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Early Appropriate Therapy of Invasive Aspergillosis: Lessons from Global Study

Explore the importance of early and appropriate therapy for invasive aspergillosis, including treatment options, efficacy, and potential drug interactions. Learn about the role of polyenes, extended spectrum azoles, echinocandins, and the use of lipid formulations of amphotericin B.

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Early Appropriate Therapy of Invasive Aspergillosis: Lessons from Global Study

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  1. The Importance of Early Appropriate Therapy of Invasive Aspergillosis Helen Whamond Boucher, MD Division of Infectious Diseases Tufts University-New England Medical Center Boston, Massachusetts

  2. Early Appropriate Therapy for Invasive Aspergillosis • Treatment of documented (definite or probable) invasive aspergillosis • Lessons from the Global Aspergillosis Study • One drug or two (or three) ? • Does cost matter ? • Empirical Therapy • Prophylaxis

  3. Therapy for Invasive Aspergillosis • Polyenes • Lipid Formulations of Amphotericin B • Extended spectrum azoles • Voriconazole – 1st line* • Posaconazole • Echinocandins • Caspofungin, Micafungin, Anidulafungin • IDSA Practice Guidelines for Aspergillus Update Pending * Steinbach and Stevens. CID 2003; 37(Suppl 3): S157-87.

  4. Polyene Therapy for Invasive Aspergillosis L-AMB 52% ABLC 42% Response % DAMB 29% Hx Control 23% DAMB 23% ABCD 18% Hiemenz JW, et al. Blood 1995;86(suppl 1):849a; Leenders ACAP et al. Br J Haem 1998;103:205; Bowden RA et al. Clin Infect Dis 2002;35:359-66.

  5. Acute Renal Failure and Dose of Amphotericin B Bates et al. CID 2000;32:689

  6. Clinical Significance of Nephrotoxicity • 239 pts receiving AmB; mean duration 20 d • Cr >2.5 mg/dL: 29% • Dialysis: 14% • Mortality: 60% • Risk of dialysis: • Allo BMT (HR 6.34) • Auto BMT (HR 5.06) • Cr >2.5 (HR 42.02) • Increased mortality: • Dialysis (HR 3.05) • AmB duration (HR 1.03/d) • Nephrotoxic agents (HR 1.96) Wingard et al. CID 1999;29:1402

  7. Me F HO HO N N N N N N N N N N N F F F F Voriconazole Fluconazole Voriconazole

  8. Global Comparative Aspergillosis StudyDRC-Assessed Success at Week 12 (MITT) Satisfactory (CR/PR) responses at week 12 • Difference: 21.2% (95 % CI [9.9, 32.6]) Responses at end of initial randomized therapy • Vori: 54% • AmB: 22% • Median duration of IRT: • Vori: 77 days • AmB: 11 days 76/144 53% 42/133 32% Difference (raw) = 21.2%, 95 % CI (9.9, 32.6) Difference (adjusted) = 21.8%, 95% CI (10.5, 33.0) Herbrecht R et al NEJM 2002;347:408-15 * OLAT = Other licensed antifungal therapy

  9. Vori +/- OLAT Ampho B +/- OLAT Global Comparative Aspergillosis StudySurvival • Survival at Week 12 • Vori ± OLAT 71% • AmB ± OLAT 58% Discontinuations due to AE/lab abnormality • Vori 20% / AmB 56% • Poor efficacy of AmB prior “gold standard” • Vori recommended for primary therapy • Questions? • Role of OLAT • Lipid for primary therapy • Efficacy in high risk (HSCT) • Combinations Probability of Survival Hazard ratio = 0.60 95% CI (0.40, 0.89) Number of days of Therapy Herbrecht R et al. NEJM 2002;347:408-15.

