Update on the Treatment of Invasive Fungal Infections for ... · Empiric treatment for suspected invasive candidiasis in neutropenic patients: LF-AmB 3-5 mg/kg daily IV, Caspofungin

Update on the Update on the Treatment of Invasive Treatment of Invasive Fungal Infections for Fungal Infections for

the Oncologistthe OncologistColeman Coleman RotsteinRotstein MDMDUniversity of TorontoUniversity of Toronto

University Health NetworkUniversity Health NetworkToronto, OntarioToronto, Ontario

Epidemiology of Invasive Epidemiology of Invasive Fungal Infections in Fungal Infections in

Cancer PatientsCancer Patients

Distribution of Distribution of NosocomialNosocomialPathogens in Cancer PatientsPathogens in Cancer Patients

77 %

4 % 2 %

0

10

20

30

40

50

60

70

80

% Nosocomial Infections

Bacterial Fungal ViralPathogen

(Rotstein C et al. Infect Control Hosp Epidemiol 1988;9:13(Rotstein C et al. Infect Control Hosp Epidemiol 1988;9:13--19)19)

EpidemiologyEpidemiology

Invasive fungal infections cause Invasive fungal infections cause considerable morbidity & mortality in considerable morbidity & mortality in cancer patients particularly those with cancer patients particularly those with neutropenianeutropenia..

(Schwartz et al. Cancer 1984;53:411(Schwartz et al. Cancer 1984;53:411--419)419)(Bodey et al. Eur J Clin Microbiol Infect Dis 1992;11:99(Bodey et al. Eur J Clin Microbiol Infect Dis 1992;11:99--109)109)

(Bow et al. Clin Infect Dis 1995;21:361(Bow et al. Clin Infect Dis 1995;21:361--369)369)

Gradation of Risk of Invasive Gradation of Risk of Invasive Fungal Infection In Cancer PatientsFungal Infection In Cancer Patients

2%2%551%1%--5%5%Solid TumorsSolid TumorsNANA10%10%--20%20%LymphomaLymphoma

19%19%--47%47%4420%20%--30%30%Acute LeukemiaAcute Leukemia

21%21%--57%57%2,32,320%20%--30%30%HSCTHSCT

Rates of Invasive Fungal InfectionRates of Invasive Fungal Infection1960s & 1970s1960s & 1970s1 1 1980s & 1990s1980s & 1990s

DiseaseDisease

(1. (1. WingardWingard JR, Leather HL. Oncology 2001;15:351JR, Leather HL. Oncology 2001;15:351--369. 2. De La Rosa GR, 369. 2. De La Rosa GR, ChamplinChamplin RE, RE, KontoiannisKontoiannis DP. DP. TransplTranspl Infect Infect DisDis 2002;4:32002;4:3--9. 3. 9. 3. WakayamWakayam M, M, ShibuayShibuay K, Ando T et al. Mycoses 2002;45:146K, Ando T et al. Mycoses 2002;45:146--151. 4. Bow 151. 4. Bow E. Br J E. Br J HaematolHaematol 1998;101(suppl1):11998;101(suppl1):1--4. 5. 4. 5. MontesinosMontesinos J, J, SolaSola C, C, MarotoMaroto P et al. P et al. EurEur J J ClinClin MicrobiolMicrobiol Infect Infect DisDis 2001;20:5692001;20:569--572.)572.)

Clinical Characteristics of Clinical Characteristics of Patients with Patients with IFIsIFIs

6/82 (7)6/82 (7)5/85 (6)5/85 (6)8/147 (5)8/147 (5)MyelodysplasticMyelodysplasticSyndromeSyndrome

5/82 (6)5/82 (6)6/85 (7)6/85 (7)8/147 (5)8/147 (5)OtherOther

9/82 (11)9/82 (11)3/85 (4)3/85 (4)8/147 (5)8/147 (5)CLLCLL

9/82 (11)9/82 (11)9/85 (11)9/85 (11)15/147 (10)15/147 (10)NHLNHL

5/82 (6)5/82 (6)5/85 (6)5/85 (6)25/147 (17)25/147 (17)CMLCML

17/82 (21)17/82 (21)16/85 (19)16/85 (19)23/147 (16)23/147 (16)ALLALL

30/82 (37)30/82 (37)41/85 (48)41/85 (48)60/147 (41)60/147 (41)AMLAML

53 (1953 (19--77)77)49 (249 (2--83)83)44 (1544 (15--87)87)Median AgeMedian Age(range)(range)

19991999--2003200319941994--989819891989--9393CharacteristicCharacteristic

No. of Patients (%)No. of Patients (%)

((ChamilosChamilos G et al. G et al. HaematologicaHaematologica 2006;91:9862006;91:986--989)989)

Epidemiology (contEpidemiology (cont’’d)d)

High mortality from High mortality from IFIsIFIs::

Mortality rates due to fungal Mortality rates due to fungal infections in pt. with malignancies infections in pt. with malignancies range from 6% range from 6% -- 60%60%

(EORTC. Am J Med 1989;86:668(EORTC. Am J Med 1989;86:668--672)672)((GuiotGuiot et al. et al. ClinClin Infect Infect DisDis 1994;18:5251994;18:525--532)532)

Pathogenic FungiPathogenic Fungi

Etiology of Fungal Infection in Etiology of Fungal Infection in Cancer PatientsCancer Patients

Candida Candida sppspp (48%)(48%) Other (21%)Other (21%)

Aspergillus spp (31%)Aspergillus spp (31%)

