Fungicides alter the distribution and diversity of bacterial and fungal communities in ginseng fields.

The present study was focused on comparison of four typical fungicides in ginseng field to evaluate the impact of the different fungicides on the soil bacterial and fungal communities' composition and diversity by using high-throughput sequencing. Five treatments were designed comprising carbendazim (D), dimethyl disulfide (E), dazomet (M), calcium cyanamide (S), and control (C). The application of fungicide obviously altered the distribution of dominant fungal and bacterial communities and remarkably decreased the diversity (1099-763 and 6457-2245). The most abundant Proteobacteria obviously degenerate in fungicide-treated soil and minimum in E (0.09%) compared to control (25.72%). The relative abundance of Acidobacteria was reduced from 27.76 (C) to 7.14% after applying fungicide and minimum in E. The phylum Actinobacteria are both decomposers of organic matter and enemies of soil-borne pathogens, elevated from 11.62 to 51.54% and are high in E. The fungi community mainly distributed into Ascomycota that enriched from 66.09 to 88.21% and highin M and E (88.21 and 85.10%), and Basidiomycota reduced from 21.13 to 3.23% and low in M and E (5.27 and 3.23%). Overall, environmentally related fungicides decreased the diversity and altered the composition of bacterial and fungal communities, highest sensitivity present in dimethyl disulfide-treated soil.

Impact of locking solutions on conditioning biofilm formation in tunnelled haemodialysis catheters and inflammatory response activation.

INTRODUCTION: The surface of tunnelled cuffed catheters provides an optimal environment for the development of biofilms, which have recently been described as conditioning films because of the presence of adherent biological materials. These biofilms are associated with infection and thrombosis and potentially increase patients' inflammatory response. These complications could be reduced by the use of locking solutions. OBJECTIVE: To analyse biofilm formation, using confocal and electron microscopy, in tunnelled cuffed catheters locked with three different solutions and to determine the relationship between these solutions and inflammatory response. STUDY DESIGN: This prospective study included 35 haemodialysis patients with tunnelled cuffed catheter removal for non-infection-related reasons. The participants were divided into three groups according to the lock solution used: (1) heparin 1: 5000 IU; (2) citrate 4%; and (3) taurolidine 1.35%, citrate 4% and heparin 500 IU (taurolock); in the latter group, 25,000 IU taurolidine-urokinase was used in the last weekly session. All tunnelled cuffed catheters were cultured, and the inner surface was evaluated with confocal and electron microscopy. The inflammatory profile of included patients was determined at tunnelled cuffed catheter removal. RESULTS: There were no differences in clinical or demographic variables between the three subgroups. Biofilm thickness was lower in the taurolidine group than in the citrate 4% and heparin groups (28.85 ± 6.86 vs 49.99 ± 16.56 vs 56.2 ± 15.67 µm, respectively; p < 0.001), as was biofilm volume (1.01 ±1.18 vs 3.7 ± 2.15 vs 5.55 ±2.44, µm3, respectively; p < 0.001). The mean interleukin-6 value was 39%, which was 50% lower than in the citrate and heparin groups, but without significance differences. CONCLUSION: Our results show that biofilms were found in all tunnelled cuffed catheters, but the thickness and volume were significantly lower in tunnelled cuffed catheters locked with taurolidine solution. Therefore, the type of locking solution used in tunnelled cuffed catheters should maintain tunnelled cuffed catheter sterility and prevent catheter-related bloodstream infections. No significant difference was observed in the inflammatory profile according to the type of locking solution.

Relapsing peritonitis and taurolidine peritoneal catheter lock: One center experience.

BACKGROUND: Relapsing peritonitis due to the development of a biofilm in the catheter's lumen remains an important complication of peritoneal dialysis therapy that endangers technique continuity. Taurolidine catheter lock has proven efficient reducing infection rates in permanent hemodialysis catheters based on its biocidal activity and biofilm detachment effect. Efficacy evidence on its use in peritoneal dialysis catheters is lacking. METHODS: We retrospectively analyzed all relapsing peritonitis episodes from June 2018 until October 2019 in our center. Patients were identified and data were collected from our electronic renal registry and patient's records. RESULTS: Six patients were identified during the study period. Most patients (66.6%) were on automated peritoneal dialysis and the median duration of peritoneal dialysis before the episode of taurolidine was started was 43.66 ± 29.64 months. Mean taurolidine doses were 10 (range: 9-11) and 83.3% (five patients, with peritonitis caused by Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Corynebacterium propinquum) had a favorable response and microbial eradication without relapses after taurolidine treatment. Only one patient relapsed by the same organism (Corynebacterium amycolatum) due to non-adherence to the antibiotic treatment prescribed. None of the patients experienced any relevant adverse events, with only two out of six presenting mild transient abdominal discomfort. CONCLUSION: We believe that peritoneal catheter taurolidine lock could be considered in cases of relapsing or refractory peritonitis, as it could prevent catheter removal and permanent switch to hemodialysis in selected cases, although literature is scarce and further studies are needed.

Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer's disease.

BACKGROUND: Verubecestat, a BACE1 inhibitor that reduces Aß levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH. METHODS: EPOCH was a randomized, double-blind, placebo-controlled 78-week trial evaluating verubecestat 12 mg and 40 mg in participants with mild-to-moderate AD diagnosed clinically. The trial was terminated due to futility close to its scheduled completion. Of 1957 participants who were randomized and took treatment, 652 were assigned to verubecestat 12 mg, 652 to verubecestat 40 mg, and 653 to placebo. Adverse events and relevant laboratory, vital sign, and ECG findings were assessed. RESULTS: Verubecestat 12 mg and 40 mg were associated with an increase in the percentage of participants reporting adverse events versus placebo (89 and 92% vs. 82%), although relatively few participants discontinued treatment due to adverse events (8 and 9% vs. 6%). Adverse events that were increased versus placebo included falls and injuries, suicidal ideation, weight loss, sleep disturbance, rash, and hair color change. Most were mild to moderate in severity. Treatment differences in suicidal ideation emerged within the first 3 months but did not appear to increase after 6 months. In contrast, treatment differences in falls and injuries continued to increase over time. CONCLUSIONS: Verubecestat was associated with increased risk for several types of adverse events. Falls and injuries were notable for progressive increases over time. While the mechanisms underlying the increased adverse events are unclear, they may be due to BACE inhibition and should be considered in future clinical development programs of BACE1 inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov NCT01739348 , registered on 29 November 2012.

Lessons that can be learnt from the failure of verubecestat in Alzheimer's disease.

Introduction: The amyloid-beta (Aß) cascade hypothesis is that reducing Aß levels in the brain will be beneficial in treating Alzheimer's disease. Aß is formed by the cleavage of amyloid precursor protein by ß-site amyloid precure protein cleaving enzyme (BACE1) and the BACE1 inhibitor verubecestat was developed to lower the brain levels of Aß. However, in the EPOCH trial of verubecestat in mild-to-moderate Alzheimer's disease, it was not beneficial and increased adverse effects.Areas covered: Prior to completing EPOCH, APECS, which trialled verubecestat in prodromal Alzheimer's disease, was commenced. Like EPOCH, APECS was terminated early. In APECS, verubecestat 40 mg worsened cognition and increased adverse effects.Expert opinion: In recruiting subjects to clinical trials in Alzheimer's disease, a clinical diagnosis involving the measurement of Aß should be undertaken for all subjects, as this may help to clarify the findings. In my opinion, the failure of verubecestat in EPOCH and APECS probably could have been avoided if a safety and potential efficacy trial (phase 2) had been completed prior to starting phase 3. It seems to me that, as we have a poor understanding of the underlying mechanisms/cause of Alzheimer's disease, this is where the research emphasis should be, not phase 3 clinical trials.

Safety, Tolerability, and Pharmacokinetics of the ß-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor Verubecestat (MK-8931) in Healthy Elderly Male and Female Subjects.

ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is required for the production of ß-amyloid peptides, which are implicated in the etiology of Alzheimer's disease. The safety and pharmacokinetics of the BACE1 inhibitor verubecestat have previously been studied in young adults aged 19-45 years. In this randomized, placebo-controlled, phase I study (protocol MK-8931-006), we investigated the safety, tolerability, and pharmacokinetics of a single dose (100 mg) or multiple doses (30, 80, and 120 mg) once daily for 28 days of verubecestat in healthy elderly subjects. Safety end points were assessed at baseline and during the duration of the study period and indicated that verubecestat was generally well tolerated. Verubecestat pharmacokinetics were similar between healthy elderly male and female subjects and similar to those reported in healthy young males in previous studies. These data supported subsequent studies to assess the potential efficacy of verubecestat in subjects with Alzheimer's disease.

Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease.

BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aß). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).