  10. Vori vs Ampho Trial in Invasive Aspergillosis: Success According to Drug After Switch to OLAT Herbrecht R et al. NEJM 2002;347:408-15; Boucher HW et al ICAAC 2003

  11. What About Lipid Formulations of Amphotericin B (LFAB) for Primary Therapy? • 35% of Amphotericin B patients received LFAB for intolerance or disease progression • Received a median 13 days LFAB therapy • Success in 13 of 46 patients (28%) at week 12 Herbrecht R et al. NEJM 2002;347:408-15; Boucher HW et al, ICAAC 2003

  12. Limited Efficacy of Antifungal Therapy for Invasive Aspergillosis in Allogeneic BMT: Need for Better Therapy? • Allo BMT outcomes at 12 weeks Vori AMB (n=37)(n=30) • Response 32% 13% • Survival 70% 40% • AMB: unacceptable response • Vori: week 12 responses better than AMB (but less than optimal) • However, improved survival shows benefit of early therapy even in high- risk patients! 1.0 0.8 0.6 Probability of Survival 0.4 307 Voriconazole → OLAT 307 Amphotericin B → OLAT 0.2 602 Voriconazole → OLAT 602 Amphotericin B → OLAT 0.0 0 14 28 42 56 70 84 Time (days)

  13. Voriconazole in Invasive Aspergillosis: Important Considerations • Oral therapy if possible • Hepatic dysfunction • Reduce dose • Consider increased drug levels • Drug interactions • Monitor immunosuppressive therapy • Metabolism • Increased levels in patients likely to metabolize drug poorly • May be associated with increased adverse events • ? Emergence of zygomycetes

  14. Echinocandin Antifungal Therapy H H2N OH N HO OH O O O O HO HO OC5H11 H N NH N H3C NH N H2N H O N N HN OH O O CH3 HN HO O H H H H O CH3 NH HO O NH OH H N H3C H O N O 2 HOAC N NH HO HO OH H O OH O OH OH Anidulafungin VER-002 Caspofungin MK0991 HO HO Micafungin OH HO O O H H O H HO N O(CH2)4CH3 NH H3C H NH O N CH3 HO O HN O H H O NH H OH H O N H2N HO NH H OH O H H H H OH O NaO S O FK463 O HO

  15. Caspofungin in Salvage Therapy ofInvasive Aspergillosis • Well-documented disease • Efficacy • High-risk patients (72% heme malignancy/SCT) • Progressive infection (86%) • Multiple prior antifungals • Minimal toxicity • Clinical questions • Use as primary therapy? • Role in combinations? • Optimal dose? Proven/Probable IA 47 CR/PR, % 17 Maertens et al. Clin Infect Dis. 2004; 39: 1563-71.

  16. Itraconazole and Posaconazole N N N CH3 O O H3C N O N O N N N Cl H Cl Itraconazole N N H3C N O O H3C N N O N N HO N F F H Posaconazole

  17. Open-Label Posaconazole (SCH56592)Salvage Therapy of Invasive Aspergillosis Walsh et al. Blood 2003; 102(11); 45th ASH Abstract 682.

  18. Cost of Voriconazole and Amphotericin B for Primary Therapy of Invasive Aspergillosis • Drug acquisition costs determined from the Global Aspergillosis Trial (Herbrecht, 2002) • “Real-world” drug acquisition costs from our University Hospital • Total drug costs (including OLAT): Cost per Patient Cost per Success AmB arm $6,210 $19,409 Vori arm $5,438 $10,262 • Primary therapy with voriconazole was $722 less per patient than initial AmB Lewis JS, Boucher HW, Luboski TJ, et al. Pharmacotherapy 2005; 25(6): 839-46

  19. Cost of Selected AntifungalsUniversity Hospital in Boston Aug 2004 Caspo 70mg load = $262.22; **vori 6mg/kg x 2 load = $370.44 www.doctorfungus.org/thedrugs/cost1.htm

  20. Early Appropriate Treatment Empirical Therapy and Systemic Prophylaxis • Increased risk of fungal infection with persistent fever and neutropenia • Candida spp. early (neutropenia > one week) • Prophylaxis effective • Aspergillus spp. later (neutropenia >2-3 weeks) • Prophylaxis under study • Winston et al, Ann Int Med 99; 131(10): 729-37, Hadley et al, MSG 44, IDSA 2003 • Winston et al, Transplantation 2002; 74(5): 688-95; Goodman. N Engl J Med. 1992;326:845; Winston et al. Annals of Internal Medicine 2003; 138(9): 705-13. Marr et al, Blood 2004; 103(4): 1527-33; VanBurik et al, CID 2004; 39: 1407-16.

