Treatment of catheter-related infections

1. Treatment of catheter-related infections Jean-François TIMSIT CHU Albert Michallon Université Joseph Fourrier, INSERM U578, Grenoble France Slides available on http://www.outcomerea.org

2. Epidemiology of catheter-related bacteremia in HD patientsAllon M – Am J Kidney Dis – 2004; 44:779

3. Epidemiology of catheter-related bacteremia in HD patientsAllon M – Am J Kidney Dis – 2004; 44:779 • 25% of the 300,000 US HD patients • 2-fold: infection-related hospitalization and death • 2.5 to 5.5 cases/1000 pts days = 0.9 to 2 episodes/patient-year  67,500 to 150,000 episodes/year  10%= 7,000 to 15,000 with serious complications

4. CR- Infection in HD patients • 11.7% of septicemia in HD pts • Temporary uncuffed cath. 1.6 to 7.7 bacteremias / 1000 catheter-days • Tunneled or cuffed cath. 0.2 to 0.5 bacteremias / 1000 catheter-days • Staphylococci coag neg. 40-77%, methicillin resistant 40-75% • Enterococci, gram neg rod. • Metastatic complications: 8.7 to 50% (med 25%) • Studies • Microbes •  cuffed cath. Peleman et al – Nephrol dial transplant 2000; 15:1281

5. Complications associated with cuffed HD Cath. Nephrol Dial transplant 2001; 16:2194 1 episode of CRS per 25.6 Pts months 24% in the first insertion week

6. CR- Infection in HD patients

7. Contamination From the hub Cross contamination Cutaneous flora Extraluminal cutaneous Colonization SKIN VEIN Hematogeneous Colonisation Mechanisms of colonization From Maki DG et coll., in "Hospital Infections", Bennett JE & Brachman PS, 1992, 849-98.

8. Extraluminal Colonization Short term CVCs Colonisation Of the endoluminal surface Long term CVCs Slime

10. Predisposing factors

11. Spectrum of CRBSI associated bacterial flora Saxena AK et al – Swiss Med Wkly 2005; 135:127

12. Spectrum of CRBSI associated bacterial flora

13. CRS : The treatment is depending on the • Severity of the sepsis • Underlying illness (immunosuppression, prothesis). • Micro-organisms identified or suspected • Results of the blood cultures (positive or not). • Need and easiness of a central venous access

14. CRS: What should be the questions? • What should be done with the CVC? • Should we prescribe systemic antimicrobials ? • If Yes, which one? • What should be done in case of failure ? • What should be the duration of treatment ?

15. What should be done with the CVC? • Should we prescribe systemic antimicrobials ? • If Yes, which one? • What should be done in case of failure ? • What should be the duration of treatment ?

16. What should be done with the catheter ? Two constraints : To avoid useless removal of CVCs (75% cases) and further risks of catheter insertion  To save patients and avoid complications of infection

17. CRB diagnosis in HD patients • 59-81% of HD patients with fever or chills have positive BC • ¾ related to CRI (pneumonia, foot infections) • Use DTP methods (???) • When? before dialysis session, during the session? • BC via peripheral vein often difficult (39%) • Significance of a positive BC via the cath. Lumen? • Bacteriologic evaluation in freestanding HD units? Classification system: Definite: C/P quantitative BC> 10 Probable: Positive BC and no evidence of other infectious site Possible: neg BC and resolution of fever at CVC removal

18. Severe sepsis of unknown origin Catheter removal (or Guidewire exchange) Which antimicrobials? How to diagnose complications? Fever, chills without severe sepsis Positive blood culture Is it possible to keep the CVC without risks? 2 situations

19. Type et incidence of severe complications (n = 102) Shock Sepsis Thrmb. Sept. Other Total (%)* CNS 3 1 1 1 6/33 (18) S. aureus 3 3 4 8 12/32 (38) Enterococci 0 0 0 0 0/3 GNB 2 0 0 0 2/10 (20) P.aeruginosa 1 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

20. Is catheter removal associated with a higher cure rate and with an improved outcome?

21. The Slime… Slime production (SCN) 24h cellulose (x 5000) SCN culture

22. MICs (107 cfu/ml) (mg/l) MH Slime 1.56 6.25 4 6.25 >100 >32 0.19 12.5 64 1.56 25 16 0.79 >100 >126 0.79 25 32 CNS-Carsenti-Etesse 2000 Oxacillin Vancomycin Clindamycin Ciprofloxacin Gentamicin Netilmicin MBC of attached bacterias increased by 128-256 fold 1- Bacterias with slime production have an increased MICs and MBCs to ABt 2- The Biofilm increase the resistance of bacteria to ABt

