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ANKARA,
FEBRUARY 2007
Clinical Management of Invasive
Fungal Infections:
An Evidence-Based Approach
According to Odds
INCREASE IN FUNGAL INFECTIONS
• less mortality from other causes
-underlying disease
-better antibacterial therapy
• higher age
• better diagnostic tools
• more complex interventions
Rate per 100,000 population
MORTALITY DUE TO INVASIVE MYCOSES
McNeil et al. Clin Infect Dis 2001;33:641-7
United States, 1980-1997
0,6
0,4
0,2
0
Mycoses other than Candida albicans
DEVELOPMENT OF FUNGAL INFECTIONS
OVER TIME
3,5
Incidence (%)
3
2,5
Aspergillus
2
Candida
1,5
1 other yeasts
0,5
0
other moulds
1999
2000
2001
2002
2003
number of cases
LETHALITY OF THE VARIOUS INVASIVE
FUNGAL INFECTIONS
400
300
200
100
0
42%
33%
61% 53%
cases
50% 29%
casualties
BASIC RISK FACTORS FOR FUNGAL INFECTIONS
OPPORTUNISTS!
immunosuppression
epidemiologic
exposure
technical /
anatomic
factors
Adapted from RH Rubin, Boston
COURSE OF DEFENSE SYSTEMS UNDER
MODERN THERAPEUTIC REGIMENS
T-cell function
Humoral immunity
Commensal flora
Granulocytes
Mucosa
time
antibiotics
PACE OF DEVELOPMENT OF
NEW ANTIFUNGAL AGENTS
Adapted from
Rex & Edwards, 1997
Amphotericin B
AmBisome
Amphocil
Abelcet
itraconazole
fluconazole
terbinafine
ketoconazole
miconazole
5-flucytosine
Nystatin
Griseofulvin
1950
1960
1970
1980
1990
2000
WHAT’S NEW?
posaconazole
micafungin
anidulafungin
voriconazole
amphotericin B
caspofungin
flucytosine
fluconazole
itraconazole
RECOMMENDATIONS
RANDOMISED
I TRIAL
CONSISTENT
II SERIES
EXPERT / CONSENSUS
III
A
SOLID CLINICAL EVIDENCE
B
REASONABLE CLINICAL EVIDENCE
C
TRIVIAL CLINICAL EVIDENCE
RECOMMENDATIONS
I
II
III
A
B
early start of
antifungal
treatment
lipid ampho B for
primary treatment
C
ampho B followed by
itraconazole
biological response
modifiers // surgery
487 FUNGAL INFECTIONS IN
TRANSPLANT RECIPIENTS
Pappas et al. ICAAC, Chicago 2003; abstr M-1010
Endemic
Crypto
Pneumocystis
Aspergillus and
other moulds
Candida
FUNGAL INFECTIONS IN TRANSPLANT
RECIPIENTS
Pappas et al. ICAAC, Chicago 2003; abstr M-1010
Candida
species
POPULATION WITH INVASIVE CANDIDIASIS
Invasive candidasis
Diagnosed
eligible
for while
clinical
alive
trial
COMPARISON OF RESULTS FROM
CLINICAL TRIALS ON CANDIDAEMIA
response
mortality
Fluconazole 400 mg/day 72%
39%
Amphotericin B
79%
62%
40%
40%
Caspofungin
Micafungin
Anidulafungin
Voriconazole
74%
74%
76%
65%
30%
23%
36%
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 100
Favorable 80
Response
60
40
premature
73%
70%
premature
76%
67%
20
0
micafungin
2mg/kg/d
(n=48)
AmBisome
3 mg/day
(n=50)
COMPARISON OF RESULTS FROM
CLINICAL TRIALS ON CANDIDAEMIA
response
mortality
Fluconazole 400 mg/day 72%
39%
Amphotericin B
79%
62%
40%
40%
Caspofungin
Micafungin
Anidulafungin
Voriconazole
74%
74%
76%
65%
30%
23%
36%
COMPARISON OF RESULTS FROM
CLINICAL TRIALS ON CANDIDAEMIA
response
mortality
Fluconazole 400 mg/day 72%
39%
Amphotericin B
79%
62%
40%
40%
Caspofungin
Micafungin
Anidulafungin
Voriconazole
74%
74%
76%
65%
30%
23%
36%
COMPARISON OF RESULTS FROM
CLINICAL TRIALS ON CANDIDAEMIA
response
mortality
Fluconazole 400 mg/day 72%
39%
Amphotericin B
40%
40%
34%
30%
Ambisome
Caspofungin
Micafungin
Anidulafungin
Voriconazole
79%
62%
71%
74%
74%
76%
65%
23%
36%
RELATION INITIATION FLUCONAZOLE
THERAPY AND OUTCOME OF CANDIDAEMIA
Garey et al. Clin Infect Dis 2006; 43:25-31
230 cases of candidaemia