  21. Efficacy of Empirical Antifungal Therapy in Neutropenic Patients 2/16* 5/16 1/18 *No. Fungal Infections/Total Treated Pizzo et al. Am J Med 1982;72:101

  22. 69 % 53 % EORTC Empirical Antifungal Therapy in Febrile Neutropenia • Overall response • Not different • Decreased fungal mortality (0 vs 4 pts) • Improved responses • No prophylaxis • Severely neutropenic • Clinical infection • Older patients (>15 yrs) • Utility in HIGH RISK patients EORTC Am J Med 1989;86:668-72

  23. Efficacy of Empirical L-AmB vs Amphotericin B Deoxycholate in Neutropenic Patients* L-AmB (343) AmB Deoxycholate (344) Composite Success 50% 49% Breakthrough Infections: 17 (5.0%) 30 (8.7%) Etiological Agents Aspergillus 12 15 Candida 3 12 Fusarium 1 1 Zygomycetes 1 0 Other 0 2 *Proven or probable breakthrough fungal infection Walsh TJ et al, New Eng J Med, 1999;340:764-71

  24. Efficacy of Empirical Antifungal Therapy in Neutropenic Patients – Study MSG-42 • Vori vs L-AmB: • Composite success: 26% vs 31% • High risk pts: 18% Allo BMT • Similar survival, fever resolution, toxicity/lack of efficacy • Fewer breakthrough infections • Efficacy in high risk: • Breakthrough infections: 2/143 (2%) vs 13/143 (9%) 21/422 (5%) 8 13 8/415 (1.9%) 4 4 Walsh TJ et al, NEJM; 2002;346:225-34

  25. Empirical Therapy Study (MSG42) Breakthrough Infections by Risk/Prophylaxis

  26. Empirical Therapy Study (MSG42) Toxicity Vori (415) L-AmB (422) • Severe infusion reactions 6.3% 37.2% • Nephrotoxicity (Cr >1.5X) 10.4% 19.0% • Hepatatoxicity (ALT >5X) 7.0% 8.1% • Visual changes 21.9% 0.7% • Hallucinations 4.3% 0.5% Walsh TJ, et al. New Engl J Med 2002;346:225-34.

  27. Itraconazole vs. Amphotericin B asEmpirical Antifungal Therapy in Febrile Neutropenia • Overall response • Not different • Few BT IFIs (5, 2.8% each arm) • Success – defervescence/RFN • Failure – • BT IFI • Death • No defervescence by day 28 • Additional antifungal tx • Discont. due to intolerance • No BMT patients included • Mean daily AmB dose 0.7 mg/kg • Itra levels > 250ng/ml • IV and PO 47 % 38 % Boogaerts M, et al. Annals of Internal Medicine 2001; 135(6): 412-422

  28. Amphotericin B vs. Liposomal Amphotericin B forPyrexia of Unknown Origin in Neutropenic Patients • Safety study • Children and adults (adults allowed to switch to L-AmB for toxicity) • Overall response • L-AMB safer than AmB • L-AMB as effective as AmB • L-AMB 3mg/kg/d more effective than AmB (ITT and PP) • Success – defervescence x 3d/RFN • Failure – • IFI • No defervescence • Additional antifungal tx • Mean daily AmB dose 0.76 mg/kg 64 % 58 % 49 % Prentice HG, et al. British Journal of Haematology 1997; 98: 711-718

  29. Efficacy of Empirical Caspofungin vs. L-AmB in Neutropenic Patients Caspo (556) L-AmB (539) Composite Success 33.9% 33.7% Breakthrough Infections: 29 (5.2%) 24 (4.5%) Etiological Agents Aspergillus 10* 9 Candida 16 15 Fusarium 1 0 Zygomycetes 2 0 Trichosporon spp. 1 0 Other 0 1 Walsh TJ et al, New Eng J Med, 2004;351:1391-1402 * one mixed aspergillosis and C.glabrata infection

