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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.
IDSA2008 Guidelines for the IDSA2008 Guidelines for the Treatment of Treatment of CandidemiaCandidemia/Invasive /Invasive
CandidiasisCandidiasis (Cont(Cont’’d)d)
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)
IDSA2008 Guidelines for the IDSA2008 Guidelines for the Treatment of Treatment of CandidemiaCandidemia/Invasive /Invasive
CandidiasisCandidiasis (Cont(Cont’’d)d)
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].
IDSA2008 Guidelines for the IDSA2008 Guidelines for the Treatment of Treatment of CandidemiaCandidemia/Invasive /Invasive
CandidiasisCandidiasis (Cont(Cont’’d)d)
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].
IDSA2008 Guidelines for the IDSA2008 Guidelines for the Treatment of Treatment of CandidemiaCandidemia/Invasive /Invasive
CandidiasisCandidiasis (Cont(Cont’’d)d)
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
IDSA2008 Guidelines for the IDSA2008 Guidelines for the Treatment of Treatment of CandidemiaCandidemia/Invasive /Invasive
CandidiasisCandidiasis (Cont(Cont’’d)d)
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 %%
OR (random) OR (random) 95% CI95% CI
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
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: 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
1.14 (0.15, 8.76)1.14 (0.15, 8.76)4.434.4322/2422/2425/2725/27SchoffskiSchoffski 19981998
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
OR (random) OR (random) 95% CI95% CI
Weight Weight %%
OR (random) OR (random) 95% CI95% CI
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
٠٠
٠٠
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: 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
4.80 (0.22, 105.22)4.80 (0.22, 105.22)4.634.630/270/272/272/27SchoffskiSchoffski 19981998
0.11 (0.02, 0.66)0.11 (0.02, 0.66)11.8111.819/169/162/162/16Moreau 1992Moreau 1992
OR (random) OR (random) 95% CI95% CI
Weight Weight %%
OR (random) OR (random) 95% CI95% CI
Conventional AmBConventional AmBn/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
٠٠٠٠
٠٠
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: 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
OR (random) OR (random) 95% CI95% CI
Weight Weight %%
OR (random) OR (random) 95% CI95% CI
AmBAmBn/Nn/N
AzoleAzolen/Nn/N
Study Study or subor sub--categorycategory
0.010.01 0.10.1 11 1010 100100
٠٠
FavoursFavours controlcontrol FavoursFavours treatmenttreatment
٠٠
٠٠٠٠
٠٠
٠٠
٠٠
٠٠
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: 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
OR (random) OR (random) 95% CI95% CI
Weight Weight %%
OR (random) OR (random) 95% CI95% CI
AmBAmBn/Nn/N
AzoleAzolen/Nn/N
Study Study or subor sub--categorycategory
0.010.01 0.10.1 11 1010 100100
٠٠
FavoursFavours controlcontrol FavoursFavours treatmenttreatment
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].
IDSA2008 Guidelines for the IDSA2008 Guidelines for the Treatment of Treatment of CandidemiaCandidemia/Invasive /Invasive
CandidiasisCandidiasis (Cont(Cont’’d)d)
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.