(Data from Walsh et al. Rev Infect Dis. 1991;Bodey et al. (Data from Walsh et al. Rev Infect Dis. 1991;Bodey et al. EurEur J J ClinClin MicrobiolMicrobiol Infect Infect Dis. 1992; Vazquez et al. J Infect Dis. 1993; Dis. 1992; Vazquez et al. J Infect Dis. 1993; PannutiPannuti et al. Cancer. 1992; et al. Cancer. 1992; AnaisseAnaisse et et

al. Rev Infect Dis. 1989; Morrison et al. Am J Med. 1994)al. Rev Infect Dis. 1989; Morrison et al. Am J Med. 1994)

Prevalence of Prevalence of IFIsIFIs in Hematological in Hematological Malignancies: Autopsy Study 1989Malignancies: Autopsy Study 1989--93, 93, 19941994--98 & 199998 & 1999--2003 2003 -- MD AndersonMD Anderson

0

5

10

15

20

25

30

35

1989-93 1994-99 1999-2003

Total IFI

Invasive MoldInfectionAspergillus

Candida

Per

cen

tP

erce

nt

Time PeriodTime Period((ChamilosChamilos G et al. G et al. HaematologicaHaematologica 2006;91:9862006;91:986--989)989)

Total Total Pathogens Pathogens

N=466N=466

IFIIFI’’ss in in HSCTsHSCTs

41.6

28.3

8.8

7.6

5.5

3.1 2.9

AspergillusCandidaOther MouldsUnspecified MouldsZygomycetesFusariumPCP

(Pappas PG. FOFI 2005)(Pappas PG. FOFI 2005)

Time to Onset of IFI for Time to Onset of IFI for HSCTsHSCTs

0

20

40

60

80

100

120

Early Onset (0-30days)

Intermediate Onset(30-60 days)

Late Onset (90+ days)

# o

f IF

I's

IACandidiasisFusariumOther mouldPCPUnspec. mouldZygomycetes

(PG Pappas: Transplant Associated Infection Surveillance Network(PG Pappas: Transplant Associated Infection Surveillance Network))

Origin of Origin of Pathogenic FungiPathogenic Fungi

Origin of Fungal PathogensOrigin of Fungal Pathogens

Candida sppCandida spp..Endogenous organisms Endogenous organisms –– normal commensals normal commensals of skin, GI tract & GU tractof skin, GI tract & GU tract

Aspergillus sppAspergillus spp..Ubiquitous in environmentUbiquitous in environmentInhaledInhaled

Strategies for Treatment Strategies for Treatment of Invasive Fungal of Invasive Fungal

Infections in Cancer Infections in Cancer PatientsPatients

(Marr K. (Marr K. CurrCurr Treatment Options in Infect Diseases 2001)Treatment Options in Infect Diseases 2001)

Treatment for Treatment for CandidemiaCandidemia/Invasive /Invasive

CandidiasisCandidiasis and and Invasive Invasive AspergillosisAspergillosis

Treatment of Treatment of CandidemiaCandidemia//

Invasive Invasive CandidiasisCandidiasis

Two Key Principles of Two Key Principles of TreatmentTreatment

Hit EarlyHit Early

Hit RightHit Right

Mortality Rates with Delay in Mortality Rates with Delay in Therapy for Therapy for CandidemiaCandidemia

0

5

10

15

20

25

30

35

40

45

Day 0 Day 1 Day 2 Day >= 3

Mor

talit

y R

ate

Mor

talit

y R

ate

Time to Initiation of Time to Initiation of FluconazoleFluconazole for for CandidemiaCandidemia

((GareyGarey KW et al. CID 2006;43:25KW et al. CID 2006;43:25--31)31)

41% ICU Patients41% ICU Patients

15%15%

24%24%

37%37% 41%41%

Test for trend p=.0009Test for trend p=.0009

Bloodstream infectionBloodstream infection--related mortality rate related mortality rate higherhigher for patients receiving for patients receiving inadequate inadequate antimicrobial therapy 29.9%antimicrobial therapy 29.9% vs. vs. 11.9% with 11.9% with adequate antimicrobial therapyadequate antimicrobial therapy (p<.001).(p<.001).

Multiple logistic regression analysis showed that: Multiple logistic regression analysis showed that: Candida Candida sppspp.. associated with inadequate therapy associated with inadequate therapy (AOR 51.86, 95% CI 24.57 to 109.49, p<.001).(AOR 51.86, 95% CI 24.57 to 109.49, p<.001).

Increased Hospital Mortality with Increased Hospital Mortality with Inadequate Antimicrobial Therapy Inadequate Antimicrobial Therapy

for for CandidemiaCandidemia

((IbrahimIbrahim EH et al. Chest 2000;118:146EH et al. Chest 2000;118:146--155)155)

2008 IDSA Guidelines for the 2008 IDSA Guidelines for the Treatment of Treatment of CandidemiaCandidemia/Invasive /Invasive

CandidiasisCandidiasisNonNon--NeutropenicNeutropenic patients patients -- Clinically Clinically stable and no recent stable and no recent azoleazole exposure:exposure:

FluconazoleFluconazole 800mg then 400 mg daily IV/800mg then 400 mg daily IV/popo(preferred) or an (preferred) or an echinocandinechinocandin ((AnidulafunginAnidulafungin 200mg 200mg IV then 100 mg IV daily, IV then 100 mg IV daily, CaspofunginCaspofungin 70 mg then 50 70 mg then 50 mg IV daily or mg IV daily or MicafunginMicafungin 100 mg IV daily) [A100 mg IV daily) [A--I].I].

Transition from an Transition from an echinocandinechinocandin to to fluconazolefluconazole for for fluconazolefluconazole susceptible organisms & patients clinically susceptible organisms & patients clinically stable [Astable [A--II].II].

For For C. C. glabrataglabrata an an echinocandinechinocandin is preferred. is preferred. Transition to Transition to fluconazolefluconazole or or voriconazolevoriconazole should not be should not be done unless isolate susceptible. If done unless isolate susceptible. If fluconazolefluconazole used used initially and patient improved and cultures negative initially and patient improved and cultures negative then continue with then continue with fluconazolefluconazole [B[B--III].III].

