1 Treatment of Fungal infections in Hematologic Malignancies George Samonis M.D. PhD Professor of...

1

Treatment of Fungal infections in Hematologic Malignancies

George Samonis M.D. PhD

Professor of Medicine

The University of Crete

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Challenges of Diagnosing Opportunistic Infections at the Bedside

3

Challenges of Diagnosing Opportunistic Infections at the Bedside

3

Challenges of Diagnosing Opportunistic Infections at the Bedside

4

Usual fungal infections in immunocompromised patients

Candidiasis

Aspergillosis

Mucormycosis

Fusariosis

Cryptococcosis

Candidiasis

Aspergillosis

Mucormycosis

Fusariosis

Cryptococcosis

5

Risk factors for development of IFIs

Neutropenia

Lymphopenia

Corticosteroids

Immunosuppressives

Chemotherapy

Bone Marrow Transplantation

Broad-spectrum antibiotics

Mucositis

Parenteral alimentation

Central venous catheters (CVCs)

Hospital construction

Neutropenia

Lymphopenia

Corticosteroids

Immunosuppressives

Chemotherapy

Bone Marrow Transplantation

Broad-spectrum antibiotics

Mucositis

Parenteral alimentation

Central venous catheters (CVCs)

Hospital construction

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14

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25

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31

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Wingard1987

Wingard1987

O’Donnell1994

O’Donnell1994

Morrison1994

Morrison1994

Baddley2001

Baddley2001

Martino2002

Martino2002

Increased Incidence of Mould Infection

Martino R, Subira M. Ann Hematol. 2002;81:233-243. Martino R, Subira M. Ann Hematol. 2002;81:233-243.

Aspergillus sppAspergillus spp

1996-20001996-2000

1997-19981997-1998

1974-19891974-1989

1983-19891983-1989

1976-19851976-1985

4.0%4.0%

6.0%6.0%

11.4%11.4%13.0%13.0%

11.0%11.0%

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Distribution of IA in the Post-Engraftment Phase of HSCT

Marr KA et al. Blood. 2002;100:4358-4366.Marr KA et al. Blood. 2002;100:4358-4366.

0%

10%

20%

30%

40%

50%

60%

30%30%

40-180(n=99)40-180(n=99)

>180(n=31)>180

(n=31)

Number of Days Post HSCTNumber of Days Post HSCT

Inci

den

ce o

f IA

in

HS

CT

Inci

den

ce o

f IA

in

HS

CT

53%53%

17%17%

<40(n=57)

<40(n=57)

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Incidence of Aspergillosis in HSCT Recipients Is Growing

1-Year Cumulative Incidence of Aspergillosis at FHCRC* (%)1-Year Cumulative Incidence of Aspergillosis at FHCRC* (%)

Allograft recipientsAllograft recipients Autograft recipientsAutograft recipients

Data from 1990 through 1992 were obtained from another study.*FHCRC, Fred Hutchinson Cancer Research CenterAdapted from Marr KA et al. Clin Infect Dis. 2002;34:909-917.

Data from 1990 through 1992 were obtained from another study.*FHCRC, Fred Hutchinson Cancer Research CenterAdapted from Marr KA et al. Clin Infect Dis. 2002;34:909-917.

00

22

44

66

88

1010

1212

1414

19901990 19911991 19921992 19931993 19941994 19951995 19961996 19971997 19981998

Inci

den

ce (

%)

Inci

den

ce (

%)

YearYear

35

IA Risk

NeutropeniaNeutropenia

Invasive Aspergillosis Risk Increases During the Post-Engraftment Period

1. Marr KA. Oncology. 2001;15:15-19. 2. Hagen EA et al. Clin Infect Dis. 2003;36:9-15.1. Marr KA. Oncology. 2001;15:15-19. 2. Hagen EA et al. Clin Infect Dis. 2003;36:9-15.

