Clinical Infectious Diseases Advance Access published August 25, 2014 1
Antimicrobial Lock Solutions as a Method to Prevent Central Line-Associated
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Bloodstream Infections: A Meta-Analysis of Randomized Controlled Trials
Ioannis M. Zacharioudakis1,2,*, Fainareti N. Zervou1,2,*, Marios Arvanitis1,2,*, Panayiotis D. Ziakas1,2, Leonard A. Mermel1,2, Eleftherios Mylonakis1,2
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Warren Alpert Medical School of Brown University, Providence, RI
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Infectious Diseases Division, Rhode Island Hospital, Providence, RI
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Corresponding Author: Eleftherios Mylonakis, Infectious Diseases Department, Rhode Island Hospital, 593 Eddy Street, POB, 3rd Floor, Suite 328/330, Providence, RI, 02903,
These authors contributed equally to this work and the names are listed in random order.
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*
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[
[email protected]], Tel: 401-444-7856 / Fax: 401-444-8179
Summary: Antimicrobial lock solutions are an effective method to prevent catheter-associated bloodstream infections and their effect is additive to standard prevention measures. Non-
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antibiotic antimicrobial solutions are an equally effective alternative to antibiotic lock therapy
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and their use may have a lower associated risk of antibiotic resistance.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e‐mail:
[email protected].
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Abstract Background: Antimicrobial lock solutions may be an effective strategy to prevent catheter-
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associated infections. However, there remains concern about their efficacy and safety.
Methods: In order to investigate the efficacy of antimicrobial lock therapy to prevent central-
line-associated bloodstream infections (CLABSI), we performed a systematic search of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov, from the
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trials comparing antimicrobial lock solutions to heparin and if they provided an appropriate
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definition of infection.
Results: The 23 included studies reported data on 2,896 patients, who were predominantly adult
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hemodialysis patients (16/23 studies), but also adult and pediatric oncology patients, critically ill neonates and patients receiving total parenteral nutrition. The use of antimicrobial lock solutions led to a 69% reduction in CLABSI rate (RR=0.31, 95%CI 0.24-0.40) and a 32% reduction in
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exit-site infections rate (RR=0.68, 95%CI 0.49-0.95) compared to heparin, without significantly affecting catheter failure due to non-infectious complications (RR=0.83, 95%CI 0.65-1.06). Allcause mortality was not different between the groups (RR=0.84, 95%CI 0.64-1.12). Neither the type of antimicrobial solution, nor the population studied, affected the relative reduction in
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CLABSIs which also remained significant among studies reporting baseline infection rates of less than 1.15/1000 catheter-days, and studies providing data for CRBSIs. Publication and
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selective reporting bias are a concern in our study and should be acknowledged. Conclusions: Antimicrobial lock solutions are effective in reducing risk of CLABSI and this
effect appears to be additive to traditional prevention measures.
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earliest date up to December 31 2013. Studies were eligible if they were randomized controlled
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Introduction Central line-associated bloodstream infections (CLABSI) are the most costly healthcare-
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associated infections (HAIs), averaging $45,814 on a per-case basis [1]. A recent analysis found that 65-70% of CLABSIs could be prevented with the proper institution of catheter care
measures [2]. Despite high compliance with such measures, the incidence of CLABSIs is
An intervention that is the source of much discussion at the national and international level is the
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use of antimicrobial lock solutions. Indeed, over the past few years, randomized trials have addressed the issue with promising results [4, 5]. However, concerns regarding the emergence of
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resistant organisms [6], non-infectious complications [7], and the inability of previous studies to prove the additive benefit of lock solutions in conjunction with catheter care bundles [8], have
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prevented the recommendation to use this strategy as part of routine catheter care in the recent guidelines [3, 9, 10]. On the other hand, therapeutic antimicrobial locks have been incorporated in the guidelines for the management of catheter-related infections [11]. In order to evaluate the efficacy and safety of antimicrobial lock therapy we conducted a meta-analysis of randomized
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controlled trials (RCTs) comparing antimicrobial lock solutions to heparin.
Materials and Methods
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Literature search
A systematic literature search of PubMed (1951-December 2013), EMBASE (1951-December 2013), the Cochrane Central Register of Controlled Trials (1984-December 2013), and
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preventative interventions have been investigated.
