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Randomised clinical trial: 2% taurolidine versus 0.9% saline locking in patients on home parenteral nutrition

Summary Background The catheter lock solutions 2% taurolidine and 0.9% saline are both used to prevent catheter‐related bloodstream infections (CRBSIs) in home parenteral nutrition patients. Aims To compare the effectiveness and safety of taurolidine and saline. Methods This multicentre double‐blinded trial randomly assigned home parenteral nutrition patients to use either 2% taurolidine or 0.9% saline for 1 year. Patients were stratified in a new catheter group and a pre‐existing catheter group. Primary outcome was the rate of CRBSIs/1000 catheter days in the new catheter group and pre‐existing catheter group, separately. Results We randomised 105 patients, of which 102 were analysed as modified intention‐to‐treat population. In the new catheter group, rates of CRBSIs/1000 catheter days were 0.29 and 1.49 in the taurolidine and saline arm respectively (relative risk, 0.20; 95% CI, 0.04‐0.71; P = 0.009). In the pre‐existing catheter group, rates of CRBSIs/1000 catheter days were 0.39 and 1.32 in the taurolidine and saline arm respectively (relative risk, 0.30; 95% CI, 0.03‐1.82; P = 0.25). Excluding one outlier patient in the taurolidine arm, mean costs per patient were $1865 for taurolidine and $4454 for saline (P = 0.03). Drug‐related adverse events were rare and generally mild. Conclusions In the new catheter group, taurolidine showed a clear decrease in CRBSI rate. In the pre‐existing catheter group, no superiority of taurolidine could be demonstrated, most likely due to underpowering. Overall, taurolidine reduced the risk for CRBSIs by more than four times. Given its favourable safety and cost profile, taurolidine locking should be considered as an additional strategy to prevent CRBSIs. Trial registration: Clinicaltrials.gov, identifier: NCT01826526.


| INTRODUCTION
Home parenteral nutrition entered the clinical arena in the late 1960s and has since remained the mainstay for the support of patients with chronic intestinal failure. [1][2][3] This type of nutritional support requires the presence of a central venous access device (CVAD), most commonly a catheter, for the supplementation of nutrients and fluids at home. Despite ongoing technical improvements, catheter-related bloodstream infections (CRBSIs) remain the Achilles' heel of home parenteral nutrition treatment. 4 The reported CRBSI incidence ranges from 0.38 to 2.99 CRBSI per 1000 catheter days and accounts for approximately 70% of all home parenteral nutrition-related hospital admissions. 5,6 As such, CRBSIs compromise venous access and patient survival, and may lead to home parenteral nutrition failure because of a permanent loss of vascular access.
Strict adherence to aseptic protocols when handling CVADs remains the key strategy to prevent CRBSIs. The use of anti-microbial catheter lock solutions has also been advocated, but the search for the optimal locking agent remains ongoing. 4 Several catheter lock solutions have been studied for their effectiveness in preventing CRBSIs, including antiseptic agents, antibiotics and anticoagulants. Most catheter lock solutions have been abandoned because of side effects, concern about the development of microbial resistance or mere lack of effect. 4 Historically, heparin was the most commonly used catheter lock solution, also because of the supposed need for an anticoagulant. However, its use potentially increases the risk for CRBSIs by promoting intraluminal biofilm formation and is no longer recommended. 4,7,8 In 1998, use of the broadspectrum antiseptic agent taurolidine as catheter lock solution was first described. 9 The background for the effect of taurolidine is that this agent prevents endoluminal biofilm formation by inhibiting microbial adhesion to the inner surface of the catheter and that it destroys microbial cell membranes and toxins. [10][11][12][13] Subsequent studies and a meta-analysis confirmed that taurolidine, when compared to heparin, decreases CRBSI incidence in patients with catheters. [14][15][16] None of these previous studies, however, discriminated between beneficial effects of taurolidine and/or the detrimental effects of heparin. Currently, 0.9% saline solution is commonly used as an alternative to taurolidine because of its safety profile and low cost, despite a lack of evidence from well-powered studies. 4,17 These issues, and the fact that it remains unclear whether the use of taurolidine should be restricted to patients with a high risk for CRBSIs, urged us to test the hypothesis that 2% taurolidine is a superior catheter lock solution to 0.9% saline in preventing CRBSIs. This hypothesis was tested in home parenteral nutrition patients who were stratified in two patient categories. Patients in the first group had a new catheter without any biofilm, and in this group, the potency of taurolidine to prevent the development of biofilms (and hence CRBSIs) could be shown.
Patients in the second group had previously experienced CRBSIs and had a pre-existing CVAD that possibly had acquired an infection-promoting biofilm on the inner catheter surface. These patients were at a higher risk to develop a CRBSI.

