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 – 1st 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
L-AMB
52%
ABLC
42%
Response % Hx
Control
23%
DAMB
29%
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:

6. Acute Renal Failure and Dose of Amphotericin B
Bates et al. CID 2000;32:689 47

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 Me HO F N HO F
Voriconazole
Fluconazole

9. Global Comparative Aspergillosis Study DRC-Assessed Success at Week 12 (MITT)
Satisfactory (CR/PR) responses at week 12
Difference: %
(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)
* OLAT = Other licensed antifungal therapy
Herbrecht R et al NEJM 2002;347:408-15

10. Global Comparative Aspergillosis Study Survival
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
Ampho B +/- OLAT
Vori +/- OLAT
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:

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. Probability of Survival
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 % %
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 14 28 42 56 70 84
Time (days)

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
H2N H N OH HO OH O HO O O HO O N H
OC5H11 N NH N
H3C NH
H2N N H O HN OH N O O HO HN
CH3 O H H H O H HO NH
CH3 NH O OH O H H N
H3C N
2 HOAC O N HO NH HO H O OH O OH OH OH
Caspofungin
Anidulafungin
MK0991
VER-002 HO HO
Micafungin HO OH O H H O HO H O N NH
O(CH2)4CH3
H3C H NH N O HO O HN
CH3 O H H H NH O OH O N H
H2N HO O H NH OH H H H H
NaO S O OH O
FK463 O HO

16. 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?
Proven/Probable IA 47
CR/PR, % 17
Maertens et al. Clin Infect Dis. 2004; 39:

17. Itraconazole and Posaconazole
CH3 O O
H3C N N N N O O N H Cl Cl
Itraconazole N N
H3C N O O
H3C N N N N O HO N H F F
Posaconazole

18. Open-Label Posaconazole (SCH56592) Salvage Therapy of Invasive Aspergillosis
Historical Control
N = 86
Underlying Disease:
n (%)
Heme Malignancy
79 (74%)
70 (81%)
HSCT
55 (51%)
38 (44%)
Results:
Overall success
Data Review Committee
45 (42%)
22 (26%)
Walsh et al. Blood 2003; 102(11); 45th ASH Abstract 682.

19. 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, $19,409
Vori arm $5, $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):

20. Cost of Selected Antifungals University Hospital in Boston Aug 2004
Drug
Dose
Cost/Day
Fluconazole
400mg iv
$36.32
400mg po
$1.00
Caspofungin
50mg iv
$301.80*
L-AMB
3 mg/kg/d (70kg)
$608.80
5 mg/kg/d (70 kg) $
ABLC
$427.92
Voriconazole
4 mg/kg Q 12 (70 kg)
$255.60**
200mg po BID
$ 51.05
Caspo 70mg load = $262.22; **vori 6mg/kg x 2 load = $370.44

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
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
2/16*
5/16
1/18
*No. Fungal Infections/Total Treated
Pizzo et al. Am J Med 1982;72:101 1 19 1

23. EORTC Empirical Antifungal Therapy in Febrile Neutropenia
69 %
53 %
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
75% + leukemia
Emp tx began after 4 days of persistent fever
Outcome: clinical success or failure (fever, doc IFI, mortality due to IFI)
6 documented IFIs (4 severe)/64 pateints (9.4%) in control group
1/68 IFIs in AmB group (1.5%); p=.1
4 deaths due to IFI in control group; none in AmB group; p=.05
EORTC Am J Med 1989;86:668-72

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: (5.0%) 30 (8.7%)
Etiological Agents
Aspergillus
Candida
Fusarium
Zygomycetes
Other
*Proven or probable breakthrough fungal infection
Walsh TJ et al, New Eng J Med, 1999;340:764-71

25. Efficacy of Empirical Antifungal Therapy in Neutropenic Patients – Study MSG-42
Vori vs L-AmB:
Composite success: % 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%) 13 8
8/415
(1.9%) 4 4
Walsh TJ et al, NEJM; 2002;346:225-34 1 19 1

26. Empirical Therapy Study (MSG42) Breakthrough Infections by Risk/Prophylaxis
Source: Source: Walsh manuscript. ‘Table 4’ - see copy of table in paper QC file.
QC review performed by A J Ingamells on 28th Jun01.
Findings on this slide:
none, p-value has been removed (HWB)
25th Sept 01: QC’ed against the BD by A. Ingamells (p88)
Findings:
none

