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Gestione pratica delle infezioni
fungine in terapia intensiva
Matteo Bassetti
Clinica Malattie infettive
A.O.U. San Martino
Genova
Hospital mortality (%)
Relationship between hospital mortality
and the timing of antifungal treatment
35
30
25
20
15
10
5
0
< 12
12–24
24–48
> 48
Delay in start of antifungal treatment (hours)
Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5
Mortality associated with Candida
infections in ICU
Variable
Mortality rate (%)*
Department
Medical
Surgical
58
37
Candida species
C. albicans
C. parapsilosis
C. glabrata
36
33
69
Overall
41
*Crude mortality.
Tortorano AM, et al. 3rd TIMM. Turin, Italy,28–31 Oct 2007; Oral
communication O.07
Fluco in High-risk SICU patients
Proportion infected
260 surgical ICU patients (stay > 3days) randomized
to double-blind oral antifungal prophylaxis
0.6
Placebo
0.5
0.4
0.3
Fluconazole
0.2
0.1
p < 0.01 by log-rank test
0
7
14
21
28
Days
Pelz Ann Surg 233:542-548, 2001
Prophylaxis in the (S)ICU


Pelz et al., Ann Surg 233:542-548, 2001
- Fluco vs. placebo in extremely high risk ICU
- Placebo: 16% rate of invasive candidiasis
 This rates equals that in BMT
- Fluco 400/d: 8% rate
- P < 0.01
A very unusual population
- Median APACHE III = 60, lots of liver transplant
- Applicability in most ICUs is unclear
Sandven et al.: Low-risk surgical patients
Double-blind single-dose antifungal prophylaxis in
109 patients with intra-abdominal perforation
60
%
NS
50
43%
40
30
34%
NS
NS
20
10
0
14%
10% 10%
Emergence of
colonization
7,5%
Complications
Death
Sandven CCM
2002
RESULTS OF CANDIDA PROPHYLAXIS IN ICU
PATIENTS
Garbino et al. Intensive Care Med 2002;28:1708-1717
P<0.01
100 %
P<0.001
80
Fluconazole 100 mg/d
Placebo
78%
66
53
60
NS
39 41%
40
20
0
30%
NS
7%
3%
P=0.014
0
6%
Success Emergence Death
Invasive Candidemia
of
colonization from
candidosis
prophylaxis by Candida any cause
Antifungals in critically ill and
surgical patients: meta-analysis
Impact on Candidal infections



Impact on mortality
NNT= 94
NNT in high-risk= 9
NNT in low risk= 188
Playford et al. JAC 2006; 57: 628–638
PROPHYLACTIC FLUCONAZOLE…..
• HAS ELIMINATED CANDIDA COLONISATION!
More patient comfort
……..BUT
• HAS ELIMINATED CANDIDA COLONISATION!
More patient comfort
• DID NOT REDUCE MORTALITY
• HAS SELECTED RESISTANT CANDIDA SPECIES
◊ incidence of candidemia episodes/10 000 patient-days/year;
■ DDD’s of fluconazole x 100 pts/days
Figure 1.
Shift from CA to CNA
3,50
2000
1800
Incidence of candidemia
1600
2,50
1400
1200
2,00
1000
1,50
800
600
1,00
400
Fluconazole DDD's x 100 pts/days
3,00
0,50
200
0
0,00
Y 1999
Y 2000
Y 2001
Y 2002
Y 2003
Years observed
Bassetti M et al. BMC Infect Dis 2006; 10: 621
Restriction of prophylactic fluconazole use
Bassetti et al – JAC 2009; 64:625-629
Med-surg ICU (500 adm./an)
108 months (Jan 99-Dec 2007)
Overall prevention of NI unchanged
213 candidemia (1.42/10 000 patient-days)
albicans (46%), parapsillosis (22%), glabrata 13%
Intervention:
Janv 1999-Janv 2003: Extensive Prophylaxis
Janv 2003-Dec 2007:Incitation not to do
Statistical analysis:
Segmented linear regression
Incidence of Candidemia and
fluconazole in ICU
Stop fluco
Stop fluco
X
Non-albicans candidaemia
C. albicans candidaemia
Bassetti M et al. J Antimicrob Chemother 2009: 64:625-9.
So what about preemptive therapy with
predicitive rules?
Candida Score
Leon C et al. Crit Care Med 2006; 34:730- 737
Candida score validation
León C et al Crit Care Med. 2009;37:1624-33
Other Predictive rules
The best performing predictive rule was:
Patients in the ICU >4 days
AND
Any systemic antibiotic (days 1–3)
OR
Central venous catheter (days 1–3)
AND at least two:
 Total parenteral nutrition (days 1–3)
 Any dialysis (days 1–3)
 Major surgery (days -7–0)
 Pancreatitis (days -7–0)
 Any use of steroids (days -7–3)
 Immunosuppressive agents (days -7–0)
Ostrosky-Zeichner et al. Eur J Clin Microbiol Infect Dis 2007
(13)-β-D-GLUCAN CONCENTRATIONS
600
BG values
Pg/ml
500
_____
400
300
_____
200
100
_____
_____
0
CBSI
PCBSI
NCBSI
CONTROLS
CBSI: proven Candida BSI PCBSI: possible Candida BSI NCBSI: no Candida BSI
CONTROLS: healthy volunteers
Horizontal bars indicate median values
Del Bono V et al. 49th ICAAC, 2009
Criteria to start pre-emptive
antifungal therapy
Pz. In ICU ≥ 4 days.
Abx in the last 7 days
O
CVC from 7 days
•Start antifungal
2 of the following:
•Total parenteral nutrition (days 1–3)
• Any dialysis (days 1–3)
• Major surgery (days -7–0)
• Pancreatitis (days -7–0)
• Any use of steroids (days -7–3)
• Immunosuppressive agents (days -7–0)
Candida colonization or
(1-3)-ß-D-glucan
Different antifungal strategies
Bassetti M et al. Crit Care 2010 December 1
Bassetti M et al. Crit Care 2010 December 1
Empiric use of antifungals in the ICU
setting




