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The Importance of Early Appropriate Therapy of Invasive Aspergillosis

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. Early Appropriate Therapy for Invasive Aspergillosis.

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The Importance of Early Appropriate Therapy of Invasive Aspergillosis

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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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