Transcript From guidelines to bedsides: practical issues in the

DESC Réanimation 6 fevrier 2011
Faut-il traiter les malades colonisés à
Candida sp. en réanimation?
Jean-François Timsit MD PhD
Medical polyvalent ICU
CHU Albert Michallon
U 823
Grenoble, France
Questions
• Le traitement des candidoses invasives
doit être précoce et efficace
• Faiblesse des tests diagnostiques
• La colonisation fongique est très fréquente
et possède une VPP faible pour le
diagnostic de candidémie
• Qui traiter avec quelles conséquences
potentielles?
International Study of the Prevalence and Outcomes
Of Infection in Intensive Care Units
17%
Jean Louis Vincent et al – JAMA – 2009; 302(21):2323-2329
Candidémies en réanimation
%
SCN
Enterobacteria
S. aureus
Candida spp.
P. aeruginosa
Enterococcus
Other BGN
Streptococcus
Others
Raisin
REACAT
NNIS
Raisin
2007
2000-2003
1990-1999
2007
874
132
30701
939
Bacteremia
Colonization
CVC
37,3
10,6
12,6
5
3,8
13,5
35,5
27,8
9,1
6,6
12,2
3,6
2,2
0,8
1,9
Bacteremia Bacteremia
22,2
28,2
13,6
9,9
9,4
6,4
3,4
2,4
4,2
34
16,3
28,8
6,5
8,5
2,6
2
1,3
17,2
Nosocomial BSI in ICU
OR=8.83
Garrouste-Orgeas et al – Clin Infect Dis – 2006; 42:1118
Delay in instauration of appropriate treatment
is prejudicial to candidaemic ICU-patients
Mortality %
• early treatment (≤ 48 h) is associated with a better
survival rate
Nolla-Salas J et al. Intensive Care Med 1997; 23: 23-30
• Late treatment is
independently
associated with
death (odds ratio
1,52 ; p < 0,05)
50
45
40
35
30
25
20
15
10
5
0
Culture
day
Day 1
Day 2
Day ≥ 3
Days to start of fluconazole
Garey KW et al. Clin Infect Dis 2006; 43: 25-31.
Early antifungal treatment: a mouse
model
• Challenge with 2 X 104
and 105 C albicans
intravenously
Example of the 105 challenge
CAS
• Treatment at D-1, Day0,
Day1, 2 and 3
• AmB, Flu, CAS
• 12 mice per experiments
Placebo

FLU
Start d-1 
Start d0
Start D+1 
Start D+2 
Mac-Callum AAC; 2004: 4911-4914

Patients en réanimation:
plusieurs facteurs de risque
Intervention chirurgicale
Sepsis
Antibiotiques
Sévérité
Patient en réanimation
Durée de séjour
Alimentation
parentérale
MSJ
Procédures “invasives“
- cathéters vasculaires
- sonde vésicale
- intubation
Hémodialyse
Questions
• Le traitement des candidoses invasives
doit être précoce et efficace
• Faiblesse des tests diagnostiques
• La colonisation fongique est très fréquente
et possède une VPP faible pour le
diagnostic de candidémie
• Qui traiter avec quelles conséquences
potentielles?
Timing to positivity of Blood cultures in
humans
• Eukariotic cells
• Usual aerobic.
anaerobic bottles,
• Slow growth, weak CO2 production
automated systems
– time to positivity
– Se detection
Simulation 50 X 2 BC
103 CFU 10 ml
4/50 missed
Role of terminal subcultures
of negative bottles?
Horvarth et al - JCM 2003:4714
Timing to positivity of blood cultures in
humans: the role of selective bottles
• Eukariotic cells
• Slow growth, weak CO2 production
–  time to positivity
–  Se detection
• Selective bottles:
• Better sensitivity + 24% (92.5 vs 75.9%)
• Especially for C glabrata + 42% (100 vs 58.1)
• Or concomitant bacteria + 53% (79.9 vs 26.9%)
• Decrease in the mean time to positivity
• All yeasts: 28.9 h vs 36.5 h
• C glabrata: 17.8 h vs 61.5 h
Meyer MH et al - JCM 2004:773
Diagnostic tests
Mannan
13/32
BD Glucan
17/32
0
0
3
10
5
10
PCR
18/32
Alam et al - BMC Infectious Diseases 2007, 7:103
0
(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
Questions
• Le traitement des candidoses invasives
doit être précoce et efficace
• Faiblesse des tests diagnostiques
• La colonisation fongique est très fréquente
et possède une VPP faible pour le
diagnostic de candidémie
• Qui traiter avec quelles conséquences
potentielles?
