ankara, february 2007. clinical management of invasive fungal infections: an evidence-based approach

ANKARA, FEBRUARY 2007

ANKARA, FEBRUARY 2007

Clinical Management of Invasive Fungal Infections:

An Evidence-Based Approach

Clinical Management of Invasive Fungal Infections:

An Evidence-Based Approach

According to Odds

INCREASE IN FUNGAL INFECTIONSINCREASE IN FUNGAL INFECTIONS

• less mortality from other causesless mortality from other causes

-underlying disease-underlying disease

-better antibacterial therapy-better antibacterial therapy• higher agehigher age• better diagnostic toolsbetter diagnostic tools• more complex interventionsmore complex interventions

MORTALITY DUE TO INVASIVE MYCOSESMORTALITY DUE TO INVASIVE MYCOSESMcNeil et al. Clin Infect Dis 2001;33:641-7McNeil et al. Clin Infect Dis 2001;33:641-7

MORTALITY DUE TO INVASIVE MYCOSESMORTALITY DUE TO INVASIVE MYCOSESMcNeil et al. Clin Infect Dis 2001;33:641-7McNeil et al. Clin Infect Dis 2001;33:641-7

00

0,20,2

0,40,4

0,60,6

1980

1980

1981

1981

1982

1982

1983

1983

1984

1984

1985

1985

1986

1986

1987

1987

1988

1988

1989

1989

1990

1990

1991

1991

1992

1992

1993

1993

1994

1994

1995

1995

1996

1996

1997

1997

Rate

per

100,0

00 p

op

ula

tion

Rate

per

100,0

00 p

op

ula

tion

United States, 1980-1997United States, 1980-1997

Mycoses other than Candida albicans

19991999 20002000 20012001 20022002 20032003

00

0,50,5

11

1,51,5

22

2,52,5

33

3,53,5

Incid

en

ce (

%)

Incid

en

ce (

%)

DEVELOPMENT OF FUNGAL INFECTIONS DEVELOPMENT OF FUNGAL INFECTIONS OVER TIMEOVER TIME

DEVELOPMENT OF FUNGAL INFECTIONS DEVELOPMENT OF FUNGAL INFECTIONS OVER TIMEOVER TIME

other mouldsother moulds

Aspergillus

Candida

other yeasts

nu

mb

er

of

cases

Asper

gillu

s

Zygo

myc

etes

Fusa

rium

Cand

ida

Cryp

toco

ccus

Tricho

spor

on0

100200

300400

LETHALITY OF THE VARIOUS INVASIVE LETHALITY OF THE VARIOUS INVASIVE FUNGAL INFECTIONSFUNGAL INFECTIONS

LETHALITY OF THE VARIOUS INVASIVE LETHALITY OF THE VARIOUS INVASIVE FUNGAL INFECTIONSFUNGAL INFECTIONS

cases casualties

42%

61% 53%

33%

50% 29%

BASIC RISK FACTORS FOR FUNGAL INFECTIONSBASIC RISK FACTORS FOR FUNGAL INFECTIONS

immuno-

suppressionepidemiologic

exposure

technical /technical /anatomic anatomic factorsfactors

Adapted from RH Rubin, Boston

OPPORTUNISTS!OPPORTUNISTS!

