American Journal of Kidney Diseases
Volume 51, Issue 2 , Pages 165-168, February 2008

Prophylaxis Against Dialysis Catheter–Related Bacteremia: A Glimmer of Hope

  • Michael Allon, MD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Michael Allon, MD, Division of Nephrology, University of Alabama at Birmingham, PB, Room 226, 728 Richard Arrington Blvd, Birmingham, AL 35294.

University of Alabama at Birmingham, Birmingham, Alabama

Article Outline

 

Related Article, p. 233

Bacteremia is the major complication of catheter use in hemodialysis patients, occurring at a frequency ranging from 2.5 to 5.5 episodes per 1,000 catheter-days, the equivalent of 0.9 to 2.0 episodes per year.1 The majority of episodes of catheter-related bacteremia are relatively uncomplicated, but 10% to 20% are complicated by metastatic infections, including endocarditis, osteomyelitis, septic arthritis, or epidural abscess. At best, patients with catheter-related bacteremia require administration of systemic antibiotics in the outpatient setting, but at worst, they require prolonged hospitalization and multiple diagnostic and therapeutic procedures. The risk of catheter-related bacteremia is proportionate to the duration of central venous catheter use, occurring in 35% of patients within 3 months, and in 48% within 6 months.2 A possible unfortunate byproduct of the Fistula First initiative has been a progressive increase in catheter use in hemodialysis patients in the United States, from 18% in 1998 to 27% in 2003.3 Not surprisingly, the explosive increase in catheter use has been paralleled by a sharp increase in the number of episodes of catheter-related bacteremia.

Bacterial biofilm forms rapidly and universally in central venous catheters and is the major source of catheter-related bacteremia in patients with tunneled hemodialysis catheters.4 This observation suggests that prevention of biofilm formation may reduce the likelihood of catheter-related bacteremia in dialysis patients. Unlike bacteria in broth, those in biofilm are relatively resistant to therapeutic plasma concentrations of antibiotics, but are susceptible to supraphysiologic (approximately 100-fold higher) concentrations in vitro. In addition, nonantibiotic antimicrobial agents, such as taurolidine,5 30% citrate (but not 15% or lower),6 and 70% ethanol have broad-spectrum bactericidal activity against biofilm in vitro. These laboratory observations have raised the hypothesis that instillation of an antimicrobial solution into the catheter lumen (“antimicrobial locks”) at the end of each dialysis session would thereby reduce catheter-related bacteremia.

During the past 5 years, 7 randomized clinical trials have been reported comparing the frequency of catheter-related bacteremia in patients receiving a prophylactic antimicrobial catheter lock solution versus patients receiving standard heparin locks. The meta-analysis by Jaffer et al appearing in this month’s issue of AJKD7 evaluates these 7 studies. Five studies used an antibiotic lock (gentamicin, cefazolin with gentamicin, minocycline, or cefotaxime),8, 9, 10, 11, 12 1 used taurolidine,13 and 1 used 30% citrate.14 Each of these studies revealed a dramatically lower frequency (50%-100%) of catheter-related bacteremia in patients randomized to an antimicrobial lock, as compared with those receiving a conventional heparin lock (Fig 1). It is difficult to ascertain whether any agent was superior to others in terms of prophylaxis against catheter-related bacteremia, as no head-to-head comparisons among individual antimicrobial lock solutions have been published.

  • View full-size image.
  • Figure 1. 

    Summary of frequency of catheter-related bacteremia with antimicrobial locks versus heparin locks in published randomized clinical trials. Five trials used an antibiotic lock, 1 used taurolidine, and 1 used 30% citrate. In each study, the catheter-related bacteremia frequency was 50% to 100% lower in the group with antimicrobial lock, as compared with the heparin controls.

Given the high morbidity and cost associated with catheter-related bacteremia, and the impressive efficacy of these agents in prophylaxis against catheter-related bacteremia, why aren’t antimicrobial locks used more often in patients with hemodialysis catheters? There are a number of potential barriers. First, all the randomized studies have followed patients for fewer than 6 months. Tunneled catheters are often used for longer periods of time, and there is a very real concern that longer-term use of prophylactic antibiotics may result in selection for highly antibiotic-resistant microorganisms and infections. A French dialysis unit routinely using prophylactic gentamicin locks in dialysis catheters obtained monthly cultures of the bacteria colonizing the catheter lumen.15 After 2 years, 100% of the Staphylococcus epidermidis isolates were resistant to gentamicin, methicillin, and quinolones. At that point, prophylactic antibiotic locks were discontinued. After an additional 2 years, only 50% of S epidermidis isolates were resistant to methicillin, 16% were resistant to gentamicin, and 50% were resistant to quinolones. Given that bacteria in the catheter biofilm are the major source of catheter-related bacteremia, this microbiological surveillance report suggests that prolonged prophylactic antibiotic locks may lead to an increase in highly resistant catheter-related bacteremias. This concern is particularly relevant given the increase in methicillin-resistant Staphylococcus aureus in the dialysis population. The use of prophylactic taurolidine, 30% citrate, or 70% ethanol may be of lesser concern, as bacterial resistance has not been reported to these agents.

