gestione pratica delle infezioni fungine in terapia intensiva
DESCRIPTION
Gestione pratica delle infezioni fungine in terapia intensiva. Matteo Bassetti Clinica Malattie infettive A.O.U. San Martino Genova. Relationship between hospital mortality and the timing of antifungal treatment. 35. 30. 25. 20. Hospital mortality (%). 15. 10. 5. 0. < 12. 12–24. - PowerPoint PPT PresentationTRANSCRIPT
Gestione pratica delle infezioni fungine in terapia intensiva
Matteo BassettiMatteo Bassetti
Clinica Malattie infettiveClinica Malattie infettive
A.O.U. San Martino A.O.U. San Martino
GenovaGenova
Relationship between hospital mortality and the timing of antifungal treatment
Ho
spit
al m
ort
alit
y (%
)
0
35
30
25
20
15
10
5
< 12
Delay in start of antifungal treatment (hours)
12–24 24–48 > 48
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
p < 0.01 by log-rank test
0 7 14 21 28
0.1
0.2
0.3
0.4
0.5
0.6
Days
Pro
port
ion
in
fect
ed
Placebo
Fluconazole
260 surgical ICU patients (stay > 3days) randomizedto double-blind oral antifungal prophylaxis
Pelz Ann Surg 233:542-548, 2001
Fluco in High-risk SICU patients
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 CCM 2002
Sandven et al.: Low-risk surgical patientsDouble-blind single-dose antifungal prophylaxis in
109 patients with intra-abdominal perforation
10%
43%
7,5%10%
34%
14%
0
10
20
30
40
50
60 %
Emergence ofcolonization
Complications Death
NS
NS
NS
RESULTS OF CANDIDA PROPHYLAXIS IN ICU PATIENTS
RESULTS OF CANDIDA PROPHYLAXIS IN ICU PATIENTS
0
20
40
60
80
100 %
Successof
prophylaxis
Emergencecolonizationby Candida
Deathfrom
any cause
Invasivecandidosis
Candidemia
Fluconazole 100 mg/dPlacebo
53
78%
P<0.01
66
30%
P<0.001
39 41%
NS
3%7%
NS
06%
P=0.014
Garbino et al. Intensive Care Med 2002;28:1708-1717
Antifungals in critically ill and surgical patients: meta-analysis
NNT= 94 NNT in high-risk= 9 NNT in low risk= 188
Impact on Candidal infections Impact on mortality
Playford et al. JAC 2006; 57: 628–638
PROPHYLACTIC FLUCONAZOLE…..PROPHYLACTIC FLUCONAZOLE…..
• HAS ELIMINATED CANDIDA COLONISATION!
More patient comfort
• HAS ELIMINATED CANDIDA COLONISATION!
More patient comfort
……..BUT……..BUT
• HAS ELIMINATED CANDIDA COLONISATION!
More patient comfort
• DID NOT REDUCE MORTALITY
• HAS SELECTED RESISTANT CANDIDA SPECIES
• 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.
0,00
0,50
1,00
1,50
2,00
2,50
3,00
3,50
Y 1999 Y 2000 Y 2001 Y 2002 Y 2003
Years observed
Inci
denc
e of
can
dide
mia
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Fluc
onaz
ole
DD
D's
x 1
00 p
ts/d
ays
Shift from CA to CNA
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
Bassetti M et al. J Antimicrob Chemother 2009: 64:625-9.
Non-albicans candidaemia
C. albicans candidaemiaX
So what about pre-So what about pre-emptive therapy with emptive therapy with
predicitive rules?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 daysAND 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
0
100
200
300
400
500
600
_____
_____
_____ _____
(13)-β-D-GLUCAN CONCENTRATIONS
CBSI: proven Candida BSI PCBSI: possible Candida BSI NCBSI: no Candida BSICONTROLS: healthy volunteers
Horizontal bars indicate median values
CBSI PCBSI NCBSI CONTROLS
BG valuesPg/ml
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 daysO
CVC from 7 days
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
•Start antifungal
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
Fluconazol Placebo 95% CI / P-value
n (ITT) 133 137
Success 44 (36%) 48 (38%) 0.69–1.32; P = 0.78
Invasive mycosis 6 (5%) 11 (9%) RR 0.57; 0.22–1.49
30-Day mortality 29 (24%) 22 (17%) RR 1.36; 0.82–2.24
Schuster et al, Ann Intern Med 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
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)
In vitro susceptibility to fluconazole Species Distribution
n tested S S-DD or R Candida albicans 174 (57%) 113 96% 4% Candida glabrata 51 (17%) 38 50% 50% Candida parapsilosis 23 (7.5%) 19 90% 10% Candida krusei 16 (5.2%) 6 17% 83% Candida tropicalis 15 (4.9%) 14 86% 14% Candida kefyr 11 (3.6%) 9 100% 0 Candida guilliermondii 5 (1.6%) 5 80% 20% Candida lusitaniae 2 (0.7%) 2 100% 0 Other Candida species 8 (2.6%) 4 50% 50% Total 305 210 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 non-neutropenic
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)
yes (A-III)No (A-III)
fluconazole echinocandin
Azole exposure