| Study oversight
This multicentre, double-blinded superiority trial was conducted in six referral centres (Denmark, Israel, Italy, the Netherlands and the United Kingdom), in which home parenteral nutrition patients were randomly assigned to use either a catheter lock solution containing 2% taurolidine or 0.9% saline for 1 year. The study design was conceived by the final author and followed close consultation with members of the Home Artificial Nutrition and Chronic Intestinal Failure special interest group of the European Society for Clinical Nutrition and Metabolism. The institutional review board or ethics committee at each participating centre approved the study protocol.
Geistlich Pharma AG (Wolhusen, Switzerland) provided 2% taurolidine (TauroSept) and 0.9% saline solution, but had no role in the study design, data analysis or preparation of the manuscript. Acromion GmbH (Frechen, Germany), an independent contract research organisation, provided data management. Acromion GmbH and the first author performed the data analyses. The CONSORT guidelines were followed to report this study. 18

| Participants
Eligible patients were between 18 and 80 years of age and had a benign underlying disease leading to intestinal failure. Patients received ≥2 bags per week of nutrition and/or fluids (saline and/or glucose) over a single-lumen CVAD. Other eligibility criteria included an estimated life expectancy ≥1 year and complete understanding of the nature of the proposed trial.
Patients were stratified into two groups. Patients in the first group, called "new catheter group", received a new CVAD (ie without biofilm) and were either new patients (home parenteral nutrition naive) or patients who already used home parenteral nutrition. The latter patients may or may not have had a history of CRBSIs. The second group was called "pre-existing catheter group", and consisted of supposed "high-risk" patients, defined as patients having a CVAD that had already been in place for at least 6 months and thus possibly contained an intraluminal biofilm. In addition, patients had been on home parenteral nutrition ≥1 year and had previously experienced a CRBSI rate of ≥0.82/1000 catheter days during their treatment period. The cut-off rate of 0.82/1000 catheter days was chosen based on a systematic review from Dreesen et al who found that the median CRBSI rate of studies including 50% or more intestinal failure patients with a benign underlying disease was 0.82 episodes per 1000 catheter days. 19 The pre-existing catheter group was designed based on expert opinion, since no exact criteria for high-risk patients have been defined in the home parenteral nutrition literature.
Exclusion criteria were antibiotic therapy <2 months prior to trial inclusion, implantation of antibiotic coated, silver impregnated or antimicrobial cuff catheters, a current CRBSI, compromised skin integrity of catheter exit site, use of taurolidine locks in the current WOUTERS ET AL. | 411 CVAD, known hypersensitivity to taurolidine and significant cardiovascular disease (unstable angina pectoris, acute myocardial infarction or recent cerebral vascular accident (within 6 weeks), or a cardiac rhythm, which in the investigators judgement may result in significant hemodynamic effects). Other exclusion criteria included clinically significant abnormalities in coagulation requiring intervention, thrombolytic therapy 6 weeks prior to CVAD insertion (80-325 mg acetylsalicylic acid daily was acceptable), and concurrent pregnancy or lactation.

| Randomisation and blinding
Patients were screened for eligibility during regular outpatient clinical check-ups or during hospitalisation. After the local principal investigator determined eligibility and obtained written informed consent, the patients were stratified into the new catheter group or pre-existing catheter group, and randomised according to a random computer-permuted block scheme (1:1, with block sizes of four patients) to either 2% taurolidine or 0.9% saline by the sponsor in a validated environment. All vials were identical in appearance, smell and method of administration. All patients, investigators and site personnel as well as persons involved in field monitoring, data handling or the conduct of the trial were blinded to the randomisation data and the trial medication.