La colonisation à Candida
• Le tube digestif est la porte d’entrée principale des
candidémies chez le neutropénique
• La peau est une importante source de candidémie
chez le non-neutropénique
• Le nombre de sites et l’intensité de la colonisation
augmente le risque d’IFI
• La colonisation trachéale est le reflet de la
colonisation oropharyngée est n’est pas associée à
la pneumonie à candida chez les patient nonneutropénique
Colonization index
(preemptive treatment)
Infected
Colonized
• Cohort prospective surg. ICU - 5,3 sites /patient
– 29 patients/11 IFI
(8 candidaemias)
1,0
0,8
• Colonization index
N. site(s) colonized
N. sites sampled
0,6
0,4
0,2
colonization
Se
Sp
PPV
NPV
0
>2 sites
100
22
44
100
≥3 sites
45
72
50
68
100
69
66
100
Index >0,5
0
Pittet et al. Ann Surg 1994 Dec;220(6):751-8
10
20
30
40
60
80 100 140
Colonization index in medical ICU
1
0,9
Candida spp. colonization significance in
critically ill medical patients: a prospective
study
0,8
0,7
*
*
*
CI ≥ 0,5 = 39%
0,6
No
candidaemia
0,5
0,4
0,3
0,2
0,1
0
* Indicate statistical difference as compared with baseline value
P.E. Charles et al., Intensive Care Med (2005) 31:393-400
Significance of the isolation of Candida species
from airway samples in critically ill patients: a
prospective, autopsy study
1587 admissions
301 (19%) died
232 autopsies
135 (58%) with
pneumonia
77 patients with Candida in LRT
0 Candida pneumonia
W. Meersseman et al.; Intensive Care Med. (2009) 35:1526-1531
97 (42%) without
pneumonia
58 patients without Candida in
LRT
0 Candida pneumonia
Clinical prediction rule for
candidiasis in the ICU
•
2,890 patients (> 4 days in nine hospitals).
•
Incidence of candidiasis was 3% (88 cases).
•
The best performing rule was as follows:
– Any systemic antibiotic OR presence of a CVC
– AND at least TWO of the following:
– total parenteral nutrition (days 1-3),
– any dialysis (days 1-3),
–
any major surgery (days -7-0),
– pancreatitis (days -7-0),
– any use of steroids (days -7-3),
– or use of other immunosuppressive agents (days -7-0).
Ostrosky-Zeichner L, Eur J Clin Microbiol Infect Dis. 2007
Clinical prediction rule validation on a
retrospective international cohort
Se
Sp
PPV
NPV
% patients with IC
% patients treated
% patients captured
Ostrosky-Zeichner – 48th ICAAC- M 1853
CPR
CPR + Colo
86%
66%
65%
88%
3%
8%
99%
99%
4.7%
9.3%
35.5%
12.7%
83%
67%
Candida score
• Construction n =1699 pts (Leon CCM 2006)
–
–
–
–
Parenteral nutrition
Surgical admission
Multiple Colonization
Severe sepsis
1pt
1pt
1pt
2pts
OR
OR
OR
OR
=
=
=
=
2,48
2,71
3,04
7,68
IC95:1,16
IC95:1,45
IC95:1,45
IC95:4,14
-
5,31
5,06
6,39
14,22
• External Validation n =1107 pts (Leon CCM 2009)
Candida score ≥3
(95% CI)
Colonization index ≥0.5
(95% CI)
0.774 (0.715-0.832)
0.633 (0.557-0.709)
Sensitivity
77.6 (66.9-88.3)
72.4 (60.0-83.9)
Specificity
66.2 (63.0-69.4)
47.4 (44.0-50.8)
Positive predictive value
13.8 (10.0-17.5)
8.7 (6.2-11.3)
Negative predictive value
97.7 (96.4-98.9)
96.1 (94.2-98.0)
Relative risk for invasive
candidiasis
5.98 (3.28-10.92)
2.24 (1.28-3.93)
Area under ROC curve
PPV (Candida score)=Proba (Dis+/CS +) = 13.8%…
PPV (Colonization index)=Proba (Dis/CI+) = 8.7%…
Leon et al - Crit Care Med 2006; 34:730–737 and Crit Care Med 2009; 37:1624 –1633
Questions
• Le traitement des candidoses invasives
doit être précoce et efficace
• Faiblesse des tests diagnostiques
• Qui traiter avec quelles conséquences
potentielles?
Who needs to be treated
(MV patients >4 days)?
