p. aeruginosa… et un peu - spilf - infectiologie · single-center studycomparedcefepimefor...
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Traitement des infections liées à P. aeruginosa… et un peu
Acinetobacter….B Guery
Maladies InfectieusesCHRU Lille-EA7366
1
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Cas cliniqueMr D
– Insuffisant respiratoire chronique– Intoxication mixte
Admis en réanimation pour une nouvelle décompensation respiratoire sur exacerbation de sa BPCO. L’antibiothérapie de première ligne en l’absence d’arguments en faveur d’une pneumonie repose sur une monothérapie par ceftriaxone seule.
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L’évolution initiale est favorable
A J7 de son hospitalisation, il présente – Température à 39°C– Dégradation de son état
respiratoire avec augmentation des besoins en oxygène
– Image de pneumonie à la radiographie de thorax
– Au niveau clinique, Mr D a présenté une hypotension qui a répondue au remplissage (2L sur 1h).
Quel est votre prise en charge anti-infectieuse?
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AmoxicillineC1g, c2gCéfotaxime...
KanamycineNéomycineSpectinomycine
Chloramphénicol
TétracyclinesTriméthoprimeSulfamides
Nitrofuranes
Anciennes quinolonesPéfloxacine...
MacrolidesLincosamidesSynergistines
Nitroimidazoles
Glycopeptides
Résistance naturelle de P. aeruginosa
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ß-lactamines- ticarcilline ± clavu- pipéracilline ± tazo- aztréonam- cefsulodine- céfopérazone- ceftazidime- cefpirome- céfépime- imipénème- méropénème- doripénème
Aminosides- gentamicine- nétilmicine- tobramycine- amikacine- isépamicine
Fluoroquinolones- ofloxacine- ciprofloxacine- Lévofloxacine
Autres- colistine- polymyxine B- rifampicine- fosfomycine
Antibiotiques anti-pyocyanique
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Frequency of occurrence and antimicrobial susceptibility patterns of Gram-negative bacteria pneumonia in USA (n = 28) and Europe and the Mediterranean region (EMR) (n = 25) in 2009 2012.
12851 isolates collected (6873/5978 in USA/EMR).
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La sélection de mutant est –elle comparable quelque soit la molécule utilisée?
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Émergence de résistantsModèle de péritonite expérimentale à P. aeruginosa (108
CFU)
(Pechere et al, JAC 1986
Molécule % d’émergenc
eCeftazidime 25Céfépime <10Imipénème <5Ciprofloxacine
>60
Amikacine <5
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Carmeli et al AAC 1999
271 patients/ Emergence de résistance chez 28 (10,2%)
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Boffi El Amari et al, CID 2001
267 bactériémies, 25% avec une exposition à un anti-pyo
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Obritsch et al, AAC 2004
National surveillance of antimicrobialresistancein Pseudomonas aeruginosa isolatesobtained fromintensive care unit patients from 1993 to 2002
13999 souches
ceftazidime, ciprofloxacin,tobramycin, and imipenem
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Obritsch et al, AAC 2004
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Vous mettez en place– Une monothérapie?– Une association?
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Intensive care units of 28 academic and community hospitals in three countries between 1996 and 2007.
A total of 4662 eligible cases of culture-positive, bacterial septic shock treated with combination or monotherapy from which 1223 propensity-matched pairs were generated.
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The use of aminoglycoside (AG), fluoroquinolone (FQ), or a macrolide/clindamycin (ML/CL) in addition to a -lactam was associated with a reduced hazard ratio for death compared to -lactam alone.
No other drug combinations demonstrated evidence of significant benefit.
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La bactériologie objective la présence d’une souche de P. aeruginosa aux hémocultures et sur les prélèvements respiratoiresSi Mr D n’avait pas présenté de signes en
faveur d’un sepsis sévère auriez vous réalisé une association?
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ETUDES CLINIQUES PAVM
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CCM 2008;36: 737- 745
740 patients– Meropéneme + ciprofloxacine vs Meropénème seul
Pas de différence – mortalité à 28 jours– Durée séjour– Réponse clinique et microbiologique– Émergence de résistance
Si P. aeruginosa, Acinetobacter, ou MDR – adéquation meilleure dans le groupe association mais pas de
différence sur le pronostic Pour les patients à haut risque une association pourrait être
meilleure
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A total of 314 patients presented 393 PA-VAP. Failure occurred for 112 of them, Factors associated with treatment failure were
age (P . 0.02); presence of at least one chronic illness (P . 0.02); limitation of life support (P . 0.0004); a high Sepsis-Related Organ Failure Assessment score (P , 0.0001); PA bacteremia (P .0.003); previous use of FQ before the first PA-VAP (P . 0.0007).
The failure risk was not influenced by the strain resistance profile or by the biantibiotic treatment, but decreased in case of VAP treatment that includes FQ (P .0.0006).
Better evaluation of the potential benefit of an initial treatment containing FQ requires further randomized trials.