MucosaMucosa

GranulocytesGranulocytes

COURSE OF DEFENSE SYSTEMS UNDER MODERN THERAPEUTIC REGIMENS

COURSE OF DEFENSE SYSTEMS UNDER MODERN THERAPEUTIC REGIMENS

time

Commensal floraCommensal flora

Humoral immunityHumoral immunity

T-cell functionT-cell function

antibiotics

PACE OF DEVELOPMENT OF NEW ANTIFUNGAL AGENTSPACE OF DEVELOPMENT OF NEW ANTIFUNGAL AGENTS

19501950 19601960 19701970 19801980 19901990 20002000

Adapted from Rex & Edwards, 1997Adapted from Rex & Edwards, 1997

AmBisomeAmBisomeAmBisomeAmBisome

fluconazolefluconazolefluconazolefluconazole

AmphocilAmphocilAmphocilAmphocil

AbelcetAbelcetAbelcetAbelcet

itraconazoleitraconazoleitraconazoleitraconazole

ketoconazoleketoconazoleketoconazoleketoconazole

miconazolemiconazolemiconazolemiconazole

5-flucytosine5-flucytosine5-flucytosine5-flucytosine

terbinafineterbinafineterbinafineterbinafine

Amphotericin BAmphotericin BAmphotericin BAmphotericin B

NystatinNystatinNystatinNystatin

GriseofulvinGriseofulvinGriseofulvinGriseofulvin

isavuconazole

isavuconazole

caspofungin

caspofungin

anid

ulaf

ungi

n

anid

ulaf

ungi

n

mica

fungin

mica

fungin

voriconazole

voriconazole posaconazole

posaconazole

WHAT’S NEW?WHAT’S NEW?

voriconazole caspofungin

micafungin

anidulafungin

amphotericin B flucytosine fluconazole itraconazole

posaconazole

RECOMMENDATIONSRECOMMENDATIONS

A

B

C

I II IIIRANDOMISED TRIAL CONSISTENT SERIES EXPERT / CONSENSUS

SOLID CLINICAL EVIDENCE

REASONABLE CLINICAL EVIDENCE

TRIVIAL CLINICAL EVIDENCE

RECOMMENDATIONSRECOMMENDATIONS

A

B

C

I II III

lipid ampho B for primary treatment

ampho B followed by itraconazole

biological response modifiers // surgery

early start of antifungal treatment

487 FUNGAL INFECTIONS IN TRANSPLANT RECIPIENTS

Pappas et al. ICAAC, Chicago 2003; abstr M-1010

487 FUNGAL INFECTIONS IN TRANSPLANT RECIPIENTS


Candida

Aspergillus and other moulds

CryptoEndemic Pneumocystis

FUNGAL INFECTIONS IN TRANSPLANT RECIPIENTS




Candida species

POPULATION WITH INVASIVE CANDIDIASISPOPULATION WITH INVASIVE CANDIDIASIS

Invasive candidasis Diagnosed while aliveeligible for clinical trial

COMPARISON OF RESULTS FROM CLINICAL TRIALS ON CANDIDAEMIA


Fluconazole 400 mg/day

Amphotericin B

CaspofunginMicafunginAnidulafunginVoriconazole

72%

79%62%

74%74%76%65%

39%

40%40%

30%

23%36%

responsresponsee

mortalitmortalityy

MICAFUNGIN versus AMBISOME IN CHILDREN WITH INVASIVE CANDIDOSIS

Arrieta et al. ICAAC, San Francisco 2006; Abstract M-1308b

MICAFUNGIN versus AMBISOME IN CHILDREN WITH INVASIVE CANDIDOSIS

Arrieta et al. ICAAC, San Francisco 2006; Abstract M-1308b

Double-blind comparison, n = 98

Rate of Favorabl

e Respons

e

2mg/kg/d

(n=48)

AmBisome3 mg/day(n=50)

micafungin

7373%% 7766%%

0

20

40

60

80

100premature

7070%% 6767%%

premature




Amphotericin B

CaspofunginMicafunginAnidulafunginVoriconazole

72%

79%62%

74%74%76%65%

39%

40%40%

30%

23%36%

responsresponsee

mortalitmortalityy




Amphotericin B

AmbisomeAmbisomeCaspofunginMicafunginAnidulafunginVoriconazole

72%

79%62%71%71%74%74%76%65%

39%

40%40%3434%%30%

23%36%

responsresponsee

mortalitmortalityy

RELATION INITIATION FLUCONAZOLE THERAPY AND OUTCOME OF CANDIDAEMIA

Garey et al. Clin Infect Dis 2006; 43:25-31



230 cases of candidaemia

start fluconazoleday 0 day 2 day 3 day 4





230 cases of candidaemia

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

mortality

start fluconazoleday 0 day 2 day 3 day 4

A

B

C

I II III

Continue therapy for 2 weeks after

disappearance of signs and symptoms

Lower doses suffice inLower doses suffice in less critically illless critically ill