Clinical outcomes of home parenteral nutrition patients using taurolidine as catheter lock: A long-term cohort study.

BACKGROUND & AIMS: Central venous access device (CVAD)-related complications, such as central-line associated bloodstream infections (CLABSIs), CVAD-related venous thromboses (CRVTs) and -occlusions frequently occur in home parenteral nutrition (HPN) patients. A preventive strategy to decrease the incidence of CLABSIs is the use of CVAD lock solutions, such as 2% taurolidine. The aim of this study was to evaluate long-term clinical outcomes of our HPN cohort while using taurolidine as lock solution. In addition, we explored risk factors associated with CVAD-related complications. METHODS: We conducted a retrospective analysis of complications (CLABSIs, CRVTs and CVAD occlusions) and adverse events in adult HPN patients while using taurolidine as lock solution. Patients with a benign underlying disease leading to intestinal failure were included between 2006 and 2017 at our tertiary referral centre for intestinal failure. Primary outcome was the effectiveness of taurolidine, as described by complication incidence rates. Secondary objectives were to assess adverse events of taurolidine, complication rates of patients who subsequently discontinued taurolidine and started using 0.9% saline alternatively, and risk factors associated with complications. RESULTS: In total, 270 HPN patients used taurolidine during 338521 catheter days. CLABSIs, CRVTs and CVAD occlusions occurred at a rate of 0.60 (CI95% 0.52-0.69), 0.28 (CI95% 0.23-0.34), and 0.12 (CI95% 0.08-0.16) events per 1000 catheter days, respectively. In 24 (9%) patients, mild to moderate adverse events resulted in discontinuation of 2% taurolidine. A subsequent switch to 0.9% saline resulted in an increased CLABSI rate (adjusted rate ratio 4.01 (95%CI 1.23-13.04), P = 0.02). Several risk factors were identified for CLABSIs (a lower age, nontunneled catheters, infusion frequency), CRVTs (site of vein insertion), and CVAD occlusions (type of CVAD). CONCLUSION: Complication rates remained low in the long-term, and use of taurolidine was generally safe. The identified risk factors may help to create new strategies to further prevent CVAD-related complications and improve HPN care in the future.

RandomiSed clinical trial assessing Use of an anti-inflammatoRy aGent in attenUating peri-operatiVe inflAmmatioN in non-meTastatic colon cancer - the S.U.R.G.U.V.A.N.T. trial.

BACKGROUND: Peri-operative inflammation has been extensively highlighted in cancer patients as detrimental. Treatment strategies to improve survival for cancer patients through targeting peri-operative inflammation have yet to be devised. METHODS: We conducted a multi-centre, randomised controlled clinical trial using Taurolidine in non-metastatic colon cancer patients. Patients were randomly assigned to receive Taurolidine or a placebo. The primary endpoint for the study was the mean difference in day 1 IL-6 levels. Secondary clinical endpoints included rates of post-operative infections and tumor recurrence. RESULTS: A total of 293 patients were screened for trial inclusion. Sixty patients were randomised. Twenty-eight patients were randomised to placebo and 32 patients to Taurolidine. IL-6 levels were equivalent on day 1 post-operatively in both groups. However, IL-6 levels were significantly attenuated over the 7 day study period in the Taurolidine group compared to placebo (p = 0.04). In addition, IL-6 levels were significantly lower at day 7 in the Taurolidine group (p = 0.04). There were 2 recurrences in the placebo group at 2 years and 1 in the Taurolidine group. The median time to recurrence was 19 months in the Placebo group and 38 months in the Taurolidine group (p = 0.27). Surgical site infection was reduced in the Taurolidine treated group (p = 0.09). CONCLUSION: Peri-operative use of Taurolidine significantly attenuated circulating IL-6 levels in the initial 7 day post-operative period in a safe manner. Future studies are required to establish the impact of IL-6 attenuation on survival outcomes in colon cancer. TRIAL REGISTRATION: The trial was registered with EudraCT (year = 2008, registration number = 005570-12 ) and ISRCTN (year = 2008, registration number = 77,829,558 ).

Clinical and economic impact of the taurolidine lock on home parenteral nutrition.