day 0
day 2
day 3
day 4 start fluconazole
RELATION INITIATION FLUCONAZOLE
THERAPY AND OUTCOME OF CANDIDAEMIA
Garey et al. Clin Infect Dis 2006; 43:25-31
230 cases of candidaemia
45%
40%
35%
30%
25%
mortality
20%
15%
10%
5%
0%
day 0
day 2
day 3
day 4 start fluconazole
RECOMMENDATIONS FOR TREATMENT OF
ACUTE CANDIDIASIS -- 2007
I
II
III
A
First line
•Fluconazole
•Ampho B
•Candins
•Voriconazole
B
C
Flu-resistance
• Combination
therapy
Early start therapy
Flu-resistant strains
•AmphoB formulations
•Candins
•Voriconazole
Continue therapy for
2 weeks after
disappearance of
signs and symptoms
Lower doses suffice in
less critically ill
patients
Combination of
antifungals
•Biological response
modifiers
FROM TREATMENT OF
CHOICE TO CHOICES
OF TREATMENT
FROM TREATMENT OF
CHOICE TO CHOICES
OF TREATMENT
STRATEGY FOR THE TREATMENT OF
DISSEMINATED CANDIDIASIS
Spellberg
Filler
Edwards
Spellberg et al. Clin Infect Dis 2006; 42:244-251
flucon
azole
invasive candidiasis
proven / probable
NO
(risk of)
C.glabrata
C.krusei ?
YES
NO
hemodynamically
unstable?
lipid ampho-B
voriconazole
echinocandin
YES
FUNGAL INFECTIONS IN TRANSPLANT
RECIPIENTS
Pappas et al. ICAAC, Chicago 2003; abstr M-1010
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?
STRATEGY vs DRUG SELECTION
When?
What?
STRATEGY vs DRUG-EFFICACY
When?
What?
STRATEGY vs DRUG-EFFICACY
When?
RELATION OUTCOME AND STATE OF
FUNGAL INFECTION
time
odds to control the infection
evolution of the infection
IMPORTANCE OF EARLY TREATMENT OF
INVASIVE ASPERGILLOSIS
Patterson et al. Medicine 2000
Type of infection
Survival
Pulmonary only
40% (n=330)
Disseminated
18% (n=144)
RECOMMENDATIONS IDSA 2000
Stevens et al. Clin Infect Dis 2000; 30:696-709
I
II
III
A
B
C
Early start of
antifungal treatment
PROBABILITY OF DEVELOPING
PULMONARY ASPERGILLUS
Gerson et al. Ann Intern Med 1984
PERCENTAGE
INFECTED
100
80
Empirical therapy
incidence aspergillosis 4-6%
60
40
20
0
0 10 20 30 40 50 60 70 80 90 100
DAYS WITH NEUTROPENIA
DIAGNOSTIC TOOLS ANNO 2007
Sandwich-ELISA
galactomannan
High-resolution CT-scan
Ultrasound
Bronchoalveolar lavages
Biopsy techniques
Glucan-test
PCR
PET-scanning
TRADITIONAL EMPIRICAL MANAGEMENT
OF INVASIVE ASPERGILLOSIS
Maertens et al. Clin Infect Dis 2005;41:1242-1250
19
no fever
35%
136
episodes
117
febrile episodes
82
defervesence
30
11
persistent fever unexplained relapses
41 candidates
empirical antifungals
GALACTOMANAN AND CT-SCAN-GUIDED EARLY
TREATMENT OF INVASIVE ASPERGILLOSIS
Maertens et al. Clin Infect Dis 2005;41:1242-1250
136 treatment episodes haematological malignancies
117 febrile episodes
negative
daily galactomannan
5 days
refractory fever
2x >0.5
CT
BAL
antifungal
typical
CT
no
antifungal
PRE-EMPTIVE MANAGEMENT OF
INVASIVE ASPERGILLOSIS
Maertens et al. Clin Infect Dis 2005;41:1242-1250
136
episodes
16%
117
febrile episodes
19
no fever
+
82
defervesence
9 cases
suspicious CT
10
seropositive
19 cases for
pre-emptive antifungals
PRE-EMPTIVE MANAGEMENT OF
INVASIVE ASPERGILLOSIS: MORTALITY
Maertens et al. Clin Infect Dis 2005;41:1242-1250
88
patients
Fungal mortality
fungal
mortality
8%
Walsh I
7%
Walsh II
8%
Walsh III 8%
Boogaerts 11%
ESTIMATING TIME FOR INTERVENTION
Aspergillus
Persisting fever +
• very high risk
or
• a suggestive symptom
or
• a suspected sign
or
• any positive test
day 1
5
infiltrate
antigen
7
12 //
28
> 42
HOW TO PROCEED?
STRATEGY vs DRUG-EFFICACY
When?
