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Antimicrobial Lock Solutions for the Prevention of Infections Associated with Intravascular Catheters in Patients Undergoing Hemodialysis: Systematic Review and Meta-analysis of Randomized, Controlled Trials

  1. Dafna Yahav1,5a,
  2. Benaya Rozen-Zvia,2,5,
  3. Anat Gafter-Gvili3,5,
  4. Leonard Leibovici1,5,
  5. Uzi Gafter2, and
  6. Mical Paul4,5
  1. 1Departments of Medicine E, Petah-Tiqva
  2. 2Departments of Nephrology, Petah-Tiqva
  3. 3Departments of Hematology, Petah-Tiqva
  4. 4Departments of Infectious Disease Unit, Rabin Medical Center, Beilinson Campus, Petah-Tiqva
  5. 5Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel
  1. Reprints or correspondence: Dr. Dafna Yahav, Dept. of Medicine E, Rabin Medical Center, Beilinson Campus, 49100 Petah-Tiqva, Israel (dafna.yahav{at}gmail.com).

  • ↵D.Y. and B.R.-Z. contributed equally to this article.

 
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Abstract

Background. Prevention of catheter-related bloodstream infections in patients undergoing hemodialysis by use of antimicrobial catheter lock solutions has been examined in several trials, but no consensus is available for clinical practice.

Methods. A systematic review and meta-analysis were performed of randomized controlled trials that compared single or combination antimicrobial catheter lock solutions with heparin or another antimicrobial for the prevention of infections in patients undergoing hemodialysis. The primary outcomes assessed were bloodstream infections, catheter-related bloodstream infections, and the need for catheter removal. Relative risks with 95% confidence intervals (CIs) for individual trials were pooled.

Results. Eleven trials (924 patients) that assessed antibiotic catheter lock solutions and 5 trials (661 patients) that assessed nonantibiotic antimicrobial catheter lock solutions met inclusion criteria. None of the trials assessed all bloodstream infections. Antibiotic catheter lock solutions significantly reduced catheter-related bloodstream infections (relative risk, 0.44; 95% CI, 0.38–0.50). Significant heterogeneity for this outcome could be explained by smaller effect estimates in larger trials that reported adequate randomization methods (relative risk, 0.60; 95% CI, 0.54–0.67). Efficacy was higher when additional preventive measures were used and to prevent the first episode of catheter-related bloodstream infection. Catheter removal rates were significantly reduced (relative risk, 0.35; 95% CI, 0.23–0.55). Resistance development was documented in a single patient. Data concerning nonantibiotic antimicrobial lock solutions were limited and heterogenous. High-quality trials that used additional preventive measures showed a significant reduction in catheter-related bloodstream infections (relative risk, 0.25; 95% CI, 0.13–0.50).

Conclusions. Antibiotic catheter lock solutions reduce catheter-related bloodstream infections, with a number needed to treat of 4 patients (95% CI, 4–5), and catheter removal rates in patients undergoing hemodialysis. The use of antibiotic catheter lock solutions should be considered in routine clinical practice in conjunction with other prevention modalities.

Central venous catheter–related bloodstream infection is an important cause of morbidity and mortality among patients undergoing hemodialysis. The incidence of dialysis-related, catheter-related bloodstream infections is reported to be 2.5–5.5 cases per 1000 catheter-days or 0.9–2 episodes per patient-year in patients using catheters as their vascular access [1]. According to the US Renal Data System, infection is the second leading cause of death in patients with end-stage renal disease [2].

Several modalities have been assessed as a means to prevent catheter-related infections. Tunneling of central venous catheters [3, 4] and cuffing of the catheter hub have been shown to reduce the rate of catheter-related bloodstream infections [5]. Topical agents applied to the catheter exit site, such as povidone iodine, mupirocin, and bacitracin zinc and polymyxin B sulfate ointments, have been proven effective [6–10]. Oral rifampin or nasal mupirocin ointment reduced the incidence of Staphylococcus aureus bacteremia [11–13]. Silver coating of tunneled catheters was not shown to reduce the incidence of catheter-related bloodstream infections in patients undergoing hemodialysis, because biofilm formation was not prevented [14, 15], but antibiotic coating of uncuffed catheters was beneficial in patients with cancer experiencing acute renal failure [16].