23. Catheter removal and duration of candidemia Rex et al -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<0.001 - GWX: 6.3 + 1.8 j Catheter removal should be prefered

24. Candidemia: CVC Removal and mortality Nguyen et al - Arch Intern Med 1995;155:2429 427 consecutive patients with candidemia Multicentric prospective study MortalityKT removed: 21% vs KT in place: 41% p<0.001 Microbio failure (multivariate analysis) Neutropenia 0.002 Intra-abdo 0.02 KT left in place 0.05 Mortality (multivariate analysis) ICU patients <0.001 Age > 60 y 0.004 Steroïds 0.02 Candidal pulmonary metastasis <0.001 KT left in place <0.001

25. Candidemia: CVC removal and mortality: meta-analysis • 4 studies with severity scores adjustment Anaissie 1998 (n=491) Retro adjusted OR: 2 (1.4-2.9, p=0.06) Nucci 1998 (n=54) Pro adjusted OR: Nucci (2) 1998 (n=145) Pro adjusted OR: 4.22 (2-11.6) Luzzatti 2000 (n=189) retro adjusted OR: 1.61 (1.01-2.63, p=0.047) Analyses are biased because CVCs removal is associated with severity… Nucci – Clin Infect dis 2002; 34:591

26. 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) %

27. Is candidemia catheter-related? Raad I et al – Clin Infect Dis 2004; 38:1119 • 111 catheter-related candidemia and 52 secondary candidemia No CS 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<0.01 Non disseminated infection * OR 9.7 (3.5-26.3), p<0.01 Good response to antifungal therapy* OR 2.9 (2.2-7.2), p=0.03 (*) Dissemination to non contiguous sites Resolution of fever and chills, BC neg.

28. Outcome of candidemia: time of catheter removal after the first positive culture Raad I et al – Clin Infect Dis 2004; 38:1119

29. Predictors of failure to respond to antifungal therapy Raad I et al – Clin Infect Dis 2004; 38:1119

30. Proposed algorythm for candidemia Raad I et al – Clin Infect Dis 2004; 38:1119

31. 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) Kuhn DM - Antimicrob Agent Chemother 2002; 1773 Ramage R - Antimicrob Agent Chemother 2002; 3634 Bachmann SP- Antimicrob Agent Chemother 2002;3591

32. Fungal biofilm and drug resistance • Mechanism not completely understood • Biofilm cells resist > planktonic cells? • Role of few persisters cells • Grew slowly in the presence of antimicrobials, • A particular resistance to program cell death (apoptosis) induced by antimicrobials?

33. S. aureus bacteremia: Catheter removal? • 50 CRB (retrospective) • Long-term (16) or short-term (34) CVCs % P=0.01 Malanovski GJ - Arch Intern Med 1995;155:1161

34. 65 S. aureus bacteremia in HD patients Marr et al – Kidney Int 1998; 54:1684

35. Absence of catheter removal is an independent predictor of treatment failure in Catheter-related-S aureus bacteremia Fowler et al – Clin Infect Dis 1998; 27:478 244 patients • Advices by the infectious diseases department • 12-month follow up • Advice followed: 112 pts (49.5%) Perform TEE, removed infected intravascular devices, perform surveillance BC, use beta-lactam as often as possible (MSSA)

36. HD is significantly associated with hematogeneous complications (multivariate analysis) Fowler et al – Clin Infect Dis 2005; 40:695

37. In vivo biofilm-bacterial killingWilcox MH et al – J antimicrob Chemother 2001; 47:171 • 50 µl blood: acridine orange Gram pos HD biofilm + quantitative colony count (100 µl of blood) • HD cath removed : VAN 1g 2 hours and then 10 ml flush of 0.9% saline • Endoluminal biofilm recovered using special brushes Eradication failed+++ Uge variation of biofilm VAN level (0.2-89 mg/g!!) Reduction of 84-100% bacterial count (med 95%) with VAN and Reduction of 0-98% (med 91%) with LNZ