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ETUDES CLINIQUES bactériémies
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AAC 1997
2124 patients Bactériémies à Gram négatifs
– 670 Tt inadéquat: mortalité 34%– 1454 Tt adéquat: mortalité 18%
Si approprié– 789 monothérapie b-lactamine: 17%– 327 associations: 19%– 249 aminoglycosides: 24%
Pas d’avantage à l’association sauf neutropéniques(multivarié), et infections liées à P. aeruginosa (monovarié)
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Etudes prospectives uniquement
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Bactériémies à P. aeruginosa
MAISDans 4 études sur 5
aminosides en monothérapie
Adéquation?
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Pseudomonas: RR 1.01
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Retrospective study analyzed data of 234 patients with P. aeruginosa bacteremiaat a 1,200-bed tertiary teaching university hospital in South Korea betweenJanuary 2010 and December 2012
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Vous décidez de débuter une association beta-lactamine/aminoside– Quels sont les arguments justifiant l’utilisation
des aminosides en monodose?– Quelle dose d’aminoside utilisez-vous?– Pendant combien de temps?
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0102030405060708090
100
2 4 6 8 10 12
Cmax/CMI
(Moore, JID 1987)
%
AminosidesRelation Cmax/CMI - Guérison clinique
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Kashuba et al, AAC, 1999
Importance de la première dose d’aminoside sur l’évolution clinique
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Résistance adaptative Bactéricidie; modèle statique in vitro
0123456
1ère dose 2ème dose 3ème dose
24 mg/24 h
8 mg/8 h
tobramycine
P. aeruginosa
contact = 2h
(Karlowsky et al, JAC 1994)
Killinglog10 CFU/ml
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Résistance adaptative
0
0,5
1
1,5
2
2,5
3
3,5
2,5xCMI 5xCMI 10xCMI 20xCMI
Ctr
AMK (5h)
AMK (8h)
AMK (12h)
AMK (16h)
AMK (24h)
AMK in vivo : 80 mg/kg(Xiong et al, AAC 1997)
Dlog CFU/ml/90min
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Vous associez votre aminoside avec une beta-lactamine– Quelle molécules?– Quelles modalités d’administration?
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Bêtalactamines:paramètres pharmacodynamiques
CMI
temps
concentrations
temps de contact à C > CMI
T= t1 + t2 + t3 (%24h) > CMI
t1>CMI t2>CMI t3>CMI 24 h
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(Craig et al, CID 2001)
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MPC
MIC
Time post-administration
Seru
mof
tiss
ue d
rug
conc
entra
tion
MutantSelectionWindow
Idealized sketch of serum or tissue drug concentration after administration of asingle dose of antibiotic to a patient. MIC and mutant prevention concentration(MPC), determined in laboratory studies, are indicated. The area betweenMPC and MIC (shaded) represents the mutant selection window
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18 patients de réanimation Dose de charge 12mg/kg, suivie de 6 g/24 h de
ceftazidime– soit en continu (n=8)– soit en 3 bolus de 2g/8h (n = 10)
Durant les 8 premières heures, concentrations sériques < 40 mg/L (5 fois la conc. crit. inf):– groupe perfusion continue: 1 patient / 8 (38 mg/L)– groupe bolus: 8 patients / 10 (2 - 33 mg/L)
Durant les 40 heures suivantes, temps avec des concentrations sériques > 40 mg/L: – groupe perfusion continue: 100% – groupe bolus: 20 - 30%
Lipman, JAC 1999; 43: 309-11
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Single-center study compared cefepime for bacteremia and/or pneumonia admitted from 1 January 2008 through 30 June 2010 (a 30-min infusion
of 2 g every 8 h) admitted from 1 July 2010 through 31 May 2011 (a 4-h infusion of 2 g
every 8 h). Extended infusion was associated to
Decreased mortality (20% versus 3%; p=0.03). Decreased mean length of stay of 3.5 days less Decreased mean length of stay was significantly less in the extended-
infusion group (18.5 days versus 8 days; P0.04). Decreased Hospital costs were $23,183 less per patient,
Extended-infusion treatment with cefepime provides increased clinical and economic benefits in the treatment of invasive P. aeruginosa infections.
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88%
2
86%
4
According to the German prescribing information, the infusion solution is sufficiently stable for 4 h at 25°C.
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Morbidité?Mortalité?
