By William H. Thompson, MD

Associate Professor of Medicine, University of Washington, Seattle

Dr. Thompson reports no financial relationships relevant to this field of study.

Since the 1929 introduction of one of the first techniques of vascular cannulation by German physician and physiologist Werner Forssmann, who later went on to share the 1956 Nobel Prize in Medicine,1 the use of vascular catheters has exploded to the point that U.S. hospitals and clinics purchase more than 150 million intravascular devices each year.2 Thus, catheter-related bloodstream infections (CRBSIs) remain one of the more common nosocomial infections today, with an estimated 250,000 CRBSIs occurring in the United States annually, of which approximately 80,000 are associated with an ICU stay.3-5 This is a costly complication of healthcare that also is associated with a significant increase in morbidity and length of stay for patients. The practices used to prevent and treat CRBSIs have evolved dramatically over the years. The science behind current practices has reduced the CRBSI rate by 50% between 2008 and 2014.6 However, the rate of infection is far from zero,7 and rates remain significantly different between states, suggesting that there is room for improvement.

DIAGNOSIS

CRBSI should be suspected in the setting of fevers and chills, which are sensitive but not specific. Other sources of infection besides line infection should be sought. The more serious the symptoms and exam findings (e.g., inflammation or purulence at the insertion site, mental status changes, hemodynamic instability), the more specific but less sensitive those findings. The decision to remove a catheter before a definitive diagnosis of CRBSI depends on: the clinician’s index of suspicion for line infection rather than another source of fever or infection, how dependent the patient is on the particular line in question, and how unstable the patient is because of the infection.

The definition of CRBSI varies dramatically from study to study,8 but the more commonly accepted definitions come from the CDC9 and the Infectious Diseases Society of America (IDSA).2 The CDC definition for central line-associated bloodstream infection (CLABSI) requires a single positive blood culture for an organism not commonly present on the skin or more than two blood cultures for an organism commonly present on the skin, including but not limited to diphtheroids (Corynebacterium spp. not C. diphtheria), Bacillus spp. (not B. anthracis), Propionibacterium spp., coagulase-negative staphylococci (including Staphylococcus epidermidis), viridans group streptococci, Aerococcus spp., Micrococcus spp., and Rhodococcus spp.10 Additionally, the CDC definition also requires that the central line has been in place within 48 hours before the onset of infection and that the infection is not related to another source in the patient. In those with two or more cultures positive for common skin organisms, the patient also should exhibit at least one of the following signs or symptoms: temperature > 38.0° C, chills, and hypotension.

The IDSA definition of CRBSI requires:

  • isolation of the same pathogen from a quantitative blood culture from the central line and from a peripheral vein, with the colony count in the central line at least three-fold higher than that from the peripheral vein; or
  • isolation of the same pathogen from the peripheral vein and from quantitative culture of the catheter tip (> 15 colony forming units [CFU]); or
  • isolation of the same pathogen from the central line and peripheral vein with a shorter time to positive culture (more than two hours) in the central line using differential time to positivity (DTP) techniques.

Many hospital labs are not equipped with the proper technology to perform quantitative blood cultures, but most can take advantage of the cheaper DTP technology. Quantitative catheter tip cultures are considered positive for colonization with:

  • growth of > 15 CFU from a 5 cm segment of the catheter (roll-plate technique); or
  • growth of > 102 CFU from a catheter by quantitative (sonication) broth culture technique.

It is also important to stress that catheter tip cultures are recommended only if the catheter is removed for suspicion of CRBSI and not when the catheter is removed routinely.

Culture techniques are outlined by the CDC9 and IDSA2 and are crucial to making an accurate diagnosis. A positive culture from the central line and the peripheral vein makes the diagnosis much more definitive. The isolated positive peripheral vein culture is more predictive of CRBSI than is the isolated positive central line blood culture. A positive culture from the catheter with a negative peripheral vein culture is much more likely to be due to contamination than true line infection.11 On the other hand, a negative culture from both the catheter and peripheral vein carries a good negative predictive value for catheter infection, especially if the patient is off antibiotics. Although there are limited data to support the practice, when a peripheral vein culture is not possible, many will recommend gathering cultures from two different lumens of the central line and with two cultures separated in time from each of the lumens. Proper labeling of the source of the cultures is important to confirm the infection.