| Study treatment
Patients or caregivers were instructed according to local training procedures on how to instil the lock solution at home. The catheter lock solutions were stored at room temperature. Each time an infusion of parenteral nutrition or fluids was completed, the CVAD was flushed with 10 mL sterile physiological saline solution. Subsequently, an identical vial containing 5 mL 2% taurolidine or 0.9% saline solution was instilled into the CVAD. The frequency of administration depended on the patient's parenteral nutrition schedule and ranged from twice per week to once daily. Patients were seen every 3 months by an investigator during regular outpatient clinic visits or during unscheduled visits and hospitalisations. At these check-ups, CVAD-related complications, concomitant medication, catheter function, catheter exit sites and adverse events were assessed. In cases where a CRBSI was proven during the study, the patient was withdrawn from the trial after a final visit procedure.

| Outcomes
A CRBSI was suspected when a patient presented with clinical evidence of systemic infection (ie body temperature >38.5°C or <36°C, chills, hypotension (systolic blood pressure <90 mm Hg or a decrease in systolic blood pressure >40 mm Hg), tachycardia (>90 beats per minute), elevated white blood cell count (>12 × 10 9 /L) and/or C-reactive protein rise), in the absence of any other apparent source of infection than the CVAD. 4 In this event, paired quantitative or qualitative blood cultures from the CVAD and from a peripheral vein were taken. A CRBSI was proven when at least one blood culture was positive from the CVAD or a peripheral vein. In the absence of positive blood cultures, defervescence after removal of an implicated catheter from a patient with clinical infectious symptoms was considered indirect evidence of a CRBSI. 4 Blood cultures were performed, analysed and treated according to investigational site protocols.
The primary outcome was the rate of CRBSIs/1000 catheter days between taurolidine and saline for the new catheter group and preexisting catheter group, separately. Predefined secondary outcomes included time to CRBSIs or CVAD removals due to CRBSIs, number of CVAD removals due to CRBSIs, exit site infections, CVAD occlusions, patient satisfaction with the assigned catheter lock solution (rated on a scale: not at all satisfied, somewhat unsatisfied, satisfied, very satisfied), adverse events and cost. The removal of a CVAD due to a CRBSI was indicated in case of a port abscess, tunnel infection, in patients with septic shock, or in case of complicated infections, such as metastatic infections, septic thrombosis or when blood cultures were positive for fungi or virulent bacteria. 4 An exit site infection was defined as a local CVAD infection (local erythema, induration, tenderness around the CVAD exit site and/or purulent discharge). A CVAD occlusion was defined as a complete obstruction of the CVAD lumen (failure to flush or aspirate or the inability to infuse sufficiently into the CVAD). Patient satisfaction and costs were assessed at the end of the trial. All other outcomes were assessed during all scheduled and unscheduled visits.

| Statistical analysis
The sample size calculation was based on assumptions for the primary endpoint in the new catheter group. At an 80% power and a 5% significance level, a minimum of 21 patients per arm would be required to detect a mean numerical difference of 1.5 between the treatment arms. A standard deviation of 0.3 in the taurolidine arm and 2 in the saline arm was incorporated, based on the study by Bisseling et al, and we assumed a dropout rate of 20%. 14 To allow testing for differences in the pre-existing catheter group, an additional 42 patients were required, resulting in a total of 84 patients. We aimed to include up to 20 patients from seven participating referral centres, resulting in a maximum of 140 patients included in the trial.
A statistical analysis plan was finished before unblinding. Originally, the primary analysis (CRBSI rate between taurolidine and saline) was tested using a two-sided Mann-Whitney U test. However, after consultation of both an epidemiologist and a statistician, new insights urged us to submit an amendment (after unblinding) of the statistical analysis plan and to use a two-sided Fisher exact test via the website OpenEpi instead. This website compares incidence rates by incorporating both events and person-time. 20,21 Of note: use of the Fisher exact test did not change any of the results and conclusions obtained with the Mann-Whitney U test (Table S2).
The primary analysis was tested in a modified intention-to-treat population, which included all randomised patients exposed to taurolidine or saline and who had at least one effectiveness assessment available. Furthermore, a per-protocol analysis was performed in which, in addition to the modified intention-to-treat criteria, patients had to meet the eligibility criteria and complete the trial for planned visits with complete test results in accordance with all relevant aspects of the protocol. Safety analyses were based on all randomised patients. Baseline characteristics, effectiveness and safety measurements were summarised using descriptive statistical methods. Time-to-event endpoints were described by Kaplan-Meier curves and were compared using a log-rank test. Costs were based on Dutch prices and consisted of catheter lock solution costs and CRBSI resource use costs (hospitalisations, unscheduled outpatient clinic consultations, CVAD changes and drug treatment). 22,23 The mean costs per patient were calculated by means of an independent samples t test after bootstrapping (1000 simulations) with 95% confidence intervals. All other outcomes were analysed using a twosided Fisher exact test. In a post hoc analysis, the results of both groups were summarised in a combined group analysis. All analyses, except for the primary analysis, were performed using Statistical Analysis System software, version 9.4.  (Table 1). A total of 85 patients were included in the per-protocol analysis.