Pre-engraftmentPre-engraftment

Immunosuppression:GVHD

CorticosteroidsDiminished T-cell function

Immunosuppression:GVHD

CorticosteroidsDiminished T-cell function

Post-engraftmentPost-engraftment

IA Risk

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Aspergillus-Related Mortality in Allogeneic HSCT Remains Relatively High

31.6%*31.6%*

Lin 20011Lin 20011 Cornet 20022Cornet 20022 Thursky 20043Thursky 20043 Cordonnier 20064Cordonnier 20064 Upton 20075Upton 20075

87.0%87.0%

71.0%71.0% 68.0%68.0%

56.0%56.0%

1. Lin SJ et al. Clin Infect Dis. 2001;32:358-366. 2. Cornet M et al. J Hosp Infect. 2002;51:288-296. 3. Thursky K et al. Bone Marrow Transplant. 2004;34:115-121. 4. Cordonnier C et al. Clin Infect Dis. 2006;42:955-963. 5. Upton A et al. Clin Infect Dis. 2007;44:531-540.

1. Lin SJ et al. Clin Infect Dis. 2001;32:358-366. 2. Cornet M et al. J Hosp Infect. 2002;51:288-296. 3. Thursky K et al. Bone Marrow Transplant. 2004;34:115-121. 4. Cordonnier C et al. Clin Infect Dis. 2006;42:955-963. 5. Upton A et al. Clin Infect Dis. 2007;44:531-540.

Studies used crude mortality rate or attributable mortality rates. *Crude mortality rate at 4 months post IA diagnosis.Studies used crude mortality rate or attributable mortality rates. *Crude mortality rate at 4 months post IA diagnosis.

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Pre-mortem

Chamilos 20062Chamilos 20062

The Majority of IFIs Are Identified Post-mortem

*Incidence of moulds and yeasts in AML patients (7.9% due to moulds). †Prevalence of invasive moulds and Candida (22% due to moulds).1. Pagano L et al. Haematologica. 2006;91:1068-1075. 2. Chamilos G et al. Haematologica. 2006;91:986-989.

*Incidence of moulds and yeasts in AML patients (7.9% due to moulds). †Prevalence of invasive moulds and Candida (22% due to moulds).1. Pagano L et al. Haematologica. 2006;91:1068-1075. 2. Chamilos G et al. Haematologica. 2006;91:986-989.

Post-mortem

33%†33%†

12.3%*12.3%*

Pagano 20061Pagano 20061

Only 1/4 Diagnosed Pre-mortem

Only 1/4 Diagnosed Pre-mortem

How Can We Better Identify Patients With

IFI During Life?

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Invasive Aspergillosis Role of Early Diagnosis & Therapy

Have We Made Progress??

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Non-Culture Based Diagnosis ofInvasive Aspergillosis

Galactomannan

– Sandwich ELISA (Platelia)

PCR

– 18s ribosomal DNA

– Multi-copy or single target genes

b-D-glucan

– Amebocyte Limulus lysate

– Chromogenic (Glucatell, FungiTec G)

– Kinetic (Wako)

Galactomannan

– Sandwich ELISA (Platelia)

PCR

– 18s ribosomal DNA

– Multi-copy or single target genes

b-D-glucan

– Amebocyte Limulus lysate

– Chromogenic (Glucatell, FungiTec G)

– Kinetic (Wako)

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Early diagnosis and treatment of invasive aspergillosis

Impact of early diagnosis of IA in patients with acute leukemia:– 90% mortality when

treatment instigated ≥ 10 days after first clinical or radiological sign of disease

– 40% mortality when treatment is instigated early

Serial HR CT scanning:– early and systematic high

resolution CT scan in high-risk patients improves outcome

(von Eiff M, et al. Ann Hematol. 1995) (Reprinted with permission from Caillot D, et al. J Clin Oncol. 1997)

100

75

50

25

00 50 100 150 200

Days After IPA

Survival (%) IA: CT Scanning

Systematic CT

Non-Systematic CT

P = 0.006 (Logrank Test)

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Relationship between hospital mortality and the timing of antifungal treatment

Ho

spit

al m

ort

alit

y (%

)

0

35

30

25

20

15

10

5

< 12

Delay in start of antifungal treatment (hours)

12–24 24–48 > 48

Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5

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Patients with Satisfactory Treatment Response categorized by Baseline CT Findings

0%

10%

20%

30%

40%

50%

60%

70%

Satisfa

cto

ry R

esp

on

se (C

R/P

R)