For For C. C. parapsilosisparapsilosis fluconazolefluconazole is preferred. If an is preferred. If an echinocandinechinocandin used and patient improved with negative used and patient improved with negative cultures can continue with cultures can continue with echinocandinechinocandin [B[B--III].III].

AmBAmB 0.5 to 1.0 mg/kg/d IV or LF0.5 to 1.0 mg/kg/d IV or LF--AmBAmB 33--5 mg/kg/d 5 mg/kg/d IV are alternatives if there is intolerance or limited IV are alternatives if there is intolerance or limited availability of other availability of other antifungalsantifungals [A[A--I].I].

IDSA2008 Guidelines for the IDSA2008 Guidelines for the Treatment of Treatment of CandidemiaCandidemia/Invasive /Invasive

CandidiasisCandidiasis (Cont(Cont’’d)d)

VoriconazoleVoriconazole is effective for is effective for candidemiacandidemia but but offers little advantage over offers little advantage over fluconazolefluconazole except except for step down therapy for for step down therapy for C. C. kruseikrusei and and voriconazolevoriconazole--susceptible susceptible C.C. glabrataglabrata..

Removal of IV catheters recommended.Removal of IV catheters recommended.

Duration of therapy 2 weeks after last Duration of therapy 2 weeks after last positive blood culture and resolution of positive blood culture and resolution of symptoms.symptoms.



NonNon--neutropenicneutropenic patients patients --moderately severe to severely ill and moderately severe to severely ill and recent recent azoleazole exposure:exposure:

EchinocandinEchinocandin ((AnidulafunginAnidulafungin 200mg IV 200mg IV →→100 mg daily IV, 100 mg daily IV, CaspofunginCaspofungin 70mg IV 70mg IV →→ 50 50 mg daily IV or mg daily IV or MicafunginMicafungin 100 mg daily IV)100 mg daily IV)



CandidemiaCandidemia in in neutropenicneutropenic patients:patients:

EchinocandinEchinocandin ((AnidulafunginAnidulafungin 200 mg 200 mg →→ 100 100 mg daily IV, mg daily IV, CaspofunginCaspofungin 70 mg 70 mg →→ 50 mg 50 mg daily IV or daily IV or MicafunginMicafungin 100 mg daily IV) or 100 mg daily IV) or LFLF--AmBAmB 33--5 mg/kg/d IV [A5 mg/kg/d IV [A--II].II].

For less critically ill patients, For less critically ill patients, fluconazolefluconazole800mg 800mg →→ 400 mg daily is alternative. 400 mg daily is alternative. VoriconazoleVoriconazole may be used in situations may be used in situations where additional mould coverage is where additional mould coverage is desired [Bdesired [B--III].III].



CandidemiaCandidemia in in neutropenicneutropenic patients patients (cont(cont’’d):d):

For For C. C. glabrataglabrata, , anan echinocandinechinocandin or LFor LF--AmBAmBis preferredis preferred. If patients are improved on . If patients are improved on fluconazolefluconazole or or voriconazolevoriconazole and blood cultures and blood cultures are negative, they can be continued [Bare negative, they can be continued [B--III].III].

For For C. C. parapsilosisparapsilosis infections, infections, fluconazolefluconazole or or LFLF--AmBAmB is preferred [Bis preferred [B--III]III]..

For For C. C. kruseikrusei,, an an echinocandinechinocandin or or voriconazolevoriconazole is preferred [Bis preferred [B--III].III].



Efficacy Results in Efficacy Results in CandidemiaCandidemia in in NonNon--neutropenicneutropenic PatientsPatients

A

58%58%50%50%

B56%56%

69%69%

0

10

20

30

40

50

60

70

80

90

CandidemiaCandidemia IIRex et al.Rex et al.

NEJM, 1994NEJM, 1994

Canadian Canadian CandidemiaCandidemiaStudy, Phillips et al.Study, Phillips et al.

EJCMID, 1997EJCMID, 1997

CandidemiaCandidemia IIIIRex et al.Rex et al.CID 2003CID 2003

Amphotericin B

Fluconazole(A = 400 mg/dayB = 800 mg/day)

Amphotericin B + fluconazole

79%79%

70%70%A

% S

ucce

ssfu

l Out

com

e%

Suc

cess

ful O

utco

me

*P=.043*P=.043

Response RatesResponse RatesVoriconazole vs. Voriconazole vs. AmBAmB for Candidemiafor Candidemia

41 41

65

71 7074

52 53

44 46

0

10

20

30

40

50

60

70

80

Res

pons

e R

ate

(%)

Primary Successat 12 Weeks Post

Therapy

SecondarySuccess

Success at End ofTreatment

Success at 2Weeks PostTreatment

Success at 6weeks PostTreatment

Voriconazole AmB

101101248248

5050122122

162162248248

8787122122

173173248248

9090122122 130130

2482486464122122

110110248248

5656122122

(Kullberg BJ et al. Lancet 2005;366:1435(Kullberg BJ et al. Lancet 2005;366:1435--1442)1442)

CASPOFUNGIN VS. AmBCASPOFUNGIN VS. AmBfor for CandidemiaCandidemia: End of IV Antifungal : End of IV Antifungal