Still no good data clinical for empiric antifungal
therapy in the non-neutropenic population
Follow fundamental principles for treating candidemia
Utilize serologic markers, surveillance cultures, and/or
a ‘scoring system’ to determine most appropriate use
Duration of therapy not specifically addressed,
although the implication is to curtail therapy in stable
patients absent positive culture/serologic data
Pappas PG, et al. Clin Infect Dis 2009; 48: 503–35
15 July 2008
Double-blind, placebo-controlled trial with fluconazol 800 mg (x 14d)
in 270 adult IC-patients:





4 days of fever (>38.3°C)
ICU stay > 96h
APACHE II ≥ 16
Broad spectrum antibiotics
Central line ≥ 24h
Fluconazol
n (ITT)
Success
133
44 (36%)
Invasive mycosis
6 (5%)
30-Day mortality
29 (24%)
Placebo
95% CI / P-value
137
48 (38%)
11 (9%)
22 (17%)
0.69–1.32; P = 0.78
RR 0.57; 0.22–1.49
RR 1.36; 0.82–2.24
Schuster et al, Ann Intern Med 2008
Susceptibility profile of
Candida species
Dodds Ashely ES et al. Clin Infect Dis 2008 ; 43: S28–39
Distribution of the Candida spp.
In vitro susceptibility to fluconazole

305 isolates identified, 210 isolates tested

17% fluconazole-R or S-DD (using validated susceptibility testing
methods)
Species
Distribution
Candida albicans
Candida glabrata
Candida parapsilosis
Candida krusei
Candida tropicalis
Candida kefyr
Candida guilliermondii
Candida lusitaniae
Other Candida species
Total
174 (57%)
51 (17%)
23 (7.5%)
16 (5.2%)
15 (4.9%)
11 (3.6%)
5 (1.6%)
2 (0.7%)
8 (2.6%)
305
In vitro susceptibility to fluconazole
n tested
S
S-DD or R
113
96%
4%
38
50%
50%
19
90%
10%
6
17%
83%
14
86%
14%
9
100%
0
5
80%
20%
2
100%
0
4
50%
50%
210
83%
17%
Leroy et al. Crit Care Med 2009; 37:1612–1618
In vitro susceptibility to fluconazole in patients naïve
and previously exposed to azoles in ICU
Leroy et al. Crit Care Med 2009; 37:1612–1618
Initial empiric antifungal treatment
(n=271)
Fluconazole
Caspofungin
Voriconazole
Caspofungin + Fluconazole
Liposomal amphotericin B
Amphotericin B deoxycholate
Itraconazole
Caspofungin + Voriconazole
Amphotericin B lipid complex
Amphotericin B deoxycholate + Fluconazole
Amphotericin B deoxycholate + Flucytosine
Amphotericin B deoxycholate + Voriconazole
Liposomal amphotericin B + Caspofungin
Liposomal amphotericin B + Flucytosine
65,7%
18,1%
5,5%
3,0%
2,2%
1,1%
1,1%
1,1%
0,4%
0,4%
0,4%
0,4%
0,4%
0,4%
Leroy et al. Crit Care Med 2009; 37:1612–1618
Risk factors for fluconazole
resistance
Odds ratio
95 percent
confidence Limits
P - value
Neoplasia
2.9
1.4 – 5.9
≤ 0.005
Prior fluconazole use
3.8
1.7 – 8.2
≤ 0.001
Cisterna R et al. J Clin Microbiol 2010; doi:10.1128/JCM.00920-10
IDSA- Candidemia in nonneutropenic

If species is unknown, either fluconazole (800mg loading dose, 400 mg
daily) or an echinocandin is appropriate initial therapy for most adult patients
(AI)

An echinocandin is favored if
- Moderately severe to severe illness,
- Recent azole use for treatment or prophylaxis (AIII), or
- Isolate is known to be C. glabrata or C. krusei (BIII)

Fluconazole for patients who are
- less critically ill and
- who have no recent azole exposure (AIII).