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significantly decreased but not completely eliminated across the US [2, 3]. As such, additional
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clinicaltrials.gov databases was conducted. We used the search term “catheter* AND lock”. We
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restricted our search to articles written in English. Three investigators (IMZ, FNZ, MA) independently identified and scrutinized studies for potential inclusion. Relevant by title and abstract articles were retrieved in full text. We
complemented our search with the reference lists of eligible articles. Our meta-analysis is in line
recommendations [12].
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Eligibility criteria
To be eligible for inclusion in the meta-analysis a study should fulfill the following criteria: 1) to
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be a RCT, 2) to use an antimicrobial lock solution in the intervention group 3) to use heparin in the control group, 4) to use lock solutions, i.e. solutions that were allowed to dwell, rather than simply flushed through the catheter, and, 5) to provide an appropriate definition for CLABSI.
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CLABSI was defined as a primary bloodstream infection (laboratory confirmed bloodstream infection not related to an infection at another site) in a patient that had a central line or umbilical catheter within a 48-hour period before the development of the bloodstream infection [13]. We excluded studies that did not report the definition used, as well as studies that used a non-
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compliant definition (e.g. studies that defined a CLABSI without the need for microbiologic confirmation of bloodstream infection). In cases when a study separately reported definite,
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probable and possible CLABSI, we included only the subgroups that fell within the CDC definition. Antimicrobial lock solutions were separated into 2 categories: a. “antibiotic lock solutions” (all compounds approved by the FDA and used against human infections), and b.
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with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis)
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“non-antibiotic antimicrobial lock solutions” (antiseptic compounds that, while being active
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antimicrobial agents, do not have an indication for systemic use against human infections). Outcomes of interest
The primary outcome of interest was the incidence of CLABSI. Secondary outcome was the rate
of catheter-related bloodstream infection (CRBSI), as defined by the Infectious Diseases Society
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peripheral vein and one of the following a. positive semiquantitative (>15CFU per catheter
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segment) or quantitative (102CFU) culture of a catheter component growing the same organism, or, b. positive quantitative blood culture drawn from CVC at a ratio of 5:1 (CVC vs. peripheral), or, c. at least 2h differential time to positivity (i.e., positive result of culture from CVC is
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obtained at least 2 h earlier than from peripheral blood). Only RCTs that used this definition, or RCTs whose results were detailed enough to be re-adjudicated according to the aforementioned
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definition, were included in this sub-analysis. We also assessed the rate of catheter failure, exit site infections, and all-cause mortality. Catheter failure was a composite outcome of catheter removal because of non-infectious complications and of persistent inadequate flow rate despite flushing, reposition of the catheter, or use of thrombolytic agents.
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Data extraction
Data from eligible studies were independently extracted by three reviewers (IMZ, FNZ, MA)
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into a spreadsheet (Supplemental Material). Discrepancies between authors were resolved by consensus. The following information was extracted: author, year of publication, country of origin, study period, population, age, number of analyzed patients, number of catheters and catheter-days for each group, site of catheter insertion, interventions used, CLABSIs and
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of America [11]. Specifically, as CRBSI were defined cases with a positive blood culture from a
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CRBSIs/1000 catheter-days, catheter failures and exit site infections, all-cause mortality, and
Quality assessment
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other adverse events.
The methodological quality of each trial was evaluated independently by three authors (IMZ, FNZ, MA) using the Cochrane Collaboration tool [14].
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Incidence rate ratios were pooled for CLABSI and 95% confidence intervals (CIs) were
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calculated using random-effects DerSimonian and Laird weights. A sensitivity analysis was performed to estimate incidence rate ratio among studies that reported a low rate of CLABSI,
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defined as rate of CLABSI less than 1.15/1000 catheter-days [15]. We used the I2 statistic in order to evaluate the presence of heterogeneity [16]. We evaluated for publication bias using the
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Harbord-Egger’s test (along with the corresponding funnel plot) [17], and the trim and fill method was employed to adjust for potentially missing studies [18]. Subgroup analyses were performed using a random effects meta-regression, and an interaction p value was reported to compare the effect size between different subgroups [19]. By using the same random model, we
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pooled incidence rate ratios for CRBSIs and exit site infections, and risk ratios for catheter failure (per catheters), and all-cause mortality (per patient). Studies that did not report data on secondary outcomes were excluded from the relevant sub-analyses. An estimate is considered
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significant when the 95% CI does not include the unit. All calculations were performed using the Stata v13 software package (Stata Corporation, College Station, TX).