patientspatients

First line•Fluconazole•Ampho B•Candins•Voriconazole

Combination of Combination of

antifungals antifungals •Biological response modifiers

FFlu-resistancelu-resistance

• CCombinationombination therapytherapy

RECOMMENDATIONS FOR TREATMENT OF ACUTE CANDIDIASIS -- 2007

RECOMMENDATIONS FOR TREATMENT OF ACUTE CANDIDIASIS -- 2007

Early start therapyFlu-resistant strains •AmphoB formulations•Candins•Voriconazole

FROM TREATMENT OF CHOICE TO CHOICES

OF TREATMENT

FROM TREATMENT OF CHOICE TO CHOICES

OF TREATMENT

STRATEGY FOR THE TREATMENT OF DISSEMINATED CANDIDIASIS

Spellberg et al. Clin Infect Dis 2006; 42:244-251

STRATEGY FOR THE TREATMENT OF DISSEMINATED CANDIDIASIS

Spellberg et al. Clin Infect Dis 2006; 42:244-251

invasive candidiasis proven / probable

invasive candidiasis proven / probable

NO

fluconazolefluconazole

lipid ampho-Bvoriconazoleechinocandin

lipid ampho-Bvoriconazoleechinocandin

SpellbergFillerEdwards

(risk of) C.glabrataC.krusei ?

(risk of) C.glabrataC.krusei ?

NONO

hemodynamically unstable?

YESYES YESYES





Aspergillus species

QUESTIONS REGARDING INVASIVE ASPERGILLOSIS


Why is there an increase?When will it occur?Where will it strike?

When should we treat?What is the best therapy?

Treatment

Treatment

checklistchecklist

azolesazoles

polyenespolyenes

lipid formulations

lipid formulations

candinscandins

combinations

combinations

diagnostics

a plan

I FD

Treatment

Treatment

checklistchecklist

azolesazoles

polyenespolyenes

lipid formulations

lipid formulations

candinscandins

combinations

combinations

diagnostics

diagnostics

a plana plan

I FD

STRATEGY vs DRUG SELECTIONSTRATEGY vs DRUG SELECTION

When?

What?

Treatment

Treatment

checklistchecklist

azolesazoles

polyenespolyenes

lipid formulations

lipid formulations

candinscandins

combinations

combinations

diagnostics

diagnostics

a plana plan

I FD

STRATEGY vs DRUG-EFFICACYSTRATEGY vs DRUG-EFFICACY

When?

What?

Treatment

Treatment

checklistchecklist

azolesazoles

polyenespolyenes

lipid formulations

lipid formulations

candinscandins

combinations

combinations

diagnostics

diagnostics

a plana plan

I FD


When?

RELATION OUTCOME AND STATE OF FUNGAL INFECTION

RELATION OUTCOME AND STATE OF FUNGAL INFECTION

evolution of the infectionevolution of the infection evolution of the infectionevolution of the infection

odds to control the infectionodds to control the infection odds to control the infectionodds to control the infection

timetime timetime

IMPORTANCE OF EARLY TREATMENT OF INVASIVE ASPERGILLOSIS

Patterson et al. Medicine 2000

IMPORTANCE OF EARLY TREATMENT OF INVASIVE ASPERGILLOSIS

Patterson et al. Medicine 2000

Type of infection

Pulmonary only

Disseminated

Survival

40% (n=330)

18% (n=144)

RECOMMENDATIONS IDSA 2000Stevens et al. Clin Infect Dis 2000; 30:696-709RECOMMENDATIONS IDSA 2000Stevens et al. Clin Infect Dis 2000; 30:696-709

