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Discussion and analysis of the major trials in invasive aspergillosis

Discussion and analysis of the major trials in invasive aspergillosis. David W. Denning Director, National Aspergillosis Centre University Hospital of South Manchester [Wythenshawe Hospital] The University of Manchester Myconostica Ltd. Disclosures. Invasive aspergillosis.

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Discussion and analysis of the major trials in invasive aspergillosis

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  1. Discussion and analysis of the major trials in invasive aspergillosis David W. Denning Director, National Aspergillosis Centre University Hospital of South Manchester [Wythenshawe Hospital] The University of Manchester Myconostica Ltd

  2. Disclosures

  3. Invasive aspergillosis IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

  4. Why most and not all? Invasive aspergillosis IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

  5. Arguments for not using voriconazole • Amphotericin B is a broader spectrum agent

  6. Frequency of mucormycosis in leukaemia 391 pts with leukaemia (225 with AML) and a filamentous fungal infection 80% neutropenia for >14 days, and 71% neutropenic at time of diagnosis 85% pulmonary infection Antemortem diagnosis in 79% Aspergillus 296 (76%) Mucorales 45 (11.5%) Fusarium 6 Other 4 Unidentified in 40 Overall mortality in 3 months 74%, 51% attributable Pagano et al, Hemtaologia 2001;86:862

  7. Intrinsic and acquired resistance among the Aspergilli Amphotericin B resistance A. flavus A. terreus A. nidulans Azole resistance A. fumigatus A. niger

  8. Antifungal susceptibility of Aspergillus nidulans MIC90 ranges (μg/mL) Amphotericin B 4 1–8 (52.3% ≥4) micafungin 0.062 0.062- 0.125 itraconazole 2 0.25–4 voriconazole 2 0.062–2 posaconazole 1 0.25–1 Peláez et al, ECCMID 2009; P1297

  9. Caspofungin Voriconazole Posaconazole % frequency 75 5 5 2 1101 1 Filamentous fungi and antifungal drug activity Highly active Scedosporium apiospermum Very active Scedosporium prolificans Paeciilomyces varioti Paeciilomyces lilanicus Active A. fumigatus Fusarium spp A. terreus A. nidulans A. flavus Mucorales Inactive A. niger Amphotericin B

  10. Arguments for not using voriconazole • Amphotericin B is a broader spectrum agent – No • AmBisome is equivalent to voriconazole in IA

  11. } } 13% 21% Randomised study of invasive aspergillosis with voriconazole versus amphotericin B 391 pts received either 1) Voriconazole 4 mg/d BID (after loading) for 12wks (or OLAT) or 2) AmB 1.0 mg/kg/d for 12wks (or OLAT) mITT analysis Success (%) Severe AEs (%) Renal tox (%) Died (all) (%) Vori 53 13 1 29 AmB 32 24 10 42 Herbrecht, Denning et al, NEJM 2002;347:408

  12. 100 80 60 Survival (percent) 40 Voriconazole Amphotericin B 20 0 0 2 4 6 8 10 12 Weeks Number of patients at risk 144 131 125 117 111 107 102 Voriconazole 133 117 99 87 84 80 77 Amphotericin B Overall logrank test p=0.015 Survival after primary Rx with Amphotericin B or Voriconazole Herbrecht, Denning et al, NEJM 2002;347:408

  13. Impact of second line treatment after voriconazole versus amphotericin B Success (CR+PR)/Total (%) VoriconazoleAmpho B Initial randomised Rx only 51/99 (51) 1/26 (4) Patients who switched Rx 25/52 (48) 41/107 (38) Lipid Ampho B 5/14 (36) 14/47 (38) Itraconazole 11/17 (65) 18/38 (50) Combination 0/1 0/9 Reason for switch Intolerance 8/16 (50) 27/72 (38) Insufficient clinical response 5/19 (26) 4/21 (19) Chronic suppression 11/14 (79) 6/10 (60) Overall success 76/144 (53) 42/133 (32) Patterson et al, Clin Infect Dis 2005;41:1448