TherapyTherapy

73.461.7

80.7

64.9

0102030405060708090

100

CaspofunginAmB

MITTMITT EvaluableEvaluable

Res

pons

e R

ate

%R

espo

nse

Rat

e %

(Mora(Mora--Duarte J et al. NEJM 2002;347:2020Duarte J et al. NEJM 2002;347:2020--2029) 2029)

p = 0.03p = 0.03

0

10

20

30

40

50

60

70

80

PrimaryEndpoint-End of IVTherapy

SecondaryEndpoint End

of AllTherapy

SecondaryEndpoint-2Week F/U

SecondaryEndpoint-6Week F/U

AnidulafunginFluconazole

AnidulafunginAnidulafungin vs. vs. FluconazoleFluconazole for for CandidemiaCandidemia and Invasive and Invasive CandidiasisCandidiasis

Glo

bal R

espo

nse

G

loba

l Res

pon

se

Mic

robi

olog

ical

In

ten

t to

Tre

atM

icro

biol

ogic

al I

nte

nt

to T

reat

75.675.6

56.856.8

64.664.6

49.249.255.955.9

44.144.1

**

**

*= statistically *= statistically significantsignificant

74.074.0

**60.260.2

((ReboliReboli AC, Rotstein C, Pappas P, et al. N AC, Rotstein C, Pappas P, et al. N EnglEngl J Med 2007;356:2472J Med 2007;356:2472--2482)2482)

Response Rates of Response Rates of MicafunginMicafungin vs. vs. CaspofunginCaspofunginfor for CandidemiaCandidemia/Invasive /Invasive CandidiasisCandidiasis

0

10

20

30

40

50

60

70

80

PrimaryEndpoint End of

Blinded IVtherapy

End of AllTherapy

2 Weeks Post-Therapy

4 Weeks Post-Therapy

Micafungin 100

Micafungin150Caspofungin

Res

pon

se R

ate

%R

espo

nse

Rat

e %

76.476.471.471.4

72.372.374.974.9

68.368.3 70.270.2

54.554.552.852.8 50.550.5 46.646.6

44.744.742.642.6

(Pappas P, (Pappas P, RotsteinRotstein C, Betts RF et al. C, Betts RF et al. CID 2007;45:883CID 2007;45:883--893893))

EndpointsEndpoints

0

5

10

15

Caspovs.

AmB

Anidvs.

Fluco

Micavs.

Caspo

CaspofunginAmBAnidulafunginFluconazoleMicafungin 100Micafungin 150

Persistence of Invasive Candida Persistence of Invasive Candida Infections with Infections with EchinocandinsEchinocandins

1.1. MoraMora--Duarte J et al. N Duarte J et al. N EnglEngl J Med 2002;347:2020J Med 2002;347:2020--202920292.2. ReboliReboli AC, AC, RotsteinRotstein C, Pappas P et al. NEJM 2007;356:2472C, Pappas P et al. NEJM 2007;356:2472--248224823.3. Pappas P, Pappas P, RotsteinRotstein C, Betts RF et al. CID 2007;45:883C, Betts RF et al. CID 2007;45:883--893893

Per

cen

tage

Per

cen

tage 8.38.3

8.78.7 6.36.3

14.414.4 (p=.06)(p=.06)

9.69.6

5.55.5

11.611.6

Empiric Antifungal Empiric Antifungal Therapy for Therapy for CandidiasisCandidiasisin in NeutropenicNeutropenic PatientsPatients

Empiric treatment for suspected invasive Empiric treatment for suspected invasive candidiasiscandidiasis in in neutropenicneutropenic patients:patients:

LFLF--AmBAmB 33--5 mg/kg daily IV, 5 mg/kg daily IV, CaspofunginCaspofungin 70 mg 70 mg →→ 50 50 mg daily IV or mg daily IV or VoriconazoleVoriconazole 6 mg/kg q12h IV X2 then 6 mg/kg q12h IV X2 then 3 mg/kg q12h IV followed by 200 mg bid 3 mg/kg q12h IV followed by 200 mg bid popo..

FluconazoleFluconazole 800 mg load then 400 mg daily or 800 mg load then 400 mg daily or ItraconazoleItraconazole 200 mg bid are alternatives.200 mg bid are alternatives.

AmBAmB use is discouraged due to the risk of use is discouraged due to the risk of nephrotoxicitynephrotoxicity..

Azoles should not be used for empiric therapy if they Azoles should not be used for empiric therapy if they have been used as prophylaxis in patientshave been used as prophylaxis in patients



Review:Review: Empiric Antifungal Therapy in Febrile Neutropenia: A MetaEmpiric Antifungal Therapy in Febrile Neutropenia: A Meta--Analysis Analysis of Randomized Controlled Trialsof Randomized Controlled Trials

Comparison: Comparison: LF AmB LF AmB vsvs Conventional AmB Conventional AmB –– Including patients with Including patients with suspected infectionsuspected infection

Outcome: Outcome: SurvivalSurvival

1.49 (0.87, 2.54)1.49 (0.87, 2.54)60.8860.88308/344308/344318/343318/343Walsh 1999Walsh 1999

Total (95% CI)Total (95% CI)Total events: 464 (LF AmB) 450 (Conventional AmB)Total events: 464 (LF AmB) 450 (Conventional AmB)Test for heterogeneity: ChiTest for heterogeneity: Chi2 2 =2.00, =2.00, dfdf=3 (P=0.57), I=3 (P=0.57), I22=0%=0%Test for overall effect: Z=1.23 (P=0.22)Test for overall effect: Z=1.23 (P=0.22)

1.30 (0.86, 1.97)1.30 (0.86, 1.97)100.00100.00507507510510TotalTotal

0.81 (0.37, 1.80)0.81 (0.37, 1.80)27.5627.5682/9582/9582/9882/98White 1998White 1998

1.92 (0.47, 7.83)1.92 (0.47, 7.83)8.768.7618/2418/2423/2723/27SchoffskiSchoffski 19981998