27. Empirical Therapy Study (MSG42) Toxicity
Vori (415) L-AmB (422)
Severe infusion reactions % %
Nephrotoxicity (Cr >1.5X) % %
Hepatatoxicity (ALT >5X) % %
Visual changes % %
Hallucinations % %
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
47 %
38 %
75% + leukemia
Emp tx began after 4 days of persistent fever
Outcome: clinical success or failure (fever, doc IFI, mortality due to IFI)
6 documented IFIs (4 severe)/64 pateints (9.4%) in control group
1/68 IFIs in AmB group (1.5%); p=.1
4 deaths due to IFI in control group; none in AmB group; p=.05
Boogaerts M, et al. Annals of Internal Medicine 2001; 135(6):

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
64 %
58 %
49 %
75% + leukemia
Emp tx began after 4 days of persistent fever
Outcome: clinical success or failure (fever, doc IFI, mortality due to IFI)
6 documented IFIs (4 severe)/64 pateints (9.4%) in control group
1/68 IFIs in AmB group (1.5%); p=.1
4 deaths due to IFI in control group; none in AmB group; p=.05
Prentice HG, et al. British Journal of Haematology 1997; 98:

30. Efficacy of Empirical Caspofungin vs. L-AmB in Neutropenic Patients
Caspo (556) L-AmB (539)
Composite Success % %
Breakthrough Infections: (5.2%) 24 (4.5%)
Etiological Agents
Aspergillus *
Candida
Fusarium
Zygomycetes
Trichosporon spp
Other
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 % %
Successful tx of Baseline Infections n/N (%)
14/27 (51.9%) 7/27 (25.9%)
Etiological Agents
Aspergillus /12 (41.7) /12 (8.3)
Candida /12 (66.7) 5/12 (41.7)
Fusarium /2
Zygomycetes /
Dipodascus capitatus /
Other mould, not id’d /1 0/1
Walsh TJ et al, New Eng J Med, 2004;351:

32. Empirical Therapy: Historical Breakthrough Fungal Infections
Caspo vs L-AMB5
603/ MSG 42
MSG 321
Boogaerts et al2
EORTC3
Pizzo et al4
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
Caspofungin
28 (5.0)
No treatment
6 (9.4)
5 (31.3)
Year(s) of Therapy
Caspo
1998 – Vori
1995 – 96 MSG 32
1996 – 97 Itra
Mid 1980s EORTC
1975 – 1979 Pizzo
1Walsh et al. N Engl J Med. 1999;340: ; 2Boogaerts et al. Ann Intern Med. 2001;135: ; 3EORTC. Am J Med. 1989;86: ; 4Pizzo et al. Am J Med. 1982;72: ; 5Walsh TJ et al, New Eng J Med, 2004;351:

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 Clinical Practice Guidelines in Oncology: Fever and Neutropenia – v Available from accessed 15 June 04.
Hughes WT, et al Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer. CID 2002; 34;
CDC Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients. MMWR 2000; Vol 49, No. RR-10. Available from accessed 15 June 04.
CDC Campaign to Prevent Antimicrobial Resistance. Available from accessed 15 June 04.
*National Comprehensive Cancer Network 2004;
Hughes WT, et al. CID 2002; 34; ; MMWR 2000; Vol 49, No. RR-10. Available from ** Wingard, ICAAC 2004

34. Micafungin vs Fluconazole Prophylaxis/MSG-46 Analysis of Primary Endpoint (MITT)
Consistent with Table 7-43 of the Briefing Document. L. Jenkins 11 Sept 2001
Rechecked L. Jenkins 22 Sept 2001
changed title added new heading in table
VanBurik et al, CID 2004; 39:

35. Micafungin vs Fluconazole Prophylaxis/MSG-46 Documented Breakthrough Fungal Infections
Consistent with Table 7-45 in Briefing Document. L Jenkins 11 Sept 2001
Rechecked L. Jenkins 22 Sept 2001

36. Prophylaxis vs Invasive Fungal Infections Ongoing 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

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
Significant costs
Limited safety, pK data
Definitions, timing critical

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
Significant costs
Limited safety, pK data
Definitions, timing critical