1. Infectious complications during dialysis

2. Scope  Infectious disease in dialysis Epidemiology and importance Epidemiology and importance Diagnosis and management Diagnosis and management Prevention Prevention  Conclusions

3. Infectious disease in dialysis   Mortality:   General population perspective, Mortality rates attributable to bacterial infection have declined in many countries E.g. overall unadjusted death rate was 841.9 per 100 000 in the United States in 2003 Cardiac diseases (28.0%), malignancy (22.7%), and cerebrovascular disease (6.4%) Influenza/pneumonia (7 th rank, 2.7% ) and septicemia (10 th rank, 1.4% of mortality events) Natl Vital Stat Rep 2006; 54:1–120

4. Infectious disease in dialysis (Contd)   Mortality:   Infectious causes have consistently Ranked second to cardiovascular disease in reported causes of death in dialysis populations E.g. during the years 2002–2004, mortality rates in dialysis populations were 19.8 times those in the general population, and Mortality was attributed to septicemia in 9.7% and 2.5% of all deaths respectively Perit Dial Int 2008; 28(S3):S167–S171

5. Infectious disease in dialysis (Contd)   Infectious complications continue to be among the foremost causes of morbidity and mortality in hemodialysis (HD) patients The USRDS:1991-92, infection accounted for 12% of all deaths among HD patients In a subsequent report for the 1993-95, USRDS infection accounted for 15.5% of adult end-stage renal disease (ESRD) causes of death USRDS: United States Renal Data System

6. Infectious disease in dialysis (Contd) Kidney International 2001 (60):1–13

8. Infectious disease in dialysis (Contd)   A noteworthy study* Compared mortality attributed to sepsis in dialysis patients with corresponding rates in the general population for the years 1994 through 1996 Even when disparities in age, sex, race, and diabetes mellitus were taken into account, Mortality rates in dialysis patients were higher by a factor of 100 to 300 *Kidney Int 2000; 58:1758–64

11. Infectious disease in dialysis (Contd)  Trends  Infection hospitalizations substantially increasing over past 10 years, largely due to catheters  Infection hospitalizations increasing at a rate greater than cardiovascular hospitalizations  Much higher costs in patients with catheters  There is even likely a linkage between one access infection and associated ongoing risk of death  Higher mortality in catheter patients and facilities with more catheters (and grafts)

12. Infectious disease in dialysis (Contd)   Thus, Mortality from infectious diseases is much more prominent than might otherwise be expected in chronic dialysis patients

13. Infectious disease in dialysis (Contd)   Even though dialysis populations generally have pessimistic survival expectations, and infectious mortality is more prominent than in the general population, Remarkably few studies have examined the clinical epidemiology of septicemia in maintenance dialysis patients Perit Dial Int 2008; 28(S3):S167–S171

14. Infectious disease in dialysis (Contd)   Widely believed that Central venous catheters are primarily responsible for excessive rates of septicemia in HD populations

15. Relationships between factors associated with hemodialysis central venous catheter- related blood stream infections Nature Clinical Practice Nephrology 2007; 3(5): 256-266

16. Catheters are the major source of dialysis access infections Complications: Endocarditis Osteomyelitis Epidural abscess Septic shock Septic arthritis Septic thrombophlebitis Death

17. Infectious disease in dialysis (Contd)   Prospective study from France reported Catheter use was associated with a covariate- adjusted hazard ratio for septicemia 7.6 times that of native arteriovenous fistulae J Am Soc Nephrol 1998; 9:869–76.

18. Infectious disease in dialysis (Contd)   US group study Using HD patients with fistulae as reference group, rates of septicemia were shown to be similar in those patients, in PD patients, and in HD patients with synthetic grafts In contrast, septicemia rates in patients with central venous catheters were approximately twice as high as expected, a disparity that remained after extensive adjustment was made for baseline comorbidity patterns Perit Dial Int 2008; 28(S3):S167–S171

19. Consequences of Catheters  22% infectious complications, with septic arthritis, endocarditis and osteomyelitis  43% higher cardiovascular related death rate than fistulas in some studies  AVF after 90 days with 29% reduction in all- cause mortality compared to catheters  Greater all cause and infection related hospitalizations  Reduced dialysis adequacy, poorer quality of life and greater costs

20. Infectious disease in dialysis (Contd) Kidney International 2001 (60):1–13

21. Time to first CRB in patients with tunneled HD catheters Lee, AJKD, 2005

22. Infectious disease in dialysis (Contd)   Because the risk of serious bacterial infection and mortality is strongly related to mode of arteriovenous access, intensive efforts at creating native arteriovenous fistulas have been recommended U.S. National Kidney Foundation (NKF). Home > Professionals >KDOQI > Clinical Practice Guidelines > Vascular Access’ Fistula First” as a CMS breakthrough initiative: improving vascular access through collaboration. Nephrol Nurs J 2005; 32:686–7.