Not estimableNot estimable8/88/87/77/7PascualPascual 19951995

2.00 (0.17, 24.07)2.00 (0.17, 24.07)2.802.8018/2018/2018/1918/19CaillotCaillot 19941994

not estimablenot estimable16/1616/1616/1616/16Moreau 1992Moreau 1992

OR (random) OR (random) 95% CI95% CI

Weight Weight %%


Conventional Conventional AmBAmBn/Nn/N

LF AmBLF AmBn/Nn/N

Study Study or subor sub--categorycategory

0.010.01 0.10.1 11 1010 100100

٠٠

FavoursFavours controlcontrol FavoursFavours treatmenttreatment

٠٠

٠٠٠٠



Outcome: Outcome: Avoidance of Fungal Breakthrough InfectionsAvoidance of Fungal Breakthrough Infections

1.10 (0.67, 1.79)1.10 (0.67, 1.79)76.3876.38307/344307/344309/343309/343Walsh 1999Walsh 1999

Total (95% CI)Total (95% CI)Total events: 689 (LF AmB) 551 (Conventional AmB)Total events: 689 (LF AmB) 551 (Conventional AmB)Test for heterogeneity: ChiTest for heterogeneity: Chi2 2 =0.48, =0.48, dfdf=5 (P=0.99), I=5 (P=0.99), I22=0%=0%Test for overall effect: Z=0.59 (P=0.55)Test for overall effect: Z=0.59 (P=0.55)

1.14 (0.74, 1.75)1.14 (0.74, 1.75)100.00100.00599599734734TotalTotal

1.03 (0.20, 5.25)1.03 (0.20, 5.25)6.996.9992/9592/9595/9895/98White 1998White 1998


1.16 (0.17, 24.07)1.16 (0.17, 24.07)6.296.2998/10098/100227/231227/231PrenticePrentice

2.00 (0.17, 2.00 (0.17, 24.07)24.07)

2.982.9818/2018/2018/1918/19CaillotCaillot 19941994

2.14 (0.17, 26.33)2.14 (0.17, 26.33)2.932.9314/1614/1615/1615/16Moreau 1992Moreau 1992


Weight Weight %%


Conventional Conventional AmBAmBn/Nn/N

LF AmBLF AmBn/Nn/N


0.010.01 0.10.1 11 1010 100100

٠٠


٠٠

٠٠٠٠

٠٠

٠٠



Outcome: Outcome: Renal Toxicity (Creatinine > 1.5 x Baseline)Renal Toxicity (Creatinine > 1.5 x Baseline)

0.43 (0.31, 0.58)0.43 (0.31, 0.58)47.0247.02170/344170/344101/343101/343Walsh 1999Walsh 1999

Total (95% CI)Total (95% CI)Total events: 125 (LF AmB), 230 (Conventional AmB)Total events: 125 (LF AmB), 230 (Conventional AmB)Test for heterogeneity: ChiTest for heterogeneity: Chi2 2 =7.43, =7.43, dfdf= 3 (P=0.06), I= 3 (P=0.06), I22=59.6%=59.6%Test for overall effect: Z=3.17 (P=0.002)Test for overall effect: Z=3.17 (P=0.002)

0.32 (0.16, 0.65)0.32 (0.16, 0.65)100.00100.00483483488488TotalTotal

0.23 (0.31, 0.58)0.23 (0.31, 0.58)36.5436.5451/9951/9920/10220/102White 1998White 1998


0.11 (0.02, 0.66)0.11 (0.02, 0.66)11.8111.819/169/162/162/16Moreau 1992Moreau 1992


Weight Weight %%


Conventional AmBConventional AmBn/Nn/N

LF AmBLF AmBn/Nn/N


0.010.01 0.10.1 11 1010 100100

٠٠


٠٠٠٠

٠٠


Comparison: Comparison: Azoles vs. AmB compoundsAzoles vs. AmB compounds–– Including patients with suspected Including patients with suspected sites of infectionsites of infection

Outcome: Outcome: SurvivalSurvival

0.73 (0.43, 1.25)0.73 (0.43, 1.25)29.6929.69397/422397/422382/415382/415Walsh 2002Walsh 2002

1.35 (0.71, 2.55)1.35 (0.71, 2.55)22.7822.78156/181156/181160/179160/179BoogaertsBoogaerts 20012001

1.34 (0.63, 2.85)1.34 (0.63, 2.85)16.9216.92142/159142/159145/158145/158Winston 2000Winston 2000

Total (95% CI)Total (95% CI)Total events: 878 (Azole), 889 ( AmB)Total events: 878 (Azole), 889 ( AmB)Test for heterogeneity: ChiTest for heterogeneity: Chi2 2 =7.74, =7.74, dfdf=7 (P=0.36), I=7 (P=0.36), I22=9.5%=9.5%Test for overall effect: Z=0.17 (P=0.86)Test for overall effect: Z=0.17 (P=0.86)

1.03 (0.74, 1.44)1.03 (0.74, 1.44)100.00100.00989989973973TotalTotal

1.36 (0.58, 3.20)1.36 (0.58, 3.20)13.6213.6232/4832/4838/5238/52MalikMalik 19981998

0.65 (0.11, 4.07)0.65 (0.11, 4.07)3.273.2754/5654/5653/5653/56ViscoliViscoli 19961996

0.32 (0.08, 1.21)0.32 (0.08, 1.21)5.935.9319/2519/258/168/16Ellis 1995Ellis 1995

5.08 (0.24, 5.08 (0.24, 107.83)107.83)

1.191.1964/6664/6665/6565/65Marie 1993Marie 1993

1.51 (0.42, 5.38)1.51 (0.42, 5.38)6.606.6025/3225/3227/3227/32Walsh 1991Walsh 1991