| Outcomes
In the new catheter group, three CRBSIs occurred during 10 248 catheter days in the taurolidine arm, while in the saline arm, 13 CRBSIs occurred in 8708 catheter days, resulting in 0.29 and 1.49 CRBSIs/1000 catheter days for taurolidine and saline respectively (relative risk, 0.20; 95% CI, 0.04-0.71; P = 0.009). The cumulative proportion of CRBSI-free patients after 1 year was 89% for taurolidine and 43% for saline (P = 0.002) ( Figure 2). The remaining secondary outcomes were non-significant between taurolidine and saline. The results of the per-protocol analysis were generally similar to the modified intention-to-treat analysis (Table S1 and Figure S1).
In the pre-existing catheter group, two CRBSIs occurred during 5070 catheter days in the taurolidine arm, while in the saline arm, five CRBSI occurred in 3785 catheter days, resulting in 0.39 and 1.32 CRBSIs/1000 catheter days for taurolidine and saline respectively (relative risk, 0.30; 95% CI, 0.03-1.82; P = 0.25). The remaining secondary outcomes were non-significant between taurolidine and saline. The results of the per-protocol analysis were generally similar to the modified intention-to-treat analysis (Table S1 and Figure S1).
In the combined group analyses, five CRBSIs occurred during 15 318 catheter days in the taurolidine arm, while in the saline arm, 18 CRBSIs occurred in 12 493 catheter days, resulting in 0.33 and 1.44 CRBSI/1000 catheter days for taurolidine and saline respectively (relative risk, 0.23; 95% CI, 0.07-0.63; P = 0.002) ( Table 2). The cumulative proportion of CRBSI-free patients after 1 year was 88% in the taurolidine arm and 49% in the saline arm (P = 0.002) (Figure 2). The number of patients with a CRBSI-related catheter removal was two (4%) in the taurolidine arm and eight (16%) in the saline arm (P = 0.049). The time to CVAD removal due to CRBSI was significantly prolonged in the taurolidine arm (P = 0.02) (Figure 2). The remaining secondary outcomes were non-significant between taurolidine and saline. The per-protocol analyses were generally similar to the modified intention-to-treat analyses (Table S1 and Figure S1).

| CRBSI-causing microorganisms
During the study, all CRBSIs were proven by at least one positive blood culture. In the taurolidine arm, three patients experienced a monobacterial Gram-positive CRBSI, one patient a polybacterial CRBSI and one patient had an episode with a microorganism that was not specified (Table 3). In the saline arm, six monobacterial Gram-positive and eight Gram-negative CRBSIs occurred. One patient experienced a polybacterial CRBSI, one patient had an isolated fungaemia and two patients experienced an episode with a microorganism that was not specified. The CVAD salvage rate in patients with a CRBSI was 60% for taurolidine and 56% for saline.

| Adverse events
A total of 71 (68%) patients reported adverse events. Except for occurrence of CRBSIs, there was no difference in adverse events between taurolidine and saline (Table 4). CVAD-related complications were the most frequently reported adverse event. Drug-related adverse events were rare and either mild to moderate. Two patients deceased in the taurolidine arm, but neither demise was considered to be drug-related.