Tunnel infection is suggested by tenderness or erythema over the subcutaneous tract of a tunneled catheter extending beyond the exit site by > 2 cm and generally requires line removal. On the other hand, inflammation < 2 cm beyond the exit site is suggestive of an exit site infection, which often can be managed more conservatively with topical and potentially IV antimicrobial agents, along with close monitoring.

TREATMENT

Besides considering antibiotic coverage, treatment of CRBSI consists of catheter management, with options that include removal, exchange, or salvage of the catheter. The decision to remove the catheter is based on the certainty of catheter infection, stability of the patient, need for central venous access, ease of replacing the catheter, and the particular organism growing in cultures. Once CRBSI is confirmed, all non-tunneled catheters should be removed. Even tunneled catheters require removal for the following: hemodynamic instability suggesting sepsis, any evidence of endocarditis or other metastatic infection, persistent bacteremia or symptoms of infection after 72 hours of appropriate antibiotic therapy, and also suppurative thrombophlebitis.

Certain bacteria also preclude any consideration of salvage therapy. Pseudomonas aeruginosa, Staphylococcus aureus, fungi, mycobacteria and low-virulence but difficult-to-eradicate-bacteria (Micrococcus spp., Bacillus spp., Cutibacterium spp., etc.) necessitate catheter removal. Growth of gram-negative bacilli or enterococci also requires removal of short-term catheters (in place for < 14 days).

In the absence of the above conditions and organisms, salvage therapy with IV antibiotics and antibiotic lock therapy (ALT) can be considered for long-term catheters, including tunneled hemodialysis catheters, in patients with limited vascular access and uncomplicated CRBSI.2,12 Salvage therapy can be considered for coagulase-negative Staphylococcus infection, but patients still will be at high risk of recurrent infection.13 Salvage therapy consists of systemic antibiotics coupled with antimicrobial lock therapy. ALT is ineffective against extraluminal infections as well as any infection due to S. aureus, P. aeruginosa, Candida, or drug-resistant, gram-negative bacilli.

Generally, ALT occurs with an antibiotic to which the organism is susceptible, at high concentration, and often with heparin to prevent occlusion of the catheter. Justo and Bookstaver provided a table of suggested antibiotic concentrations and heparin doses.14 It is important that pharmacy and nursing coordinate care closely and that lumens with the lock therapy are labeled clearly. Persistent symptoms after 36 hours or positive cultures repeated at 72 hours require catheter removal.

Guidewire exchange is supported only by small, uncontrolled studies and should be considered only when a catheter requires removal and the risk of mechanical or bleeding complications with placement of a new catheter is high. The risk of recurrent infection with guidewire exchange may be lower when an antimicrobial surface-treated catheter is used,15 but further studies will be required to confirm this. In the dialysis-dependent patient with poor venous access, exchange over a guidewire could be considered when symptoms of infection resolve within two to three days of IV antibiotic therapy through the infected catheter, when the causative microorganism is not one of the resistant organisms listed above, and when there is no evidence of metastatic infection.12

Empiric antimicrobial therapy is recommended when there is a high index of suspicion for CRBSI — even before cultures return positive. Because of the high rate of gram-positive infections, empiric therapy almost always includes vancomycin or, when resistance is suspected, daptomycin or other agents against gram-positive organisms. Linezolid generally is not considered because it is bacteriostatic rather than bactericidal and it produces problematic side effects. Questions related to lower survival rates compared to vancomycin have led the FDA to issue a warning against use of linezolid for the empiric treatment of CRBSI.16 Gram-negative coverage also is included in the setting of sepsis, neutropenia, and known gram-negative colonization, and when the local incidence of gram-negative infection is high. Coverage against candidemia should be considered in the setting of candidal colonization, a femoral line, transplant patients, those with hematologic malignancies, recent treatment with broad-spectrum antibiotics, or if the patient is receiving parenteral nutrition. Empiric antifungal therapy would include echinocandin or azole agents. For candidemia, fluconazole can be considered for selected patients without azole exposure in the previous three months and in settings in which the risk of Candida krusei or Candida glabrata infection is very low. Empiric therapy always should be tailored to the specific infection once identification and sensitivities return.

