Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


Presentation on theme: "The Importance of Early Appropriate Therapy of Invasive Aspergillosis Helen Whamond Boucher, MD Division of Infectious Diseases Tufts University-New England."— Presentation transcript:

1

2 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

3 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

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

5 Polyene Therapy for Invasive Aspergillosis Response % 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: Hx Control 23% DAMB 29% DAMB 23% ABCD 18% L-AMB 52% ABLC 42%

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

7 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

8 Voriconazole N N N NN Me HO F F F Fluconazole NN N N HO F F N N Voriconazole

9 Global Comparative Aspergillosis Study DRC-Assessed Success at Week 12 (MITT) Difference (raw) = 21.2%, 95 % CI (9.9, 32.6) Difference (adjusted) = 21.8%, 95% CI (10.5, 33.0) 76/144 42/133 * OLAT = Other licensed antifungal therapy 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 53% 32% Herbrecht R et al NEJM 2002;347:408-15

10 Global Comparative Aspergillosis Study Survival Number of days of Therapy Probability of Survival Ampho B +/- OLAT Vori +/- OLAT Hazard ratio = % CI (0.40, 0.89) Herbrecht R et al. NEJM 2002;347: 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

11 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

12 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

13 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! Probability of Survival Time (days) 307 Voriconazole OLAT 307 Amphotericin B OLAT 602 Voriconazole OLAT 602 Amphotericin B OLAT

14 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

15 Echinocandin Antifungal Therapy Caspofungin Anidulafungin H2NH2NH2NH2N H N OH O H N O OH CH 3 HN H O O O OH O N N N H2NH2NH2NH2N HO O NH HN N H H HO HO HO OH H H 2 HOA C MK0991 H3CH3CH3CH3C OH HO HO H3CH3CH3CH3C O O O O O O O OH HO OH N HN NH NH NH CH 3 H OH NH HO H HO OC 5 H 11 VER-002 Micafungin HO OH O O N CH 3 H H O O NH H NH N HN O O H H HO H3CH3CH3CH3C HO OH H NH H O H2NH2NH2NH2N HO H H OH H H OH N NH H O O O NaO S O OHO O(CH 2 ) 4 CH 3 H FK463 N

16 Maertens et al. Clin Infect Dis. 2004; 39: Caspofungin in Salvage Therapy of Invasive 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? CR/PR, % Proven/Probable IA 47 17

17 Itraconazole and Posaconazole Posaconazole Itraconazole H3CH3CH3CH3C N N N NN N N N O CH 3 O O O H Cl Cl N H3CH3CH3CH3C N N N NN N N F F H O O HO H3CH3CH3CH3C O

18 Open-Label Posaconazole (SCH56592) Salvage Therapy of Invasive Aspergillosis Posaconazole N = 107 Historical Control N = 86 Underlying Disease:n (%) Heme Malignancy79 (74%)70 (81%) HSCT55 (51%)38 (44%) Results: Overall success Data Review Committee 45 (42%)22 (26%) Walsh et al. Blood 2003; 102(11); 45 th ASH Abstract 682.

19 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): Cost of Voriconazole and Amphotericin B for Primary Therapy of Invasive Aspergillosis

20 Cost of Selected Antifungals University Hospital in Boston Aug 2004 DrugDoseCost/Day Fluconazole400mg iv$36.32 Fluconazole400mg po$1.00 Caspofungin50mg iv$301.80* L-AMB3 mg/kg/d (70kg)$ L-AMB5 mg/kg/d (70 kg)$ ABLC5 mg/kg/d (70 kg)$ Voriconazole4 mg/kg Q 12 (70 kg)$255.60** Voriconazole200mg po BID$ Caspo 70mg load = $262.22; **vori 6mg/kg x 2 load = $

21 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): , Hadley et al, MSG 44, IDSA 2003 Goodman. N Engl J Med. 1992;326:845; Winston et al. Annals of Internal Medicine 2003; 138(9): Winston et al, Transplantation 2002; 74(5): ; Goodman. N Engl J Med. 1992;326:845; Winston et al. Annals of Internal Medicine 2003; 138(9): Marr et al, Blood 2004; 103(4): ; VanBurik et al, CID 2004; 39:

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

23 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: % 53 %

24 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 Candida 3 12 Fusarium 1 1 Zygomycetes 1 0 Other 0 2 Walsh TJ et al, New Eng J Med, 1999;340: *Proven or probable breakthrough fungal infection

25 Efficacy of Empirical Antifungal Therapy in Neutropenic Patients – Study MSG-42 Walsh TJ et al, NEJM; 2002;346: /422 (5%) 8/415 (1.9%) 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%)

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

27 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:

28 Itraconazole vs. Amphotericin B as Empirical 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 Boogaerts M, et al. Annals of Internal Medicine 2001; 135(6): % 38 %

29 Amphotericin B vs. Liposomal Amphotericin B for Pyrexia 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 Prentice HG, et al. British Journal of Haematology 1997; 98: % 64 % 58 %

30 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 Fusarium 1 0 Zygomycetes 2 0 Trichosporon spp. 1 0 Other 0 1 Walsh TJ et al, New Eng J Med, 2004;351: * one mixed aspergillosis and C.glabrata infection

31 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 Infectionsn/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 01/2 Zygomycetes 0/1 0 Dipodascus capitatus 0/1 0 Other mould, not idd 1/10/1 Walsh TJ et al, New Eng J Med, 2004;351:

32 Empirical Therapy: Historical Breakthrough Fungal Infections 1 Walsh et al. N Engl J Med. 1999;340: ; 2 Boogaerts et al. Ann Intern Med. 2001;135: ; 3 EORTC. Am J Med. 1989;86: ; 4 Pizzo et al. Am J Med. 1982;72: ; 5 Walsh TJ et al, New Eng J Med, 2004;351: Caspo vs L-AMB 5 603/ MSG 42 MSG 32 1 Boogaerts et al 2 EORTC 3 Pizzo et al 4 Drug Number (%) of Breakthrough IFIs Voriconazole 8 (1.9) L-AMB 22 (4.1)21 (5.0)17 (5.0) Amphotericin B 30 (8.7)5 (2.8)1 (1.5)1 (5.5) Itraconazole 5 (2.8) Caspofungin 28 (5.0) No treatment 6 (9.4)5 (31.3)

33 Empirical Therapy What 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; Hughes WT, et al. CID 2002; 34; ; MMWR 2000; Vol 49, No. RR-10. Available from ** Wingard, ICAAC 2004www.CDC.gov

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

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

36 Prophylaxis vs Invasive Fungal Infections Ongoing Studies NHLBI Study of Voriconazole vs. Fluconazole for prophylaxis of IFI in BMT –Prophylaxis day –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 1 st 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

37 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

38 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


Download ppt "The Importance of Early Appropriate Therapy of Invasive Aspergillosis Helen Whamond Boucher, MD Division of Infectious Diseases Tufts University-New England."

Similar presentations


Ads by Google