Instilling an antimicrobial solution into the catheter lumen limits biofilm formation [17–19]. The use of antimicrobial catheter lock solutions for the prevention of catheter-related bloodstream infections in hemodialysis has been examined in several randomized controlled trials, but to date no consensus is available for clinical practice [20, 21]. We therefore performed a systematic review of all randomized controlled trials that assessed antimicrobial catheter lock solutions for the prevention of catheter-related infections in patients undergoing hemodialysis.

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Methods

Inclusion criteria and outcomes. We included randomized controlled trials that assessed adults or children with end-stage renal disease undergoing hemodialysis through central catheters. We allowed up to 30% of patients with acute renal failure to be included in the study. We included trials that compared any single or combination antimicrobial (antibiotic, citrate, taurolidine, or alcohol) catheter lock solution with heparin or another antimicrobial catheter lock solution. All antimicrobial solutions could be given with heparin or EDTA. Analyses were separated by antibiotic and nonantibiotic antimicrobial locks.

The primary outcomes assessed were clinically significant bacteremia of any cause, catheter-related bloodstream infections, and removal of the catheter for any cause. Secondary outcomes included all-cause mortality, exit site infections, tunnel infections, catheter thrombosis (defined as thrombosis or need for thrombolytic therapy or removal of the catheter because of flow problems), need for hospitalization and hospitalization duration, emergence of resistance (defined as development of catheter-related bloodstream infections or colonization by bacteria resistant to the antibiotic given), fungal infections, and adverse events.

Search strategy and selection criteria. We searched the Cochrane Register of Controlled Trials (Central) and PubMed databases. Unpublished trials were sought in references of all selected studies, relevant conference proceedings, trial registries, ongoing trial databases, new drug application documents, and personal contacts with the investigators of included trials. No language or date restrictions were imposed. The last search was performed in November 2007. The terms lock*, flush, solution*, antibiotic*, and specific lock solutions were combined with the medical subject heading terms dialysis or kidney disease and intravascular catheters. All were combined with the Cochrane filter for randomized controlled trials in PubMed [22].

Study selection and data extraction. Two reviewers (D.Y. and B.R.-Z.) independently performed the search, applied inclusion criteria, and extracted the data. Outcomes were extracted preferentially by intention to treat. For the primary outcomes, we extracted the number of episodes both per patients and per catheter-days. Study follow-up was documented, and outcomes were extracted at the end of follow-up. We extracted data on baseline patient characteristics, catheter characteristics, and additional prophylactic measures used that may have affected outcomes. Missing data were requested from the authors.

Methodologic quality assessment was performed using the individual component approach, and its effect was assessed through sensitivity analyses. Allocation concealment and generation were graded as adequate, unclear, or inadequate, by use of criteria suggested in the Cochrane handbook [22].

Statistical analysis. Relative risks with 95% CIs were calculated for individual trials. Meta-analysis was performed using the Mantel-Haenszel fixed-effects model (Review Manager 4.2). Heterogeneity in the results of the trials was assessed using the χ2 test for heterogeneity and the I2 measure of inconsistency [23]. Substantial heterogeneity (I2>50%) was investigated through subgroup analyses and metaregression (Comprehensive Meta-analysis 2.2) for catheter tunneling and incident (<90 days) versus prevalent (longer-term) hemodialysis. A funnel plot was visually inspected, and the small-studies effect was formally assessed using Egger's test of the intercept.

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Results

The search yielded 162 potentially relevant studies, of which 127 were irrelevant. Thirty-five studies were further evaluated, of which 19 were excluded [24–42] (figure 1). Sixteen randomized controlled trials, conducted from 1998 through 2006, were included in the review [43–58] (table 1).

Figure 1
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Figure 1

Flowchart for selection of trials

Eleven trials assessed antibiotic catheter lock solutions. The antibiotics assessed were gentamicin in 3 trials [46, 52, 58], gentamicin and citrate in 3 trials [47, 53, 54], gentamicin and vancomycin in 1 trial [43], gentamicin and cefazolin in 1 trial [50], cefotaxime in 2 trials [55, 56], and minocycline with EDTA in 2 trials [45, 53]. These trials included 924 patients with 176,332 catheter-days. Eight trials included tunneled catheters, 2 included nontunneled catheters, and 1 included both types.