Length of therapy also is dependent on the particular organism and whether any metastatic infection is identified. For uncomplicated Staphylococcus aureus infections with confirmed sensitivities, 14 days of vancomycin (for MRSA) or nafcillin/oxacillin usually is recommended. Length of therapy would be extended in the setting of metastatic S. aureus infection. With S. aureus bacteremia, the risk of endocarditis can be as high as 25-32%; thus, transesophageal echocardiogram (TEE) should be considered five to seven days after onset of bacteremia.17 The risk for metastatic infection with S. aureus increases with community-acquired infection, intravascular devices, immunocompromised state (renal failure, diabetes, dialysis, etc.), valvular abnormality, suppurative thrombophlebitis, and delay in catheter removal.18

For coagulase-negative Staphylococcus, five to seven days with catheter removal often is sufficient, although some would consider up to three weeks when endovascular hardware is present. Infection with gram-negative bacilli or with enterococci generally are treated with catheter removal and 10-14 days of antibiotics. The risk of endocarditis is low with Enterococcus faecium19 but much higher with Enterococcus faecalis. Thus, TEE should be considered when E. faecalis is cultured or with any CRBSI with persistently positive cultures at 72 hours or any other evidence of prolonged infection. Typically, candidemia is treated for 10-14 days after catheter removal and after the first day of negative blood cultures. With any organism, persistently positive blood cultures or any documented metastatic infection usually will require extending the length of therapy.

Conditions that generally do not require antibiotic therapy include phlebitis or thrombosis without other evidence of infection and positive catheter tip culture without signs and symptoms of infection. Depending on the organism cultured, a positive blood culture through the catheter with a negative peripheral vein culture often is due to contamination and may not need to be treated. Catheter removal also may not be necessary with unexplained fever in the hemodynamically stable patient without any endovascular prosthetic material (vascular graft, prosthetic valve, etc.).

PREVENTION

For the sake of patient care and because treatment of CRBSI generally is a very costly and preventable complication that is often not reimbursed by Medicare, resources spent on prevention usually are cost effective. Guidelines for the prevention of CRBSI are well documented4,12 and will not be reviewed in detail here. Such guidelines have been used to develop protocols for employee education, central line insertion, routine line care, daily chlorhexidine skin cleansing, and accessing the central line in most institutions.

For the clinician, some of the more important points to remember include choice of location of the central line. Parienti et al7 compared risks of complications at the subclavian, jugular, and femoral venous sites. They found the risk of bloodstream infection (0.5%, 1.4%, 1.2%, respectively) and symptomatic deep-venous thrombosis (0.5%, 0.9%, 1.4%) were significantly lower in the subclavian location, while the risk of pneumothorax/mechanical complications (2.1%, 1.4%, 0.7%) was higher in the subclavian lines.

Use of ultrasound guidance usually will reduce the number of cannulation attempts and risk of mechanical complications. Hand hygiene, maximal sterile barrier precautions (cap, mask, sterile gown, sterile gloves, sterile full body drape), and the use of > 0.5% chlorhexidine skin preparation are some of the central line insertion techniques most important for preventing central line infection. When use of a strict aseptic technique cannot be ensured as in emergent lines, the catheter should be replaced as soon as possible. Dressing techniques are well described and include replacing the dressing when damp, loose, or visibly soiled. Topical antibiotic ointment should not be used at insertion sites except for dialysis catheters because of the potential to promote infection with fungi or antimicrobial-resistant organisms. It has been shown that the risk of dialysis catheter infection decreases with the use of antibiotic or povidone-iodine ointment to catheter exit sites.12 Central lines also should be removed when no longer necessary.

The benefits of antimicrobial-impregnated catheters (chlorhexidine-silver sulfadiazine, minocycline-rifampin) and silver-impregnated catheters remain unclear.2,20,21 While many centers use these catheters routinely, others favor their use only when a center’s CRBSI rate is higher than national surveillance rates despite adherence to other standard prevention protocols.4

In short, CRBSI is a common, costly, and often preventable cause of morbidity and extended length of stay in the ICU. Prevention, diagnosis, and treatment guidelines are well documented and, when strictly followed, can significantly improve outcomes in patients.