Nodular lesion with Halo Nodular lesion without Halo*

ALL Treated

Vori Arm

Ampho Arm

42%

52%

41%

29%

16%

62%

*Note: Required positive mycologyGreene R et al. ECCMID 2003

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Utility of Galactomannan Detection in BAL Samples

# pt

160

Sens

(%)

Spec

(%)

PPV

(%)

NPV

(%)

Serum 47 93 73 82

BAL 85 100 100 88

GM detection in CT-based BAL fluid has a high PPV for diagnosing IPA early in untreated patients

Becker et al. Br J Haematol 2003; 121: 448

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Treatment definitions

Prophylactic therapy: Use of antifungals from chemotherapy until prolonged febrile neutropenia

Chance of infection: remote

Empirical therapy: Use of antifungals from febrile neutropenia to culture and/or tissue evidence of fungal infection

Chance of infection: possible

Preemptive therapy: Use of antifungals based on early clinical and/or laboratory markers of invasive disease

Chance of infection: probable

Prophylactic therapy: Use of antifungals from chemotherapy until prolonged febrile neutropenia

Chance of infection: remote

Empirical therapy: Use of antifungals from febrile neutropenia to culture and/or tissue evidence of fungal infection

Chance of infection: possible

Preemptive therapy: Use of antifungals based on early clinical and/or laboratory markers of invasive disease

Chance of infection: probable

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Lack of Consensus on the Use of Empirical Antifungal Therapy

ProsPros

Development of resistance

ToxicityCost

Development of resistance

ToxicityCost

ConsCons

Reduces mortalityAddresses

diagnostic concerns

Reduces mortalityAddresses

diagnostic concerns

Broad-Spectrum antibiotics

>96 h

Broad-Spectrum antibiotics

>96 h

Persistent or recurring fever of unknown origin

>38C

Persistent or recurring fever of unknown origin

>38C

Persistent neutropenia Absolute neutrophil

count <500 cells/mm3

Persistent neutropenia Absolute neutrophil

count <500 cells/mm3

Wingard JR. N Engl J Med. 2002;346:225-234.Wingard JR. N Engl J Med. 2002;346:225-234.

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Antifungal treatment evolution

AMB deoxycholate

5-fluocytosine

1st generation azoles (ketoconazole, miconazole)

2nd generation triazoles (fluconazole, itraconazole)

Lipid and liposomal formulations of AMB

Extended spectrum triazoles (voriconazole, posaconazole)

Echinocandins (caspofungin, micafungin, anidulafungin)

AMB deoxycholate

5-fluocytosine

1st generation azoles (ketoconazole, miconazole)

2nd generation triazoles (fluconazole, itraconazole)

Lipid and liposomal formulations of AMB

Extended spectrum triazoles (voriconazole, posaconazole)

Echinocandins (caspofungin, micafungin, anidulafungin)

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Cellular Targets of Antifungal Therapy

Polyenes:Target membrane function

Echinocandins:Target cell wall synthesis

Azoles: Target ergosterol synthesis

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Pts on azole prophylaxis

Pts with sinusitis or pneumonia

Pts with prolonged neutropenia (e.g. leukemia)

Pts with history of invasive aspergillosis (IA) or positive

surveillance cultures for Aspergillus spp.

Pts at institutions undergoing construction

Fluconazole: Not a good choice for empirical therapy in certain patients

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L-AMB vs. AMB for empirical therapy of febrile neutropenia

Ambisome AMB

Patients 343 344

Acute Leukemia 168 165

Success 50 49

BFI (%) * 3.2 7.8

Infusion Fever (%) † 17 44

Nephrotoxicity (%) 19 34

* p=0.009 † p<0.001 Walsh NEJM 1999; 340:764

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Polyene Therapy for Invasive Aspergillosis

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.