What?
STRATEGY vs DRUG-EFFICACY
What?
WHAT IS THE BEST ANTIFUNGAL DRUG?
For prophylaxis?
For empirical purposes?
For treatment of established disease?
PROPHYLAXIS
EMPIRICAL
invasive
fungal
infection
NOT
PRESENT
invasive
fungal
infection
NOT
EXCLUDED
(PRE-EMPTIVE)
THERAPY
invasive
fungal
infection
INCIPIENT
INTERRELATIONS
PROBABLE & PROVEN FUNGAL DISEASE
BUG
efficacy
DRUG
RESPONSE TO TREATMENT FOR
ASPERGILLOSIS IN NORMAL PRACTICE
Patterson et al. Medicine 2000;79:250-260
n
P
A
T
I
E
N
T
S
200
190
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
ampho B
32%
RECOMMENDATIONS IDSA 2000
Stevens et al. Clin Infect Dis 2000; 30:696-709
I
A
B
II
III
Lipid ampho B in
compromised kidneys
Ampho B and
itraconazole for
primary treatment
Early start of
antifungal treatment
Lipid ampho B for
primary treatment
C
Ampho B followed by
itraconazole
Biological response
modifiers // surgery
REFERENCE POPULATION
Invasive aspergillosis
4% in trials !!
Diagnosed
ineligiblewhile alive
REPRESENTATIVE !?
EORTC
IFICG
VORICONAZOLE VERSUS AMPHOTERICIN B FOR
INVASIVE ASPERGILLOSIS: SUCCESS AT WEEK 12
Herbrecht et al N Engl J Med 2002; 347:408-415
%
60
Amphotericin B
50 Voriconazole
40
30
20
10
0
76/144
(53%)
42/133
(32%)
AMBISOME versus AMPHOTERICIN B
in PROVEN AND PROBABLE ASPERGILLOSIS
Leenders et al. Brit J Haematol. 1998
Complete
response
AmBisome
5 mg/kg/day
n = 32
amphotericin B
1 mg/kg/day
n = 34
44%
18%
66%
38%
Partial
22%
Failure
34%
44%
Mortality
22%
38%
56%
HIGH VERSUS STANDARD DOSE AMBISOME
FOR INVASIVE MOULD INFECTIONS
Cornely et al. Blood 2005; 106:900a, Abstract 3222
AmBisome
10 mg/kg x 14
followed by
3 mg/kg/day
94
AmBisome
201
3 mg/kg/day
proven & probable
Invasive mould infections
107
46%
End of treatment
Favorable response
50%
31%
nephrotoxicity
14%
30%
hypokalaemia
16%
59%
Survivors 12 weeks
72%
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
overall
G-CSF +
caspofungin
70  50 mg/d
18 (56%)
favorable
responses
n=32
ASSESSMENT OF EFFICACY
PROBABLE & PROVEN FUNGAL DISEASE
BUG
efficacy
DRUG
untreated
patients
patients failing
antifungal therapy
PANDORRA’S BOX OF SALVAGE CASES
creatinine
increase
3 days
stable
renal
failure
treatment
refractory
toxicity
a single
shiver
life-threatening
progression
hyperpyrexia
intolerance
!subjective criteria!
PANDORRA’S BOX OF SALVAGE CASES
comedication?
toxicity
treated
with what?
how much??
intolerance
evolvement
underlying
disease??
treatment
refractory
SALVAGE FOR INVASIVE ASPERGILLOSIS
Refractory / intolerant amphotericin B
response
40%
caspofungin
n=146
posaconazole
n=107
40%
voriconazole
n=144
ampho B
lipid complex
40%
40%
C.L.E.A.R. PROGRAM ON ABLC
BETTER 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
APPRECIATION
Response rate improved
from 30 to 60%!
Failure rate still
50%……
VORICONAZOLE WITH CASPOFUNGIN AS
RESCUE FOR INVASIVE ASPERGILLOSIS
Marr et al. Clin Infect Dis 2004; 39:797-802
Observational study with historical controls in 47 BMT recipients
Proven/probable
invasive aspergillosis
ampho B 1 mg/kg
kidney: lipid 5 mg/kg
progression (time?)
voriconazole
1997-2001 intolerance
n=31
nephrotoxicity
voriconazole
+
2001caspofungin
n=16
survival 3 months after diagnosis
difference
in survival
SURVIVAL AFTER COMBINATION
THERAPY FOR ASPERGILLOSIS
Marr et al. Clin Infect Dis 2005; 40:1074-6
100
90
80
70
60
Combination
50
40
30
20
360
330
300
270
240
210
180
150
120
90
60
Voriconazole
30
10
0
0
Overall
Survival
days after diagnosis
VORICONAZOLE PLUS CASPOFUNGIN FOR
ASPERGILLUS IN SOLID ORGAN TRANSPLANTS
Singh et al. Transplantation 2006; 81:320-325
VORICONAZOLE
+
CASPOFUNGIN
34
26%
2003-2005
multicenter
compare
mortality day 90
LIPID AMPHO B
HISTORICAL
CONTROLS
38
50%
SINGLE AGENT OR COMBINATION TO TREAT
INVASIVE ASPERGILLOSIS?