Five trials assessed nonantibiotic antimicrobial catheter lock solutions, including citrate in 4 trials [48, 49, 51, 57] and citrate with taurolidine in 1 trial [44]. We did not identify trials that assessed alcohol lock therapy for prevention. The trials included 661 patients with 63,345 catheter-days. Three trials included tunneled catheters, and 2 included both tunneled and nontunneled catheters.

All trials compared the intervention with heparin. The follow-up duration ranged from 6 to 16 months. None of the trials assessed bloodstream infections of any cause. The need for hospitalization was reported in only 2 trials, whereas none of the trials reported the length of hospitalization. All-cause mortality at the end of follow-up was reported in 7 trials.

Adequate allocation concealment and allocation-sequence generation were described in 7 trials. Three additional trials described only adequate allocation generation, and another trial described only adequate allocation concealment. Six trials were double-blind, whereas all others were open-label trials (table 1).

Any antibiotic lock versus heparin. The rates of catheter-related bloodstream infections were significantly lower with antibiotic catheter lock solutions compared with heparin lock alone both per patient (relative risk, 0.44; 95% CI, 0.38–0.50; all 11 trials included) and per catheter-day (relative risk, 0.37; 95% CI, 0.30–0.47) (figure 2). Statistically significant heterogeneity was present in both analyses. Heterogeneity could not be explained by catheter tunneling, incident hemodialysis (reported in 6 trials), diabetes, or definitions used for catheter-related bloodstream infections. Effect estimates for catheter lock solutions were statistically significantly higher when additional prophylaxis measures were used, with longer duration of catheter lock solution treatment, when only the first catheter-related bloodstream infection was assessed and with advancing year of the study (table 2). In addition, the funnel plot revealed a statistically significant small-studies effect (figure 3), and sensitivity analyses for the trials' methodologic quality showed that adequate randomization methods and double-blinding were consistently associated with effect estimates of lower magnitude.

Figure 2
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Figure 2

Catheter-related bloodstream infections per patient (A) and per catheter-day (B) for trials that compared any antibiotic catheter lock solution with heparin. The analysis is subcategorized by the concomitant use of citrate with the antibiotic. A relative risk (RR) of <1.0 favors the antimicrobial lock solution examined. Studies are given as the first author's surname followed by the last 2 digits of the year published and an abbreviation for the substance studied: CefaGH, cefazolin-gentamicin-heparin; CefoH, cefotaxime-heparin; G, gentamicin; GC, gentamicin-citrate; GCbag, gentamicin-citrate plastic bag over catheter hub; GH, gentamicin-heparin; ME, minocycline-EDTA; VGH, vancomycin-gentamicin-heparin.

Figure 3
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Figure 3

Funnel plot of the SE of the log relative risk (RR) versus RRs for catheter-related bloodstream infections per patient, showing a statistically significant small-studies effect (Eggers intercept, −1.51312; 95% CI, −2.29929 to −0.72694; t=4.35388; 9 df; P<.001).

Figure 4
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Figure 4

Catheter-related bloodstream infections per patient (A) and per catheter-day (B) for trials comparing nonantibiotic antimicrobial catheter lock solution with heparin. The analysis is subcategorized by the type of antimicrobial. Studies are given as the first author's surname followed by the last 2 digits of the year published and an abbreviation for the substance studied: C, citrate; CT, citrate-taurolidine. RR, relative risk.

Table 1
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Table 1

Summary of clinical trials on catheter lock solutions, 1998–2006.

Table 2
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Table 2

Effect of study characteristics on the relative risk (RR) for catheter-related bloodstream infections per patient in trials comparing an antibiotic catheter lock with heparin alone.

Catheter removal rates were significantly lower in the intervention group per patient (relative risk, 0.35; 95% CI, 0.23–0.55; 5 trials; 552 patients) and per catheter-day (relative risk, 0.34; 95% CI, 0.21–0.55; 135,769 catheter-days), without significant heterogeneity. Catheter survival was reported variously as means or medians or by use of a Kaplan-Meier analysis. Results could not be compiled; however, all trials showed a benefit of antibiotic catheter lock solutions, with a median difference among trial arms in the range 4–25 days. Catheter thrombosis rates were significantly lower with the intervention (relative risk, 0.48; 95% CI, 0.32–0.72; 142,271 catheter-days), without significant heterogeneity.