A

B

C

I II III

Early start of antifungal treatment

PROBABILITY OF DEVELOPING PULMONARY ASPERGILLUS

Gerson et al. Ann Intern Med 1984

PROBABILITY OF DEVELOPING PULMONARY ASPERGILLUS

Gerson et al. Ann Intern Med 1984

0 0

2020

4040

6060

8080

100100

PER

CEN

TA

GE

PER

CEN

TA

GE

INFEC

TED

INFEC

TED

DAYS WITH NEUTROPENIADAYS WITH NEUTROPENIA

0 10 20 30 40 50 60 70 80 90 100

Empirical therapy incidence aspergillosis 4-6%

DIAGNOSTIC TOOLS ANNO 2007DIAGNOSTIC TOOLS ANNO 2007

Sandwich-ELISA galactomannanHigh-resolution CT-scanUltrasoundBronchoalveolar lavagesBiopsy techniques

Glucan-testPCRPET-scanning

TRADITIONAL EMPIRICAL MANAGEMENT OF INVASIVE ASPERGILLOSIS

Maertens et al. Clin Infect Dis 2005;41:1242-1250

TRADITIONAL EMPIRICAL MANAGEMENT OF INVASIVE ASPERGILLOSIS


11 unexplained relapses

11 unexplained relapses

30 persistent fever

30 persistent fever

8282 defervesencedefervesence


41 candidates empirical antifungals

41 candidates empirical antifungals

35%35%35%35%

1919 no feverno fever


117 febrile episodes


136episodes

136episodes

GALACTOMANAN AND CT-SCAN-GUIDED EARLY TREATMENT OF INVASIVE ASPERGILLOSIS


GALACTOMANAN AND CT-SCAN-GUIDED EARLY TREATMENT OF INVASIVE ASPERGILLOSIS



nonoantifungalantifungalanti-anti-

fungalfungal

2x >0.5

CTCTBALBALCTCT

BALBAL

136 treatment episodes haematological malignancies

typicaltypicaltypicaltypical

negativenegativenegativenegative

CTCTCTCT5 daysrefractory fever

daily galactomannandaily galactomannan

PRE-EMPTIVE MANAGEMENT OF INVASIVE ASPERGILLOSIS


PRE-EMPTIVE MANAGEMENT OF INVASIVE ASPERGILLOSIS


136episodes

136episodes

10 seropositive

10 seropositive

9 cases suspicious CT

9 cases suspicious CT



19 cases for pre-emptive antifungals

19 cases for pre-emptive antifungals

16%16%16%16%





++

PRE-EMPTIVE MANAGEMENT OF INVASIVE ASPERGILLOSIS: MORTALITY


PRE-EMPTIVE MANAGEMENT OF INVASIVE ASPERGILLOSIS: MORTALITY


88patients

88patients

fungalfungalmortalitymortality

8%8%

fungalfungalmortalitymortality

8%8%

Fungal mortality

Walsh I 7%Walsh II 8%Walsh III 8%Boogaerts 11%

ESTIMATING TIME FOR INTERVENTIONESTIMATING TIME FOR INTERVENTION

AspergillusAspergillus

day 1 5 7 12 // 28 > 42day 1 5 7 12 // 28 > 42

infiltrateinfiltrateinfiltrateinfiltrateantigenantigenantigenantigen

Persisting fever +

• very high risk or• a suggestive symptom or• a suspected sign or• any positive test

HOW TO PROCEED?HOW TO PROCEED?

Treatment

Treatment

checklistchecklist

azolesazoles

polyenespolyenes

lipid formulations

lipid formulations

candinscandins

combinations

combinations

diagnostics

diagnostics

a plana plan

I FD


When?

What?

Treatment

Treatment

checklistchecklist

azolesazoles

polyenespolyenes

lipid formulations

lipid formulations

candinscandins

combinations

combinations

I FD


What?

WHAT IS THE BEST ANTIFUNGAL DRUG?WHAT IS THE BEST ANTIFUNGAL DRUG?

For prophylaxis?

For empirical purposes?

For treatment of established disease?

