Faut-il traiter les malades colonisés à Candida sp. en réanimation?

1. 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 U823 Grenoble, France

2. 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?

3. 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

4. Candidémies en réanimation

5. Nosocomial BSI in ICU OR=8.83 Garrouste-Orgeas et al – Clin Infect Dis – 2006; 42:1118

6. early treatment (≤ 48 h) is associated with a better survival rate Nolla-Salas J et al. Intensive Care Med 1997; 23: 23-30 Delay in instauration of appropriate treatment is prejudicial to candidaemic ICU-patients • Late treatment is independently associated with death (odds ratio 1,52 ; p < 0,05) 50 45 40 35 30 Mortality % 25 20 15 10 5 0 Culture Day 1 Day 2 Day ≥ 3 day Days to start of fluconazole Garey KW et al. Clin Infect Dis 2006; 43: 25-31.

7. Early antifungal treatment: a mouse model Example of the 105 challenge • Challenge with 2 X 104 and 105C albicans intravenously • Treatment at D-1, Day0, Day1, 2 and 3 • AmB, Flu, CAS • 12 mice per experiments CAS Placebo  Start d-1  Start d0  Start D+1  Start D+2  FLU Mac-Callum AAC; 2004: 4911-4914

8. Patients en réanimation: plusieurs facteurs de risque Intervention chirurgicale Sepsis Antibiotiques Patient en réanimation Durée de séjour Sévérité Alimentation parentérale MSJ Procédures “invasives“ - cathéters vasculaires - sonde vésicale - intubation Hémodialyse

9. 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?

10. Eukariotic cells Slow growth, weak CO2 production time to positivity Se detection Timing to positivity of Blood cultures in humans • Usual aerobic. anaerobic bottles, automated systems 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

11. 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

12. Diagnostic tests Mannan 13/32 BD Glucan 17/32 0 0 0 10 3 5 10 PCR 18/32 Alam et al - BMC Infectious Diseases 2007, 7:103

13. (13)-β-D-GLUCAN CONCENTRATIONS _____ BG values Pg/ml _____ _____ _____ PCBSI NCBSI CONTROLS CBSI 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

14. 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?

15. 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 non-neutropénique

18. Infected Colonized Colonization index (preemptive treatment) • 29 patients/11 IFI (8 candidaemias) • Colonization index N. site(s) colonized N. sites sampled • Cohort prospective surg. ICU - 5,3 sites /patient 1,0 0,8 0,6 0,4 0,2 0 140 0 10 20 30 40 60 80 100 Pittet et al. Ann Surg 1994 Dec;220(6):751-8

19. Candida spp. colonization significance in critically ill medical patients: a prospective study 1 0,9 * * 0,8 * 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 day 7 (n=92) day 42 (n=5) day 49 (n=4) day 14 (n=49) day 21 (n=26) day 28 (n=15) day 35 (n=12) baseline (n=92) * Indicate statistical difference as compared with baseline value Colonization index in medical ICU CI ≥ 0,5 = 39% No candidaemia P.E. Charles et al., Intensive Care Med (2005) 31:393-400

20. 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 97 (42%) without pneumonia 135 (58%) with pneumonia 58 patients without Candida in LRT 0 Candida pneumonia 77 patients with Candida in LRT 0 Candida pneumonia W. Meersseman et al.; Intensive Care Med. (2009) 35:1526-1531

21. 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

22. Clinical prediction rule validation on a retrospective international cohort Ostrosky-Zeichner – 48th ICAAC- M 1853

23. Candida score • Construction n =1699 pts (Leon CCM 2006) • Parenteral nutrition 1pt OR = 2,48 IC95:1,16 - 5,31 • Surgical admission 1pt OR = 2,71 IC95:1,45 - 5,06 • Multiple Colonization 1pt OR = 3,04 IC95:1,45 - 6,39 • Severe sepsis 2pts OR = 7,68 IC95:4,14 - 14,22 • External Validation n =1107 pts (Leon CCM 2009) 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

24. Questions • Le traitement des candidoses invasives doit être précoce et efficace • Faiblesse des tests diagnostiques • Qui traiter avec quelles conséquences potentielles?