Exit site infections were reduced without statistical significance per patient (relative risk, 0.69; 95% CI, 0.48–1.01; 6 trials; 574 patients) and per catheter-day (relative risk, 0.73; 95% CI, 0.48–1.12; 152,056 catheter-days), without significant heterogeneity. Tunnel infections were not reported. The emergence of clinically significant resistant strains was reported in 5 trials, including 316 patients receiving intervention and 211 control patients. Only 1 case of gentamicin-resistant S. aureus was reported in a patient receiving gentamicin and citrate during 16 months of follow-up. Colonization rates were not assessed. No fungal infections in the intervention group were documented in 7 trials.

Adverse events were addressed by 5 trials that included 425 patients. No adverse events occurred in 3 trials, whereas 2 trials that assessed gentamicin and citrate reported 1 case of rash that required treatment discontinuation [53] and 4 cases of dizziness without vertigo [47] among patients receiving intervention. Overall mortality was reported in 5 comparisons. No deaths occurred in 3 trials, and in 1 trial, including 2 comparisons, no statistically significant difference was found among the trial arms.

Because we combined antibiotic regimens with a heterogeneous spectrum of coverage in the main analysis, we separated the analysis for trials that assessed gentamicin alone or with citrate and other trials that assessed gentamicin combined with vancomycin or cefazolin, cefotaxime alone, or minocycline (table 3). Outcomes with gentamicin as a single antibiotic were not inferior to those obtained from trials that used additional or other antibiotics. Seven trials reported the specific isolates that caused catheter-related bloodstream infections. Both gentamicin and other antibiotics statistically significantly reduced the rates of catheter-related bloodstream infections caused by gram-negative and gram-positive bacteria. Both gentamicin and other antibiotics reduced S. aureus catheter-related bloodstream infections, with only the latter achieving statistical significance. Six trials specifically reported methicillin-resistant S. aureus infections. Three methicillin-resistant S. aureus catheter-related bloodstream infections occurred in trials that assessed gentamicin (2 trials), 2 with heparin treatment and 1 with gentamicin treatment, whereas no cases occurred in trials that assessed other antibiotics.

Table 3
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Table 3

Effects of catheter lock solutions using gentamicin as a single antibiotic compared with other single or combination antibiotics.

Nonantibiotic antimicrobial locks versus heparin. Rates of catheter-related bloodstream infections were significantly lower with antimicrobial catheter lock solutions than with heparin alone per patient (relative risk, 0.46; 95% CI, 0.29–0.71; 4 trials; 642 patients) and per catheter-day (relative risk, 0.48; 95% CI, 0.30–0.76; 60,149 catheter-days) (figure 4). Statistically significant heterogeneity was present overall and among trials that assessed citrate, explained by the differential use of additional prophylactic measures. Two trials used mupirocin nasal decontamination and topical iodine at the exit site, and their relative risk was 0.25 (95% CI, 0.13–0.50), whereas 2 trials that did not use additional prophylactic measures did not show a significant advantage to catheter lock solutions (relative risk, 0.90; 95% CI, 0.48–1.69; P=.01 for the difference). The same trials that used mupirocin and iodine reported adequate allocation concealment and generation, and 1 trial was double blinded. Relative risks were similar for tunneled and nontunneled catheters.

Catheter removal rates were significantly lower in the study group per patient (relative risk, 0.61; 95% CI, 0.45–0.81; 3 trials; 581 patients) and per catheter-day (relative risk, 0.62; 95% CI, 0.44–0.88; 56,089 catheter-days), without significant heterogeneity. No difference was found between study groups with regard to catheter thrombosis (relative risk, 0.97; 95% CI, 0.72–1.30; 4 trials; 27,237 catheter-days), without significant heterogeneity. Catheter survival at 3 months was higher with catheter lock solutions in 2 trials that assessed citrate (relative risk, 1.28; 95% CI, 1.04–1.57). Exit site infections were significantly reduced by catheter lock solutions per patient (relative risk, 0.58; 95% CI, 0.40–0.84; 5 trials; 661 patients) and per catheter-day (relative risk, 0.60; 95% CI, 0.40–0.90; 63,345 catheter-days). Tunnel infections were not reported.