Move from candin to fluconazole when isolates likely susceptible to
fluconazole (e.g., C. albicans) and patient is clinically stable (AIII)

Remove or exchange intravenous catheters

Treat for two weeks after clearance of bloodstream
Treatment in ICU
Empirical treatment(IA)
Azole exposure
No (A-III)
yes (A-III)
High risk of C. glabrata or
krusei ? Or severe (AIII)
No
fluconazole
yes
echinocandin
Clinical Infectious Diseases 2009; 48:503–35
Secondary adapted to results. Invasive candidiasis IDSA 2009
Clinical Infectious Diseases 2009; 48:503–35
Clinicaly stable
Yes
No
Known fungi
C. Glabrata (B-III)
Sensitive to fluconazole
C krusei (A-I)
C. parapsilosis
Yes (B-III)
fluconazole
No
AmB-L
echinocandin
Major changes from the previous
IDSA Guidelines (2004)
 Emphasis
on fluconazole and
echinocandins as the ‘preferred choices’
for proven/suspected IC
 De-emphasis on AmB and LFAmB under
most circumstances
 Concept of step down therapy is strongly
encouraged
 There is little distinction made between the
echinocandins
Antifungal drug studies candidaemia
P=.39
P=.04
P=.09
73%
69%
P=.82
71% 72%
P=.27
74%
P=.009
76%
60%
56%
Fluconazole
AMB
Flu
AMB + Flu
AMB
Caspofungin
Phillips, 1995
Rex, 2003
Mora-Duarte, 2002
Amfotericine B
Fluconazol
Voriconazole
Fluconazole
Anidulafungin
L-Amfotericine B
Micafungin
Micafungin
Caspofungin
Caspofungin
Amfotericine B
Amfotericine B + Flu
Fluconazol (800)
53%
Amfotericine B
Fluconazol
50%
72% 72%
70%
62%
P=.64
Micafungin
Caspofungin
Anidulafungin Voriconazole
Micafungin Liposomal AMB Fluconazole
AMB->Flu
Pappas, 2007
Kuse, 2007
Reboli, 2007
MITT - Investigator-Assessed Response at End of Treatment (%)
Kullberg, 2005
Chemical Structures
Caspofungin
Micafungin
Anidulafungin
Glarea lozoyensis
Coleophoma empetri
Aspergillus nidulans
HO
H2N
NH
HO
N
HO
O
OH
NH
H3 C
H2N
O
O HN
H
H
NH O
H
H
H
N
O
OH
N
H3C
CH3
HO
O
HO
CH3
O
O
NH
CH3
HO
O
N
H
N