PROPHYLAXIS EMPIRICAL (PRE-EMPTIVE) THERAPY

PROPHYLAXIS EMPIRICAL (PRE-EMPTIVE) THERAPY

invasivefungal

infectionNOT

PRESENT

invasivefungal

infectionNOT

PRESENT

invasivefungal

infectionNOT

EXCLUDED

invasivefungal

infectionNOT

EXCLUDED

invasivefungal

infectionINCIPIENT

invasivefungal

infectionINCIPIENT

INTERRELATIONSINTERRELATIONS

BUG

BUG

efficacy DRUG

DRUG

PROBABLE & PROVEN FUNGAL DISEASE

RESPONSE TO TREATMENT FOR ASPERGILLOSIS IN NORMAL PRACTICE

Patterson et al. Medicine 2000;79:250-260

RESPONSE TO TREATMENT FOR ASPERGILLOSIS IN NORMAL PRACTICE

Patterson et al. Medicine 2000;79:250-260

200190180170160150140130120110100

908070605040302010

ampho B

32%

PATIENTS

n

RECOMMENDATIONS IDSA 2000Stevens et al. Clin Infect Dis 2000; 30:696-709RECOMMENDATIONS IDSA 2000Stevens et al. Clin Infect Dis 2000; 30:696-709

A

B

C

I II III

Lipid ampho B in compromised kidneys

Ampho B and itraconazole for primary treatment

Lipid ampho B for primary treatment

Ampho B followed by itraconazole

Biological response modifiers // surgery

Early start of antifungal treatment

REFERENCE POPULATIONREFERENCE POPULATION

Invasive aspergillosis Diagnosed while alive ineligible ineligible

REPRESENTATIVE !REPRESENTATIVE !??

4% in trials !!

VORICONAZOLE VERSUS AMPHOTERICIN B FORINVASIVE ASPERGILLOSIS: SUCCESS AT WEEK 12

Herbrecht et al N Engl J Med 2002; 347:408-415

VORICONAZOLE VERSUS AMPHOTERICIN B FORINVASIVE ASPERGILLOSIS: SUCCESS AT WEEK 12

Herbrecht et al N Engl J Med 2002; 347:408-415

EORTC EORTC IFICGIFICG

0

10

20

30

40

50

60

Voriconazole Amphotericin B

76/14476/144(53%)(53%)

42/13342/133(32%)(32%)

%

AMBISOME versus AMPHOTERICIN Bin PROVEN AND PROBABLE ASPERGILLOSIS

Leenders et al. Brit J Haematol. 1998

AMBISOME versus AMPHOTERICIN Bin PROVEN AND PROBABLE ASPERGILLOSIS

Leenders et al. Brit J Haematol. 1998

CompleteComplete responseresponse

PartialPartial

FailureFailure

MortalityMortality

44%44%

22%22%

34%34%

22%22%

18%18%

38%38%

44%44%

38%38%

66%66%66%66% 56%56%56%56%

AmBisomeAmBisome5 mg/kg/day5 mg/kg/day

n = 32n = 32

AmBisomeAmBisome5 mg/kg/day5 mg/kg/day

n = 32n = 32

amphotericin Bamphotericin B1 mg/kg/day1 mg/kg/dayn = 34 n = 34

amphotericin Bamphotericin B1 mg/kg/day1 mg/kg/dayn = 34 n = 34

HIGH VERSUS STANDARD DOSE AMBISOME FOR INVASIVE MOULD INFECTIONS Cornely et al. Blood 2005; 106:900a, Abstract 3222

HIGH VERSUS STANDARD DOSE AMBISOME FOR INVASIVE MOULD INFECTIONS Cornely et al. Blood 2005; 106:900a, Abstract 3222

