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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
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
•
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): S157-87.
Polyene Therapy for Invasive
Aspergillosis
Response %
100
90
80
70
60
50
40
30
Lipid Formulation of AmB
ABLC
42%
DAMB
L-AMB
52%
Hx
Control
23%
DAMB
29%
20
10
0
Hiemenz Salvage
Leenders Includes
Suspected IA
DAMB
ABCD
23%
18%
Bowden Primary Tx
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;35:359-66.
Acute Renal Failure and Dose
of Amphotericin B
Pts with ARF (%)
60
40
20
0
<0.5
0.5-0.9
1.0-1.4
1.5-1.9
Total AmB Dose (gm)
Bates et al. CID 2000;32:689
2.0 or More
Clinical Significance of
Nephrotoxicity
• 239 pts receiving AmB; mean duration 20
d
– Cr >2.5 mg/dL:
– Dialysis:
– Mortality:
29%
14%
60%
 Increased mortality:
• Risk of dialysis:
• Dialysis (HR 3.05)
– Allo BMT (HR 6.34)
• AmB duration (HR 1.03/d)
– Auto BMT (HR 5.06)
• Nephrotoxic agents (HR
– Cr >2.5 (HR 42.02)
1.96)
Wingard et al. CID 1999;29:1402
Voriconazole
HO
N
Me
F
N
N
N
HO
N
N
F
F
Voriconazole
N
N
N
N
N
F
F
Fluconazole
Global Comparative Aspergillosis Study
DRC-Assessed Success at Week 12 (MITT)
60
Voriconazole +/- OLAT*
Amphotericin B +/- OLAT*
76/144
50
% Success
53%
40
42/133
30
32%
20
10
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
0
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
Global Comparative Aspergillosis Study
Survival
1.0
Survival at Week 12
• Vori ± OLAT 71%
• AmB ± OLAT 58%
Vori +/- OLAT
Ampho B +/- OLAT
Probability of Survival
0.8
Discontinuations due to
AE/lab abnormality
• Vori 20% / AmB 56%
Poor efficacy of AmB prior
“gold standard”
Vori recommended for
primary therapy
Questions?
0.6
0.4
Hazard ratio = 0.60
95% CI (0.40, 0.89)
0.2
0.0
0
14
28
42
56
70
Number of days of Therapy
Herbrecht R et al. NEJM 2002;347:408-15.
84
•
•
•
•
Role of OLAT
Lipid for primary therapy
Efficacy in high risk
(HSCT)
Combinations
Vori vs Ampho Trial in Invasive Aspergillosis:
Success According to Drug After Switch to OLAT
Initial Therapy
Voriconazole
N = 144
Amphotericin B
N = 133
No Switch (improved or died)
51/92 (55.4)
1/26(3.9)
Switch All Regimens
25/52 (48.1)
41/107 (38.3)
Lipid Amphotericin B Preparations
5/13 (38.5)
14/47 (29.8)
Itraconazole
11/17 (64.7)
18/36 (50.0)
Decreased Dose Amphotericin B
9/20 (45.0)
9/14 (64.3)
Caspofungin
0
0/1
Combination
0/2
0/9
Herbrecht R et al. NEJM 2002;347:408-15; Boucher HW et al ICAAC 2003
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
Limited Efficacy of Antifungal Therapy for Invasive
Aspergillosis in Allogeneic BMT: Need for Better
Therapy?
• Allo BMT outcomes at 12
weeks
• Response
• Survival
32%
70%
13%
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!
1.0
Probability of Survival
Vori
AMB
(n=37)(n=30)
0.8
0.6
0.4
307 Voriconazole → OLAT
307 Amphotericin B → OLAT
602 Voriconazole → OLAT
602 Amphotericin B → OLAT
0.2
0.0
0
14
28
42
56
Time (days)
70
84
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
Echinocandin Antifungal Therapy
H2 N
HO
H2 N
HO
HO
O
O
H
N
HO
O
HO O
H
N
N
N
N H HN O
OH
O
H H
CH3
NH O
HH N
N
H O
OH
OH
HO
OH
NH
H3C
N
HO
H
H3 C
2 HOAC
HO
O
NH
OH
MK0991
Caspofungin
O
NH
OH
OC5H11
NH
HN
O
O
O
N
O CH3
H
OH
OH
Anidulafungin
HO
Micafungin
OH
HO
HO
HO H H
NH
H3 C
H
NH
O
N
CH3
HO
O HN
OH
H
H NH O
OH
N H
H2 N O
HO H
NH
OH
O
H
H
H
OH O H
NaO S O
O
O
HO
NO
O(CH2)4CH3
FK463
VER-002
Caspofungin in Salvage Therapy of
Invasive Aspergillosis
100
Proven/Probable IA
CR/PR, %
80
60
• Well-documented
disease
• Efficacy
– High-risk patients (72%
heme malignancy/SCT)
– Progressive infection
(86%)
– Multiple prior antifungals
47
40
17
20
0
Caspofungin
(n=83)
Historical
Controls
(n=206)
• Minimal toxicity
• Clinical questions
Maertens et al. Clin Infect Dis. 2004; 39: 1563-71.