  30. Efficacy of Empirical Caspofungin vs. L-AmB in Neutropenic Patients Caspo (556) L-AmB (539) Composite Success 33.9% 33.7% Successful tx of Baseline Infections n/N (%) 14/27 (51.9%) 7/27 (25.9%) Etiological Agents Aspergillus 5/12 (41.7) 1/12 (8.3) Candida 8/12 (66.7) 5/12 (41.7) Fusarium 0 1/2 Zygomycetes 0/1 0 Dipodascus capitatus 0/1 0 Other mould, not id’d 1/1 0/1 Walsh TJ et al, New Eng J Med, 2004;351:1391-1402

  31. Empirical Therapy: Historical Breakthrough Fungal Infections 1Walsh et al. N Engl J Med. 1999;340:764-771; 2Boogaerts et al. Ann Intern Med. 2001;135:412-422; 3EORTC. Am J Med. 1989;86:668-672; 4Pizzo et al. Am J Med. 1982;72:101-111; 5Walsh TJ et al, New Eng J Med, 2004;351:1391-1402

  32. Empirical TherapyWhat is Best in 2005? Options for persistent fever and neutropenia following 3-5 days Abx therapy and aggressive work-up - consider* • Infectious Diseases/Medical Microbiology Consultation • CT Scan of Chest • G-CSF/GM-CSF • BAL • Goal: early diagnosis and identify patients at high risk of mould infection Add mould-active antifungal • Lipid Formulation of AmB 5mg/kg/day iv • Voriconazole 3mg/kg q 12 h iv or po (preferred) if no prior azole prophylaxis • Caspofungin for • Documented intolerance of Lipid Formulation • Prior voriconazole prophylaxis Consider no empirical therapy for patients with negative work-up?** *National Comprehensive Cancer Network 2004; http://www.nccn.org/prosessionals/physician_gls/PDF/fever.pdf; Hughes WT, et al. CID 2002; 34; 730-51; MMWR 2000; Vol 49, No. RR-10. Available from www.CDC.gov; ** Wingard, ICAAC 2004

  33. Micafungin vs Fluconazole Prophylaxis/MSG-46Analysis of Primary Endpoint (MITT) VanBurik et al, CID 2004; 39: 1407-16

  34. Micafungin vs Fluconazole Prophylaxis/MSG-46Documented Breakthrough Fungal Infections

  35. Prophylaxis vs Invasive Fungal InfectionsOngoing Studies • NHLBI Study of Voriconazole vs. Fluconazole for prophylaxis of IFI in BMT • Prophylaxis day 0-180 • Addition of LFAB for empirical therapy • Prospective use of galactomannan as guide to intervention • Posaconazole (200mg TID) vs. Itra (susp 200 BID) or Flu (susp 400 qd) in High Risk Neutropenic Patients • High risk = New AML, AML in 1st relapse, or MDS in transformation/2º AML • Dur tx = period of neutropenia/max 12 wks (84 days) • Endpoint = incidence of IFI in both arms from rando to EOT + 7 days

  36. Early Appropriate Therapy for Invasive Aspergillosis Therapy of documented infection • Poor responses • Role of new azoles • Primary therapy of aspergillosis: voriconazole • Improved responses with early initiation of therapy • Combination therapy • Randomized trial needed for primary therapy Empirical therapy • Voriconazole: reduction of breakthrough infections (including Aspergillus) in high-risk patients • Caspofungin • LFAB Prophylaxis • Epidemiologic assessment of risk • Patients at increased risk of Aspergillus/moulds • Changing etiological agents, timing of infections

  37. Early Appropriate Therapy for Invasive Aspergillosis Future directions: • Strategies that focus on patients at highest risk • Prophylaxis vs. Candida in short duration neutropenia • Prophylaxis vs. Aspergillus and other moulds in longer duration neutropenia (higher risk) • Focus on early, prompt diagnosis • Galactomannan, PCR, other noninvasive diagnostics • Early imaging with CT, bronchoscopy • Pre-emptive vs. empirical therapy

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