High risk of C. glabrata or krusei ? Or severe (A-III)
yesNo
Clinical Infectious Diseases 2009; 48:503–35
NoYes
fluconazole echinocandin
Clinicaly stable
Known fungi
Sensitive to fluconazole
C. parapsilosis
C. Glabrata (B-III)
C krusei (A-I)
Yes (B-III) No
Secondary adapted to results. Invasive candidiasis - IDSA 2009Clinical Infectious Diseases 2009; 48:503–35
AmB-L
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
Fluconazole
AMBPhillips, 1995
P=.04
FluAMB + FluRex, 2003
Antifungal drug studies candidaemia
MITT - Investigator-Assessed Response at End of Treatment (%)
VoriconazoleAMB->Flu
Kullberg, 2005
P=.82
CaspofunginMicafunginPappas, 2007
MicafunginLiposomal AMB
Kuse, 2007
P=.27
AMBCaspofungin
Mora-Duarte, 2002
P=.09
Adapted from Kullberg BJ, et al. Lancet. 2005
P=.64
AnidulafunginFluconazoleReboli, 2007
P=.009
Flu
con
azo
l (8
00)
Flu
con
azo
l (8
00)
Am
fote
rici
ne
B +
Flu
Am
fote
rici
ne
B +
Flu
Cas
po
fun
gin
Cas
po
fun
gin
Mic
afu
ng
inM
icaf
un
gin
L-A
mfo
teri
cin
e B
L-A
mfo
teri
cin
e B
Mic
afun
gin
Mic
afun
gin
Cas
po
fun
gin
Cas
po
fun
gin
Am
fote
rici
ne
BA
mfo
teri
cin
e B
Am
fote
rici
ne
B
F
luco
naz
ol
Am
fote
rici
ne
B
F
luco
naz
ol
Vo
rico
naz
ole
Vo
rico
naz
ole
Flu
con
azo
leF
luco
naz
ole
An
idu
lafu
ng
inA
nid
ula
fun
gin
Am
fote
rici
ne
BA
mfo
teri
cin
e B
Flu
con
azo
lF
luco
naz
ol
56%
69%71% 72% 74%
70% 62%
73% 72%72%
60%
76%
53%50%
P=.39
AnidulafunginCaspofungin MicafunginGlarea lozoyensis Aspergillus nidulansColeophoma empetri
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.
Chemical Structures
NO
O
O
NH
O
H
H
H HO
HCH3
O
O
H2N
OH
NHHO
H2N
HO NH
HN
OH
OH
HN OH
NH
HO
H3C
CH3 CH3
O
O
O
N
O
O
HN
N
O
O
O
O
O
N
O
H3C
SO
O
HO
OH
HO
HO
OH
HN
NH
NHH3C
H2N
HO
HO
OH
NH
OH
OH
CH3
O
O
N
H3C
O
N
O
O
O
O
O
HO
HO
HO
OH
HN
NH
OH
HO
HO OH
NH
HN
CH3
OH
NH
H3C
H3C
Side chains are key determinants of lipophilicity, solubility, antifungal activity, and toxicity
Attività in vitro delle echinocandinenei confronti di Candida spp.
Organismo
MIC90 (µg/ml)
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
Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Dodds Ashley ES et al. Clin Infect Dis. 2006;43:S28–S39.
Caspofungin Micafungin Anidulafungin
Metabolism Hepatic metabolism
by hydrolysis and N-acetylation
Spontaneous nonhepatic chemical
degeneration
Hepatic metabolism
by arylsulfatase and catechol-O-
methyltransferase
Nonhepatic chemical
degradation
Elimination/excretion
Urine 41%
Feces 34%
Urine + feces 82.5%
Feces 71%
Urine <1%
Feces ≈30%
Protein Binding 97% >99% >99%
Oral Bioavailability
<5% <5% <5%
Dialyzable No No No
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 IndicationsEMEA
Empirical Therapy in Febrile
Neutropenic Pts
Therapy in Proven Infections
Therapy of Oesophageal Candidiasis
Prophylaxis of Candida-
Infections in HSCT Patients
Candida spp.Aspergillus spp.
Caspofungin
Children Yes YesYes
(Salvage therapy)
No No
Adults Yes YesYes
(Salvage Therapy)
No No
Anidulafungin
Adults No Yes No No No
Micafungin*
Children No Yes No Yesa Yes
Adults No Yes No Yes Yes
* 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
pneumonia
97 (42%) without
pneumonia
77 patients with Candida in LRT
0 Candida pneumonia
58 patients with Candida in LRT
0 Candida pneumonia
1587 admissions
301 (19%) died
232 autopsies
135 (58%) with
pneumonia
97 (42%) without
pneumonia
77 patients with Candida in LRT
0 Candida pneumonia
58 patients with Candida in LRT
0 Candida pneumonia
Is Candida colonization of CVC in non-
candidemic 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 1997-99IMPACT OF CATHETER MANAGEMENT
OUTCOME OF CANDIDEMIA IN THE UK 1997-99IMPACT OF CATHETER MANAGEMENT
No line removal + antifungal (n=29) 31%
Line removal + antifungal (n=91) 14%
No treatment (n=31)58%
26%Day 30 mortality overall (n = 163)
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)OR (95% CI) PP
Inadequate antifungal therapy
2.35 (1.09-5.10)2.35 (1.09-5.10) 0.030.03
Infection biofilm-forming Candida species
2.33 (1.26-4.30)2.33 (1.26-4.30) 0.0070.007
APACHE score 1.03 (1.01-1.15)1.03 (1.01-1.15) 0.0010.001
Tumbarello et al JCM 2007
Biofilm Production by Candida spp
0
10
20
30
40
50
60
70
80
90
100 P = 0,04
0102030405060708090
100
Biofilm-positive Biofilm-negative
Mo
rtal
ity
(%)
P<0,001
P=0,003
Mortality by Biofilm-Producing Isolates
Activity against Candida biofilms
Kuhn et al AAC 2002 46:1773
L-AMB
L-AMB