23. Infectious disease in dialysis (Contd)   It seems unlikely that Catheters can be avoided in all HD patients even with well-organized, fully-integrated systems Developing strategies to minimize infection risk in patients with catheters therefore remains important Perit Dial Int 2008; 28(S3):S167–S171

24. Diagnosis and management   The acute onset of fever and chills in a patient with a HD catheter and no localizing signs is easily recognized and is generally considered to be a CRB until proven otherwise Such an explosive presentation is often observed during the hemodialytic procedure, but could occur at any time during the interdialytic period Kidney International 2001 (60):1–13

25. Diagnosis and management (Contd)   Less acute presentations of CRB are also frequent, Especially in the older population and the immunocompromised May include any of the following the insidious onset of low-grade fever, hypothermia, lethargy, confusion, hypotension, hypoglycemia, or diabetic ketoacidosis Kidney International 2001 (60):1–13

26. Diagnosis and management (Contd) Main diagnostic approaches for Gram-positive bacteremia in dialysis patients UTI = Urinary tract infection Nephrol Dial Transplant 2008;23: 27–32

27. Diagnosis and management (Contd)   HD patients with suspicion of CRB must have blood cultures done immediately and should be promptly initiated on empiric antimicrobial therapy Kidney International 2001 (60):1–13

28. Nature Clinical Practice Nephrology 2007; 3(5): 256-266

29. Diagnosis and management (Contd)   Management of CRB in the HD patient has two aspects:   1. Antimicrobial therapy   2. Removal of the HD catheter, which is the source of the bacteremia Kidney International 2001 (60):1–13

30. Diagnosis and management (Contd)  1.  1. Antimicrobial therapy Initial empiric antibiotic therapy should take into consideration the frequency of the bacterial isolates in such settings Staphylococcal species have repeatedly been demonstrated to be the most prevalent (60 to 100%) bacterial isolates in HD patients with CRB The prevalence of S. aureus and coagulase negative staphylococci bacteremia is similar in most series Enterococci have been found in 11 to 19% of CRB Gram-negative rods are reported in up to 33% of cases Kidney International 2001 (60):1–13

31. Diagnosis and management (Contd)  1.  1. Antimicrobial therapy Some patients both gram-positive and gram- negative organisms have been isolated from the blood stream, indicating mixed bacteremia These data mandate that empiric antibiotic therapy should target both gram-positive and gram-negative organisms Specific antimicrobial therapy should replace empiric therapy as soon as the identity of the bacterial isolate is determined Kidney International 2001 (60):1–13

32. Nature Clinical Practice Nephrology 2007; 3(5): 256-266

34. Kidney International 2001 (60):1–13

35. Rx of catheter-related bacteremia: Principles and practice Allon, AJKD, 2004

36. Nephrol Dial Transplant 2008;23: 27–32

37. Treatment of CRB: What to do with the catheter?   2. Removal of the HD catheter, which is the source of the bacteremia Scientifically the most correct, it poses certain practical problems, especially in HD patients whose vascular access sites have been exhausted Kidney International 2001 (60):1–13

38. Strategies for treatment of catheter-related bacteremia   Systemic antibiotics alone (low rate of catheter salvage ~25%)--Ignore   Catheter removal with delayed placement of new catheter   Catheter exchange over guidewire

39.   New catheter Catheter with biofilm Can antibiotic locks kill bacteria in catheter biofilm?

40. Rationale for antibiotic lock   Bacterial biofilm develops within 24 hours in all indwelling catheters, and is the major source of catheter-related bacteremia   IV antibiotics do not treat the biofilm.   If antibiotic lock can kill bacteria in catheter biofilm, management of CRB would be simplified (no need to replace catheter)

45. Antibiotic lock protocol: Definition of outcomes   Failure: Persistent fever OR Positive surveillance cultures   Success: Resolution of symptoms at 48 hours AND Negative surveillance cultures one week after completing antibiotics

46. Poole, NDT, 2004

47. Antibiotic lock for treatment of CRB (summary)   Use of an antibiotic lock, in conjunction with systemic antibiotics, can eradicate catheter related bacteremia while salvaging the catheter in about 2/3 of cases   In 9 studies, 307/405 of CRB episodes (76%) were cured with an antibiotic lock

48. Success of antibiotic lock depends on the organism Poole, NDT, 2004

49. Prevention of CRB

51. Rate of catheter related bloodstream infections with antimicrobial lock solution versus heparin: Randomized studies CRB 7.7 times less likely with anti-microbial lock than with heparin lock. Jaffer, AJKD, 51: 233-241, 2008 Allon, AJKD 2008;51:165-168