38. LNZ, VAN, GEN, eperezolid in vitro S. epidermidis catheter-related biofilm infectionsCurtin J et al – Antimicrob Agent Chemother 2003; 47:3145 • Biofilm: modified rubbins device 12 sampling ports of 50 mm2 + SE ATCC 35984 + continuous flow of MH broth 24 hours + 24 hours of sterile MH broth feeding • AB lock of VAN (10mg/ml),LNZ (4),GEN (10),EPZ (2mg/ml) 24, 72, 168 and 240 hours

39. 149 Patients with bacteremia (Pseudomonas spp et Xanthomonas) Elting et al - Medicine 1990;69:296 % P<0.00001 49/49 4/4 32/62 2/6

40. Coagulase negative staphylococci Raad et al ICHE 1992 70 patients Cath. removed n=36 Catheter not removed n=34 4 Deaths due to sepsis 4 Deaths due to sepsis 6 bacteremia recurrences after 3 months 1 bacteremia recurrence after 3 months

41. Enterococcal CR-BSISandoe JA –JAC 2002; 50:577 • 3-year cohort (n=268)  61 CRBSIs Cured 4 2 100 1 27 76 0 11 65 45 Failed 0 0 0 1 4 13 0 2 10 7 Recurred 0 0 0 3 1 11 4 1 25 9 Appropriate cell wall agent + aminoglycoside Catheter maintained (n=4) Catheter removed (n=2) % Appropriate cell wall agent alone Catheter maintained (n=5) Catheter removed (n=30) % Inappropriate or no antimicrobial Catheter maintained (n=4) Catheter removed (n=16) % Total

42. CRB and dialysis: catheter removal? 102 patients 41 pts/62 bacteremias • 102 patients/16081 days tunneled cath. • 62 bacteremias (30% MRSA, 33 % other Gram+, 24% GNB, 5% P. aeruginosa) 38 without removal 24 removal< 3 days 12 success 9/41 (22%) complications always Gram+ (4 IE, 6 osteomyelitis, 1 arthritis) 26 failures 6 catheter removed without infection 6 cath still in place (3 months) Maar KA Ann. Intern Med 1997;127:275

43. CRB and CVC removal • The CVC maintained • Success: Gram + 6/26 (23%) vs Gram- 6/12 (50%) (NS) • NOT associated with more secondary infections/deaths RR:0,8, IC95%, 0,2-2,7 • BUT with more relapses: 68% vs 17% (RR:4,1, IC95%, 1,6-10,3) • Marr et al - Ann. Intern Med 1997;127:275

44. Tunnelitis Antimicrobials alone Microorganisms Cured Failures (n=5) (n=15) S. aureus1 1 P. aeruginosa0 7 polymicrobial1 5* Negative culture3 2 * 4 with P. aeruginosa et 1 with P. maltophilia Benezra et al, Am. J. Med., 1988, 85, 495

45. Catheter removal: Yes vs No • S. aureus: 50 CRB (retrospective) • Persistent BC:11 vs 56% (p=0.01), Deaths: 5 vs 20% Malanovski GJ - Arch Intern Med 1995;155:1161 • X. maltophilia: • % cured: 49/49 vs 32/62 (p<0.0001) Elting et al - Medicine 1990;69:296 • Gram negative bacili • % relapse: 1/67 vs 5/5 (p<0.001) Hanna et al – ICHE 2004; 25:646 • Enterococci (n=61) • % cured: 5/13 vs 40/47 (p<0.01) • especially if aminoglycosides are not associated with cell-wall agent Sandoe JA –JAC 2002; 50:577 • CNS: • Deaths: 4/36 vs 4/34, recurrence after 3 months: 1/36 vs 6/34 Raad et al ICHE 1992

46. CRB:CVC removal or not Situation/microorganism CVC maintained Severe Sepsis No Local signs No Thrombosis (Doppler) No S. aureus No Pseudomonas No Candida sp No CNS and no severe sepsis Yes Other Gram neg. ???

47. Recommendations • Catheter removal • Exit site or tunnel infections Preferentially catheter change • If impossible • Catheter salvage attempted • With BC (peripheral and via the catheter) • 2-day AB trial • If fever>2 days or hemodynamic unstability: catheter removal • If persistent fever or positive BC after catheter removal: metastatic complications Peleman et al – Nephrol dial transplant 2000; 15:1281

48. The CVC… 1. CVC removal 2. Diagnosis catheter in place 3. Guidewire exchange (GWX)

49. 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

50. Watchful waiting vs immediate CVC removal in the ICU - Rijnders BJ et al – Intens Care Med 2004; 30: 1073-80 (2)