Conduite à tenir devant une suspicion dinfection liée aux cathéters en réanimation Jean-François TIMSIT CHU Grenoble UJF/Inserm U 823 Nice - Juin 2007

Conduite tenir devant une suspicion dinfection lie aux cathters en ranimation Jean-Franois TIMSIT CHU Grenoble UJF/Inserm U 823 Nice - Juin 2007

Faible niveau de preuve ILC : Le traitement depend de svrit du sepsis svrit du sepsis maladies sous-jacente (immunodpression, prothses). maladies sous-jacente (immunodpression, prothses). Micro-organismes identifis ou suspects Micro-organismes identifis ou suspects HC positives ou ngatives HC positives ou ngatives Utilit et facilit de labord veineux central Utilit et facilit de labord veineux central

Deux constraintes : Eviter lablation inutile des CVCs (75% cases) et le risque associ de complications mcaniques Sauver les malades et viter que linfection se complique En cas de sepsis grave le cathter DOIT tre enlev

2 situations Sepsis svre de cause inconnu Ablation du CVC (or ou change sur guide?) Quels antibiotiques? Comment dpister les complications et les traiter? Fivre sans signes de sepsis svre en ranimation Hmoculture positive Est il possible de conserver le cathter sans risques?

Le cathter? 1.Ablation du cathter Est associe un plus grand nombre de gurison et une amlioration du pronostic 2. Diagnostic cathter en place 3. Echange sur guide (GWX)

Biofilm formation Schneegurt, MA. Wichita St. University, Microbiology 103.

Why form a bioflim? Jefferson KK. FEMS. 2004;236:163-73.

Susceptibility of biofilm organisms OrganismAntibiotic MIC or MBC (mcg/mL) Effective [ ] vs. biofilm (mcg/mL) S. aureus (NCTC 8325-4) Vancomycin2 (MBC)20 P. aeruginosa (ATCC 27853) Imipenem1 (MIC)>1,024 E. coli (ATCC 25922) Ampicillin2 (MIC)512 P. pseudomalleiCeftazidime8 (MBC)800 S. sanguisDoxycycline0.063 (MIC)3.15 Adapted from Donlan RM, et al. Clin Microbiol Rev. 2002;15:167-93. Minimal biofilm eradication

1- Bacterias with slime production have an increased MICs and MBCs to ABx 2- The Biofilm increases the resistance of bacteria to ABt SCN culture CVC maintenance is always risky

-Decrease of the duration of the candidemia New site 5.6 days vs Other 2.6 days - Bias: APACHE II 14.5 vs 16.9 p=0.03 Other catheter: 1.2 vs 1.8,p

Management of CVCs in patients with cancer and candidemia Raad I et al Clin Infect Dis 2004; 38:1119 1993-1998: 404 episodes of candidemia (50% ICU) with 1 CVCs for more than 1 days 3 categories Primary candidemia : 241 (60%) Secondary candidemia: 52 (13%) CVC related candidemia : 111 (27%) + tip cult (66) or quantitative BC > 5:1 (45) %

Is candidemia catheter-related? Raad I et al Clin Infect Dis 2004; 38:1119 111 catheter-related candidemia and 52 secondary candidemia No corticosteroids within 1 month:OR 3.5 (1.3-9.4), p=0.02 No chemotherapy within 1 month: OR 4.3 (1.5-13.3), p 15 cfu/ml Maki et al. N Engl J Med 1977; 296: 1305-1309 Culture quantitative: Portion endo et extra-luminale prfrable ultrasonication Sherertz et al J Clin Microbiol 1990 Vortexage dans 1 ml de RL strile Brun-Buisson - Arch Int Med 1987; 147:873

Influence de la culture des KT sous antibiotiques actifs KT intrapritonaux/souris Infects S. epi puis trait par TEICO ou RMP A J1 culture neg ou micro-colonies Culture vs dtection du mRNA (bactries viables)+PCR quanti J2 Vandecasteele et al Diagnostic Microbiology and Infectious Disease 48 (2004) 8995 Contrle 94% (30/32) TEICO 72% (49/68) 81% (55/68) Sensibilit >1000 cfu/ml >100 cfu/ml RMP 86% (62/72) 94% (68/72)