25. Who needs to be treated (MV patients >4 days)? 31,192 patients Length ICU stay >7days 1,205 patients Inadequate data collection 85 patients Short life expectancy (APACHE II > 35) 13 patients Study population 1,107 patients Neither colonized nor infected 215 patients 834/1107= 75% Candida spp. Colonization 834 patients 4.8% pts>7d 6.9% colo+ Proven Candida infection 58 patients Leon et al - Crit Care Med 2009; 37:1624 –1633

26. Fongiday 169 centres 2047 patients 1893 without systemic antifungals (SAT) 154 (7.5%) with SAT d28 follow-up ok 2032 patients (99.3%) Timsit et al – ICAAC 2009 Azoulay et al – Crit Care Med submitted

27. Fongiday Timsit et al – ICAAC 2009 Azoulay et al – Crit Care Med submitted

28. Who needs to be treated (MV patients >4 days)? Risk factors + colonization +- 30-80% Prophylactic Colonization + Risk factors + Sepsis +- (>30%) Preemptive Risk factors + Sepsis + Colonization+- Empirical (Probabilistic) Invasive candidasis 1-3% Curative British Society for Antimicrobial Chemotherapy Working Party. Int Care Med 1994; 20: 522-8.

29. SAT decreased colonization index Garbino, Intensive Care Med 2002

30. Prophylactic treatment: Meta-analyses Playford G et al – JAC 2006; 57:628-638; Vardakas KZ et al – Crit Care Med 2006; 34:1216-1224; Ho KM et al – Crit Care 2005;9:R710 ; Cruciani M et al – Intensive care Med 2005; 1477-1485; Shorr A et al Crit Care Med 2005; 33:1928-35;

31. Traitement prophylactiqueMeta-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; Vardakas KZ et al – Crit Care Med 2006; 34:1216-1224; Ho KM et al – Crit Care 2005;9:R710 ; Cruciani M et al – Intensive care Med 2005; 1477-1485; Shorr A et al Crit Care Med 2005; 33:1928-35;

32. 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

33. Fluco use Restriction of fluconazole use for prophylaxis Non-albicans candidaemia C. albicans candidaemia X Bassetti et al – JAC 2009; 64:625-629

34. Antifungals infection pressure DDD/1000 pt-days C. parapsilosis rate Forrest GN et al – J infect 2008; 56:126

35. Caspo and fluco exposure influenced the epidemiology of candidaemia Lortholary O et al - AAC Accepts, published online ahead of print on 15 November 2010

36. Caspo and fluco exposure influenced the epidemiology of candidaemia Lortholary O et al - AAC Accepts, published online ahead of print on 15 November 2010

37. Évolution des écosystèmes fongiques et utilisation des antifongiques Grenoble Rea Med 1511 premières souches Fournier P et al – SFMM 2010

38. Evolution des écosystèmes fongiques et utilisation des antifongiques DDD/1000HD Fournier P et al – SFMM 2010

39. Treatment of colonized patients in ICU? • No RCTs

40. Antifungals for CVC tip > 103Cfu/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

41. 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: • Patients colonised with CCI ≥ 0,4 • 20% of the cohort: • fluconazole: 800 mg D1 and then 400 mg/j IV x 14days # highly positive samples # samples R. Piarroux et Al - Crit Care Med 2004; 32:2443–2449

42. Assessment of preemptive treatment to prevent severe candidiasis in critically ill patients R. Piarroux et Al - Crit Care Med 2004; 32:2443–2449

43. 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

44. 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

45. RCT double blind Fluconazole 200 mg (n=18) vs placebo (n=19) Septic shock with nosocomial pneumonia or intra-abdominal sepsis Empirical fluconazole vs placebo 30-days death: Fluco 22% vs Placebo 54% p = 0,015 But only one candidemia! And parameters imbalanced Jacobs S et al. CCM 2003

46. 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 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 Assessment criteria = composite score Initial fever resolution No emerging IFI No toxicity-related trial stopping No use of another systemic AF Empirical Fluconazole vs Placebo for ICU Patients Schuster et Al, Annals of Internal Medicine

47. Empirical Fluconazole vs Placebo for ICU Patients Schuster et Al, Ann Intern Med. 2008 Jul 15;149(2):83-90

48. 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

49. Quels traitements?

50. 2009; 8:23 11 RCTs Candidose invasive tout confondu 1 étude sur les neutropéniques