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Data analysis
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Results
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Our initial database search identified 2,371 non-duplicate citations (our last access was December 31, 2013), of which 2,328 were excluded based on title and abstract review as they did not fulfill our inclusion criteria. Forty-three studies were assessed in full text for further evaluation and 23 of them were included in the final analysis (Figure 1).
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and 383,710 catheter days. The characteristics of the individual studies (Supplemental Methods)
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are summarized in Table 1. These studies assessed the use of gentamicin(5), vancomycin(2), minocycline(1), cefotaxime(1), cefazolin-gentamicin(1), linezolid(1), and amikacin(1). One study evaluated 2 different antimicrobial agents (vancomycin and linezolid) [20]. Of note, we
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were unable to include in our analysis the linezolid arm of this study because of missing data on the duration of follow-up for patients in this group. Non-antibiotic antimicrobial lock solutions
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were assessed in 12 studies. Taurolidine was the most commonly used non-antibiotic lock solution(4/12 studies), followed by ethanol and citrate (2 studies each), and 26% NaCl, methylene blue, fusidic acid, and recombinant tissue plasminogen activator (rt-PA) (1 study each). The frequency of lock and duration of dwell, as well as the concentration of antimicrobial
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lock and heparin used in individual studies are presented in eTable 2.
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Quality assessment
Based on the Cochrane Collaboration tool, 20 of 23 studies reported appropriate methods for random sequence generation, 12 of 23 had a clearly defined method to conceal allocation of patients, and 13 of 23 were double-blinded (eTable1).
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The included studies were published between 2002 and 2013 and reported data on 2,896 patients
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Antimicrobial locks reduce the rate of CLABSI
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We found that prophylactic use of antimicrobial lock solutions significantly reduced the rate of CLABSI (Relative Risk, RR 0.31, 95%CI 0.24-0.40) (Figure 2), with no statistically significant heterogeneity (I2=12.3%) (Table 2). The Harbord-Egger’s test revealed publication bias (bias -
2.84, 0.01). By performing the trim and fill statistical methodology (eFigure 1) the effect did not
Subgroup analysis of the comparative effectiveness of antibiotic vs. non-antibiotic lock solutions
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revealed a CLABSI relative risk of 0.29 (95%CI 0.21-0.41) in the non-antibiotic antimicrobial group and 0.29 (95%CI 0.19-0.44) in the antibiotic group (interaction p=1.0).
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A second subgroup analysis was performed to assess the impact of the underlying medical conditions on the effect size. Sixteen of the 23 studies involved adult patients receiving hemodialysis through central venous catheters. Two studies included pediatric hematology
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patients, 3 critically ill neonates, and 1 each adult hematology patients and patients receiving total parenteral nutrition. The relative risk for CLABSI was 0.33 (95%CI 0.24-0.46) in the adult hemodialysis group, 0.16 (95%CI 0.05-0.46) in the non-hemodialysis adult population
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(interaction p=0.22) and 0.26 (95%CI 0.16-0.43) in the pediatric population (interaction p=0.43). In order to measure the effect of lock solutions in centers with a low rate of CLABSI, we performed a sensitivity analysis excluding all studies with a baseline rate over 1.15/1000
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catheter-days, a rate that was suggested by a large multicenter trial to be achievable with optimal implementation of currently used preventive measures [15]. Six trials were included in this analysis. These studies reported full barrier precautions during catheter insertion, routine exit site care using antiseptic agents, and use of masks and sterile gloves when assessing catheter hubs or
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alter (RR=0.36, 95%CI 0.28-0.46).
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ports after insertion. We found that the relative reduction in the CLABSI rate remained
Effect of antimicrobial lock on secondary outcomes
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significant in this sub-analysis (RR=0.32, 95%CI 0.17-0.60).