The CVC ? 1.CVC removal 2.Diagnosis catheter in place Direct examination Other methods based on culture results 3. Guidewire exchange (GWX)

Modes de colonisations Endoluminale Extraluminale

Endo ou extra-luminale? Cercenado 1990 Fan 1988 Cicco 1989 Salzman 1993 Linares 1985 Segura 1993 Weightman 1988 Nb KT/dure 139/8.6 156/ 15 109/18.2 113/23.9 22/20 400/23 42/ 114 Nb inf sys 53 11 6 28 20 24 11 Hub 12 1 3 21 14 9 8 Peau 30 4 3 7 2 5 Mixte 8 2

Diagnostic catheter in place A negative cutaneous swab culture of skin entry 100% Negative predictive value Paired (Peripheral/central) quantitative BC > 5/1 or Differential time to positivity of BC > 120 mn Se/Sp > 90%

Test diagnostic rapide 100 L de sang par le KTC Traitement par l'acide dtique lyse et centrifugation puis pastilles de cytocentrifugation puis coloration acridine orange et Gram 100 champs, 2 colorations Kite et al Lancet 1999; 354:1504 ILC+ 48 2 ILC- 5 57 Gram + AOLC test Positif Ngatif

Endoluminal brush and Acridine Orange stain Diagnosis of Catheter - Related Infections Tighe et al. J Parent Enter Nutr 1996; 20: 215-218 Group 1: Acridine orange stain Group 2: Acridine orange stain and endoluminal brush 50 CVC 2 AOLC + 15 AOLC + 50 CVC 17 cult + 18 cult + Se: 18% Se: 83%

Culture cutane: valeur prdictive 134 CVC de ranimation, 70% S.clav. Dure d'insertion:10 + 6 jours couvillonnage de 25 cm 2 site d'insertion 75 cultures peau positives / 26 CVC > 10 3 cfu/ml concordance bactrienne avec la culture du KT dans 23/24 cas de colonisation de CVC Se 92.3% Sp 52.7% VPP: 32% VPN 96.7% VPP moins bonne pour les G+ (24% vs 47%) Mah I et al. Reanim Urg 1998;7:17

Prlvements cutans orients 132 Kt, hmatologie, culture (Maki +Sheretz) Cultures systmatiques tous les mois vs Culture en cas de suspicion d'infection N 87 15 Se 18 75 Sp 83 100 VPP 13 100 VPN 88 92 Systmatiques Orients Raad Clin Infect Dis 1995; 20:593 (*) couvillon de 24 cm 2, culture quantitative en milieu liquide

Hmoculture quantitative comparative en ranimation 14/283 infects, 19 ont au moins une HC sur CVC + Seuil KT/P=2Se 98 %Sp 98% Seuil KT/P=8Se 92.8 %Sp 98.8% Seuil KT/P=100Se 79%Sp 99% Que faire des HC centrales positives isoles? Quilici - CID 1997; 25:1066

Dlai de positivit des hmocultures (DTP) Dlai de positivit des hmocultures (DTP) HC sur cathter HC sur cathter HC priph. Turbidit du sang fonction de linoculum bactrien 0 4 8 heures DPT = 4 h.

