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 ShareholderF2G Myconostica Consultant (last 5 years) Basilea, Vicuron (now Pfizer), Pfizer, Schering Plough, Indevus, F2G, Nektar, Daiichi, Sigma Tau, Astellas, Gilead and York Pharma Research grant (last 5 years) Astellas, Merck, Pfizer, F2G, OrthoBiotech, Indevus, Basilea, AstraZeneca, the Fungal Research Trust, the Wellcome Trust, the Moulton Trust, the Medical Research Council, the Chronic Granulomatous Disease Research Trust, the National Institute of Allergy and Infectious Diseases, NIHR, and the European Union Speakers bureauSchering Plough, Astellas, Merck, GSK, Myconostica Dianippon and Pfizer

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

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

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

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 A. niger A. fumigatus A. nidulans Amphotericin B resistance A. flavus A. terreus Azole resistance

8. Antifungal susceptibility of Aspergillus nidulans MIC90 ranges (μg/mL) Amphotericin B 4 1–8 (52.3% 4) micafungin 0.0620.062- 0.125 itraconazole 20.25–4 voriconazole 20.062–2 posaconazole 10.25–1 Peláez et al, ECCMID 2009; P1297

9. Amphotericin B Filamentous fungi and antifungal drug activity Active Very active Highly active Inactive A. fumigatus A. flavus A. niger Mucorales Scedosporium apiospermum A. terreus A. nidulans Scedosporium prolificans Fusarium spp Paeciilomyces varioti Paeciilomyces lilanicus Voriconazole Posaconazole Caspofungin 75 5 5 2 1 10 1 1% frequency

10. 1.Amphotericin B is a broader spectrum agent – No 2.AmBisome is equivalent to voriconazole in IA Arguments for not using voriconazole

11. 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) or2) AmB 1.0 mg/kg/d for 12wks (or OLAT) Herbrecht, Denning et al, NEJM 2002;347:408 mITT analysis Success (%) Severe AEs (%) Renal tox (%) Died (all) (%) Vori 53 13 129 AmB 32 241042 } 21% } 13%

12. 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 Patterson et al, Clin Infect Dis 2005;41:1448 Success (CR+PR)/Total (%) VoriconazoleAmpho B Initial randomised Rx only51/99(51)1/26 (4) Patients who switched Rx25/52 (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)

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 or2) 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 832359 (22) AmB 15 834167 (20) Bowden et al Clin Infect Dis 2002;35:359

15. Response rates to 2 Ambisome doses in invasive aspergillosis in neutropenia Clinical Radiological Clinical Radiological Response Rate % 1mg/kg4mg/kg 60 50 80 10 70 20 40 30 0 100 90 Ellis et al, Clin Infect Dis 1998;27:1046

16. Maximally tolerated dose study, 7.5 - 15mg/kg daily 44 patients, 21 proven / probable mould infection MTD >15mg/kg Responses in MITT, >7d Rx 7.51012.515 mg/kg All (%) Response rates (CR/PR) 5/73/7 4/5 4/12 16/29 (55) Failure 2/71/7 1/5 5/12 13/29 (45) High-dose liposomal amphotericin B 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) or2) L-AmB 10 mg/d for 2+wks (162 randomised; 94 in MITT) 44/201 (22%) high risk (HSCT, AIDS) Cornely et al, Clin Infect Dis 2007;44:1289 MITT analysis CR + PR Stop Rx Renal tox Died L-AmB 3 50% 20% 14% 28% L-AmB 10 46% 32%31% 41%

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

19. Denning, CID 2007:45:1106

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

22. 1.Amphotericin B is a broader spectrum agent – No 2.AmBisome is equivalent to voriconazole in IA – No 3.Patient was on itraconazole prophylaxis Arguments for not using voriconazole

23. 1.Amphotericin B is a broader spectrum agent – No 2.AmBisome is equivalent to voriconazole in IA – No 3.Patient was on itraconazole prophylaxis Arguments for not using voriconazole

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. 1.Amphotericin B is a broader spectrum agent – No 2.AmBisome is equivalent to voriconazole in IA – No 3.Patient was on itraconazole prophylaxis – No 4.The patient has cerebral aspergillosis Arguments for not using voriconazole

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

28. 1.Amphotericin B is a broader spectrum agent – No 2.AmBisome is equivalent to voriconazole in IA – No 3.Patient was on itraconazole prophylaxis – No 4.The patient has cerebral aspergillosis – No (beware interactions) 5.The patient might have azole resistant Aspergillus Arguments for not using voriconazole

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

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

31. Manchester azole MIC distributions Howard unpublished Itraconazole MIC (mg/L) Voriconazole MIC (mg/L) Posaconazole MIC (mg/L) modified EUCAST method - 0.5 x 10 5 not 1-2.5 x 10 5 cfu/mL

32. 1.Amphotericin B is a broader spectrum agent – No 2.AmBisome is equivalent to voriconazole in IA – No 3.Patient was on itraconazole prophylaxis – No 4.The patient has cerebral aspergillosis – No (beware interactions) 5.The patient might have azole resistant Aspergillus – maybe 6.Major drug interactions Arguments for not using voriconazole

33. Cytochrome P450 interactions FlucItraPosaVori Inhibitor 2C19 ++++ 2C9 +++ 3A4 +++++ ++ Substrate 2C19 +++ 2C9 + 3A4 ++++ Dodds Ashley & Alexander. Drugs Today 2006;41:393.

34. 1.Amphotericin B is a broader spectrum agent – No 2.AmBisome is equivalent to voriconazole in IA – No 3.Patient was on itraconazole prophylaxis – No 4.The patient has cerebral aspergillosis – No (beware interactions) 5.The patient might have azole resistant Aspergillus – maybe 6.Major drug interactions – yes sometimes 7.Renal failure Arguments for not using voriconazole

35. 1.Amphotericin B is a broader spectrum agent – No 2.AmBisome is equivalent to voriconazole in IA – No 3.Patient was on itraconazole prophylaxis – No 4.The patient has cerebral aspergillosis – No (beware interactions) 5.The patient might have azole resistant Aspergillus – maybe 6.Major drug interactions – yes sometimes 7.Renal failure – only IV therapy needed for any duration 8.My patient is a young child and I am worried about blood levels Arguments for not using voriconazole

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

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

38. 1.Amphotericin B is a broader spectrum agent – No 2.AmBisome is equivalent to voriconazole in IA – No 3.Patient was on itraconazole prophylaxis – No 4.The patient has cerebral aspergillosis – No (beware interactions) 5.The patient might have azole resistant Aspergillus – maybe 6.Major drug interactions – yes sometimes 7.Renal failure – only IV therapy needed for any duration 8.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 Arguments for not using voriconazole

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 1.Start treatment as fast as possible, with voriconazole, if no contra-indications 2.If sinus, centrally located pulmonary, endocarditis, brain abscess or osteomyelitis, plan on surgery 3.Resolve neutropenia, if present, but dont over correct

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

43. Aspects of good care - aspergillosis 1.Start treatment as fast as possible, with voriconazole, if no contra-indications 2.If sinus, centrally located pulmonary, endocarditis, brain abscess or osteomyelitis, plan on surgery 3.Resolve neutropenia, if present, but dont over correct 4.Reduce steroids and other immunosuppressants as much as possible 5.Check voriconazole levels 6.If culture positive, arrange species ID and MICs 7.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 IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327 Check plasma voriconazole levels and MICs If neutropenic Amphotericin B/AmBisome or posaconazole preferred If not neutropenic Echinocandin or Posaconazole or AmBisome 3mg/Kg (3 rd choice)