Using the 12 studies that provided data on exit site infections, we found that antimicrobial lock solutions are effective in reducing the rate of exit site infections (RR=0.68, 95%CI 0.49-0.95,
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removal and the pooled effect revealed no statistical significant difference between antimicrobial
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and heparin lock patients (RR=0.83, 95%CI 0.65-1.06) (eFigure 3). Furthermore, no statistically significant difference was observed among the 13 studies that provided extractable data on allcause mortality (RR=0.84, 95%CI 0.64-1.12) (eFigure 4). Of note, 1 study with data on the
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mortality rate did not delineate the number of patients per group and the data were considered non-extractable [20]. Finally, from the analysis of the four studies that reported CRBSI, lock
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therapy proved effective in reducing the rate of CRBSI (RR=0.12, 95%CI 0.03-0.47), an effect consistent across the studies (I2 = 0%) (eFigure 5).
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Discussion
Several basic infection control interventions have been implemented leading to a reduction in the
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CLABSI rate in the US [21]. However, greater reductions in risk of catheterized patients may require additional preventative measures such as use of antimicrobial lock solutions. Our metaanalysis revealed a 69% reduction in the risk of CLABSI among patients using antimicrobial lock therapy and suggests that routine use of antimicrobial lock solutions could prevent 7 out of 10 such events. Interestingly, this effect size was relatively consistent across studies that used
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I2=0%) (eFigure 2). Eighteen studies reported non-infectious complications necessitating catheter
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different antimicrobial agents, different locking regimens, and across studies reporting data on
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different patient populations. This finding raises the question of whether antimicrobial lock solutions can reduce the risk of
CLABSI in centers that already report a low incidence with traditional prevention measures [8]. By separately analyzing studies that reported a control group event rate of less than 1.15/1000
reasonable to assume that antimicrobial locks have an additive effect in the reduction of CLABSI risk and would be useful as an adjunct to traditional preventive measures. Most studies included
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in our meta-analysis focused on hemodialysis patients, which is reasonable given the predominant intraluminal source of catheter-related infections in patients with long-term
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catheters [22]. However, our findings support that the protective effect of lock solutions is not limited to this patient population (Table 2). Since CLABSI as an outcome indicator may
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overestimate the beneficial effect of catheter lock, we separately analyzed the effect of lock solutions on the incidence of CRBSI, requiring bloodstream infection to be confirmed by percutaneously-drawn blood cultures, and we found that catheter lock use significantly reduced CRBSI.
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Taking into consideration that treatment of CLABSI frequently necessitates catheter removal [11], it is anticipated that antimicrobial lock solutions will reduce the likelihood of premature
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catheter removal [4]. However, it is important to assess whether antimicrobial lock solutions could have a negative impact on existing catheters, either by directly impairing catheter integrity or by increasing the risk of thrombosis [23, 24]. Importantly, we found that that the use of lock solutions did not increase the incidence of catheter malfunction, but different lock solutions, concentrations, and catheter materials should be separately investigated in future studies.
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catheter-days, we found that the effect of antimicrobial locks remains significant. Therefore, it is
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Exit site infections are an additional cause of morbidity in patients with central venous catheters and these infections can lead to subsequent bloodstream infections, often necessitating catheter
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removal [25]. Our meta-analysis demonstrated that antimicrobial lock solutions have a
significant effect in reducing the risk of these infections, thus suggesting their impact beyond the prevention of bloodstream infections. Although this seems counter-intuitive, two possible
explanations may account for this finding. Firstly, most of the studies of exit site infections were
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depending on solution density, catheter type, anatomic location of catheter insertion and body
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position [26]. As such, at the concentrations used in some lock solutions, leakage into the bloodstream may reach at or near the minimal inhibitory concentration of common pathogens
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such as staphylococci and the concentration may be maintained in the blood and subcutaneous tissue at the catheter exit site during the interdialytic period minimizing the risk of exit site infection. Alternatively, it is known from animal models [27] that microbes directly injected into
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an implanted port reservoir can, with continued access of the port, eventually lead to finding the identical microbes in the surrounding subcutaneous tissue. In this scenario, a lock solution could reduce risk of such fluid leakage causing infection in the surrounding tissue of an implanted port.