Dlai de positivit Validation in-vitro Blot F et al - J Clin Microbiol. 1998;105-109 Validation in-vivo (ranimation cancrologique) Seuil DTP= 120 mn Blot F - Lancet 2000; 354: 1071 MAIS Que faire de hmocultures dissocies? Explore essentiellement le mode de contamination endoluminaleutilit en ranimation? Rijnders BJ et al - Crit Care Med. 2001 Jul;29(7):1399-403 Cependant valeur diagnostique aussi bonne pour les CVCs de moins ou de plus de 30 jours Raad et al Ann Intern Med 2004; 140:18-25

14 mois, 93 suspicions d ILC CVC courte et longue dure, dispositifs implantables Paires d hmocultures et ablation du KT dans les 48 heures Sp: 91 (95% CI 59 -100%) Se: 94 (95% CI 71 - 100%) Blot F - Lancet ; 354: 1071-77

Paired blood cultures Total CRI Absence of CRI Positive (H+/P+) 28 17 11 DTP >120 min 17 16 1 DTP

Endoluminal colonization: in which lumen? Dobbins et al CCM 2003; 31: 1688 CVCs not suspected No CRBSI (n=50) CVCs suspected No CRBSI (n=25) CVCs suspected CRBSI (n=25) N lumens colonized* 1 2 3 630630 430430 10 5 N CVCs Maki roll +281420 (*) endoluminal brushes> 100 CFUs

In situ diagnosis of intravascular catheter-related bloodstream infection: A comparison of quantitative culture, differential time to positivity, and endoluminal brushing Catton et al Crit Care Med 2005; 33:787

Watchful waiting vs immediate CVC removal in the ICU - Rijnders BJ et al Intens Care Med 2004; 30: 1073-80 Exclusion: Neutropenia, foreign body, transplantation BSI (positive BC) Erythema, induration or purulence HD instability Previous DNR

Watchful waiting vs immediate CVC removal in the ICU - Rijnders BJ et al Intens Care Med 2004; 30: 1073-80 (2) New Abx after inclusion: 13 of 32 patients in the WW 22 of 32 in the SOC-(P=0.04).

limitations Weak and subjective exclusion criterias Low power Rate of non bacteremic sepsis not reported Decrease in the rate of suspicion of CR-BSI during the study: First half 85/704 vs 2nd half 59 / 790 p=0.003 Rijnders BJ et al Intens Care Med 2004; 30: 1073-80

The CVC ? 1. CVC removal 2. Diagnosis catheter in place 3. Guidewire exchange (GWX) Associated with fewer mechanical complications OR: 0.48 [[0.89-3.33] But a trend toward a higher risk of infection of the 2nd CVCs OR: 1.72 [0.89-3.33] Cook DJ Crit Care Med 1997;25:1417

Changement sur guide 158 changements sur guide / 13 cultures de guide positives (8.2%) Mme germes sur les 2 CVCs et le guide dans 6 / 7 cas Colonisation du guide prdictif de la colonisation du CVC pos (p=0.05) Palmer S ICHE 2005; 26:506

Guidewire exchange (GWX) 1. When to start antimicrobials? Before the guidewire exchange Before the guidewire exchange 2. Attitude with the second CVC Keep it if culture neg. Keep it if culture neg. Remove it if culture pos. Remove it if culture pos. It might be possible to keep the 2nd CVC in case of CNS or Enterobacteriaceae???? It might be possible to keep the 2nd CVC in case of CNS or Enterobacteriaceae????

Critres diagnostiques Infection bactriemique CVC + ou HC diffrentielles + ou culture du site dinsertion + et HC au mme germe Absence dautre site + expliquant les HC ILC non bact ri mique C.V.C.+ Et Une r gression totale ou partielle dans les 48 h ou Orifice purulent ou tunnelite. Ractualisation du consensus Ranimation 2003;12: 258-265

Catheter tip colonization: a surrogate? Meta-analysis 1990- 2002 randomized study 29 studies selected Quantitative or semiquantitative cult and CR- BSI Correlation: R squared= 0.48, p< 0.001 BSI=0.77 + 0.73(CTC) Rijnders et al Clin Infect Dis 2002; 9:1053

Should we always prescribe systemic antimicrobials ? Always if severe sepsis or septic shock Always if severe sepsis or septic shock Positive blood cultures Positive blood cultures - Yes, always - For CNS (2 positive BC) In case of negative BC ????