INTRODUCTION: catheter-related bloodstream infections (CRBSI) are one of the most serious concerns in patients on home parenteral nutrition (HPN) which involve high morbidity and cost for the healthcare system. In the last years, taurolidine lock has proven to be beneficial in the prevention of CRBSI; however, the evidence of its efficiency is limited. OBJECTIVE: to determine if taurolidine lock is a cost-effective intervention in patients on HPN. MATERIALS AND METHODS: retrospective study in patients on HPN with taurolidine lock. We compared the CRBSI rate and cost of its complications before and during taurolidine lock. RESULTS: thirteen patients, six (46%) males and seven (54%) females, with a mean age of 61.08 (SD = 14.18) years received taurolidine lock. The total days of catheterization pre and per-taurolidine were 12,186 and 5,293, respectively. The underlying disease was benign in five patients (38.5%) and malignant in eight (61.5%). The CRBSI rate pre vs per-taurolidine was 3.12 vs 0.76 episodes per 1,000 catheter days (p = 0.0058). When the indication was a high CRBSI rate, this was 9.72 vs 0.39 (p < 0.001) in pre and per-taurolidine period respectively. No differences have been observed in the occlusion rates. None of the patients reported any adverse effects. The total cost of CRBSI in the pre-taurolidine period was 151,264.14 euros vs 24,331.19 euros in the per-taurolidine period. CONCLUSIONS: our study shows that taurolidine lock is a cost-effective intervention in patients on HPN with high risk of CRBSI.

Clinical and economic impact of the taurolidine lock on home parenteral nutrition / Impacto clínico y económico de la utilización de taurolidina en pacientes con nutrición parenteral domiciliaria

Introduction: catheter-related bloodstream infections (CRBSI) are one of the most serious concerns in patients on home parenteral nutrition (HPN) which involve high morbidity and cost for the healthcare system. In the last years, taurolidine lock has proven to be beneficial in the prevention of CRBSI; however, the evidence of its efficiency is limited. Objective: to determine if taurolidine lock is a cost-effective intervention in patients on HPN. Materials and methods: retrospective study in patients on HPN with taurolidine lock. We compared the CRBSI rate and cost of its complications before and during taurolidine lock. Results: thirteen patients, six (46%) males and seven (54%) females, with a mean age of 61.08 (SD = 14.18) years received taurolidine lock. The total days of catheterization pre and per-taurolidine were 12,186 and 5,293, respectively. The underlying disease was benign in five patients (38.5%) and malignant in eight (61.5%). The CRBSI rate pre vs per-taurolidine was 3.12 vs 0.76 episodes per 1,000 catheter days (p = 0.0058). When the indication was a high CRBSI rate, this was 9.72 vs 0.39 (p < 0.001) in pre and per-taurolidine period respectively. No differences have been observed in the occlusion rates. None of the patients reported any adverse effects. The total cost of CRBSI in the pre-taurolidine period was 151,264.14 euros vs 24,331.19 euros in the per-taurolidine period. Conclusions: our study shows that taurolidine lock is a cost-effective intervention in patients on HPN with high risk of CRBSI

Introducción: las infecciones asociadas al catéter (IAC) son una de las complicaciones más serias en pacientes con nutrición parenteral domiciliara (NPD), generando una alta morbilidad y costes sanitarios. En los últimos años, el sellado con taurolidina ha demostrado ser eficaz en su prevención, si bien la evidencia en cuanto a su eficiencia es escasa. Objetivo: determinar si el sellado del catéter con taurolidina es una intervención coste-efectiva en pacientes con NPD. Materiales y métodos: estudio retrospectivo de pacientes con NPD que recibieron sellados con taurolidina. Comparamos la incidencia de IAC antes y durante el tratamiento y los costes asociados. Resultados: el estudio incluyó trece pacientes, seis (46%) varones y siete (54%) mujeres, con edad media de 61,08 (± 14,18) años y un seguimiento de 12.186 y 5.293 días antes y durante el uso de taurolidina. La enfermedad de base era benigna en cinco pacientes (38,5%) y maligna en ocho (61,5%). La tasa de IAC antes y durante el sellado con taurolidina fue de 3,12 vs. 0,76 episodios por 1.000/días de catéter (p = 0,0058). Cuando la indicación fue por alta tasa de IAC, esta fue de 9,72 vs. 0,39 (p < 0,001) episodios por 1.000/días de catéter antes y durante el tratamiento. No hubo diferencias en la tasa de oclusión del catéter en ambos periodos. No se reportaron efectos adversos. El coste total de las IAC antes y durante el uso de taurolidina fue de 151.264,14 euros vs. 24.331,19 euros

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

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.

Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is characterized by the deposition of amyloid-beta (Aß) plaques in the brain. Aß is produced from the sequential cleavage of amyloid precursor protein by ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aß level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS: A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).

Administration of taurolidine-citrate lock solution for prevention of central venous catheter infection in adult neutropenic haematological patients: a randomised, double-blinded, placebo-controlled trial (TAURCAT).

BACKGROUND: Catheter-related bloodstream infection (CRBSI) is one of the most frequent complications in patients with cancer who have central venous catheters (CVCs) implanted and is associated with substantial morbidity and mortality. Taurolidine is a non-antibiotic agent with broad-spectrum antimicrobial activity, which has been used as a lock solution to prevent CRBSI in some settings. However, little is known about its usefulness in high-risk adult neutropenic patients with cancer. This prospective randomised clinical trial aims to test the hypothesis that taurolidine-citrate lock solution is more effective than placebo for preventing catheter infection in neutropenic haematological patients. METHODS: This study is a prospective, multicentre, randomised, double-blinded, parallel, superiority, placebo-controlled trial. Patients with haematological cancer who are expected to develop prolonged neutropenia (> 7 days) and who have a non-tunnelled CVC implanted will be randomised to receive prophylactic taurolidine-citrate-heparin solution using a lock technique (study group) or heparin alone (placebo group). The primary endpoint will be bacterial colonisation of the CVC hubs. The secondary endpoints will be the incidence of CRBSI, CVC removal, adverse events, and 30-day case-fatality rate. DISCUSSION: The lock technique is a preventive strategy that inhibits bacterial colonisation in the catheter hubs, which is the initial step of endoluminal catheter colonisation and the development of infection. Taurolidine is a nontoxic agent that does not develop antibiotic resistance because it acts as an antiseptic rather than an antibiotic. Taurolidine has shown controversial results in the few trials conducted in cancer patients. These studies have important limitations due to the lack of data on adult and/or high-risk neutropenic patients, the type of catheters studied (tunnelled or ports), and the lack of information regarding the intervention (e.g. dwelling of the solution, time, and periodicity of the lock technique). If our hypothesis is proven, the study could provide important solid evidence on the potential usefulness of this preventive procedure in a population at high risk of CRBSI, in whom this complication may significantly impair patient outcome. TRIAL REGISTRATION: ISRCTN, ISRCTN47102251 . Registered on 9 September 2015.

Postmarketing experience with Neutrolin® (taurolidine, heparin, calcium citrate) catheter lock solution in hemodialysis patients.

Catheter-related bloodstream infections (CRBSI) are major complications for patients with life-threatening conditions requiring chronic vascular catheterization. The wide range of etiologic microbes and the ongoing development of resistance to antimicrobials with specific mechanisms of action make this an appropriate target for applying a nonspecific antimicrobial therapeutic. Taurolidine hydrolyzes into two antimicrobial moieties, formaldehyde and methylene glycol, which react with microbial surfaces. Neutrolin® (taurolidine, heparin, calcium citrate) was recently introduced in Germany as an antimicrobial catheter lock solution. This postmarketing experience collected data on 201 patients at 20 centers from January 2014 through September 2016. Likely CRBSI was observed in 13 episodes in 47,118 days (0.2759 per 1000 days [0.1468, 0.4718]). Thrombosed catheter was observed in seven catheters in 47,118 days (0.1486 per 1000 days [0.0595, 0.3061]). No adverse drug reactions that led to the discontinuation of Neutrolin® use were reported. Two patients experienced occasional transient dysgeusia. Neutrolin®, when used in conjunction with guideline-based catheter care, showed reduction in the rate of both CRBSI and catheter thrombosis relative to recent historical controls.

Taurolidine-based catheter lock regimen significantly reduces overall costs, infection, and dysfunction rates of tunneled hemodialysis catheters.