A second concern is the potential for systemic toxicity when some of the antibiotic solution leaks from the catheter lumen into the circulation. Thus, for example, in the study by Dogra et al,8 enough gentamicin was absorbed systemically to produce a median predialysis plasma gentamicin concentration of 2.8 mg/L, which is close to the therapeutic goal. Moreover, 10% of the patients randomized to a gentamicin (40 mg/mL) lock, but none of those receiving heparin, developed symptoms consistent with aminoglycoside ototoxicity. The risk might be even higher with a long-term prophylactic gentamicin lock. On the other hand, 2 subsequent studies demonstrated a comparable prophylactic effect using a 10-fold lower concentration of gentamicin (4-5 mg/mL).10, 11 Use of the lower gentamicin dose may avoid ototoxicity. There is also concern that concentrated citrate, a calcium chelator, may cause significant hypocalcemia if it leaks from the catheter lumen into the systemic circulation. In the year 2000, the US Food and Drug Administration (FDA) recalled 47% citrate after a single patient experienced a fatal cardiac arrest resulting from inadvertent instillation of a large volume through a dialysis catheter.16 This concern should be tempered by the lack of significant side effects observed with over 6,000 instillations of 30% citrate in the study by Weijmer et al.14 Leakage of taurolidine from the catheter into the bloodstream is not likely to be a safety issue, as patients have received large volumes of intravenous taurolidine without experiencing adverse effects.

The third barrier is economic. In the absence of a mechanism for separate reimbursement as a drug, in the United States the antimicrobial lock would need to be administered by the dialysis unit at no charge. This would create a major economic hardship for dialysis units, given the narrow profit margin for an outpatient dialysis session at many dialysis units in the United States. It is quite likely that the inpatient savings realized from the reduction of catheter-related bacteremia would far outweigh the cost of administering the antimicrobial lock. Unfortunately, under the current reimbursement scenario, the Centers for Medicare and Medicaid Services would realize the savings, whereas the dialysis providers would have to absorb the cost. The US situation may be dramatically different if the healthcare system moves towards global capitation for all medical care of dialysis patients. Under that alternative scenario, it would be economically advantageous for the dialysis provider to administer antimicrobial locks.

What is the economic cost of catheter-related bacteremia in the United States? If 27% of the 300,000 United States-based hemodialysis population use catheters, there would be 81,000 patients with catheters. Assuming an average of 2 episodes of catheter-related bacteremia per patient per year, there would be 162,000 catheter-related bacteremia episodes per year. The estimated average cost of treating a catheter-related bacteremia episode is $14,448 for inpatients and $2,414 for outpatients.17 Assuming that 20% of these episodes (32,400) require hospitalization, and 80% (129,600) involve outpatient treatment, the total annual cost of inpatient treatment would be $466 million ($14,448 × 32,400 catheter-related bacteremia episodes) and the total cost of outpatient treatment would be $311 million ($2,414 × 129,600 catheter-related bacteremia episodes). Thus, in the United States, the total annual cost of treating all catheter-related bacteremia episodes and their complications would amount to $777 million ($466 million + $311 million) for 81,000 catheter-dependent patients, or about $10,000 per catheter-year.

What is the cost-benefit ratio of using prophylactic antimicrobial lock solutions in all catheter-dependent patients? If we assume (conservatively) that lock solutions reduce the frequency of catheter-related bacteremia episodes by 50%, this could save an average of $5,000 per year in medical costs for each patient using a catheter. Now assuming that the lock solution costs $2.50 per dialysis session, and it is instilled thrice weekly (156 sessions annually), the total annual cost of the lock solution would be approximately $400 per patient. In other words, an annual expenditure of $400 per patient-year could save $5,000 per year in costs for treating catheter-related bacteremia. Of course, if prophylactic antimicrobial locks reduce the frequency of catheter-related bacteremia by more than 50%, as appears likely from the randomized studies, the cost-benefit of using them could be even more favorable. Of course, the cost-benefit ratio may be lost if long-term prophylaxis results in a substantial increase in multidrug resistant bacteremia requiring hospitalization.

The final barrier to the widespread use of prophylactic antimicrobial locks is regulatory. The FDA has not approved any of the antimicrobial lock solutions for this clinical indication. This does not preclude individual nephrologists from prescribing this treatment. However, in the United States, it is unlikely that any of the dialysis chains would be willing to assume the liability for potential lawsuits arising from administration of therapy that is not FDA approved. Since the vast majority of dialysis units in the United States are owned by large dialysis chains, antimicrobial lock solutions would be used in only a small minority of units, absent FDA approval.

In summary, catheter-related bacteremia is a major source of morbidity, hospitalization, and economic costs in catheter-dependent patients. Since catheter use is not likely to decrease any time soon, there is a desperate need for a safe and effective antimicrobial lock solution for prevention of catheter-related bacteremia. Achieving this critical goal will require (1) well-designed, long-term studies evaluating the safety and efficacy of potential lock solutions, (2) FDA approval of their use, and (3) reimbursement from the Centers for Medicare and Medicaid Services for antimicrobial lock solutions as a separate pharmaceutical item, rather than as part of the dialysis capitation fee.

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Acknowledgements 

The author thanks Charmaine Lok for her review and comments regarding this manuscript.

Support: None.

Financial Disclosure: Dr Allon reports having served in the past as a consultant to Arrow International, Inc, a manufacturer of catheter-related therapeutic products.

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References 

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  2. Lee T, Barker J, Allon M. Tunneled catheters in hemodialysis patients: Reasons and subsequent outcomes. Am J Kidney Dis. 2005;46:501–508
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PII: S0272-6386(07)01602-2

doi:10.1053/j.ajkd.2007.12.003

Refers to article:

  • A Meta-analysis of Hemodialysis Catheter Locking Solutions in the Prevention of Catheter-Related Infection

    Yasmin Jaffer, Nicholas M. Selby, Maarten W. Taal, Richard J. Fluck, Christopher W. McIntyre
    American Journal of Kidney Diseases February 2008 (Vol. 51, Issue 2, Pages 233-241)

American Journal of Kidney Diseases
Volume 51, Issue 2 , Pages 165-168, February 2008

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