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

%

HistoricalControl

23%

DAMB29% DAMB

23%ABCD18%

L-AMB52%ABLC

42%

Note: ABLC=amphotericin B lipid complex; L-AmB=liposomal amphotericin B; ABCD=amphotericin B colloidal dispersion; D-AMB=amphotericin B deoxycholate

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Comparative Aspergillosis Study: Better Outcomes & Survival of Voriconazole

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

Amphotericin B arm

Voriconazole arm

Hazard ratio = 0.6095% CI (0.40, 0.89)

• Outcomes at wk 12 Vori AmB

■ Survival 70.8% 57.9%■ Response 56.8% 31.6%

Poor efficacy of AmB prior “gold standard”

Vori recommended for primary therapy

• Questions?■ Role of Other Licensed

Antifungal therapy■ Lipid for primary therapy■ Efficacy in high risk■ Combinations

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

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Voriconazole vs. Ambisome in febrile neutropenia

Vorico

(N=415)

LAMB (N=422)

P

Composite success 26% 31% NS

Breakthrough fungal

infections 1.9% 5% 0.002

Survival rate 87% 90% NS

Toxicity-related withdrawal

13% 10% NS

Nephrotoxicity (SCr>1.5) 11% 19% <0.001

Visual changes 4.3% 0.5% <0.001

Walsh et al. N Engl J Med. 2002; 346: 225-34

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Voriconazole: need for monitoring

ΒορικοναζόληΠότε χρειάζεται «monitoring»;

• Υποψία δυσαπορρόφησης (βλεννογονίτιδα, GvHD)

• Επιδείνωση νόσου

• Συγχορήγηση φαρμάκων που επάγουν το P-450

• Παχυσαρκία

• Παιδιατρικό πληθυσμό

• Rx > 30 μέρες

• Μετάβαση σε μονοθεραπεία από του στόματος

• Σε υποψία μη συμμόρφωσης στη θεραπεία

• Ανεξήγητη ηπατοτοξικότητα

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Voriconazole Treatment

Cyclodextrin Toxicity

• Unmodified cyclodextrins, namely a- and b-cyclodextrins, are typically reabsorbed and concentrated in the renal tubule, interacting with and extracting cholesterol and other lipid membrane components from cellular structures.

• >300 mg/kg/d in rats produced reversible renal tubular vacuolation

• Human dose = 48 mg/kg/d (toxicity?)

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Subtherapeutic Voriconazole - Omeprazole

Omeprazole = competitive inhibitor of CYP2C19

40 mg omeprazole daily Voriconazole AUC 141%

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Posaconazole

Posaconazole: broad spectrum of activity

only oral formulation

variable absorption

variable bioavailability

Established for prophylaxis in acute leukemia and HSCT

Posaconazole: broad spectrum of activity

only oral formulation

variable absorption

variable bioavailability

Established for prophylaxis in acute leukemia and HSCT

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Posaconazole

Παράγοντες που επηρεάζουν την απορρόφηση της ποσακοναζόλης

Posaconazole NDA. www.accessdata.fda.gov/

H2 ή PPI θεραπεία

Πτωχή απορρόφηση PO

Καταστροφή φραγμού

βλεννογόνων

GvHD (γαστρεντερικό σύστημα)

Σοβαρή διάρροιαΥποθεραπευτικέ

ς ή μη ανιχνεύσιμες συγκεντρώσειςποσακοναζόλης

Συμμόρφωση!

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Echinocandins

· Latest class of antifungal drugs

First discovered in 1970s in screening

programs for new antibiotics

Cell-wall active agents:

nhibition of (1, 3)-β-D glucan synthetase cell wall glucan depletion

osmotic instability cell lysis

· Latest class of antifungal drugs

First discovered in 1970s in screening

programs for new antibiotics

Cell-wall active agents:

nhibition of (1, 3)-β-D glucan synthetase cell wall glucan depletion

osmotic instability cell lysis

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Echinocandins

· Formerly known as Pneumocandins due to activity

against Pneumocystis carinii

· Rapidly fungicidal against most Candidae including azole-resistant strains

· Fungistatic against most Aspergillus spp

· Limited or no activity against Fusarium spp and Zygomycetes.

· No activity against Cryptococcus neoformans

· Formerly known as Pneumocandins due to activity

against Pneumocystis carinii

· Rapidly fungicidal against most Candidae including azole-resistant strains

· Fungistatic against most Aspergillus spp

· Limited or no activity against Fusarium spp and Zygomycetes.