Adverse events were addressed by 4 trials. No events were reported in the trial that assessed citrate and taurolidine [44]. Two trials reported a higher frequency of adverse events, mainly bleeding, in the control group [51, 57], and 1 trial reported a higher rate of treatment discontinuations with citrate (20 of 132 patients) compared with heparin (0 of 100 patients), without specifying the causes [48]. Overall mortality was reported in the 2 high-quality trials, without a significant difference (relative risk, 0.65; 95% CI, 0.34–1.24).

When all trials that assessed citrate were pooled (alone, with gentamicin, or with taurolidine; 7 trials; 818 patients; 75,185 catheter-days), significant reductions were found in catheter-related bloodstream infections (relative risk, 0.36; 95% CI, 0.24–0.55), the need for catheter removal (relative risk, 0.56; 95% CI, 0.42–0.74), and exit site infections (relative risk, 0.34; 95% CI, 0.19–0.61) per patient (similar results per catheter day; data not shown). No difference was found in the incidence of catheter thrombosis.

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Discussion

The objective of our systematic review was to assess the efficacy of antimicrobial lock solutions for the prevention of catheter-associated infections in patients undergoing hemodialysis. We assessed separately antibiotic locks and other nonantibiotic antimicrobial locks.

Antibiotic catheter lock solutions significantly reduced catheter-related bloodstream infection rates (relative risk, 0.44; 95% CI, 0.38–0.50) and catheter removal rates (relative risk, 0.35; 95% CI, 0.23–0.55) compared with heparin lock alone. All studies showed a benefit for lock solutions with regard to catheter-related bloodstream infections. However, the size of the effect varied significantly, with some studies demonstrating large effect estimates (risk reduction of up to 93%) and others demonstrating more modest protective effects. Catheter lock solutions were more effective when additional preventive measures, such as nasal decontamination with mupirocin and iodine dressing at the exit site, were used. A statistically significant effect of trial methodologic quality and size on effect estimates was found, with smaller studies and those not reporting adequate randomization methods exaggerating the beneficial effect of antibiotic lock solutions. However, the protective effect remained statistically significant, although of lower magnitude, among the other trials as well.

Only 5 trials compared nonantibiotic catheter lock solutions, mainly citrate, with heparin. When the catheter lock solution was used in conjunction with nasal mupirocin and exit site iodine dressing in good-quality trials, the intervention was highly effective (relative risk, 0.25; 95% CI, 0.13–0.50). No statistically significant effect could be shown for nonantibiotic catheter lock solution alone. Citrate catheter lock solution, with or without antibiotics, was assessed in 7 trials and statistically significantly reduced infection and catheter-removal rates, with no effect on catheter thrombosis. Taurolidine was assessed in a single small randomized trial (58 patients), which showed nonsignificant reductions in infection-related outcomes.

Our results are in accordance with a previous systematic review that assessed vancomycin catheter lock solutions in patients not undergoing hemodialysis [59]. Safdar and Maki demonstrated that catheter lock solutions retained in the catheter, as for patients undergoing hemodialysis, provide significantly higher protection than flush catheter lock solutions. Various antibiotic regimens were used in the trials included in our review. Gentamicin alone was as effective as combination therapy or other broader-spectrum antibiotic catheter lock solutions and prevented equally gram-positive and gram-negative infections. Minocycline-EDTA was also effective, but the number of evaluated patients was small (88 patients in 2 trials). Gentamicin and minocycline have a broad spectrum of activity against gram-negative and gram-positive bacteria [60, 61], especially with drug levels achieved in the catheter lumen. An advantage of both is that they are not used empirically for the treatment of sepsis in patients undergoing hemodialysis [62]. In vitro and animal studies show good efficacy of minocycline plus EDTA in prevention of colonization and eradication of the relevant bacteria in biofilms, whereas vancomycin was found to be less effective [17–19]. Concerns regarding the use of gentamicin locks include potential ototoxicity. In our review, no cases of ototoxicity were reported. So far, only 1 case of ototoxocity with use of an amikacin lock has been reported [63].