16%30%30%

14%31%31%

9494 107107

46% 50%

59%59% 72%72%

End of treatmentFavorable response

Survivors 12 weeks

End of treatmentFavorable response

Survivors 12 weeks

AmBisomeAmBisome10 mg/kg x 1410 mg/kg x 14

followed byfollowed by3 mg/kg/day3 mg/kg/day

AmBisomeAmBisome10 mg/kg x 1410 mg/kg x 14

followed byfollowed by3 mg/kg/day3 mg/kg/day

AmBisomeAmBisome3 mg3 mg//kgkg//dayday

AmBisomeAmBisome3 mg3 mg//kgkg//dayday

201proven & probable

Invasive mould infections

nephrotoxicity

hypokalaemia

FIRST-LINE THERAPY WITH CASPOFUNGIN FOR PULMONARY ASPERGILLOSIS Candoni et al. Eur J Haematol 2005; 75:227-233

FIRST-LINE THERAPY WITH CASPOFUNGIN FOR PULMONARY ASPERGILLOSIS Candoni et al. Eur J Haematol 2005; 75:227-233

7 proven / 25 probable cases

31 neutropenic at start

n=32

overall

18 (

56%

) f

avora

ble

resp

on

ses

G-CSF +caspofungin

70 50 mg/d

G-CSF +caspofungin

70 50 mg/d

hem

ato

log

ical

malig

nan

cie

s

ASSESSMENT OF EFFICACYASSESSMENT OF EFFICACY

BUG

BUG

efficacy DRUG

DRUG

PROBABLE & PROVEN FUNGAL DISEASE

patients failing antifungal therapy

untreatedpatients

treatment refractory

intolerance

toxicity

PANDORRA’S BOX OF SALVAGE CASESPANDORRA’S BOX OF SALVAGE CASES

a single shiver hyperpyrexiahyperpyrexia

creatinine increase

renalfailure

3 days stable

life-threateningprogression

!subjective criteria!

treatment refractory

intolerance

toxicity

PANDORRA’S BOX OF SALVAGE CASESPANDORRA’S BOX OF SALVAGE CASES

treatedwith what?

how much??

treatedwith what?

how much??

evolvementunderlyingdisease??

evolvementunderlyingdisease??

co-medication?

co-medication?

SALVAGE FOR INVASIVE ASPERGILLOSIS SALVAGE FOR INVASIVE ASPERGILLOSIS

caspofungin n=146

Refractory / intolerant amphotericin B

posaconazole

n=107

ampho B lipid

complex

resp

on

se

40%

40% 40% 40%

voriconazol

e n=144

C.L.E.A.R. PROGRAM ON ABLCBETTER THAN NOTHING?

Clin Infect Dis 2005; 40:Supplement 6

C.L.E.A.R. PROGRAM ON ABLCBETTER THAN NOTHING?

Clin Infect Dis 2005; 40:Supplement 6

•Retrospective

•Collection of data on a voluntary basis

•Mix of superficial and disseminated infections

•No discrimination “proven-probable-possible”

•Own definitions for response / success

•Variations in dosing regimens

APPRECIATIONAPPRECIATION

Response rate improved from 30 to 60%!

Failure rate still 50%……

survival 3 months after diagnosis

VORICONAZOLE WITH CASPOFUNGIN AS RESCUE FOR INVASIVE ASPERGILLOSIS

Marr et al. Clin Infect Dis 2004; 39:797-802

VORICONAZOLE WITH CASPOFUNGIN AS RESCUE FOR INVASIVE ASPERGILLOSIS


Observational study with historical controls in 47 BMT recipients

Proven/probableProven/probable

invasive aspergillosisinvasive aspergillosis

ampho B 1 mg/kgampho B 1 mg/kg

kidney: lipid 5 mg/kgkidney: lipid 5 mg/kg

progression (time?)progression (time?)

intoleranceintolerance

nephrotoxicitynephrotoxicity

progression (time?)progression (time?)

intoleranceintolerance

nephrotoxicitynephrotoxicity

1997-20011997-2001 2001-2001-voriconazole

n=31

voriconazole+

caspofunginn=16

difference in survival

survival 3 months after diagnosis

SURVIVAL AFTER COMBINATION THERAPY FOR ASPERGILLOSISMarr et al. Clin Infect Dis 2005; 40:1074-6

