1. Antifungal management in the haematology patient
David W. Denning
University Hospital of South Manchester
The University of Manchester

2. Treatment

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

4. Invasive aspergillosis
Why most and not all?
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. terreus
A. nidulans
A. flavus
Azole resistance
A. fumigatus
A. niger

8. Species of Aspergillus causing IA
Voriconazole RCT (MITT)
TransNet (surveillance)
MSG multicentre study
A. fumigatus
85 (77%)
136 (74%)
171 (67%)
A. flavus 7 16 41
A. niger 9 13 14
A. terreus 6 10 8
Other 3 4
Not speciated
167 18
Multiple 28 8

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

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

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)
or 2) AmB 1.0 mg/kg/d for 12wks (or OLAT)
mITT analysis
Success (%) Severe AEs (%) Renal tox (%) Died (all) (%)
Vori
AmB }
21%
13%
Herbrecht, Denning et al, NEJM 2002;347:408

12. Survival after primary Rx with amphotericin B or voriconazole2 4 6 8 10 12 20 40 60 80
100
Weeks
Number of patients at risk
Voriconazole
Amphotericin B
Overall logrank test p = 0.015
Voriconazole
Amphotericin B
Survival (percent)
This is a graph of the survival of pts up to 12 weeks after enrollment.
The dotted line of amphotericin shows a poorer survival rate from 3rd week of therapy
Herbrecht, Denning et al, NEJM 2002;347:408

13. Impact of second line treatment after voriconazole versus amphotericin B
Success (CR+PR)/Total (%) Voriconazole Ampho 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) /72 (38)
Insufficient clinical response 5/19 (26) 4/21 (19)
Chronic suppression 11/14 (79) 6/10 (60)
Overall success /144 (53) /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 (22)
AmB (20)
Bowden et al Clin Infect Dis 2002;35:359

15. 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 % % % %
L-AmB % % % %
Cornely et al, Clin Infect Dis 2007;44:1289

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

17. Denning, CID 2007:45:1106

18. AmbiLoad study favours Ambisome compared to voriconazole because of better responding patient population, earlier diagnosis and possibly softer response criteria
Denning, CID 2007:45:1106

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

20. Open study of invasive aspergillosis with caspofungin as primary therapy
61 pts with chemotherapy or auto HSCT received
Caspofungin 70 then 50mg IV daily 
33% response rate
Survival by day 84 = 33/61 (54%)
Viscoli et al, JAC 2009;64:1274

21. Herbrecht at al, New Engl J Med 2002:347:408-15

22. Open study of invasive aspergillosis with caspofungin as primary therapy
42 pts with allo HSCT , 24 eligible,
Rx Caspofungin 70 then 50mg IV /d
Unrelated donors in 16 patients; acute or chronic GVHD was present in 15, 12 patients were neutropenic (<500) at baseline,
Median duration of caspofungin treatment was 24 days.
At EOT, 10 (42%) had complete or partial response,
12 (50%) had progressing disease.
At 12 wks, 8 patients (33%) had complete or partial response.
Survival rates at week 6 and 12 were 79 and 50%, respectively.
Herbrecht et al, BMT 2010; 45:1227

23. Herbrecht at al, New Engl J Med 2002:347:408-15

24. Impact of voriconazole in real life
Nivoix et al, Clin Infect Dis 2008;47:1176

25. Voriconazole versus amphotericin B
[Spectrum/activity]
Favours voriconazole
Much more active for IA (~20% better)
Active against A. terreus
Active against A. nidulans
More active A. flavus
Active against S. apiospermum
Favours Amp B
Mucorales possible
Azole resistant A. fumigatus

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

27. 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

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

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

30. 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

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

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

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

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

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

36. Cytochrome P450 interactions
Fluc
Itra
Posa
Vori
Inhibitor
2C19 +
+++
2C9 ++
3A4
Substrate
Dodds Ashley & Alexander. Drugs Today 2006;41:393.

37. 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

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

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

40. 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

41. 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

42. 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

43. 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)

44. Random voriconazole concentrations in adults receiving 3mg/Kg BID
100,000
Possible toxicity
10,000
1000
Log 10 [Concentration (µg/L)]
Very small children may metabolise voriconazole very fast and need dose escalation to ?7-10mg/Kg BID or 200mg BID
100 10 1 70
140
210
280
days after first dose
Data from Denning et al, Clin Infect Dis 2002;34:563

45. Another challenge – immune reconstitution45

46. Day 0
Day 7
Miceli, Cancer 2007;110:112; Caillot Eur J Radiol 2010;74:e172

47. Rapid neutrophil recovery & invasive aspergillosis
= bleeding from the lung and usually death
Todeschini et al, Eur J Clin Invest 1999;29:453

48. Immune reconstitution in invasive pulmonary aspergillosis, in AIDS
Patient HB
Day +14, CD4 cells 84/uL
Patient HB
Day +42, after AmB and ITZ
Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628

49. Immune reconstitution in invasive pulmonary aspergillosis, in AIDS
Patient HB
Day +64, CD4 cells 340/uL, on VRC
Patient HB
Day +87, day of death
Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628

50. Conclusions
Voriconazole is the treatment of choice for invasive aspergillosis
For those with toxicity, significant drug interactions or azole resistance, an echinocandin or lipid AmB is appropriate
Current treatments are partially successful but more oral therapies are needed
Immune reconstitution poorly understood, but probably important
Opportunities for immune therapies going forward

51. Over 2M pages read monthly in >125 countries
13 years and counting
Over 2M pages read monthly in >125 countries
Supported by the Fungal Research Trust – 20 year anniversary in 2011 51