  14. Randomised study of invasive aspergillosis with Amphocil versus amphotericin B 174 pts received either 1) Amphocil 6 mg/d for >2wks after symptoms gone or 2) AmB 1.0 – 1.5 mg/kg/d >2wks after symptoms gone 70/174 (40%) in high risk (HSCT, liver Tx, AIDS, brain) ITT analysis Success (%) Tox (%) Renal tox (%) Died (due to IA)(%) Amphocil 13 83 23 59 (22) AmB 15 83 41 67 (20) Bowden et al Clin Infect Dis 2002;35:359

  15. Response rates to 2 Ambisome doses in invasive aspergillosis in neutropenia 100 90 80 70 Response Rate % 60 Clinical Radiological 50 Radiological Clinical 40 30 20 10 0 1mg/kg 4mg/kg Ellis et al, Clin Infect Dis 1998;27:1046

  16. High-dose liposomal amphotericin B Maximally tolerated dose study, 7.5 - 15mg/kg daily 44 patients, 21 proven / probable mould infection MTD >15mg/kg Responses in MITT, >7d Rx 7.5 10 12.5 15 mg/kg All (%) Response rates (CR/PR) 5/7 3/7 4/5 4/12 16/29 (55) Failure 2/7 1/7 1/5 5/12 13/29 (45) Walsh et al, AAC 2001;45:3487

  17. Randomised study of invasive aspergillosis with 2 doses of AmBisome 339 pts randomised to receive either 1) L-AmB 3 mg/d for 2+wks (169 randomised; 107 in MITT) or 2) L-AmB 10 mg/d for 2+wks (162 randomised; 94 in MITT) 44/201 (22%) high risk (HSCT, AIDS) MITT analysis CR + PR Stop Rx Renal tox Died L-AmB 3 50% 20% 14% 28% L-AmB 10 46% 32% 31% 41% Cornely et al, Clin Infect Dis 2007;44:1289

  18. Survival L-AmB 3 mg/kg L-AmB 10 mg/kg p = 0.089 Weeks AmBiload trial results Response LAmB 3 mg/kg (n = 107) LAmB 10 mg/kg (n = 94) P = NS 50 Overall Response 40 30 50 % 46% 20 10 0 End of Treatment Cornely et al, Clin Infect Dis 2007;44:1289

  19. Denning, CID 2007:45:1106

  20. Denning, CID 2007:45:1106

  21. Herbrecht et al, NEJM 2002:347:408

  22. Arguments for not using voriconazole • Amphotericin B is a broader spectrum agent – No • AmBisome is equivalent to voriconazole in IA – No • Patient was on itraconazole prophylaxis

  23. Arguments for not using voriconazole • Amphotericin B is a broader spectrum agent – No • AmBisome is equivalent to voriconazole in IA – No • Patient was on itraconazole prophylaxis

  24. Prophylactic Itraconazole Glasmacher & Prentice J Antimicrob Chemother 2005; 56 (Suppl 1): i23.

  25. Increased AmB MICs after pre-exposure of A. fumigatus to itraconazole Kontoyiannis AAC 2000;44:2915

  26. Arguments for not using voriconazole • Amphotericin B is a broader spectrum agent – No • AmBisome is equivalent to voriconazole in IA – No • Patient was on itraconazole prophylaxis – No • The patient has cerebral aspergillosis

  27. Cerebral aspergillosis and voriconazole (n=81) Schwartz et al, Blood 2005, Ruhnke personal comunication

  28. Arguments for not using voriconazole • Amphotericin B is a broader spectrum agent – No • AmBisome is equivalent to voriconazole in IA – No • Patient was on itraconazole prophylaxis – No • The patient has cerebral aspergillosis – No (beware interactions) • The patient might have azole resistant Aspergillus

  29. Resistance in context of invasive aspergillosis Verweij, NEJM 2007;356:1481

  30. 11% 5% 17% 7% 5% 3% 0% 0% 5% 7% 0% 0% Azole resistance in Manchester in A. fumigatus Howard et al, Emerg Infect Dis 2009;15:1068

  31. Posaconazole MIC (mg/L) Voriconazole MIC (mg/L) Itraconazole MIC (mg/L) Manchester azole MIC distributions modified EUCAST method - 0.5 x 105 not 1-2.5 x 105 cfu/mL Howard unpublished