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However, further laboratory and clinical trials are needed to investigate this association. Widespread use of antimicrobial compounds inevitably raises concern of antimicrobial resistance. Indeed, gentamicin-resistant bacteria causing CLABSIs have been observed among
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hemodialysis patients who are receiving gentamicin lock therapy [28], and hence it might not be prudent to be used alone in a lock regimen. To avoid such an outcome, there is interest in use of non-antibiotic antimicrobial solutions such as ethanol [29] and taurolidine [30]. Our metaanalysis shows that these agents have similar influence on risk reduction for CLABSIs as
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in dialysis patients. Some lock solutions leak from the catheter lumen into the circulation
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gentamicin or vancomycin. Studies included in our meta-analysis that assessed the effectiveness of ethanol lock were exclusively among hemodialysis patients, compared to studies using
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taurolidine lock solutions which were among hematology patients, patients receiving TPN and patients on hemodialysis. The long dwell time of ethanol lock solution, when used for
hemodialysis patients, could potentiate its effectiveness compared to critically ill or oncology
patients. Indeed, a randomized, controlled trial that compared the effectiveness of 70% ethanol
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find a significant reduction in the risk of endoluminal CRBSI [31]. Therefore, further studies
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should address the optimal dwell time of ethanol lock solutions.
A decision regarding use of an antimicrobial lock solution should be based on potential adverse
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events, ease of use, interactions with catheter material or medications infused through the same catheter lumens, stability of the product, cost, as well as the lock dwell time. Gentamicin lock
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has been linked to ototoxicity [32] and the inadvertent bolus infusion of high-dose citrate has caused the unexpected death of a patient, which led the FDA to remove it from the market as an agent for lock therapy [33]. Ethanol lock solutions have been associated with flushing, dizziness and syncope, changes in liver function tests, as well as with structural changes of the catheters
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[34]. However, among the studies included in our analysis, no debilitating or irreversible sideeffects were reported (Table 1). Another concern is systemic toxicity from distal catheter leakage of lock solutions used for prolonged periods of time and the idea that some patients, i.e.
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hemodialysis patients, may be maintained on therapeutic or subtherapeutic antimicrobial drug levels due to leakage of lock solutions. This can be minimized by use of non-femoral vein catheter insertion and by changes in density of the lock solution [26, 35]. However, within the catheter lumen colonizing organisms form a biofilm [36] and thus high concentrations of
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lock to placebo among adult hematology patients using a dwell time of only 15 minutes did not
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antimicrobial agents are needed to eradicate these organisms. This is particularly important in patients with catheters placed for a short duration of time among whom a rapidly effective lock
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solution is needed.
Previous reports have evaluated the efficacy of antimicrobial lock solutions with promising
findings [5]. However, due to the unavailability of relevant data, these studies failed to prove the
antimicrobial locks to currently implemented infection prevention practices. Despite the fact that our study addresses some of these important issues, not all concerns have been eliminated.
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Specifically, antimicrobial lock therapy may be of limited utility in critically ill and oncology patients in whom catheter lumens are in continuous use, while it might be more beneficial for
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patients who have long-term catheters and there is still not enough evidence to ascertain the optimum dwell time and concentration for different lock solutions. All these questions should be
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addressed in future trials. Publication bias is also a concern in our study and this probably indicates that studies with non-significant results may have not been published [17]. With regard to secondary outcomes, selective reporting was observed as 9 studies lacked exit site infections as secondary outcome, 5 lacked non-infectious complications necessitating catheter removal and
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10 lacked all-cause mortality.
Conclusion
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Use of antimicrobial lock solutions is an effective prevention strategy to reduce the risk of central venous catheter infections. Although the limited number of prospective, randomized studies in pediatric and hematology patients may preclude an imminent change in policy in these
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efficacy of non-antibiotic antimicrobial lock solutions or to suggest an additive effect of
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subgroups before larger trials are performed, existing evidence in patients receiving hemodialysis
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suggests that implementation of antimicrobial lock therapy should be considered.
Author Contributions
Ioannis M. Zacharioudakis: Dr. Zacharioudakis designed the study, performed the literature
search, participated in data collection, extraction, statistical analysis and interpretation, prepared
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submitted.
Fainareti N. Zervou: Dr. Zervou designed the study, performed the literature search, participated in data collection, extraction, statistical analysis and interpretation, prepared tables and figures,
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wrote and drafted the manuscript, and approved the final manuscript as submitted. Marios Arvanitis: Dr. Arvanitis designed the study, performed the literature search, participated
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in data collection, extraction, statistical analysis and interpretation, prepared tables and figures, wrote and drafted the initial manuscript, and approved the final manuscript as submitted. Panayiotis D. Ziakas: Dr. Ziakas designed the study, participated in the statistical analysis and data interpretation, prepared tables and figures, reviewed and revised the manuscript, and
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approved the final manuscript as submitted.