OH
HN
O
NH
CH3
N
H
N
O
O
H3C
OH
OH
OH
OH
O
O
O
HO
HO
O
HO
OH
O
O
H3C
O
O
OH
CH3
N
OH
HN
O
NH
O
N
H
S
O
N
OH
NH
H3C
NH
O
NH
H2N
HO
O
HO
O
OH
O
H
OH
O
HO
HO
H3C
Side chains are key determinants of lipophilicity,
solubility, antifungal activity, and toxicity
Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Debono M, Gordee RS. Annu Rev Microbiol.
1994;48:471–497; Debono M et al. J Med Chem. 1995;38:3271–3281.
Attività in vitro delle echinocandine
nei confronti di Candida spp.
MIC90 (µg/ml)
Organismo
Numero di
isolati
Micafungina
Caspofungina
Anidulafungina
C. albicans
2.869
0.03
0.06
0.06
C. parapsilosis
759
2
1
2
C. glabrata
747
0.015
0.06
0.12
C. tropicalis
625
0.06
0.06
0.06
C. krusei
136
0.12
0.25
0.06
C. guilliermondii
61
1
1
2
C. lusitaniae
58
0.25
0.5
0.5
C. kefyr
37
0.06
0.015
0.12
C. famata
24
1
1
2
Candida spp.
30
0.5
0.25
1
Pfaller MA, et al. J Clin Microbiol 2008; 46:150–6
Pharmacology: Metabolism, Elimination,
Bioavailability, and Protein Binding
Caspofungin
Metabolism
Elimination/excreti
on
Micafungin
Hepatic metabolism Hepatic metabolism
by hydrolysis and by arylsulfatase and
N-acetylation
catechol-Omethyltransferase
Spontaneous
nonhepatic
chemical
degeneration
Anidulafungin
Nonhepatic
chemical
degradation
Urine 41%
Feces 34%
Urine + feces
82.5%
Feces 71%
Urine <1%
Feces ≈30%
Protein Binding
97%
>99%
>99%
Oral
Bioavailability
<5%
<5%
<5%
No
No
No
Dialyzable
Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Dodds Ashley ES et al. Clin Infect Dis.
2006;43:S28–S39.
Echinocandin studies
Mora-Duarte
Kuse
Reboli
Caspo
AMB
Mica
L-AMB
Anidu
Fluco
Apache <20
80,7
80
72
76
80
83
Apache > 20
19,3
20
28
24
21
17
Prior antifungal therapy
56
67
NA
NA
NA
NA
C. albicans
35
54
42,6
44,2
64
59
C. parapsilosis
19,8
18,3
18,3
15,8
10
14
C. glabrata
12,8
9,2
11,4
7,9
16
25
C. krusei
4
0,9
3
3,7
Excl..
Excl.
Neutropenia (< 500)
12,8
8,7
12
7,9
2
3
Fav. response (EOT)
80,7
64,9
89,6
89,5
75,6
60.2
Mortality
34,2
30,4
NA
NA
22,8
31,4
Echinocandins Approved Indications
EMEA
Empirical Therapy
in Febrile
Neutropenic Pts
Therapy in Proven Infections
Therapy of
Oesophageal
Candidiasis
Prophylaxis of
CandidaInfections in
HSCT Patients
Candida spp.
Aspergillus
spp.
Yes
Yes
(Salvage
therapy)
No
No
Yes
Yes
Yes
(Salvage
Therapy)
No
No
No
Yes
No
No
Children
No
Yes
No
Yesa
Yes
Adults
No
Yes
No
Yes
Yes
Caspofungin
Children
Adults
Yes
Anidulafungin
Adults
No
Micafungin*
* The decision to use micafungin should take into account a potential risk for the development of liver tumours.
Micafungin should therefore only be used if other antifungals are not appropriate
Candida colonization
 Is
frequent in ICU patients
 The gut is the main portal of entry in
neutropenic patients
 The skin is an important source of
candidemia in non-neutropenic patients
 Tracheal colonization reflect
oropharyngeal colonization and is not
associated with candidal pneumonia in
non- neutropenic ICU patients
1587 admissions
301 (19%) died
232 autopsies
135 (58%) with
97 (42%) without
pneumonia
pneumonia
77 patients with Candida in LRT
58 patients with Candida in LRT
0 Candida pneumonia
0 Candida pneumonia
Is Candida colonization of CVC in noncandidemic an indication for antifungals?
 58
pts ( 91% in ICU)
 Independent predictors for outcome:
- ultimately fatal underlying disease (P = 0.02)
- severe sepsis, septic shock or multiorgan
failure (P = 0.05).
Antifungal therapy does not seem to have a
significant influence on clinical outcome
Perez-Parra A et al. Intensive Care Med 2009; 35:707–712
OUTCOME OF CANDIDEMIA IN THE UK 1997-99
IMPACT OF CATHETER MANAGEMENT
58%
No line removal + antifungal
(n=29)
31%
Day 30 mortality
overall (n = 163)
Line removal + antifungal
(n=91)
No treatment (n=31)
26%
14%
Kibbler et al. J Hosp Infect 2003; 54:18-24
Early removal of central venous catheter in patients with
candidemia does not improve outcome
Nucci M et al. Clin Infect Dis 2010; 51:295–303
Early removal of central venous catheter in patients
with candidemia does not improve outcome
Nucci M et al. Clin Infect Dis 2010; 51:295–303
Candidemia in cancer patients: Impact of
early removal of catheter
Liu CY et al. J Infect 2009; 58:154-160
OR (95% CI)
P
2.35 (1.09-5.10)
0.03
Infection biofilm-forming
2.33 (1.26-4.30)
Candida species
0.007
APACHE score
0.001
Inadequate antifungal
therapy
1.03 (1.01-1.15)
Tumbarello et al JCM 2007
Biofilm Production by Candida spp
100
P = 0,04
90
80
70
60
50
40
30
20
10
sil
os
is
.p
ar
ap
.g
la
br
at
a
C
.tr
op
ica
lis
C
C
.a
lb
ic
an
s
0
Mortality by Biofilm-Producing Isolates
100
90
80
70
60
50
40
30
20
10
0
P<0,001
Biofilm-positive
Biofilm-negative
er
O
th
ra
ta
C
.g
la
b
lis
pi
ca
.tr
o
C
ra
p
.p
a
C
C
.a
lb
i
ca
si
lo
ns
si
s
Mortality (%)
P=0,003
Activity against Candida
biofilms
L-AMB
L-AMB
Kuhn et al AAC 2002 46:1773