The Importance of Early Appropriate Therapy of Invasive Aspergillosis

Helen Whamond Boucher, MDDivision 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

0

10

20

30

40

50

60

70

80

90

100

Hiemenz Salvage Leenders IncludesSuspected IA

Bowden Primary Tx

Lipid Formulation of AmB DAMB

Re

sp

on

se

%

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.

HxControl

23%

DAMB29% DAMB

23%ABCD18%

L-AMB52%ABLC

42%

Acute Renal Failure and Dose of Amphotericin B

0

20

40

60

Pts

with

AR

F (%

)

<0.5 0.5-0.9 1.0-1.4 1.5-1.9 2.0 or More

Total AmB Dose (gm)

Bates et al. CID 2000;32:689

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

Voriconazole

N N

N N N

MeHO

F

F

F

Fluconazole

N N N

N

HO

F

F N

N

Voriconazole

Global Comparative Aspergillosis StudyDRC-Assessed Success at Week 12 (MITT)

Difference (raw) = 21.2%, 95 % CI (9.9, 32.6)Difference (adjusted) = 21.8%, 95% CI (10.5, 33.0)

0

10

20

30

40

50

60

% S

ucc

ess

Voriconazole +/- OLAT*

Amphotericin B +/- OLAT*

76/144

42/133

* OLAT = Other licensed antifungal therapy

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

53%

32%

Herbrecht R et al NEJM 2002;347:408-15

Global Comparative Aspergillosis Study

Survival

0 14 28 42 56 70 840.0

0.2

0.4

0.6

0.8

1.0

Number of days of Therapy

Pro

bab

ilit

y o

f S

urv

ival

Ampho B +/- OLAT Vori +/- OLAT

Hazard ratio = 0.6095% CI (0.40, 0.89)

Herbrecht R et al. NEJM 2002;347:408-15.

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

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

Vori AMB

(n=37)(n=30)• Response 32% 13%• Survival 70% 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!

0 14 28 42 56 70 84

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

of

Su

rviv

al

Pro

bab

ility

of

Su

rviv

al

Time (days)Time (days)

307 Voriconazole → OLAT307 Voriconazole → OLAT307 Amphotericin B → OLAT307 Amphotericin B → OLAT602 Voriconazole → OLAT602 Voriconazole → OLAT602 Amphotericin B → OLAT602 Amphotericin B → OLAT

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

Caspofungin Anidulafungin

HH22NN HHNN OHOH

OOHHNN

OOOHOH

CHCH33

HNHN

HHOO

OO

OO

OHOH

OO

NNNN

NNHH22NN

HOHO OO

NHNHHH NN

NNHH

HH

HOHO

HOHO

HOHO

OHOH

HH

HH

2 HOA2 HOACC

MK0991MK0991

HH33CC

OHOHHOHO

HOHO

HH33CC

OO

OO OO

OO

OOOO

OOOHOH

HOHO

OHOHNN

HNHN

NHNH

NHNHNHNH

CHCH33

HH

OHOH

NHNH

HOHOHH

HOHO

OCOC55HH1111

VER-002VER-002

MicafunginHOHO OHOH

OO OONN

CHCH33HHHHOO

OO

NHNHHH

NHNHNN

HNHNOO

OO

HH

HHHOHOHH33CC

HOHO

OHOHHHNHNHHHOOHH22NN HOHO

HHHHOHOH HH HH

OHOHNN

NHNHHH

OO

OOOONaONaO SS

OO

OO HOHO

O(CHO(CH22))44CHCH33

HH

FK463FK463

NN

Maertens et al. Maertens et al. Clin Infect DisClin Infect Dis. 2004; 39: 1563-71.. 2004; 39: 1563-71.

0

20

40

60

80

100

Caspofungin(n=83)

HistoricalControls(n=206)

Caspofungin in Salvage Therapy ofInvasive 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?

CR

/PR

, %C

R/P

R, %

Proven/Probable IAProven/Probable IA

4747

1717

Itraconazole and Posaconazole

PosaconazolePosaconazole

ItraconazoleItraconazole

HH33CC

NN

NNNN NN NN

NN

NNNN

OOCHCH33

OO

OO

OO

HH ClCl ClCl

NN

HH33CC

NN

NNNN NN NN

NNNN

FFFFHH

OO

OO

HOHO

HH33CC

OO

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%)

Results:

Overall success

Data Review Committee 45 (42%) 22 (26%)Walsh et al. Blood 2003; 102(11); 45th ASH Abstract 682.

• 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 $19,409Vori 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 Voriconazole and Amphotericin B for Primary Therapy of Invasive Aspergillosis

Cost of Selected AntifungalsUniversity 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) $255.60**

Voriconazole 200mg po BID $ 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 2003Winston et al, Transplantation 2002; 74(5): 688-95; Goodman. Goodman. N Engl J MedN Engl J Med. . 1992;326:845; Winston et al. Annals of Internal Medicine 2003; 138(9): 705-13. 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

0

5

10

15

20

Infe

ctio

n (N

o.)