· No activity against Cryptococcus neoformans

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Mechanism of action1-4

1- ECALTA® SPC. 2- Odds F.C., Brown A.J.P., Gow N.A.R. Antifungal agents: mechanism of action. Trends Microbiol. 2003;11:272-279. 3- Debono M., Turner W.W., LaGrandeur L. et al. Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem. 1995;38(17):3271-3281. 4- Raasch R.H. Anidulafungin: review of a new echinocandin antifungal agent. Expert Rev Anti Infect Ther. 2004;2:499-508.

Mechanism of action involves a target specific for fungus4

inhibitor of 1,3--D-glucan synthase1

Enzyme is present in fungal, but not mammalian, cells1

Glucan is essential to fungal cell wall integrity2-4

Without it, fungal cells are osmotically fragile and easily lysed4

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Echinocandins

· IV administration

· Long half life

CNS penetration: poor

Dose: once daily

Little infusion related toxicity

Little or no renal and hepatic toxicity

Drug-drug interaction limited (cyclosporin)

Potential combination with other antifungals (AMB or azoles)

· Animal data suggest synergistic effect

· Echinocandins: Caspofungin Anidulafungin Micafungin

· IV administration

· Long half life

CNS penetration: poor

Dose: once daily

Little infusion related toxicity

Little or no renal and hepatic toxicity

Drug-drug interaction limited (cyclosporin)

Potential combination with other antifungals (AMB or azoles)

· Animal data suggest synergistic effect

· Echinocandins: Caspofungin Anidulafungin Micafungin

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Echinocandins : In vitro activity1

1- Cappelletty D. et al. Reviews of therapeutics : the echinocandins Pharmacotherapy 2007, 27(3):369-388.

Anidulafungin Micafungin* Caspofungin

Candida species MIC50(µg/ml)

MIC90(µg/ml)

MIC50(µg/ml)

MIC90(µg/ml)

MIC50(µg/ml)

MIC90(µg/ml)

albicans 0.03 0.03 0.015-0.03 0.03 0.03-0.5 0.06-1

glabrata 0.03 0.13 0.015-0.03 0.015-0.06 0.03-1 0.06-2

tropicalis 0.03 0.13 0.03 0.06 0.12-0.5 0.25-1

dubliniensis 0.03 0.06 0.03 0.033 0.25-0.5 0.5

krusei 0.06 0.13 0.06-0.13 0.06-0.25 0.12-2 0.25-2

lusitaniae 0.06 0.25 0.06 2 0.5-1 1-2

parapsilosis 2 2 1 2 1-2 1-4

guilliermondii ND 1 ND 0.5 2 -> 8 2 -> 8

Minimum inhibitory concentrations of the echinocandins against Candida species

MIC50 or MIC90 = minimum inhibitory concentration for 50% or 90%, respectively, of tested strains; ND = not done.

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Caspofungin in Invasive Aspergillosis

• Well-documented disease• Efficacy

– High risk pts

– Progressive infection

– Multiple prior antifungals

•Excellent tolerability

•Clinical utility

– No data for primary therapy

– Combination therapy

– Optimal dose not known

• Well-documented disease• Efficacy

– High risk pts

– Progressive infection

– Multiple prior antifungals

•Excellent tolerability

•Clinical utility

– No data for primary therapy

– Combination therapy

– Optimal dose not known

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

Proven/Probable IA

41

17

0

20

40

60

80

100

Caspofungin(n=56)

HistoricalControls (n=206)

CR

/PR

(%

)

%

%

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Caspo (556) L-AmB (539)

Composite Success 33.9% 33.7%

Success Baseline Infections 14/27 (52%) 7/27 (26%)

Breakthrough Infections 29 (5.2%) 24 (4.5%)

Etiological Agents*

Aspergillus 10 9

Candida 16 15

Fusarium 1 0

Zygomycetes 2 0

Other 1 1

Caspo (556) L-AmB (539)

Composite Success 33.9% 33.7%

Success Baseline Infections 14/27 (52%) 7/27 (26%)

Breakthrough Infections 29 (5.2%) 24 (4.5%)

Etiological Agents*

Aspergillus 10 9

Candida 16 15

Fusarium 1 0

Zygomycetes 2 0

Other 1 1

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

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

*Patients may have had more than one organism

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Anidulafungin

Clinical data

Anidulafungin vs Fluconazole

Reboli A.C. et al.