Weight Weight %%


AmBAmBn/Nn/N

AzoleAzolen/Nn/N


0.010.01 0.10.1 11 1010 100100

٠٠


٠٠

٠٠٠٠

٠٠

٠٠

٠٠

٠٠


Comparison: Comparison: Azoles vs. Azoles vs. AmBAmB compoundscompounds–– Including patients with Including patients with suspected sites of infectionsuspected sites of infection

Outcome: Outcome: DefervescenceDefervescence

0.84 (0.63, 1.12)0.84 (0.63, 1.12)26.1226.12154/422154/422135/415135/415Walsh 2002Walsh 2002

1.16 (0.73, 1.84)1.16 (0.73, 1.84)18.5118.51127/181127/181131/179131/179BoogaertsBoogaerts 20012001

1.16 (0.73, 1.84)1.16 (0.73, 1.84)18.5118.51143/159143/159133/158133/158Winston 2000Winston 2000

Total (95% CI)Total (95% CI)Total events: 560 (Azole), 597 ( AmB)Total events: 560 (Azole), 597 ( AmB)Test for heterogeneity: ChiTest for heterogeneity: Chi2 2 =11.50, =11.50, dfdf=7 (P=0.12), I=7 (P=0.12), I22=39.1%=39.1%Test for overall effect: Z=0.63 (P=0.53)Test for overall effect: Z=0.63 (P=0.53)

0.91 (0.68, 1.21)0.91 (0.68, 1.21)100.00100.001026102610011001TotalTotal

0.60 (0.30, 1.16)0.60 (0.30, 1.16)12.0412.0422/4822/4829/5229/52MalikMalik 19981998

1.54 (0.68, 3.50)1.54 (0.68, 3.50)9.089.0837/5637/5642/5642/56ViscoliViscoli 19961996

0.19 (0.04, 0.81)0.19 (0.04, 0.81)3.523.5221/2521/258/168/16Ellis 1995Ellis 1995

1.11 (0.55, 2.27)1.11 (0.55, 2.27)11.1211.1241/6641/6642/6542/65Marie 1993Marie 1993

0.65 (0.30, 1.41)0.65 (0.30, 1.41)10.0110.0152/6952/6940/6040/60FainsteinFainstein 19871987


Weight Weight %%


AmBAmBn/Nn/N

AzoleAzolen/Nn/N


0.010.01 0.10.1 11 1010 100100

٠٠


٠٠

٠٠

٠٠

٠٠

٠٠

٠٠

٠٠

Caspofungin vs. LCaspofungin vs. L--AmB for Empiric Antifungal AmB for Empiric Antifungal Therapy in Patients with Persistent Therapy in Patients with Persistent

NeutropeniaNeutropenia

33.9 33.7

92.689.2

51.9

25.9

94.8 95.5

41.2 41.4

89.785.5

0

10

20

30

40

50

60

70

80

90

100

Succ

ess

Rat

e %

Overall Success Survival Treatment ofBaseline IFI

NoBreakthrough

IFI

FeverResolution

No PrematureDiscontinuation

P=0.04P=0.04

P=0.05P=0.05P=0.03P=0.03

▪▪ CaspofunginCaspofungin

▪▪ LL--AmBAmB

(Walsh TJ et al. NEJM 2004;351:1391(Walsh TJ et al. NEJM 2004;351:1391--1402)1402)

ProphylaxisProphylaxis

Antifungal Antifungal prohylaxisprohylaxis for invasive for invasive candidiasiscandidiasis in chemotherapy induced in chemotherapy induced neutropenianeutropenia and HSCT:and HSCT:

FluconazoleFluconazole 400mg daily [A400mg daily [A--I] or I] or PosaconazolePosaconazole 200 mg 200 mg tidtid [A[A--I] or I] or CaspofunginCaspofungin50 mg daily IV [B50 mg daily IV [B--II] are recommended.II] are recommended.

For For neutropenianeutropenia in in HSCTHSCT, , FluconazoleFluconazole 400 400 mg mg popo dailydaily, , PosaconazolePosaconazole 200 mg 200 mg popo tidtid or or MicafunginMicafungin 50 mg daily IV are recommended 50 mg daily IV are recommended [A[A--I].I].



AzoleAzole Antifungal Antifungal ProphylaxisProphylaxis

--0.870.87Overall mortalityOverall mortality47%, 5247%, 520.580.58Fungal mortalityFungal mortality

61%, 1261%, 1256%, 2256%, 22

0.290.290.440.44

Superficial Superficial infxninfxnProven IFIProven IFI

19%, 1019%, 100.570.57Need for AF RxNeed for AF RxRRR/NNTRRR/NNTOdds Ratio*Odds Ratio*EndpointEndpoint

MetaMeta--analysis, 38 trials, n=7014analysis, 38 trials, n=7014

* All favour study agent (prophylaxis) p<0.05* All favour study agent (prophylaxis) p<0.05

(Bow EJ et al, Cancer 2002;94:3230(Bow EJ et al, Cancer 2002;94:3230--46)46)

Micafungin vs. Fluconazole for Micafungin vs. Fluconazole for Prophylaxis in HSCTProphylaxis in HSCT

0

10

20

30

40

50

60

70

80

90

Per

cent

Overall Success Use of EmpiricTherapy

Mortality

Micafungin Fluconazole

(van (van BurikBurik JA et al. CID 2004;39:1407JA et al. CID 2004;39:1407--1416)1416)

†

* P<0.001; † P= 0.003

Treatment Phase 100 Day Period After Randomization

Primary Endpoint: Prevention of IFIPrimary Endpoint: Prevention of IFIAntifungal Prophylaxis: NeutropeniaAntifungal Prophylaxis: Neutropenia

((CornelyCornely OA et al. OA et al. N Engl J MedN Engl J Med 2007;356:3482007;356:348--59)59)

7 (2%)

2 (1%)

14 (5%)

4 (1%)

25 (8%)

20 (7%)

33 (11%)

26 (9%)

0

5

10

15

20

25

30

35

40

All IFIs* Aspergillosis All IFIs Aspergillosis

Posaconazole n=304Standard Azoles n=298

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0 20 40 60 80 100

Prob

abili

ty o

f Dea

thPr

obab

ility

of D

eath

Prob

abili

ty o

f Dea

th

Days After RandomizationDays After RandomizationDays After Randomization

P = .04*P = .04*

PosaconazoleFluconazole or Itraconazole

Death From Any Cause (Decreased Mortality)Death From Any Cause Death From Any Cause (Decreased Mortality)(Decreased Mortality)

*Estimated using log-rank statistics.Censoring time is the minimum of the last contact date and day 100.