31,192 patients
Length ICU stay >7days
1,205 patients
Short life expectancy
(APACHE II > 35)
13 patients
Inadequate data collection
85 patients
Study population
1,107 patients
834/1107=
75%
Neither colonized nor infected
215 patients
Candida spp. Colonization
834 patients
Proven Candida infection
58 patients
Leon et al - Crit Care Med 2009; 37:1624 –1633
4.8% pts>7d
6.9% colo+
Fongiday
169 centres
2047 patients
1893 without
systemic
antifungals (SAT)
Timsit et al – ICAAC 2009
Azoulay et al – Crit Care Med submitted
154 (7.5%) with
SAT
d28 follow-up ok
2032 patients (99.3%)
Fongiday
Reason for SAT at fongiday
(16 mould excluded) b
Curative documented infection
Febrile neutropenia
Prophylactic (only risk factors)
Empirical (sepsis + Risk Factors)
Early or pre-emptive based on
Candida colonization
Because of patient’s hemodynamic
instability
Other
Timsit et al – ICAAC 2009
Azoulay et al – Crit Care Med submitted
27.5%
10.9%
17.4%
18.1%
34.8%
13%
5.1%
Who needs to be treated
(MV patients >4 days)?
Prophylactic
Risk factors + colonization +30-80%
Preemptive
Colonization +
Risk factors +
Sepsis +- (>30%)
Empirical (Probabilistic)
Curative
British Society for Antimicrobial Chemotherapy Working
Party. Int Care Med 1994; 20: 522-8.
Risk factors +
Sepsis +
Colonization+Invasive
candidasis
1-3%
SAT decreased colonization index
Garbino, Intensive Care Med 2002
Prophylactic treatment:
Meta-analyses
N
Candidaemia
studies
Ho
Playford
7 (F)
0.2
(0.06-0.72)
12
(keto +F)
IFI
Death
F (Res.)
0.39
(0.24-0.65)
0.82
(0.62-1.08)
0.66
(0.22-1.96)
0.46
(0.31-0.64)
0.76
(0.57-0.97)
Shorr
4 (F)
(2.2%!!)
0.44
(0.27-0.72)
0.87
(0.59-1.28)
Vardakas
6 (F)
0.28
(0.09-0.86)
0.26
(0.12-0.53)
0.74
(0.52-1.05)
9
(Keto+F)
0.3
(0.1-0.82)
0.25
(0.08-0.8)
0.6
(0.45-0.8)
Cruciani
Playford G et al – JAC 2006; 57:628-638;
Ho KM et al – Crit Care 2005;9:R710 ;
Shorr A et al Crit Care Med 2005; 33:1928-35;
Vardakas KZ et al – Crit Care Med 2006; 34:1216-1224;
Cruciani M et al – Intensive care Med 2005; 1477-1485;
Traitement prophylactique
Meta-analyses
• Fluconazole chez des malades à haut
risque chirurgicaux
• Diminue l’infection fongique invasive
• Diminue la mortalité (2 Meta-analyses/ 5)
• Dans les RCT peu ou pas d’effets sur la
résistance au fluconazole
Playford G et al – JAC 2006; 57:628-638;
Ho KM et al – Crit Care 2005;9:R710 ;
Shorr A et al Crit Care Med 2005; 33:1928-35;
Vardakas KZ et al – Crit Care Med 2006; 34:1216-1224;
Cruciani M et al – Intensive care Med 2005; 1477-1485;
Restriction of fluconazole use for
prophylaxis
• Med-surg ICU (~500 adm./an)
• 108 months (Jan. 99-Dec. 2007)
• Overall prevention of NI unchanged
• 213 candidaemia (1.42/10 000 patient-days)
 albicans (46%), parapsillosis (22%), glabrata
13%
• Intervention:
 Jan. 1999-Jan. 2003: Extensive Prophylaxis
 Jan. 2003-Dec. 2007:Incitation not to do
• Statistical analysis:
 Segmented linear regression
Bassetti et al – JAC 2009; 64:625-629
Restriction of fluconazole use for
prophylaxis
X
Non-albicans candidaemia
C. albicans candidaemia
Fluco use
Bassetti et al – JAC 2009; 64:625-629
Antifungals infection pressure
DDD/1000 pt-days
C. parapsilosis rate
Forrest GN et al – J infect 2008; 56:126
Caspo and fluco exposure influenced
the epidemiology of candidaemia
Lortholary O et al - AAC Accepts, published online ahead of print on 15 November 2010
Caspo and fluco exposure influenced
the epidemiology of candidaemia
Lortholary O et al - AAC Accepts, published online ahead of print on 15 November 2010
Évolution des écosystèmes fongiques
et utilisation des antifongiques
Grenoble
Rea Med
1511 premières souches
DDD/1000HD
80
70
60
50
40
30
20
10
Années
0
2004
Polyènes
Fournier P et al – SFMM 2010
2005
2006
Fluconazole
2007
2008
Caspofungine
2009
Voriconazole
Evolution des écosystèmes fongiques
et utilisation des antifongiques
DDD/1000HD
Fournier P et al – SFMM 2010
Treatment of colonized patients in ICU?