Development of resistance is the major factor against the use of antibiotic catheter lock solutions and the reason that these locks are not routinely recommended [21]. Only 1 case of development of resistance was reported in 5 trials included in our review that addressed this issue, after a follow-up of ∼12 months in these trials [54]. No surveillance cultures were performed in all trials. In the previous meta-analysis [59], resistance to vancomycin was not encountered in all trials, including 2 trials that performed surveillance cultures. Lack of resistance was attributed to undetectable blood levels of vancomycin in all studies. A follow-up of 1 year in a dialysis unit using gentamicin locks found no increase in resistance rates compared with historical rates [29]. However, all these results do not preclude development of resistance with longer and more extensive use of antibiotic catheter lock solutions.

Several limitations of our conclusions should be stated. Bloodstream infections of any cause were not assessed in these trials. We regard this as a limitation because the outcome of catheter-related bloodstream infections might not capture the overall effect of the intervention and may permit a detection bias. Similarly, length of hospital stay was not reported, and all-cause mortality was reported in only 7 of 16 trials. We observed a small-studies effect and potential bias that favored the intervention in open trials that did not report randomization methods. We thus believe that the truer effect estimate for the reduction of catheter-related bloodstream infections is that of the higher-quality trials (relative risk, 0.60; 95% CI, 0.54–0.67). Finally, despite the inclusion of unpublished trials in our review, we cannot rule out publication bias.

Catheter lock solutions for the prevention of infection in patients with central venous catheters are not generally recommended [21]. The Kidney Disease Outcomes Quality Initiative guidelines do not advocate the use of catheter lock solutions for the prevention of catheter-related bacteremia in hemodialysis [20]. The Centers for Disease Control and Prevention guidelines state that catheter lock solutions can be considered only under special circumstances, such as multiple catheter-related bloodstream infections, despite maximal adherence to aseptic technique [21]. Our results demonstrate a statistically significant reduction in catheter-related bloodstream infections, catheter removal, and catheter thrombosis rates with the use of antibiotic locks, without the emergence of resistant organisms. The number of patients needed to treat to prevent 1 catheter-related bloodstream infection on the basis of the relative risk of the higher-quality trials (0.60) is 4 patients (95% CI, 4–5 patients), for a median treatment duration of 3 weeks (range, 1–15 weeks) in these trials. Our results do not support the role of catheter lock solutions for patients with recurrent catheter-related bloodstream infections, because the effect of antibiotic catheter lock solutions was seen mainly for the first episode of catheter-related bloodstream infection. We therefore conclude that antibiotic catheter lock solutions should be considered in routine clinical practice, with the caveat that development of resistance might not have been adequately assessed.

Catheters constitute the least desired method of vascular access for long-term hemodialysis. The US National Kidney Foundation has defined the reduction of catheter use as a goal for hemodialysis centers [20]. For those patients with no alternative vascular access, use of catheter lock solutions should be considered in conjunction with other proven infection prevention and control modalities. On the basis of our subgroup analysis and considerations of antibiotic resistance, antibiotic catheter lock solutions might be most beneficial to prevent the first episode of catheter-related bloodstream infection in patients receiving short-term catheter hemodialysis, such as patients undergoing incident hemodialysis. Locks that contain gentamicin or minocycline plus EDTA are as efficacious as broader-spectrum regimens. Currently, evidence does not show the efficacy of citrate or citrate-taurolidine catheter lock solutions as single agents, when applied without other preventive measures. Further studies are needed to determine their efficacy compared with heparin and antibiotics, stratifying for preventive measures with proven efficacy in infection prevention. Induction of resistance to antibiotic catheter lock solutions should be assessed in prospective long-term studies.

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Acknowledgments

We thank the authors who responded to our letters and supplied additional data on their trials.

Potential conflicts of interests. All authors: no conflicts.

  • Received December 3, 2007.
  • Revision received February 22, 2008.
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  1. Clin Infect Dis. (2008) 47 (1): 83-93. doi: 10.1086/588667
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