52. 70% ethanol lock prevents CRB   Randomized study (64 pts) with Hickman catheters locked with 70% ethanol or heparin.   CRB was lower in ethanol lock group (0.6 vs 3.1 per 1000 catheter-days, p=0.008). Sanders, J Antimicrob Chemother, 2008   Randomized study of 92 Greek patients (103 uncuffed HD catheters) receiving 70% ethanol vs heparin locks.   CRB was lower in ethanol lock group (2.5 vs 6.7 per 1000 catheter-days (p=0.04). Sofroniadou et al, 2009 ASN abstract (F-FC300)

53. Methylene blue prevents CRB   Randomized study of 407 pts with tunneled HD catheters receiving a lock containing citrate + methylene blue + parabens (C-MB-P) vs heparin lock   Frequency of CRB was lower with C-MB-P vs heparin (0.24 vs 0.82 per 1000 catheter-days (p=0.005) Ash et al, 2009 ASN abstract (F-FC299).

54. Can lock solutions select for antibiotic-resistant infections?   No known resistance to ethanol, 30% citrate,m or taurolidine.   The 5 studies evaluating Abx locks used them for short periods of time (<6 months), and did not observe Abx resistance   A recent abstract raised serious concerns about the risk with long-term Abx lock prophylaxis

55. Can lock solutions select for antibiotic-resistant infections?   Prospective follow-up of 1488 catheter- dependent patients in Massachusetts receiving prophylactic gentamicin locks over a 4-year period.   Overall, CRB rate decreased from 17 to 3.7 per 1000 catheter-days (78% reduction).   Within 8 months of starting the protocol, they began to observe gent-resistant bacteremias. Landry et al, 2009 ASN abstract (F-FC301)

56. Can lock solutions select for antibiotic resistant infections? (cont)   Over the next 40 months, they observed 31 gentresistant bacteremias (including 19 Staph epi and 8 Enterococcus).   No episodes of gent-resistant S. epi CRB observed in 25 HD patients without catheters.   Among pts with gent-resistant Gram-positive CRB, 4 had endocarditis, 14 were hospitalized, 2 required ICU stays, and 6 died within 60 days. Landry et al, 2009 ASN abstract (F-FC301)

57. Are lock solutions safe?   Gentamicin lock produced median pre-HD gentamicin conc of 2.8 mg/L in one study   4 /42 pts (10%) c/o of intermittent dizziness (?mild aminoglycoside ototoxicity)   No toxicity with 30%citrate in one randomized study (Weijmer, JASN, 2005)   In a recent randomized study, 15% of pts receiving 46.7% citrate were withdrawn due to metallic taste or facial and digital paresthesias (Power, AJKD, 2009)   USFDA withdrew 46.7%citrate after one pt death

58. Are lock solutions safe? (cont)   Taurolidine is safe even when large volumes are deliberately given IV.   70% ethanol locks have been used in 2 randomized studies without systemic toxicity Sanders, J Antimicrob Chemother, 2008 Sofroniadou et al, 2009 ASN abstract (F-FC300)

59. Potential antimicrobial solutions None of these are US FDA approved!

60. Kidney International 2001 (60):1–13

62. Septicemia in dialysis   General guidelines (not specific to dialysis patients and based largely on common sense rather than on randomized trials) include Sterile barrier precautions, Antiseptic solutions, and Education of health care personnel, patients, caregivers, and family members Additional interventions may be useful in catheter- dependent dialysis patients Perit Dial Int 2008; 28(S3):S167–S171

64. Boston Meeting Recommendations #1: Infection and Access  Acknowledge: The catheter problem is IATROGENIC  Hospitals, health plans, nephrologists, providers and vascular surgeons (currently, 50% primary failure rate) must be accountable for reducing catheter placement  CMS might consider moving catheters, as a CPM, to the very highest level of scrutiny and surveys and place less emphasis on CPMs that make little difference in outcomes They just concluded a TEP to make just such recommendations, which are now being considered They just concluded a TEP to make just such recommendations, which are now being considered  Vaccination, as a CPM, needs to be an important aspect of facility practice and accountability

65. Conclusions   Central venous catheter-related blood stream infection (CRBSI)—most often with Staphylococcus aureus or S. epidermis—is a common complication and cause of death among maintenance hemodialysis patients   Diagnosis of CRBSI is confirmed by isolation of the same microorganism from quantitative cultures of both the catheter and the peripheral blood of a patient that has clinical features of infection without any other apparent source

66. Conclusions   Choice of antibiotics for initial empirical treatment of CRBSIs is a major management decision, as is determining whether catheter removal is appropriate   Topical antibiotics and catheter-lock solutions are the primary means of preventing CRBSIs, but risk of antibiotic-resistant organism emergence should be considered