• No RCTs
Antifungals for CVC tip > 103 Cfu/ml
(retrospective)
• 58 patients CVC > 103 cfu/ml Candida sp. and negative blood
cultures
– Only one patient developed IC (detected as candidaemia).
– 12/33 patients (36.4%) with a clinical improvement
– 8/25 (32.0%) with a poor outcome received SAT
• RF of poor outcome:
– Ultimately fatal underlying disease OR 12; 95% CI, 1.4–105
P = 0.025
– Severe sepsis, septic shock or MOF OR 6.2; 95% CI, 1.0–38;
P = 0.05
– BUT NOT Antifungal use: OR 0.82; 95% CI, 0.27–2.47;
P = 0.73
Perez-Parra Intensive Care Med (2009) 35:707–712
Assessment of preemptive treatment to prevent
severe candidiasis in critically ill patients
• Before/after study SICU>4 days
– 8/98-7/00: no treatment, colonization sampled not known
– 12/00-11/02: screening and known results
• 5 samples (trachea, gastric, urine, oropharyngeal, rectal)
• Admission then 1/week
• + if « highly » positives: (>100 ou 105 CFU according to
samples)
• Corrected colonization index:
# highly positive samples
# samples
– Patients colonised with CCI ≥ 0,4
• 20% of the cohort:
• fluconazole: 800 mg D1 and then 400 mg/j IV x 14days
R. Piarroux et Al - Crit Care Med 2004; 32:2443–2449
Assessment of preemptive treatment to prevent
severe candidiasis in critically ill patients
R. Piarroux et Al - Crit Care Med 2004; 32:2443–2449
Fongiday – a SAT is associated with a
lower day 28 mortality…
• Cox model with left troncature
– Takes into account the elapse time between admission and fongiday
•Univariate analysis
HR = 0.81 [0.53-1.22], p=0.31
•Adjusted and stratified
HR = 0.38 [0.17-0.82], p=0.01
Adjusted on RF of SAT and % death
predicted
And stratified according to candida score
and center
(*) all the population without mould infection
Timsit et al – ICAAC 2009
Azoulay et al – Crit Care Med submitted
Traitement empirique? La question se pose
de plus en plus, pas de réponses…
• Risque d’un traitement retardé
• Pas de tests diagnostiques fiables
– HC positives tardivement (ou negative)
– Nouveaux tests pas encore convaincants
• 13 B –D glucane
• Platelia- Manane / Antimanane
• PCR
Empirical fluconazole vs placebo
• RCT double blind Fluconazole 200 mg (n=18) vs placebo (n=19)
• Septic shock with nosocomial pneumonia or intra-abdominal sepsis
30-days death: Fluco 22% vs Placebo 54% p = 0,015
Pneumonia
Fluco
28%
Intra-abdominal
Placebo
(ns)
42%
Fluco
14%
Placebo
P=0,013
65%
But only one candidemia! And parameters imbalanced
Fluco
Immunocompromised
4
Organ dysfunctions
1,7
Jacobs S et al. CCM 2003
Placebo
8
P=0,01
2,8
Empirical Fluconazole vs Placebo for
ICU Patients
• Double blind randomized
placebo-controlled trial: 270
adults, 6 years
• Fluconazole: 800 mg vs placebo
2 weeks if:
– > 18 years old
– ICU duration > 96h
– Apache 2 > 16
• Assessment criteria =
composite score
– Initial fever resolution
– No emerging IFI
– No toxicity-related trial
stopping
– No use of another
systemic AF
– Temperature > 38,3°within
72 hours
– Received large spectrum
antibiotics for at least the 4
to 6 previous days
– Central venous catheter
– 50% medical ICU
Schuster et Al, Annals of Internal Medicine
Empirical Fluconazole vs Placebo for
ICU Patients
Patient Characteristics at Baseline
characteristics
Mean age (SD), y
Women, n (%)
Median previous ICU stay (range), d
Median previous hospital stay (range), d
Median baseline APACHE II score (range)
Corticosteroids, n (%)
Total parenteral nutrition, n (%)
Renal insufficiency, n (%) †
Colonized with yeast in ≥1 site, n (%)
Diabetes mellitus, n (%)
Cancer, n (%)
Surgery within 7 d before study entry, n (%)
Schuster et Al, Ann Intern Med. 2008 Jul 15;149(2):83-90
Fluconazole
recipients
(n=122)
53 (19)
29 (24)
9.5 (4-171)
11 (5-173)
22 (9-28)
19 (16)
70 (57)
70 (57)
28 (23)
23 (19)
12 (10)
65 (53)
Placebo
recipients
(n=127)
51 (19)
28 (22)
9 (4-57)
11 (4-58)
20 (11-42)
15 (12)
65 (51)
65 (51)
24 (19)
26 (20)
8 (6)
65 (51)
Empirical Fluconazole vs Placebo for
ICU Patients
• Overall success:
– fluconazole: 36% vs PCB 38% (RR 0,95 IC95:,69-1,32)
• Per item
F
vs Placebo
– Initial fever resolution
49 vs
46%
– Candidaemia
0
vs
2
– Emerging IFI
5
vs
9%
– Other systemic AF
10 vs
16%
– Death
24 vs
17%
• N.B.: all IFIs occur in colonized patients
Schuster et Al, Annals of Internal Medicine
Quels traitements?