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Leonard A. Mermel: Dr. Mermel participated in data interpretation, reviewed and revised the manuscript and approved the final manuscript as submitted. Eleftherios Mylonakis: Dr. Mylonakis conceptualized and designed the study, interpreted the data, reviewed and revised the manuscript, and approved the final manuscript as submitted.
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tables and figures, wrote and drafted the initial manuscript, and approved the final manuscript as
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Conflict of interests LAM has been a consultant for Fresenius, Marvao Medical. All other authors have no financial
Funding Source
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us
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Slobbe L, Doorduijn JK, Lugtenburg PJ, et al. Prevention of catheter‐related bacteremia with a daily ethanol lock in patients with tunnelled catheters: a randomized, placebo‐controlled trial. PLoS One 2010; 5(5): e10840. Zhang P, Yuan J, Tan H, Lv R, Chen J. Successful prevention of cuffed hemodialysis catheter‐ related infection using an antibiotic lock technique by strictly catheter‐restricted antibiotic lock solution method. Blood Purif 2009; 27(2): 206‐211. FDA. Warning on tricitrasol dialysis catheter anticoagulant. FDA Talk Paper 2000; 16. Mermel LA, Alang N. Adverse effects associated with ethanol catheter lock solutions: a systematic review. J Antimicrob Chemother 2014. [Epub ahead of print] Polaschegg HD. Loss of catheter locking solution caused by fluid density. ASAIO J 2005; 51(3): 230‐235. Mermel LA. What is the evidence for intraluminal colonization of hemodialysis catheters? Kidney Int 2014; 86(1): 28‐33.
cr ipt
31.
18
Tables Table 1: Characteristics of eligible studies
Year
Population
Handrup
2013
Pediatric cancer
113
Taurolidine, Citrate, Heparin
0.4/1.4
Broom
2012
HD
49
Ethanol, Heparin
0.28/1.64
Dumichen
2012
Pediatric cancer
71
Taurolidine, Citrate
Moran
2012
HD
303
Gentamicin, Citrate
Sofroniadou
2012
HD
135
2012
HD
2011
HD
Hemmelgarn
2011
HD
Bisseling
2010
TPN
Ac
(N) Deaths I/C
Adverse events (I/ C)
5/2
9/11
6/6
Unpleasant taste (I)
1/0
6/4
1/0
1/0 dry lips, thirst 1/0 perioral dysesthesia, 2/0 abnormal taste, 2/0 nausea,1/0 vomiting, 1/0 chest discomfort
NR
NR
0.28/0.91
8/9
42/35
27/25
NR
Vancomycin, Heparin
0.61/5.48
10/9
9/11
3/1
No
Linezolid, Heparin
0/5.48
7/9
9/11
1/1
No
NaCl 26%, Heparin
1.19/0.65
NR
4/3
0/0
No
M
an
NR
Sodium citrate, Methylene blue, Methylparaben,Propylparaben
0.24/0.82
NR
0/4
2/9
2/0 dysgeusia, 1/0 diarrhea, 1/0 unexplained high fever, 1/0 MI, 1/0 pulmonary embolism; 0/2 major hemorrhage, 0/1 interdialytic hypotension
225
Tissue plasminogen activator, Heparin
0.4/1.37
NR
22/40
3/5
23/34 among which bleeding 13/16
30
Taurolidine
0.19/2.02
NR
0/0
NR
No
416
ce
Maki
56
(N) Catheter failures
0.3/1.24
pt ed
Oguzhan
(N) Exit site infections I/C
us
Author
(N) of patients
Downloaded from http://cid.oxfordjournals.org/ at University of Newcastle on August 26, 2014
cr ipt
Intervention (I)
Rate of CLABSIs per 1000 catheter days I/C
Zhang
2009
HD
140
Gentamicin, Heparin
0.06/0.67
3/3
0/0
4/6
1/0 tinnitus, 1/0 pruritus; 0/1 bleeding
Seliem
2009
Critically ill neonates
97
Amikacin, Heparin
4.5/19.9
NR
0/0
4/8
5/8 asymptomatic hypoglycemia
19
HD
61
Citrate
2.2/3.3
5/6
8/5
4/5
25/37 bleeding episodes; 1/2 PLTs