– Use as primary therapy?
– Role in combinations?
– Optimal dose?
Itraconazole and Posaconazole
N
N
CH3
H3C
O
O
N
N
N
N
N
N
O
O
H
Cl
Cl
Itraconazole
N
N
H3C
N
O
O
H3C
N
N
HO
N
N
N
O
H
Posaconazole
F
F
Open-Label Posaconazole (SCH56592)
Salvage Therapy of Invasive Aspergillosis
Posaconazole
N = 107
Historical
Control
N = 86
Underlying Disease:
n (%)
Heme Malignancy
79 (74%)
70 (81%)
HSCT
55 (51%)
38 (44%)
45 (42%)
22 (26%)
Results:
Overall success
Data Review Committee
Walsh et al. Blood 2003; 102(11); 45th ASH Abstract 682.
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
$6,210
$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): 839-46
Cost of Selected Antifungals
University Hospital in Boston Aug 2004
Drug
Dose
Cost/Day
Fluconazole
400mg iv
$36.32
Fluconazole
400mg po
$1.00
Caspofungin
50mg iv
$301.80*
L-AMB
3 mg/kg/d (70kg)
$608.80
L-AMB
5 mg/kg/d (70 kg)
$1065.40
ABLC
5 mg/kg/d (70 kg)
$427.92
Voriconazole
4 mg/kg Q 12 (70 kg)
Voriconazole
200mg po BID
$255.60**
$ 51.05
Caspo 70mg load = $262.22; **vori 6mg/kg x 2 load = $370.44
www.doctorfungus.org/thedrugs/cost1.htm
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): 729-37, Hadley et al, MSG 44, IDSA 2003
Winston et al, Transplantation 2002; 74(5): 688-95; Goodman. N Engl J Med.
1992;326:845; Winston et al. Annals of Internal Medicine 2003; 138(9): 705-13. Marr
et al, Blood 2004; 103(4): 1527-33; VanBurik et al, CID 2004; 39: 1407-16.
Efficacy of Empirical Antifungal
Therapy in Neutropenic Patients
20
Infection (No.)
15
2/16*
10
5/16
1/18
5
0
Abx D/C (n=16)
Other
Fungal
Abx Cont
Abx + AmB
(n=16)
(n=18)
*No. Fungal Infections/Total Treated Pizzo et al. Am J Med 1982;72:101
EORTC Empirical Antifungal Therapy in Febrile
Neutropenia
Febrile Response (%)
100
80
69 %
53 %
60
40
20
0
AmB (n=68)
• Overall response
 Not different
 Decreased fungal
mortality (0 vs 4 pts)
• Improved responses
 No prophylaxis
 Severely neutropenic
 Clinical infection
 Older patients (>15 yrs)
None (n=64)  Utility in HIGH RISK
patients
EORTC Am J Med 1989;86:668-72
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
12
15
Candida
3
12
Fusarium
1
1
Zygomycetes
1
0
Other
0
2
*Proven or probable breakthrough fungal infection
Walsh TJ et al, New Eng J Med, 1999;340:764-71
Efficacy of Empirical Antifungal Therapy in Neutropenic
Patients – Study MSG-42
Aspergillus
L-AmB
(n=422)
8
13
Vori
(n=415)
4
0
4
5
Vori vs L-AmB:
Other
21/422
(5%)
8/415
(1.9%)
10
15
20
Fungal Infections (#)
Walsh TJ et al, NEJM; 2002;346:225-34
25
• 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%)
Empirical Therapy Study (MSG42)
Breakthrough Infections by Risk/Prophylaxis
Prior Antifungal
Prophylaxis
n/N (%)
No Prophylaxis
n/N (%)
Total
n/N (%)
High Risk
Voriconazole
L-AMB
1/83 (1.2)
9/99 (9.1)
1/60 (3.3)
4/42 (9.5)
2/143 (1.4)
13/141 (9.2)
Moderate Risk
Voriconazole
L-AMB
1/139 (0.7)
4/151 (2.6)
5/133 (3.8)
4/130 (3.1)
6/272 (2.2)
8/281 (2.8)
Total
Voriconazole
L-AMB
2/222 (0.9)
13/250 (5.2)
6/193 (3.1)
8/172 (4.7)
8/415 (1.9)
21/422 (5.0)
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;346:225-34.