SURVIVAL AFTER COMBINATION THERAPY FOR ASPERGILLOSISMarr et al. Clin Infect Dis 2005; 40:1074-6

Overall Overall SurvivalSurvival

0

10

20

30

40

50

60

70

80

90

1000

30

60

90

120

150

180

210

240

270

300

330

360

days after days after diagnosisdiagnosis

CombinationCombination

VoriconazoleVoriconazole

VORICONAZOLE PLUS CASPOFUNGIN FOR ASPERGILLUS IN SOLID ORGAN TRANSPLANTS

Singh et al. Transplantation 2006; 81:320-325

VORICONAZOLE PLUS CASPOFUNGIN FOR ASPERGILLUS IN SOLID ORGAN TRANSPLANTS

Singh et al. Transplantation 2006; 81:320-325

3434 3838comparecompare

VORICONAZOLE +

CASPOFUNGIN

VORICONAZOLE +

CASPOFUNGIN

LIPID AMPHO B

HISTORICALCONTROLS

LIPID AMPHO B

HISTORICALCONTROLS

2003-20052003-2005 multicentermulticenter

mortality day 90mortality day 9026% 50%

SINGLE AGENT OR COMBINATION TO TREAT INVASIVE ASPERGILLOSIS?

Kubin et al. ICAAC, San Francisco 2006; Abstract M-899

SINGLE AGENT OR COMBINATION TO TREAT INVASIVE ASPERGILLOSIS?

Kubin et al. ICAAC, San Francisco 2006; Abstract M-899

RESPONSE RESPONSE 24%24% 21% 21%

monotherapyn = 124

47 AmBisome-33 voriconazole

monotherapyn = 124

47 AmBisome-33 voriconazole

Retrospective 146 proven/probable primary cases

caspofungin +

voriconazolen = 22

caspofungin +

voriconazolen = 22

12 wk mortality 12 wk mortality 55%55% 46% 46%

HISTORICAL CONTROLSHISTORICAL CONTROLS

Unreliable due to:

•improved diagnostic tools

•over-representation of autopsy cases•changes in therapy underlying disease•changes in doctors!



Why is there an increase?When will it occur?Where will it strike?

When should we treat?What is the best therapy?Which factors dictate outcome?

ELEMENTS TO

SUCCESS

ELEMENTS TO

SUCCESS

repair repair organorgan

damagedamage

recovery recovery hosthost

defensedefense

suppression suppression of fungalof fungal growthgrowth

CORTICOSTEROIDS AND SURVIVAL OF ASPERGILLOSIS IN HSCT

Cordonnier et al. Clin Infect Dis 2006;42:955-963

CORTICOSTEROIDS AND SURVIVAL OF ASPERGILLOSIS IN HSCT

Cordonnier et al. Clin Infect Dis 2006;42:955-963

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18weeks

low dose corticosteroidslow dose corticosteroids

high dosehigh dose

S

U

R

V

I

V

A

L

S

U

R

V

I

V

A

L

51 patients with aspergillosis 41 allo HSCT 10 auto

MOULD INFECTIONS AND AMBISOME: NEUTROPENIA AND SURVIVAL

Cornely et al. 2nd Adv Aspergillosis, Athens 2006; Abstr P122

MOULD INFECTIONS AND AMBISOME: NEUTROPENIA AND SURVIVAL

Cornely et al. 2nd Adv Aspergillosis, Athens 2006; Abstr P122

AmBisome10 mg/kg x 14

followed by3 mg/kg/day

AmBisome10 mg/kg x 14

followed by3 mg/kg/day

AmBisome3 mg/kg / day

AmBisome3 mg/kg / day

201proven & probable

invasive mould infections

0 20 40 60 80

end oftherapy

at day 14

neutropenicnon-neutropenic

% survival

EVOLUTION OF ELEMENTS DETERMINING SUCCESS OR FAILURE

EVOLUTION OF ELEMENTS DETERMINING SUCCESS OR FAILURE

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10

% success

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 100

20

40

60

80

100

1 2 3 4 5 6 7 8 9 100

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 time

antifungalantifungal

conditioncondition

hosthostdefensdefens

ee

A

B

C

I II III

RECOMMENDATIONS FOR ASPERGILLOSIS 2007

RECOMMENDATIONS FOR ASPERGILLOSIS 2007

•Lipid ampho B’s in compromised kidneys

•Caspofungin rescue

•Other ampho B’s, itrafor primary treatment•Pre-emptive works•Early intervention is important