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10 patients septiquesMeropenem 1g/8h vs 3g continuConcentration tissulaire par microdialyse
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Con
trat
ion
form
e lib
re p
iper
acill
ine
(mg/
L)
Temps (mn)
D’après JA Roberts Crit Care Med 200
0.001
0.1
1
10
100
Profil concentration-temps de la forme libre de piperacilline
Plasma
Tissu
Continu
Bolus
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Con
trat
ion
form
e lib
re p
iper
acill
ine
(mg/
L)
Temps (mn)
D’après JA Roberts Crit Care Med 200
0.001
0.1
1
10
100
Profil concentration-temps de la forme libre de piperacilline
Plasma
Tissu
Continu
Bolus
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Con
trat
ion
form
e lib
re p
iper
acill
ine
(mg/
L)
Temps (mn)
D’après JA Roberts Crit Care Med 200
0.001
0.1
1
10
100
Profil concentration-temps de la forme libre de piperacilline
Plasma
Tissu
Continu
Bolus
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Étude sur cohorte de 194 patients Deux modalités d’administration
– 3.375g en 30 min toutes les 4 à 6 H– 3.375g en 4 H toutes les 8 H
Analyse de 2 paramètres en fonction du Score Apache II– Mortalité– Durée d’hospitalisation
Lodise et al , CID, 2007
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Mode d’administration de la pipera-tazocilline et mortalité à J14
0
5
10
15
20
25
30
35
ApacheII<17 ApacheII>17
Mor
talit
é%
Perfusion prolongéeIntermittent
Lodise et al , CID, 2007
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Le bilan biologique initial met en évidence une insuffisance rénale avec une clairance de la créatinine évaluée à 30mL/min– Modifiez vous votre association initiale?
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Fluoroquinolonesparamètres pharmacodynamiques
ASC 24h
C max
CMI
temps
ASC 24h/CMI
Cmax/CMI
24 h
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FluoroquinolonesRelation ASC 24h/CMI et efficacité
0
20
40
60
80
100
0-62,5 125-250 >500
Clinical
Bacteriologic
Forrest, AAC 1993
patie
nts
cure
d
AUC/MIC à 24h
(%)64 patients
ciprofloxacine
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Craig et al CID 2001
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Craig et al CID 2001
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Fish et al, JAC 2002
CiprofloxacineCtrCeftaCefep Cipro
Cefep-Cipro
Cefta-Cipro
Levofloxacine
Gatifloxacine Moxifloxacine
Cefta-Levo
Cefta-GatiCefta-Moxi
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Mr D s’améliore à 48h– Pas besoin de remplissage supplémentaire– Pas de recours aux inotropes– Baisse de la température à 38°C
Comment adaptez vous votre traitement?– Durée de chaque molécule
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0
.2
.4
.6
.8
1
0 5 10 15 20 25 30 jours
8 jours
15 jours
p=0.6518,8%
17,2%
Mortalité à J 28 en fonction de la durée de traitement
Chastre et al, JAMA 2003
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40.6%
25.4%
0
10
20
30
40
50
“8 jours”(n=64)
“15 jours”(n=63)
p=0.06%
Chastre et al, JAMA 2003
Taux de récidive de l'infection pulmonaire
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BGN
0
50
Récidive Rechute Surinfection
RR: 13,8 (7,8-19,7) 7,6 (1,1-14,2)
8j
15j
%
Chastre et al, JAMA 2003
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Après une amélioration initiale, l’état clinique de Mr D se redégrade sur le plan respiratoire
Vous arrêtez votre antibiothérapie et réalisez de nouveaux prélèvements.
Vous débutez une nouvelle antibiothérapie empirique, quelles molécules?
Le laboratoire de bactériologie vous rend une antibiogramme isolant un Acinetobacter MDR
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Prospective study 185 patients infected with
Acinetobacter baumannii and Pseudomonas aeruginosa
Hospitalisation> 48 h– 55 colistin group– 130 non colistin group
No difference for age, APACHE II score, comorbidities, and SOFA score
Int Care Med 2005
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Clin Microb Infect 2005
Retrospective study 43 ICU patients Multi-drug-resistant pathogens (P
aeruginosa-A baumannii)
Clinical response: 74,4%
Renal function alteration 18,6%
Mortality 27,9%
Colistin is an option
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Quelle posologie ?
Recommandations actuelles (en 2 à 4 injections)colistiméthate
Vidal 50 000 UI/kg/j 280 mg/j UK 1-2 MUI x 3/j pour 70 kg 240-480 mg/jUSA 2.5-5 mg/kg/j coli base 400-800 mg/j
Révision libellé AMM75 000 à 150 000 U/kg/jsans dépasser 12 M UI par jen 2 ou 3 injections
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Cirioni et al, Crit Care Med 2007
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Taux de mutation élevé+ mécanisme d’action
Pour certaines souches (dont quelques souches coli -R)la coli restaure la sensibilité aux pénèmes
Ullman ICAAC 2009 - Souli AAC 2009
colimycine et quoi …?
En pratique tester les associations
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- 100 adults who developed Gram-negative VAP.- systemic antibiotics according to the decisions of their responsible physicians- randomized to receive an additional 4 mL of nebulized sterile normal saline
(NSS) (n.49) or nebulized CMS equivalent to 75 mg of colistin base in 4 mLof NSS (n.51) every 12 h until systemic antibiotic therapy of VAP was ended
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76 souches Acinetobacter XDR, 95 souches de Pseudomonas9 associations in vitro
Bremmer et al, ID Week 2015 poster 1830
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Bremmer et al, ID Week 2015 poster 1830