcome *Denning, et al, J. Infect. 37:173-180, 1998

  8. Aspergillus Treatment (G-CSF)*During Neutropenia 0  4500 WBC Deaths Rapid < 5 days 4/8 (50%) Slow > 5 days 2/12 (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)  _______________________________________________________ t Ellis 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. 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) Empirical Antifungal Therapy in Neutropenia (AmB vs Ambisome)*Breakthrough Fungal Infections

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

  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 immunosuppression 24 40 41 Less immunosuppression 51 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 CRPRSF ALL 170 42 17 25 13 45 Pulmonary 74 38 9 28 16 46 Disseminated 27 30 15 15 11 59 Sinus 14 64 36 29 7 29 Single organ 15 67 40 27 0 33 extrapulmonary * Walsh et al. Clin. Infect. Dis. 26:1383-1396, 1998

  21. 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 New Agents

  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) inRefractory 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!!!

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