Catheter-related infections and dysfunction are the main catheter complications causing morbidity and mortality in hemodialysis patients. However, there are no consistent data for the choice of catheter lock solutions for tunneled hemodialysis lines. In this prospective, multicenter, randomized, controlled trial, two lock regimens using three commercial catheter lock solutions were compared in 106 hemodialysis patients with a newly inserted tunneled central catheter. In the taurolidine group, TauroLock™-Hep500 was used twice per week and TauroLock™-U25,000 once a week. In the citrate group, a four percent citrate solution was used after each dialysis. Both groups were compared regarding catheter-related infections, catheter dysfunction, and costs. Over a period of 15,690 catheter days, six catheter-related infections occurred in six of 52 patients in the taurolidine group, but 18 occurred in 13 of 54 patients in the citrate group, corresponding to 0.67 and 2.7 episodes of catheter-related infections per 1000 catheter days, respectively (Incidence Rate Ratio 0.25, 95% confidence interval, 0.09 to 0.63). Catheter dysfunction rates were significantly lower in the taurolidine group (18.7 vs. 44.3/1000 catheter days) and alteplase rescue significantly more frequent in the citrate group (9.8 vs. 3.8/1000 catheter days). These differences provided significant catheter-related cost savings of 43% in the taurolidine group vs. citrate group when overall expenses per patient and year were compared. Thus, use of taurolidine-based catheter lock solutions containing heparin and urokinase significantly reduced complications related to tunneled hemodialysis catheters when compared to four percent citrate solution and was overall more cost-efficient.

Taurolidine lock is superior to heparin lock in the prevention of catheter related bloodstream infections and occlusions.

BACKGROUND AND AIMS: Patients on home parenteral nutrition (HPN) are at risk for catheter-related complications; mainly infections and occlusions. We have previously shown in HPN patients presenting with catheter sepsis that catheter locking with taurolidine dramatically reduced re-infections when compared with heparin. Our HPN population therefore switched from heparin to taurolidine in 2008. The aim of the present study was to compare long-term effects of this catheter lock strategy on the occurrence of catheter-related bloodstream infections and occlusions in HPN patients. METHODS: Data of catheter-related complications were retrospectively collected from 212 patients who received HPN between January 2000 and November 2011, comprising 545 and 200 catheters during catheter lock therapy with heparin and taurolidine, respectively. We evaluated catheter-related bloodstream infection and occlusion incidence rates using Poisson-normal regression analysis. Incidence rate ratios were calculated by dividing incidence rates of heparin by those of taurolidine, adjusting for underlying disease, use of anticoagulants or immune suppressives, frequency of HPN/fluid administration, composition of infusion fluids, and duration of HPN/fluid use before catheter creation. RESULTS: Bloodstream infection incidence rates were 1.1/year for heparin and 0.2/year for taurolidine locked catheters. Occlusion incidence rates were 0.2/year for heparin and 0.1/year for taurolidine locked catheters. Adjusted incidence ratios of heparin compared to taurolidine were 5.9 (95% confidence interval, 3.9-8.7) for bloodstream infections and 1.9 (95% confidence interval, 1.1-3.1) for occlusions. CONCLUSIONS: Given that no other procedural changes than the catheter lock strategy were implemented during the observation period, these data strongly suggest that taurolidine decreases catheter-related bloodstream infections and occlusions in HPN patients compared with heparin.

Central venous catheters and catheter locks in children with cancer: a prospective randomized trial of taurolidine versus heparin.

BACKGROUND: To determine if the catheter lock taurolidine can reduce the number of catheter-related bloodstream infections (CRBSI) in pediatric cancer patients with tunneled central venous catheters (CVC). PROCEDURE: During a study period of 34 months, 129 newly placed tunneled CVCs in 112 patients were randomly assigned to standard lock with heparin solution or experimental lock with a taurolidine solution (ClinicalTrials.gov Identifier NCT00735813). RESULTS: Sixty-five CVCs were included in the standard group and 64 CVCs in the experimental group. The groups were comparable regarding patients' characteristics. A total number of 72 bloodstream infections of which 33 were CRBSIs were observed during 39,127 CVC-days. A lower rate of CRBSI (0.4 per 1,000 CVC-days) was observed in the experimental arm compared with the standard arm (1.4 per 1,000 CVC-days, incidence rate ratio (IRR) = 0.26; 95% confidence interval (CI) 0.09-0.61; P = 0.001). A lower rate of total bloodstream infections (1.2 per 1,000 CVC-days) was also observed in the experimental arm compared with the standard arm (2.5 per 1,000 CVC-days, IRR = 0.49; 95% CI 0.29-0.82; P = 0.004). Median interval from catheter insertion until first CRBSI was significantly lower in the standard group (156 days, range 12-602) compared with the experimental group (300 days, range 12-1,176; P = 0.02). Premature removal of the CVC due to infection and overall CVC survival were similar in the two study groups. CONCLUSION: Locking of long-term tunneled CVC with taurolidine significantly reduces catheter-related bloodstream infections in children with cancer.