Anidulafungin versus Fluconazole for Invasive Candidiasis.

N Engl J Med 2007;356:2472-82.

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Global success at the end of IV therapy

ECALTA® demonstrated superiority vs fluconazole:

• Significantly greater response rate in the anidulafungin group

• Difference: 15.4% (95% CI: 3.9% to 27.0%)

Mean (median) duration of IV therapy:

fluconazole: 12.1 (11) days

anidulafungin: 13.5 (14) days

Primary endpoint1

1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:2472-82.

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*2.0 mg/kg/day in patients weighing ≤ 40 kg†Treatment continued until at least one week after resolution of clinical signs and symptoms and obtaining of two sequential negative blood cultures‡Maximum 8 weeks in chronic disseminated candidiasis, Candida osteomyelitis or Candida endocarditis

Micafungin 100 mg/day* L-AmB 3 mg/kg/day

Treatment period† 2–4 weeks‡

Randomisation(1:1)

12 weeksPost-treatment period

Phase III study micafungin vs. L-AmB Study design

Kuse ER, et al. Lancet 2007; 369:1519–27

69

Phase III study micafungin vs. L-AmB Overall treatment success

Kuse ER, et al. Lancet 2007; 369:1519–27 mITT = modified intent-to-treat; PP = per-protocol set

Trea

tmen

t su

cces

s ra

te (

%)

74.1

89.6

69.6

89.5

0

20

40

60

80

100

mITT PP

Micafungin L-AmB

n = 247 247 202 190

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*70 mg loading dose on Day 1†8 weeks in chronic disseminated candidiasis or Candida endophthalmitis; switch to oral fluconazole permitted after 10 days in patients meeting protocol-specified criteria‡Time from last dose day of protocol-defined antifungal therapy to final evaluation

Micafungin 100 mg/day

CAS 50 mg/day*

Treatment period† Max 4 weeks†

Randomisation(1:1:1)

6 weeks‡Post-treatment period

Phase III study micafungin vs. caspofungin Study design

Micafungin 150 mg/day

Pappas PG, et al. Clin Infect Dis 2007; 45:883–93 CAS = caspofungin

Patients were stratified by region and APACHE II score (≤ 20 or > 20)

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Phase III study micafungin vs. caspofungin Treatment success

Pappas PG, et al. Clin Infect Dis 2007; 45:883–93

n = 191 n = 188n = 199

Caspofungin50 mg/day*

Trea

tmen

t su

cces

s ra

te (

%) 76.4

71.4 72.3

0

20

40

60

80

n = 191 199 188

Micafungin100 mg/day

Micafungin150 mg/day

*Loading dose 70 mg; mITT population

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Micafungin vs Caspofungin in febrile neutropenia

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Conclusions

Micafungin as effective and safe as caspofungin in empirical treatment of fungal infections in patients with febrile neutropenia

Conclusions

Micafungin as effective and safe as caspofungin in empirical treatment of fungal infections in patients with febrile neutropenia

Micafungin vs Caspofungin in febrile neutropenia

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Empirical micafungin treatment of IFIs in hematologic malignancies

75

Empirical micafungin treatment of IFIs in hematologic malignancies

Efficacy

Micafungin monotherapy: 66,1% (109/165)

Mica + Ampho B and / or azoles: 78,1% (25/32)

΄΄For the patients who were in grave conditions and suffered from probable to

proven IFIs, combination of micafungin and azoles or amphotericin B could be considered.΄΄

Efficacy

Micafungin monotherapy: 66,1% (109/165)

Mica + Ampho B and / or azoles: 78,1% (25/32)

΄΄For the patients who were in grave conditions and suffered from probable to

proven IFIs, combination of micafungin and azoles or amphotericin B could be considered.΄΄

76

Micafungin vs fluconazole for prophylaxis of invasive fungal infections during neutropenia in hematopoietic stem cell transplantation patients Study endpoints

Primary endpoint: treatment success (absence of proven, probable, or suspected systemic fungal infection until the end of prophylaxis therapy and the absence of a proven or probable systemic fungal infection until the end of the 42-day post-treatment period)