((CornelyCornely OA, et al. OA, et al. N N EnglEngl J MedJ Med 2007;356:3482007;356:348--359)359)

21%21%

14%14%

33% relative reduction in

mortality

33% relative reduction in

mortality

Antifungal Prophylaxis: Antifungal Prophylaxis: NeutropeniaNeutropenia

PrePre--Emptive TherapyEmptive Therapy

Serological surrogate markers of IFI (beta Serological surrogate markers of IFI (beta glucanglucan for Candida and beta for Candida and beta galactomannangalactomannan for for AspergillusAspergillus) not ) not universally available.universally available.PrePre--emptive therapy canemptive therapy can’’t be used t be used effectively without these markers.effectively without these markers.

Treatment of Invasive Treatment of Invasive AspergillosisAspergillosis

Antifungal Therapy for Invasive Antifungal Therapy for Invasive AspergillosisAspergillosis –– IDSA GuidelinesIDSA Guidelines

IA involving lung, sinus, IA involving lung, sinus, tracheobronchialtracheobronchial tree and CNS:tree and CNS:Primary therapy Primary therapy –– VoriconazoleVoriconazole 6 mg/kg 6 mg/kg q12h X 1 d q12h X 1 d

then 4 mg/kg q12h IV then 4 mg/kg q12h IV →→ 200 mg bid 200 mg bid popo [A[A--I]I]

Alternative Alternative –– LL--AmBAmB 33--5 mg/kg/d (A5 mg/kg/d (A--I), I), caspofungincaspofungin 70 70 mg mg →→ 50 mg /d IV, 50 mg /d IV, MicafunginMicafungin 100100--150 mg/d IV, 150 mg/d IV, PosaconazolePosaconazole 200 mg 200 mg qidqid popo initially then 400 mg bid initially then 400 mg bid popoafter stabilization or after stabilization or ItraconazoleItraconazole (dose depends on (dose depends on formulation) [All Bformulation) [All B--II].II].

Empiric and preemptive antifungal therapy:Empiric and preemptive antifungal therapy:LL--AmBAmB 3 mg/kg/d IV, 3 mg/kg/d IV, CaspofunginCaspofungin 70 mg 70 mg →→ 50 mg/d 50 mg/d

IV or IV or VoriconazoleVoriconazole 6 mg/kg q12h X 1 d then 3 mg/kg/d 6 mg/kg q12h X 1 d then 3 mg/kg/d IV IV →→ VoriconazoleVoriconazole 200 mg bid 200 mg bid popo..

(Walsh TJ et al. (Walsh TJ et al. ClinClin Infect Infect DisDis 2008;46:3272008;46:327--360)360)

Antifungal Therapy for Invasive Antifungal Therapy for Invasive AspergillosisAspergillosis –– IDSA GuidelinesIDSA Guidelines

Prophylaxis against IA:Prophylaxis against IA:Primary therapy Primary therapy -- PosaconazolePosaconazole 200 mg 200 mg tidtid popo

Alternative therapy Alternative therapy –– MicafunginMicafungin 50 mg/d IV 50 mg/d IV or or ItraconazoleItraconazole 200 mg bid 200 mg bid popo

(Walsh TJ et al. (Walsh TJ et al. ClinClin Infect Infect DisDis 2008;46:3272008;46:327--360)360)

-20 -10 0 10 20 30 40 50 60

Global Comparative Aspergillosis Study Global Comparative Aspergillosis Study VoriconazoleVoriconazole vs. vs. AmBAmB Success at Week 12 (MITT)Success at Week 12 (MITT)

SuccessVoriconazole Ampho B

52.8% 31.6%

55.5% 34.8%

40.0% 14.3%

32.4% 13.3%

63.0% 38.1%

50.0% 31.6%

50.8% 31.7%

54.3% 31.5%

44.8% 19.5%

59.7% 37.0%

Difference in Success Rates (%, 95% CI)

ProbableProbable

NonNon--Neutropenic (ANC Neutropenic (ANC ≥≥ 500)500)

DefiniteDefinite

Neutropenic (ANC < 500)Neutropenic (ANC < 500)

Allogeneic BMTAllogeneic BMT

ExtrapulmonaryExtrapulmonary

PulmonaryPulmonary

OverallOverall

Other Other immunosuppressedimmunosuppressed state state ((egeg solid organ transplant, HIV/AIDS)solid organ transplant, HIV/AIDS)

Autologous BMT or other Autologous BMT or other hematological condition (hematological condition (egeg leukemia)leukemia)

-20

((HerbrechtHerbrecht et al NEJM 2002:347:408et al NEJM 2002:347:408--415)415)

At Risk (Censored)At Risk (Censored)VoriVori 144 (0)144 (0) 131 (0)131 (0) 125 (0)125 (0) 117 (0) 117 (0) 111 (0)111 (0) 107 (0) 102 (0)107 (0) 102 (0)AMBAMB 133 (0)133 (0) 117 (0)117 (0) 99 (0) 99 (0) 87 (0) 87 (0) 84 (0) 80 (0) 77 (0)84 (0) 80 (0) 77 (0)