•Ampho B followed by itraconazole

•Surgery in selected cases

•Voriconazole for first line•Liposomal minimal dose 3mg/kg /day

•Posaconazole (oral) for rescue

•Liposomal ampho B for first line•Posaconazole as prophylaxis

•Biological response modifiers•Combination therapy

STRANGE DUCKS IN THE STRANGE DUCKS IN THE IMMUNOSUPPRESSED PONDIMMUNOSUPPRESSED POND

STRANGE DUCKS IN THE STRANGE DUCKS IN THE IMMUNOSUPPRESSED PONDIMMUNOSUPPRESSED POND

Fusarium

Mucor/Rhizopus

Alternaria

Pseudallescheria boydii

Scedosporium

INVASIVE FUNGAL INFECTIONS IN RELATION TO IMMUNE DEFENSE

INVASIVE FUNGAL INFECTIONS IN RELATION TO IMMUNE DEFENSE

compromised compromised defensedefense

severelyseverely compromisedcompromised

external fungal external fungal populationpopulation

our body

EVOLUTION OF NON-ASPERGILLUS MOULDS IN BMT RECIPIENTS 1985-1999


EVOLUTION OF NON-ASPERGILLUS MOULDS IN BMT RECIPIENTS 1985-1999


0

2

4

6

8

10

12

14

16

1985-89 1990-94 1994-99

ZygomycetesZygomycetes

Fusarium spFusarium sp

ScedosporiumScedosporium

total number

POSACONAZOLE RESCUE FOR ZYGOMYCOSIS Kontoyiannis et al. ICAAC, Washington 2005; Abstract M-974

POSACONAZOLE RESCUE FOR ZYGOMYCOSIS Kontoyiannis et al. ICAAC, Washington 2005; Abstract M-974

91 patients

81refractory

10intolerant

Rhizopus

Mucor

Cunninghamella

Rhizomucor

Absidia

N=25

17

8

7

2

52%

76%

75%

28%

100%

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10

ORAL MEDICATION

MUCORMYCOSIS IN HAEMATOLOGIC PATIENTS: TREATMENT RESULTSPagano et al. Haematologica 2004; 89:207-214

MUCORMYCOSIS IN HAEMATOLOGIC PATIENTS: TREATMENT RESULTSPagano et al. Haematologica 2004; 89:207-214

59 cases 49 empirical antifungals

39 amphotericin B4 liposomal amphotericin B

30 failures 9 successes – 23%23%

7 successes – 44% 4 surgery

12 liposomal amphotericin B

8 switches

INTERRELATIONSINTERRELATIONS

BUG

efficacy DRUG

BUG

DOCTOR

damage / defense PATIENT

BUG

DOCTOR

PATIENT concern

DRUG

DOCTOR

confidence

PATIENT

DRUG

PATIENT

DRUG

DRUG

PATIENT

tolerance / toxicity

BASIS FOR LOCAL ALGORITMSBASIS FOR LOCAL ALGORITMS

STRATEGY SELECTION

DEPENDS ON:

-physician confidence/experience

-diagnostic tools available

-patient population

amphotericin B

WHAT’S NEW?WHAT’S NEW?

voriconazole caspofungin

micafungin

anidulafungin

posaconazole

liposomalamphotericin B

EVIDENCE LEADS PRACTICEEVIDENCE LEADS PRACTICE

PRACTICE

EVIDENCE

THIS AND FUTURE GENERATIONSTHIS AND FUTURE GENERATIONS

ankara, february 2007. clinical management of invasive fungal infections: an evidence-based approach

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