Secondary endpoints included: use of systemic antifungal agents for treatment of suspected fungal infections; frequency of proven or probable fungal infections throughout the post-treatment period; pathogen-based frequency of proven infections

Primary endpoint: treatment success (absence of proven, probable, or suspected systemic fungal infection until the end of prophylaxis therapy and the absence of a proven or probable systemic fungal infection until the end of the 42-day post-treatment period)

Secondary endpoints included: use of systemic antifungal agents for treatment of suspected fungal infections; frequency of proven or probable fungal infections throughout the post-treatment period; pathogen-based frequency of proven infections

van Burik JA, et al. Clin Infect Dis 2004; 39:1407–16

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Phase III study micafungin vs. fluconazole Overall treatment success

Trea

tmen

t su

cces

s (%

)

van Burik JA, et al. Clin Infect Dis 2004; 39:1407–16

p = 0.03

Micafungin Fluconazole

80.073.5

0

10

20

30

40

50

60

70

80

90

Micafungin Fluconazole

n = 425 457

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Is combination of antifungals indicated?

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Randomized blinded trial of high-dose fluconazole plus placebo vs fluconazole plus AMB as therapy for candidemia in non-neutropenic patients.

The combination of fluconazole and AMB was evaluated versus monotherapy with high-dose fluconazole in 219 non-neutropenic patients

No difference in survival between the two groups; however, candidemia cleared more rapidly with combination therapy, suggesting potential use in persistent Candida infections

Rex JH, et al. Clin Infect Dis 2003; 36:1221-8

The combination of fluconazole and AMB was evaluated versus monotherapy with high-dose fluconazole in 219 non-neutropenic patients

No difference in survival between the two groups; however, candidemia cleared more rapidly with combination therapy, suggesting potential use in persistent Candida infections

Rex JH, et al. Clin Infect Dis 2003; 36:1221-8

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. Efficacy and Toxicity of Caspofungin in Combination with L-AMB as Primary or Salvage treatment of Invasive Aspergillosis in Patients with Hematologic Malignancies. Kontoyiannis DP, et al Cancer 2003; 98: 292-9

48 patients with documented or possible IA

The majority (65%) received CAS/L-AMB as salvage therapy for progressive IA despite 7 days of previous L-AMB monotherapy

Overall response rate 42%

No significant toxicity

Factors associated with failure: documented IA, significant steroid use, duration of combination therapy < 14 days

Response rate in patients with progressive documented IA 18%

Conclusions: The CAS/L-AMB combination is a promising preemptive therapy

48 patients with documented or possible IA

The majority (65%) received CAS/L-AMB as salvage therapy for progressive IA despite 7 days of previous L-AMB monotherapy

Overall response rate 42%

No significant toxicity

Factors associated with failure: documented IA, significant steroid use, duration of combination therapy < 14 days

Response rate in patients with progressive documented IA 18%

Conclusions: The CAS/L-AMB combination is a promising preemptive therapy

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Combination antifungal therapy for invasive aspergillosis. Marr KA, et al. Clin Infect Dis. 2004; 39: 797-802

Salvage therapy with the combination of voriconazole and caspofungin was associated with reduced mortality, compared with voriconazole monotherapy

Salvage therapy with the combination of voriconazole and caspofungin was associated with reduced mortality, compared with voriconazole monotherapy

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Br J Haematol. 2004; 126: 165-75

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Conclusions

Patients at high risk may benefit from empirical therapy

Patients under close surveillance may receive preemptive treatment after early prodromal clues of infection

No clear drug of choice, decisions should be individualized

Lipid AMB, voriconazole and echinocangins: high risk pts

Fluconazole, itraconazole: lower risk pts

Limited data point out to combination treatments for selected high risk pts

Patients at high risk may benefit from empirical therapy

Patients under close surveillance may receive preemptive treatment after early prodromal clues of infection

No clear drug of choice, decisions should be individualized

Lipid AMB, voriconazole and echinocangins: high risk pts

Fluconazole, itraconazole: lower risk pts

Limited data point out to combination treatments for selected high risk pts

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Future issues

Should we move from empirical to preemptive therapy based on surrogate markers of early diagnosis of IFIs?

Is sequence of antifungals important?

Which combinations are more effective?

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