Abx D/C (n=16) Abx Cont(n=16)

Abx + AmB(n=18)

Other

Fungal

Pizzo et al. Am J Med 1982;72:101

2/16*

5/16

1/18

*No. Fungal Infections/Total Treated

EORTC Empirical Antifungal Therapy in Febrile Neutropenia

• Overall responseNot differentDecreased fungal

mortality (0 vs 4 pts)• Improved responses

No prophylaxisSeverely neutropenicClinical infectionOlder patients (>15 yrs)

Utility in HIGH RISK patients

EORTC Am J Med 1989;86:668-72

0

20

40

60

80

100

AmB (n=68) None (n=64)

Febr

ile R

espo

nse

(%)

69 %

53 %

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

Walsh TJ et al, New Eng J Med, 1999;340:764-71

*Proven or probable breakthrough fungal infection

Efficacy of Empirical Antifungal Therapy in Neutropenic Patients – Study MSG-42

0 5 10 15 20 25

Vori(n=415)

L-AmB(n=422)

Fungal Infections (#)

Aspergillus Other

Walsh TJ et al, NEJM; 2002;346:225-34

21/422 (5%)

8/415 (1.9%)

Vori vs L-AmB:• 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%)

13 8

4 4

Empirical Therapy Study (MSG42) Breakthrough Infections by Risk/Prophylaxis

Prior Antifungal Prophylaxis

n/N (%)

No Prophylaxis

n/N (%)

Total

n/N (%)

High Risk Voriconazole 1/83 (1.2) 1/60 (3.3) 2/143 (1.4) L-AMB 9/99 (9.1) 4/42 (9.5) 13/141 (9.2)

Moderate Risk Voriconazole 1/139 (0.7) 5/133 (3.8) 6/272 (2.2) L-AMB 4/151 (2.6) 4/130 (3.1) 8/281 (2.8) Total Voriconazole 2/222 (0.9) 6/193 (3.1) 8/415 (1.9) L-AMB 13/250 (5.2) 8/172 (4.7) 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 asEmpirical 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

Boogaerts M, et al. Annals of Internal Medicine 2001; 135(6): 412-422

0

20

40

60

80

100

Itra (n=179) AmB (n=181)

Over

all S

ucce

ss (%

)

47 %38 %

Amphotericin B vs. Liposomal Amphotericin B forPyrexia 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

Prentice HG, et al. British Journal of Haematology 1997; 98: 711-718

0

20

40

60

80

100

AmB(n=100)

L-AMB 1(n=117)

L-AMB 3(n=118)

Over

all S

ucce

ss IT

T (%

) 49 %64 %58 %

Efficacy of Empirical Caspofungin vs. L-AmB in Neutropenic Patients

Caspo (556) L-AmB (539)

Composite Success 33.9% 33.7%

Breakthrough Infections: 29 (5.2%) 24 (4.5%)Etiological Agents Aspergillus 10* 9 Candida 16 15 Fusarium 1 0 Zygomycetes 2 0Trichosporon spp. 1 0Other 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) L-AmB (539)

Composite Success 33.9% 33.7%

Successful tx of Baseline Infections n/N (%) 14/27 (51.9%) 7/27 (25.9%)

Etiological Agents Aspergillus 5/12 (41.7) 1/12 (8.3) Candida 8/12 (66.7) 5/12 (41.7) Fusarium 0 1/2 Zygomycetes 0/1 0Dipodascus capitatus 0/1 0Other mould, not id’d 1/1 0/1

Walsh TJ et al, New Eng J Med, 2004;351:1391-1402

Empirical Therapy: Historical Breakthrough Fungal Infections

1Walsh 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

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 5 (2.8)

Caspofungin 28 (5.0)

No treatment 6 (9.4) 5 (31.3)

Empirical TherapyWhat 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-46Analysis of Primary Endpoint (MITT)

Micafungin

Fluconazole

Number of Patients 425 457

Success 340 (80.0%) 336 (73.5%)

Difference between arms Secondary Endpoint:

+ 6.5% (0.9%, 12%)

Empirical Antifungal Use 64 (15.1%) 98 (21.4%)

VanBurik et al, CID 2004; 39: 1407-16

Organism and Site

Micafungin (N = 425)

Fluconazole (N=457)

Aspergillus 1 7

Proven 0 4 Probable 1 3

Candida 4 2

Fusarium 1 2

Zygomycetes 1 0

Total 7 (1.6%) 11 (2.4%)

Micafungin vs Fluconazole Prophylaxis/MSG-46Documented Breakthrough Fungal Infections

Prophylaxis vs Invasive Fungal InfectionsOngoing 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• LFABProphylaxis• 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