Kubin et al. ICAAC, San Francisco 2006; Abstract M-899
Retrospective 146 proven/probable primary cases
monotherapy
n = 124
47 AmBisome-33 voriconazole
caspofungin
+ voriconazole
n = 22
RESPONSE
24%
21%
12 wk mortality
55%
46%
HISTORICAL CONTROLS
Unreliable due to:
•improved diagnostic tools
•over-representation of autopsy cases
•changes in therapy underlying disease
•changes in doctors!
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?
Which factors dictate outcome?
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?
Which factors dictate outcome?
ELEMENTS
TO
SUCCESS
repair
organ
damage
recovery
host
defense
suppression
of fungal
growth
CORTICOSTEROIDS AND SURVIVAL OF
ASPERGILLOSIS IN HSCT
Cordonnier et al. Clin Infect Dis 2006;42:955-963
51 patients with
aspergillosis
100
90
80
70
60
50
40
30
20
10
0
low dose corticosteroids
S
U
R
V
I
V
A
L
0
high dose
2
4
6
8
10
12
14
16
18
weeks
41 allo HSCT
10 auto
MOULD INFECTIONS AND AMBISOME:
NEUTROPENIA AND SURVIVAL
Cornely et al. 2nd Adv Aspergillosis, Athens 2006; Abstr P122
201
proven & probable
invasive mould infections
AmBisome
10 mg/kg x 14
followed by
3 mg/kg/day
AmBisome
3 mg/kg / day
at day 14
non-neutropenic
neutropenic
end of
therapy
0
20
40
60
80
% survival
EVOLUTION OF ELEMENTS
DETERMINING SUCCESS OR FAILURE
% success
100
80
antifungal
60
condition
40
host
defense
20
0
1 time
2
3
4
5
6
7
8
9
10
I
A
B
C
RECOMMENDATIONS FOR
ASPERGILLOSIS 2007
II
III
•Voriconazole
for first line
•Liposomal
minimal dose
3mg/kg /day
•Lipid ampho B’s in
compromised kidneys
•Liposomal
ampho B
for first line
•Posaconazole
as prophylaxis
•Other ampho B’s, itra
for primary treatment
•Pre-emptive works
•Early intervention is
important
•Ampho B followed by
itraconazole
•Posaconazole (oral)
for rescue
•Biological response
modifiers
•Combination therapy
•Caspofungin rescue
•Surgery in selected
cases
STRANGE DUCKS IN THE
IMMUNOSUPPRESSED POND
Fusarium
Pseudallescheria
boydii
Mucor/
Rhizopus
Scedosporium
Alternaria
INVASIVE FUNGAL INFECTIONS IN
RELATION TO IMMUNE DEFENSE
external fungal population
compromised defense
our body severely
compromised
EVOLUTION OF NON-ASPERGILLUS
MOULDS IN BMT RECIPIENTS 1985-1999
Marr et al. Clin Infect Dis 2002; 34:909-917
16
14
12
10
total number
Zygomycetes
8
6
4
2
0
Fusarium sp
Scedosporium
1985-89
1990-94
1994-99
POSACONAZOLE RESCUE FOR ZYGOMYCOSIS
Kontoyiannis et al. ICAAC, Washington 2005; Abstract M-974
91 patients
ORAL MEDICATION
10
intolerant
81
refractory
Rhizopus
N=25
52%
Mucor
17
76%
Cunninghamella
8
75%
Rhizomucor
7
28%
Absidia
2 100%
100
80
60
40
20
0
1
2
3
4
5
6
7
8
9
10
MUCORMYCOSIS IN HAEMATOLOGIC
PATIENTS: TREATMENT RESULTS
Pagano et al. Haematologica 2004; 89:207-214
59 cases
49 empirical antifungals
4 liposomal amphotericin B
8 switches
12 liposomal amphotericin B
7 successes – 44%
4 surgery
39 amphotericin B
30 failures
9 successes – 23%
INTERRELATIONS
BUG
PATIENT
efficacy
DRUG
concern
confidence
DOCTOR
BASIS FOR LOCAL ALGORITMS
STRATEGY SELECTION
DEPENDS ON:
-physician confidence/experience
-diagnostic tools available
-patient population
WHAT’S NEW?
posaconazole
micafungin
anidulafungin
voriconazole
liposomal
amphotericin B
amphotericin B
caspofungin
EVIDENCE LEADS PRACTICE
THIS AND FUTURE GENERATIONS