REFERENCES

  1. Sette P, Dorizzi RM, Azzini AM. Vascular access: An historical perspective from Sir William Harvey to the 1956 Nobel prize to André F. Cournand, Werner Forssmann, and Dickinson W. Richards. J Vasc Access 2012;13:137-144.
  2. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infectious Dis 2009;49:1-45.
  3. Mermel LA. Prevention of intravascular catheter-related infections. Ann Intern Med 2000;132:391-402.
  4. 4. O’Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis 2011;52:e162-e193.
  5. Maki DG, Kluger DM, Crnich CJ. The risk of bloodstream infection in adults with different intravascular devices: A systematic review of 200 published prospective studies. Mayo Clin Proc 2006;81:1159-1171.
  6. Centers for Disease Control and Prevention. National and state healthcare associated infections progress report. Available at: https://bit.ly/2ItYmS2. Accessed April 4, 2018.
  7. Parienti JJ, Mongardon N, Megarbane B, et al. Intravascular complications of central venous catheterization by insertion site. N Engl J Med 2015;373:1220-1229.
  8. Tomlinson D, Mermel LA, Ethier MC, et al. Defining bloodstream infections related to central venous catheters in patients with cancer: A systematic review. Clin Infect Dis 2011;53:697-710.
  9. Centers for Disease Control and Prevention. Bloodstream infection event (central line-associated bloodstream infection and non-central line-associated bloodstream infection). Available at: https://bit.ly/2H8fGwc. Accessed April 4, 2018.
  10. Centers for Disease Control and Prevention. CDC organism list from CDC’s National Healthcare Safety Network (NHSN). Available at: https://bit.ly/2EjL8Vu. Accessed April 4, 2018.
  11. Bryant JK, Strand CL. Reliability of blood cultures collected from intravascular catheter versus venipuncture. Am J Clin Pathol 1987;88:113-116.
  12. Miller LM, Clark E, Dipchand C, et al. Hemodialysis tunneled catheter-related infections. Can J Kidney Health Dis 2016;3:1-11.
  13. Raad I, Kassar R, Ghannam D, et al. Management of the catheter in documented catheter-related coagulase-negative staphylococcal bacteremia: Remove or retain? Clin Infect Dis 2009;49:1187-1194.
  14. Justo JA, Bookstaver PB. Antibiotic lock therapy: Review of technique and logistical challenges. Infect Drug Resist 2014;7:343-363.
  15. Parbat N, Sherry N, Bellomo R, et al. The microbiological and clinical outcome of guide wire exchange versus newly inserted antimicrobial surface treated central venous catheters. Crit Care 2013;17:R184.
  16. Watkins RR, Lemonovich TL, File TM Jr. An evidence-based review of linezolid for the treatment of methicillin-resistant Staphylococcus aureus (MRSA): Place in therapy. Core Evid 2012;7:131-143.
  17. Abraham J, Mansour C, Veledar E, et al. Staphylococcus aureus bacteremia and endocarditis: The Grady Memorial Hospital experience with methicillin-sensitive S aureus and methicillin-resistant S aureus bacteremia. Am Heart J 2004;147:536-539.
  18. Fowler VG Jr, Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med 2003;163:2066-2072.
  19. Vergis EN, Hayden MK, Chow JW, et al. Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia, a prospective multicenter study. Ann Intern Med 2001;135:484-492.
  20. Casey AL, Mermel LA, Nightingale P, Elliott TS. Antimicrobial central venous catheters in adults: A systematic review and meta-analysis. Lancet Infect Dis 2008;8:763-776.
  21. McConnell SA, Gubbins PO, Anaissie EJ. Do antimicrobial-impregnated central venous catheters prevent catheter-related bloodstream infection? Clin Infect Dis 2003;37:65-72.
  22. Moretti EW, Ofstead CL, Kristy RM, Wetzler HP. Impact of central venous catheter type and methods on catheter-related colonization and bacteraemia. J Hosp Infect 2005;61:139-145.