Itraconazole vs. Amphotericin B as
Empirical Antifungal Therapy in Febrile Neutropenia
•
Overall Success
(%)
100
80
60
47 %
40
20
0
Itra (n=179)
Overall response
 Not different
 Few BT IFIs (5, 2.8% each arm)
 Success – defervescence/RFN
 Failure –
 BT IFI
 Death
 No defervescence by day 28
38 %
 Additional antifungal tx
 Discont. due to intolerance
• No BMT patients included
• Mean daily AmB dose 0.7 mg/kg
AmB (n=181)• Itra levels > 250ng/ml
– IV and PO
Boogaerts M, et al. Annals of Internal Medicine 2001; 135(6): 412-422
Amphotericin B vs. Liposomal Amphotericin B for
Pyrexia of Unknown Origin in Neutropenic Patients
•
•
Overall Success ITT
(%)
100
80
60
58 %
49 %
40
20
0
AmB
(n=100)
L-AMB 1
(n=117)
Safety study
Children and adults (adults allowed to
switch to L-AmB for toxicity)
• Overall response
 L-AMB safer than AmB
64 %
 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
L-AMB 3
(n=118)  Mean daily AmB dose 0.76 mg/kg
Prentice HG, et al. British Journal of Haematology 1997; 98: 711-718
Efficacy of Empirical Caspofungin vs. L-AmB in
Neutropenic Patients
Caspo (556)
L-AmB (539)
Composite Success
33.9%
33.7%
Breakthrough Infections:
Etiological Agents
Aspergillus
Candida
Fusarium
Zygomycetes
Trichosporon spp.
Other
29 (5.2%)
24 (4.5%)
10*
16
1
2
1
0
9
15
0
0
0
1
Walsh TJ et al, New Eng J Med, 2004;351:1391-1402
* one mixed aspergillosis and C.glabrata infection
Efficacy of Empirical Caspofungin vs. L-AmB in
Neutropenic Patients
Caspo (556)
Composite Success
33.9%
Successful tx of Baseline Infections
14/27 (51.9%)
Etiological Agents
Aspergillus
Candida
Fusarium
Zygomycetes
Dipodascus capitatus
Other mould, not id’d
L-AmB (539)
5/12 (41.7)
8/12 (66.7)
0
0/1
0/1
1/1
33.7%
n/N (%)
7/27 (25.9%)
1/12 (8.3)
5/12 (41.7)
1/2
0
0
0/1
Walsh TJ et al, New Eng J Med, 2004;351:1391-1402
Empirical Therapy:
Historical Breakthrough Fungal Infections
Caspo vs
L-AMB5
Drug
22 (4.1)
1Walsh
21 (5.0)
EORTC3
Pizzo
et al4
17 (5.0)
30 (8.7)
Itraconazole
No treatment
Boogaerts
et al2
8 (1.9)
Amphotericin
B
Caspofungin
MSG
321
Number (%) of Breakthrough IFIs
Voriconazole
L-AMB
603/
MSG 42
5 (2.8)
1 (1.5)
1 (5.5)
6 (9.4)
5 (31.3)
5 (2.8)
28 (5.0)
et al. N Engl J Med. 1999;340:764-771; 2Boogaerts et al. Ann Intern Med. 2001;135:412-422;
3EORTC. Am J Med. 1989;86:668-672; 4Pizzo et al. Am J Med. 1982;72:101-111; 5Walsh TJ et al,
New Eng J Med, 2004;351:1391-1402
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;
http://www.nccn.org/prosessionals/physician_gls/PDF/fever.pdf; Hughes WT, et al. CID 2002; 34; 730-51;
MMWR 2000; Vol 49, No. RR-10. Available from www.CDC.gov; ** Wingard, ICAAC 2004
Micafungin vs Fluconazole Prophylaxis/MSG-46
Analysis of Primary Endpoint (MITT)
Number of Patients
Micafungin
425
Fluconazole
457
Success
340 (80.0%)
336 (73.5%)
Difference between arms
+ 6.5% (0.9%, 12%)
Secondary Endpoint:
Empirical Antifungal Use
64 (15.1%)
98 (21.4%)
VanBurik et al, CID 2004; 39: 1407-16
Micafungin vs Fluconazole Prophylaxis/MSG-46
Documented Breakthrough Fungal Infections
Micafungin
(N = 425)
Organism and Site
Aspergillus
1
Proven
Probable
Fluconazole
(N=457)
7
0
1
4
3
Candida
4
2
Fusarium
1
2
Zygomycetes
1
0
7 (1.6%)
11 (2.4%)
Total
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
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
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