Which micro-organisms are associated with severe complications? ?(n = 102) Shock Sepsis Thrmb. Sept. Other Total (%)* Shock Sepsis Thrmb. Sept. Other Total (%)* CNS3 1 1 1 6/33 (18) S. aureus3 3 4 812/32 (38) Enterococci0 0 0 0 0/3 GNB2 0 0 0 2/10 (20) P.aeruginosa1 0 1 0 2/4 (50) Candida spp.0 7 0 0 7/11 (64) Polymicrob.2 1 1 0 4/9 (44) * Nb Complications/Nb of events Arnow PM et al. 1993 Clin Infect Dis

Antimicrobials (BC neg) SituationAntimicrobials Candida spp, S. aureus or P. aeruginosa Candida spp, S. aureus or P. aeruginosa Sepsis after CVC removalYes No fever after CVC removalNo ? Other micro-organisms Fever after CVC removalNo* Fever after CVC removalNo* If GWX or CVC in placeYes __________________________________________________ * Except immunosuppression

Quelles molcules doit t on utiliser? C-CLIN Sud Est 2000 C-CLIN Paris-Nord Ra Cat 2000 Colonisation CNS 40 %44 % S. aureus 10 %6 % Entrocoques 3 %- BGN dont pyocyanique 40 % 12 % 37 % 15 % Candida 3 %2 % Infection 28 % 19 % - 47 % 22 % 1 %

Grandes variations selon les centres

Lpidmiologie varie en fonction des annes et des pidmies from U.H.L.I.N Bichat: I Lolom, JC Lucet

Groupes (N /N events) S. aureus SCN Enterococcus P. aeruginosa A. baumannii E. coli Autres Gram neg. Champignons Culture >10 3 cfu/ml Tunneliss (15/14) 1 4 0 3 2 1 Controles (21/19) 1 4 1 4 1 2 7 1 Infection sytmique de KT Tunneliss (6/5) 0 2 1 Controles (17/15) 1 2 1 4 0 2 6 1 Microorganismes voie fmorale Timsit et al Ann intern Med 1999 9 21 2 4 17 2

Choice of the molecules Situations active on CNS If severe, consider immediately GNB and yeast Molecules Glycopeptide + gentamicin If GNB suspected: activity against P. aeruginosa Candida: fluconazole (800 mg laoding dose) or Ampho B (unstable patients) Rex et al N Engl J Med 1994 ;331:1325 Antimicrobials should be adapted to blood and catheter cultures Eichinocandins? AmpB - L LNZ? Lipopeptides?

Biofilm production and antifungal effects In the biofilm (C. albicans and C. glabrata): AMPHO B > Voriconazole > fluconazole Regrowth was noted in the biofilm Lewis et al Antimicrob Agent Chemother 2002; 3499 Killing of the biofilm cells better with eichinocandins (caspofungin) (activity against fungal cell wall +++) Kuhn DM - Antimicrob Agent Chemother 2002; 1773 Ramage R - Antimicrob Agent Chemother 2002; 3634 Bachmann SP- Antimicrob Agent Chemother 2002;3591

80,7 64,9 79,5 64,9 Favorable outcome : per-protocol Mora-Duarte J et al. NEJM 2002. % p = 0,03p = 0,05

Kuse et al - Lancet 2007; 369: 151927

What should be done in case of failure ? (sepsis and/or + BC > 3 days) Pharmacologic failure MRSA/glycopeptides Thrombophlebitis Thrombophlebitis New CVC colonization New CVC colonization Other septic foci (endocarditis+++) Other septic foci (endocarditis+++)

Vancomycin Pharmacocinetic variable and unpredictable: Dosage+++ Low level associated with failure Maintain trough > 15-20 g/ml especially if MIC > 1 g/ml Consider association: Gentamicin if possible, rifampin, linezolid?, dalfopristin-quinupristin? SUBSEQUENT DE-ESCALATION IF Methicillin sensitive+++

Septic thrombophlebitis Clinically silent Ultrasound Doppler. Ligation of the vein: very invasive, rarely indicated Optimizing the antimicrobial : Antibiotic dosing, 2 antimicrobials Longer duration: 4-6 weeks Heparin and fibrinolytic ?