| Resource use and costs
The mean costs per patient were comparable for taurolidine ($4422) and saline ($4454) (   12 refused to participate 7 did not meet in/exclusion criteria: 2 received treatment with systemic antibiotics 2 were hypersensitive to taurolidine 1 used high-dose thrombolytic therapy 1 had elevated C-reactive protein 1 was on short-term home parenteral nutrition F I G U R E 1 Enrollment and follow-up. *Patients were excluded from the modified intention-to-treat analysis because no effectiveness assessments were available after the baseline visit. † Patients were excluded from the per-protocol analysis because they either did not meet eligibility criteria or did not complete the trial before the planned visits with complete test results in accordance with the protocol. Some patients were excluded from the per-protocol analysis for more than one reason but were included in only one exclusion category

| DISCUSSION
This study is by far the largest multicentre double-blind randomised clinical trial ever performed in the home parenteral nutrition setting, and the first to demonstrate that 2% taurolidine prevents the development of CRBSIs in home parenteral nutrition support, when compared with 0.9% saline. Specifically in the new catheter group, the CRBSI rate was significantly decreased by taurolidine, and the time T A B L E 1 Baseline characteristics of the new catheter group and the pre-existing catheter group (modified intention-to-treat population)   Not at all satisfied For exit site infections, data were missing for one patient in the saline arm of the pre-existing catheter group. For CVAD occlusions, data were missing for one patient in the saline arm of the pre-existing catheter group. For patient satisfaction in the new catheter group, data were missing for 12 and 17 patients in the taurolidine and saline groups, respectively. For patient satisfaction in the pre-existing catheter group, data were missing for three and six patients in the taurolidine and saline groups respectively.
addition, a meta-analysis comparing 1.35% taurolidine and 4% citrate with heparin did not find any beneficial effects on CVAD occlusion rates either. 15 However, some in vitro and retrospective studies have reported beneficial effects of taurolidine over heparin, without using any concomitant anticoagulant protection. 11,25,29,30 This decrease in CVAD occlusions may be explained by a parallel decrease in CRBSIs, and thus of infection-induced activation of the coagulation system, rather than anti-coagulant properties of taurolidine.
Despite prolonged use of taurolidine, some patients still developed CRBSIs. One reason might be breaches or non-compliance of patients or caregivers to antiseptic CVAD care protocols. Another In the taurolidine and saline group, respectively two (Streptococcus salivarius and Neiserna elongata) and three (Acinetobacter ursingii, Stenotrophomonas maltophilia and Staphylococcus epidermidis) microorganisms were grown from one blood culture. c A positive blood culture was reported; however, the microorganism involved was not documented.    found no evidence for altered bacterial susceptibility to taurolidine. 14,31 This was not unexpected, given taurolidines' non-specific chemical aseptic mode of action. To date, no microbial resistance to taurolidine has been reported. 11,15,32 The CVAD salvage rate of 60% in patients with a CRBSI was similar in both arms and is comparable to rates observed in previous studies (55%-80%). 6,33,34 With regard to the microbial pathogens leading to CRBSIs, several cohort studies reported a preponderance of infections caused by Gram-positive (60%-80%) over Gram-negative bacteria (20%-40%). 4,19,35,36 One meta-analysis showed that the use of taurolidine significantly decreased CRBSIs caused by Gramnegative bacteria, whereas CRBSIs from Gram-positive organisms did not change. 15 In this trial, there was no difference in the type of pathogens leading to CRBSIs between taurolidine and saline.
Although taurolidine showed a clear beneficial effect in terms of CRBSI prevention in the new catheter group and the groups combined, patient satisfaction did not differ between taurolidine and saline, and was high in both arms. The low number of drug-related adverse events in both groups may be a likely explanation for this. Future research should focus on additional strategies to minimise CRBSI rates, apart from patient and caregiver training in catheter handling, including optimisation of (taurolidine-containing) locking formulations and its selection in subgroups of patients with a higher risk for CBRSIs, and the use of devices such as antimicrobial catheter caps. 37 In conclusion, using 2% taurolidine as catheter lock solution decreases the risk for CRBSIs in home parenteral nutrition patients with a new catheter compared with 0.9% saline. It remains unclear whether this also applies for patients with a supposed high CRBSI risk who already have had a catheter in place. Given its favourable safety and cost profile, our study supports the use of 2% taurolidine locking for CRBSI prevention in home parenteral nutrition care.

ACKNOWLEDG EMENTS
We thank the research nurses, investigators and administrative assis-

DATA SHARIN G
The full data set is available from the corresponding author at Yannick.Wouters@radboudumc.nl on reasonable request. Consent was not obtained for data sharing, but the presented data are anonymised and risk of identification is low.

TRANSPARENCY
The lead author (GW) affirms that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors operated independently from the funder. The lead author takes full responsibility for the integrity of the data, the accuracy of the data analysis and had final responsibility for the decision to submit for publication.