2009; 8:23
11 RCTs
Candidose invasive tout confondu
1 étude sur les neutropéniques
Caterpillar diagram
(taux de réponses)
Vs Fluconazole
Vs Voriconazole
Vs AmB
Vs AmB-L
Favours comparator
Mills et al - Annals of Clinical Microbiology and Antimicrobials 2009, 8:23
Caterpillar diagram
(Mortalité toutes causes)
Vs Fluconazole
Vs Voriconazole
Vs AmB
Vs AmB-L
Favours comparator
Mills et al - Annals of Clinical Microbiology and Antimicrobials 2009, 8:23
Résumé efficacité May 2009
• Fluco =Ampho B
– C krusei, Toxicité rénale
• Ampho B = AmbL
– sauf toxicité++
• VRZ= AmphoB puis Fluco
• Cas>Amb?
– meilleure efficacité ou moindre toxicité?, C parapsilosis?
• Anidula>Fluco?
– En particulier sur C albicans et C tropicalis (parapsilosis
idem)
• Micafungin = Caspofungin
• Micafungin = AmbL
– Plus de toxicité (impact pronostic?)
Optimisation?
Associations?
Traitement probabiliste des candidoses
invasives - IDSA 2008 Clinical Infectious Diseases 2009; 48:503–35
Traitement probabiliste
(IA)
Pré-exposition azolé ?
Non (A-III)
Oui (A-III)
Haut risque de C. glabrata
ou krusei ? Ou sévère
(A-III)
Non
fluconazole

Oui
echinocandine
L’amphotéricine B et ses formulations lipidiques sont des alternatives en
cas d’intolérance ou de non disponibilité des autres traitements
Adaptation thérapeutique/Candidoses invasives
Clinical Infectious Diseases 2009; 48:503–35
- IDSA 2008
Stabilité clinique
Oui
Non
Connaissance du germe
C. Glabrata (B-III)
Sensibilité au fluconazole
C krusei (A-I)
C. parapsilosis
Oui (B-III)
fluconazole



Non
AmB-L
echinocandine
Durée du traitement : 2 semaines après stérilisation de HC et résolution clinique(AIII)
Ablation des cathéters systématiques si non neutropéniques (A-II)
Voriconazole: relais oral ou tt de C. krusei (B-III)
Conclusion: Nous devons apprendre à
mieux utiliser les antifongiques…
1. Les patients de réanimation ont de plus en plus de
facteurs de risque
2. La candidémie est un événement rare difficile à
diagnostiquer
3. Nous disposons de traitements efficaces des
candidémies qui doit être administré précocement
4. Le traitement prophylactique diminue les IFI
5. Le traitement des malades colonisés n’a jamais
été testé dans une étude randomisée contrôlée
6. Les traitements antifongiques entrepris ont des
influences sur les écosystèmes fongiques.
7. Les traitements empiriques (non centrés sur la
colonisation préalable) n’ont pas prouvé leur
efficacité
%
40%
35%
30%
Kaplan-Meier en % :
D5 : 19.54 [16.48 ; 22.60]
D10 : 28.14 [24.21 ; 32.07]
D15 : 31.49 [27.10 ; 35.88]
D20 : 32.86 [28.16 ; 37.56]
D30 : 33.66 [28.76 ; 38.56]
25%
20%
1-KM (IC 95%)
15%
10%
5%
0%
0
5
10
15
20
Day of occurrence of candida
25
30