Trans-oesophagal echography and S.aureus n 7 26 * * P < 0,0005 Adapted from Fowler et al. JACC 1997

Malanovski GJ - Arch Intern Med 1995;155:1161 Duration of treatment and complications: P=0.01 S. aureus: Relapse increases if treatment is less than 10 days

S. aureus CRB : Short treatment Meta-analysis 11 studies/ 132 Pts Late complications after treatment < 14 days 6.1% [95% CI, 2.0% - 10.2%] Rare but severe: 3 Endocarditis (1 surgery) 2 epidural abscesses (1 surgery) 2 bacteremias (1 death) Jernigan et al - Ann Intern Med 1993;119:304

Duration of treatment proposals (Positive BC) MicroorganismDuration (d) S. aureus 14 ( 4-6 weeks * ) S. aureus 14 ( 4-6 weeks * ) P. aeruginosa14 P. aeruginosa14 Candida spp. 14 ( 28 * ) Candida spp. 14 ( 28 * ) CNS7 ( 14/ 21 ** ) CNS7 ( 14/ 21 ** ) Enterobacteriaceae7 ( 14/ 21 ** ) Enterobacteriaceae7 ( 14/ 21 ** )______________________________________________________ * complications ** If CVC left in place or immunosupression

Nothing!! Nothing!! Probably not justified if afebrile after CVC removal? Probably not justified if afebrile after CVC removal? S. aureus et P. aeruginosa or immunosupression S. aureus et P. aeruginosa or immunosupression ?? (7d?) ?? (7d?) Duration of treatment proposals (Negative BC)

Antibiotic lock in ICU? Antimicrobial concentration high (X 50 to 100) Volume 2 ml (+ hparine if vanco, cipro, teico) Anticrobials stable: (even with heparine) vanco, cefazolin, ticar-clavu,cipro (Anthony et al, AAC 1999;2074) New locks:Minocyclin-EDTA, Ethanol, Taurolidine CVC use is impossible during the lock Injection 2 fold a day, for 2 to 3 weeks Associated IV antimicrobials Contra-indications: fungal infections, neutropenia, thrombophlebitis, tunnelitis, septic shock

Verrou (VLA) ou AB IV AB IV seulsVLA +/- AB IV 14 essais (1982 1995) Succs: 342/514 (66,5%) CVC tunnliss 7 essais (1990 1995) Succs: 138/167 (82,6%) Chambres implantables 5 essais (1988 2001) Succs : 90/120 (75%) Problmes de dfinition des infections Sites dinfection inconstamment cits Paramtres dvaluation de lefficacit diffrents

AAC 2007; 78-83 (*)I.R. is the inventor of catheter lock technology that involves alcohol. This patent is the property of The University of Texas M. D. Anderson Cancer Center.

Arch Pediatr Adolesc Med. 2006;160:1049-1053 Treatment success was defined as resolution of fever within 24 hours, no recurrence of positive blood cultures with the same organism, and retention of the IVD. Treatment failure was defined as recurrence within 30 days with the same pathogen or removal of the IVD because of a persistent infection. 70% Ethanol lock 45/51 success

Comit d'organisation : Responsables pour la commission des rfrentiels: B Guidet, R Robert, M Wolff, S Leteurtre Charg de projet : adulte : JF Timsit, pdiatrie : Ph Durant Experts : adulte : G Nitenberg, pdiatrie : Dageville Membres de l'ancien jury : G Bleichner, Y Letulzo, M Pinsard. Experts extrieurs : JC Lucet, B Souweine, L Soufir, P Longuet, J Merrer, A Lepape, F Blot, C Martin, G Nitenberg, O Mimoz, Ph Eggiman, G Colas, C Brun-Buisson Reanimation 2003

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Conduite à tenir devant une suspicion dinfection liée aux cathéters en réanimation Jean-François TIMSIT CHU Grenoble UJF/Inserm U 823 Nice - Juin 2007