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 Allergic Bronchopulmonary Aspergillosis Steroids BIII Itraconazole BI t * Clin. Infect. Dis. 30: , 2000 t N. Engl. J. Med. 342: , 2000

Aspergillosis Outcome Heme-Onc Pts a All patients b 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: , 1998 b MSG Retrospective Study, 1995

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

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.

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)

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: , 1998

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

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)

Ambisome Aspergillosis % (No.)CR/PR 1 mg/kg t 4 mg/kg mg/kg  5 mg/kg vs 29 (AmB)  _______________________________________________________ tEllis et al. Clin. Infect. Dis. 27: , 1998  Chopra et al. Brit. J. Haem. 86: , 1994 Leenders et al. Brit. J. Haem. 103: , 1998

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

Prophylaxis Primary focus for success 10% rule Aspergillus ?

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 P >0.01 (Infusion-related Rxn) (Nephrotoxicity)

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 (9%) P = 0.03 (Infusion-related Rxn) (Nephrotoxicity)

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

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

Aspergillosis* % Response Rates (CR/PR) AmB (187) ITZ (58) AmB/ITZ (93) Severe immunosuppression Less immunosuppression * Patterson et al. Medicine 79: , 2000

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)

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: , 1999) Empirical use effective Cost Comparison of products (ABLC vs Ambisome) (Wingard, Clin. Infect. Dis. 31: , 2000) - Intravenous Itraconazole Efficacy data Use during reduce renal function

Amphotericin B Lipid Complex * Aspergillosis % No. (Pts)CR/PR CR PR S F ALL Pulmonary Disseminated Sinus Single organ extrapulmonary * Walsh et al. Clin. Infect. Dis. 26: , 1998

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

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

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

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

Voriconazole Response Rates (CR/PR) in Refractory Aspergillosis

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!!!