  32. Arguments for not using voriconazole • Amphotericin B is a broader spectrum agent – No • AmBisome is equivalent to voriconazole in IA – No • Patient was on itraconazole prophylaxis – No • The patient has cerebral aspergillosis – No (beware interactions) • The patient might have azole resistant Aspergillus – maybe • Major drug interactions

  33. Cytochrome P450 interactions Dodds Ashley & Alexander. Drugs Today 2006;41:393.

  34. Arguments for not using voriconazole • Amphotericin B is a broader spectrum agent – No • AmBisome is equivalent to voriconazole in IA – No • Patient was on itraconazole prophylaxis – No • The patient has cerebral aspergillosis – No (beware interactions) • The patient might have azole resistant Aspergillus – maybe • Major drug interactions – yes sometimes • Renal failure

  35. Arguments for not using voriconazole • Amphotericin B is a broader spectrum agent – No • AmBisome is equivalent to voriconazole in IA – No • Patient was on itraconazole prophylaxis – No • The patient has cerebral aspergillosis – No (beware interactions) • The patient might have azole resistant Aspergillus – maybe • Major drug interactions – yes sometimes • Renal failure – only IV therapy needed for any duration • My patient is a young child and I am worried about blood levels

  36. Voriconazole levels in children Pasqualotto et al, Arch Dis Child 2008;93:578

  37. Combination therapy – invasive aspergillosis Retrospective AmB failures Most HSCT 30/47 proven IA Multivariate analysis P=0.008 for combination and survival Marr et al, Clin Infect Dis 2004:39:797

  38. Arguments for not using voriconazole • Amphotericin B is a broader spectrum agent – No • AmBisome is equivalent to voriconazole in IA – No • Patient was on itraconazole prophylaxis – No • The patient has cerebral aspergillosis – No (beware interactions) • The patient might have azole resistant Aspergillus – maybe • Major drug interactions – yes sometimes • Renal failure – only IV therapy needed for any duration • My patient is a young child and I am worried about blood levels – yes use 7mg/Kg BD (200mg BD orally) and consider combination therapy with an echinocandin and measure levels

  39. Choice of antifungal for aspergillosis • Priority sequence • Voriconazole (unless drug interaction) • AmBisome 3mg/Kg (if not ‘nephro-critical’) • OR • caspofungin/micafungin (if not neutropenic) • 3. Posaconazole (oral only, if no drug interactions) • 4. Itraconazole

  40. When not to use voriconazole as primary therapy? • Absolute contraindications • Drug interactions (ie rifampicin, carbamazepine, phenytoin etc) • Voriconazole used as prophylaxis (but not itraconazole or posaconazole) • Resistance to voriconazole (esp zygomycosis, A. lentulus or azole resistance) • Relative contraindications • Renal failure (IV only) • Young children (need higher dose ?+ other agent) • Severe hepatic dysfunction • Interacting drugs (ie sirolimus)

  41. Aspects of good care - aspergillosis • Start treatment as fast as possible, with voriconazole, if no contra-indications • If sinus, centrally located pulmonary, endocarditis, brain abscess or osteomyelitis, plan on surgery • Resolve neutropenia, if present, but don’t over correct

  42. Rapid neutrophil recovery & invasive aspergillosis Todeschini et al, Eur J Clin Invest 1999;29:453

  43. Aspects of good care - aspergillosis • Start treatment as fast as possible, with voriconazole, if no contra-indications • If sinus, centrally located pulmonary, endocarditis, brain abscess or osteomyelitis, plan on surgery • Resolve neutropenia, if present, but don’t over correct • Reduce steroids and other immunosuppressants as much as possible • Check voriconazole levels • If culture positive, arrange species ID and MICs • Repeat CT scan (and GM) at ~2 weeks if rapidly progressive disease and at ~4 weeks of subacute disease

  44. Invasive aspergillosis refractory to voriconazole • Check plasma voriconazole levels and MICs • If neutropenic • Amphotericin B/AmBisome or posaconazole preferred • If not neutropenic • Echinocandin or • Posaconazole or • AmBisome 3mg/Kg (3rd choice) IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

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