0 14 28 42 56 70 840 .0

0 .2

0 .4

0 .6

0 .8

1 .0

Global Comparative Aspergillosis Global Comparative Aspergillosis VoriconazoleVoriconazole vs. vs. AmBAmB Time to Death (MITT)Time to Death (MITT)

Number of days of TherapyNumber of days of Therapy

Prob

abili

ty o

f Sur

viva

lPr

obab

ility

of S

urvi

val

AmphotericinAmphotericin B +/B +/-- OLATOLATVoriconazoleVoriconazole +/+/-- OLATOLAT

Hazard ratio = 0.60Hazard ratio = 0.6095% CI (0.40, 0.89)95% CI (0.40, 0.89)

((HerbrechtHerbrecht et al NEJM 2002:347:408et al NEJM 2002:347:408--415)415)

Invasive Mold Infection (IA, Invasive Mold Infection (IA, ZygomycosisZygomycosis): ): AmBiloadAmBiload TrialTrialRCT: invasive mold infection in pt. with RCT: invasive mold infection in pt. with hematologichematologicmalignancy (93% of pt.).malignancy (93% of pt.).Performed in Europe & Australia:Performed in Europe & Australia:

LL--AmBAmB 3mg/kg/d IV3mg/kg/d IVvs. vs.

LL--AmBAmB 10 mg/kg/d IV X 14 d 10 mg/kg/d IV X 14 d ThenThen 3 mg/kg/d IV3 mg/kg/d IVPatient entry criteria: Patient entry criteria:

PProven or probable IFI based on MSG/EORTC criteria roven or probable IFI based on MSG/EORTC criteria host factor plus clinical [CT scan halo or air crescent host factor plus clinical [CT scan halo or air crescent signs] and if available microbiological findings within signs] and if available microbiological findings within 4 days of enrollment.4 days of enrollment.

Analysis: Analysis: overall response (clinical, radiological and overall response (clinical, radiological and

microbiological) in intentmicrobiological) in intent--toto--treat population with treat population with proven or probable IFI & received proven or probable IFI & received ≥≥1 dose of drug.1 dose of drug.

((CornelyCornely OA et al. CID 2007;44:1289OA et al. CID 2007;44:1289--1297)1297)

0

10

20

30

40

50

60

70

80

FavourableResponse

IA Responses Survival at 12Weeks

Nephrotoxicity Discontinuationof Treatment

L-AmB 3 mgL-AmB 10 mg

Invasive Mold Infection (IA, Invasive Mold Infection (IA, ZygomycosisZygomycosis): ): AmBiloadAmBiload Trial (contTrial (cont’’d)d)

Per

cen

tage

Per

cen

tage

((CornelyCornely OA et al. CID 2007;44:1289OA et al. CID 2007;44:1289--1297)1297)

5050 50504646 4646

7272

5959

1414

3131

1313

2424

P=.005P=.005

0102030405060708090

100

AmBAmB LL--AmBAmB ABCDABCD ItraItra VoriVori

Res

pons

era

tes

(%)

1. Bowden. 1. Bowden. CIDCID 2002:35;359 2002:35;359 2. Lenders. 2. Lenders. Br J Br J HaematolHaematol 1998:103;2051998:103;2053. Bowden. 3. Bowden. CIDCID 2002:35;3592002:35;359

Clinical Success in the Primary Clinical Success in the Primary Treatment of Invasive Treatment of Invasive AspergillosisAspergillosis

4. 4. CaillotCaillot. . CIDCID 2001:33;e832001:33;e835. 5. HerbrechtHerbrecht. . NEJMNEJM 2002:347;4082002:347;408

Clinical Success in the Treatment of Clinical Success in the Treatment of Refractory Refractory AspergillosisAspergillosis

1. 1. KubackKuback. . FOFIFOFI 200220022. White. 2. White. CIDCID 1997:24;6331997:24;6333. 3. CaillotCaillot. . ActaActa HematolHematol 2003:109;1112003:109;1114. Perfect. 4. Perfect. CIDCID 2003:36;11222003:36;1122

5. Walsh. 5. Walsh. CIDCID 2007;44:22007;44:2--12126. 6. MaartensMaartens. . CIDCID 2004:39;15632004:39;15637. 7. RatanatharathornRatanatharathorn. . ASHASH 2002 2002 8. 8. AliffAliff. . CancerCancer 2003:97;10252003:97;1025

0102030405060708090

100

ABLCABLC ABCDABCD ItraItra VoriVori PosaPosa CaspoCaspo MicaMica LL--AmBAmB++CaspoCaspo

Res

pons

eR

ates

(%)

SummarySummaryTreatment of Treatment of candidemiacandidemia/invasive /invasive candidiasiscandidiasis(C/IC) is changing.(C/IC) is changing.EchinocandinsEchinocandins are very useful agents in both are very useful agents in both neutropenicneutropenic and and nonneutropenicnonneutropenic pt. for treatment pt. for treatment of C/IC.of C/IC.Treatment of IA involves Treatment of IA involves voriconazolevoriconazole as primary as primary therapy; Ltherapy; L--AmBAmB considered an alternative.considered an alternative.Combination therapy for IA cannot be advocated Combination therapy for IA cannot be advocated as first line but may be a consideration in as first line but may be a consideration in refractory cases.refractory cases.PosaconazolePosaconazole & & MicafunginMicafungin effective prophylaxis effective prophylaxis in HSCT recipients particularly when there is risk in HSCT recipients particularly when there is risk for IA. for IA.

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Update on the Treatment of Invasive Fungal Infections for ... · Empiric treatment for suspected invasive candidiasis in neutropenic patients: LF-AmB 3-5 mg/kg daily IV, Caspofungin