Long-term treatment with parenteral nutrition (PN) at home has become an established treatment option for adult and pediatric patients with severe intestinal failure. Based on the British Intestinal Failure Survey (BIFS) database for 2006 to 2009, 139 children on home PN were reported, which was a 4-fold increase since 1993. The regional point prevalence of home PN varied from 1.76 to 41.4 per million, with a mean of 13.7 patients per million (1). When a child has an intractable gastrointestinal disorder that fails to respond to treatment, intravenous nutritional support may be required for many months and years. Such children are discharged home with parents taking over the catheter care. Nutrition is infused via the central venous catheter (CVC) overnight, leaving the child free to join in usual childhood activities during the day. This system has enabled children with severe intestinal failure to have a much better quality of life and improved functioning of the family (2). Home PN requires the presence of a CVC for safe and effective venous access, allowing administration of infusions up to 7 days per week and as long as 10 to 14 hours overnight.
Infectious complications relating to the CVC remain the most frequent and major complication (3), with the rate of catheter-related sepsis reported to be much higher in children than in adults (4). This translates to significant mortality as well as morbidity and financial costs with the additional admissions for intravenous antibiotics and replacement of CVCs. Particularly in young patients with intestinal failure and dependence on PN, preserving venous access is paramount for survival as replacing CVCs can damage the limited precious immature veins (5).
Catheter-related bloodstream infections (CRBSIs) originate from organisms contaminating the catheter hub and subsequently growing within a luminal biofilm layer that develops rapidly within 24 hours of insertion of any indwelling catheter. Although nontunneled CVCs readily become infected by microbial colonization along the external surface from skin flora, tunneled CVC infection is usually caused by intraluminal colonization (6). These tunnel infections can rarely progress to CRBSI. Although the use of a strict aseptic technique in the handling of CVC has been proven to reduce the incidence of CRBSI (7), unfortunately septicemia can still occur. Although in practice, treatment with antibiotics is effective, on detailed examination there is often poor elimination of organisms embedded within the biofilm layer because of inadequate penetration (8), sometimes resulting in eventual removal of the CVC as a last resort. The estimated frequency of CRBSI in adult patients with PN including home PN patients ranges from 2.0 to 10.6 episodes per 1000 catheter days (9,10). Part of this variation stems from the various definitions of CRBSI in different studies. Options of CVC locks with a variety of substances such as antibiotics or alcohol are recommended for those patients at high risk for CRBSI (3). When using antibiotic CVC locks the danger of antibiotic resistance is always of concern (11). Ethanol locks do have the benefit of reducing the risks of CRBSI (12) but may be considered inappropriate if liver dysfunction exists.
TauroLock (Bio-Implant HealthCare, Winsen, Germany) is a catheter lock solution for tunneled and nontunneled CVCs and port systems. It contains taurolidine (2%) as an antimicrobial and antifungal ingredient and citrate (4%) to prevent clot formation. Taurolidine is derived from the naturally occurring aminosulphonic acid taurinamide and formaldehyde. It acts by irreversibly binding to the cell walls of organisms with its methylol groups, resulting in the prevention of bacterial adhesion to biological surfaces (13). Taurolidine has proven to have a broad spectrum of antimicrobial activity against not only Gram-positive and Gram-negative bacterial infection but also fungi (14), with no bacterial resistance reported to date (15). Taurolidine also prevents biofilm formation and therefore prophylactically minimizes colonization of catheters (16). There are no studies examining the optimal instillation time, but generally 12 hours is the accepted practice (16).
We retrospectively reviewed patients discharged home on long-term treatment with PN who had a history of CRBSI and had been using taurolidine as their routine catheter lock regime. Their rates of CRBSI before the use of taurolidine, when using a heparin catheter solution (10 U/mL), were compared to the rates after its introduction to see whether taurolidine had any effect on the incidence of infections.
There were a total of 19 patients on long-term PN at home managed by our tertiary care pediatric hospital who had used taurolidine line lock. A total of 15 patients were preselected individually for taurolidine treatment based on either the history of recurrent CRBSI or previous removal of CVCs for overwhelming infections. The remaining 4 patients were started on taurolidine lock prophylactically. In 1 case, treatment was started to simplify care because her twin (who was also being treated with intravenous nutrition) fulfilled the criteria. Two other cases were at risk of developing end-stage liver disease if they developed septicemia, and the fourth patient had just taken on his own care rather than his mother managing his connections and disconnections. All of the patients were used as their own controls in comparison of their rates of infection before and after using taurolidine. The mean patient age at initiation of taurolidine lock was 69 months (range 8–238 months). The underlying diagnoses of these patients were severe chronic small intestinal mucosal inflammation in 8 patients (which included tufting enteropathy, autoimmune enteropathy, and eosinophilic enteropathy), short bowel syndrome in 7 patients, and gastrointestinal dysmotility in 4 patients.
Single lumen tunneled Hickmann catheters were used in all of the patients. Catheters had been inserted in an aseptic manner using interventional radiological techniques with the tip of the catheter in the superior vena cava or high in the right atrium. All of the children had a single-bag system of “tailor-made” intravenous nutrition compounded by the same homecare company. The duration of each infusion/cycling was 12 to 14 hours in all cases. For all of the patients, parents had been trained as the sole carer of the catheter to manage the intravenous nutrition infusions. To do this, parents had undertaken a formal training program by intestinal care nurse specialists during a 2-week period. The training involved parents gaining competency in an aseptic nontouch technique for connecting and disconnecting the PN infusion. This was composed of a strict method for thorough hand washing and equipment preparation and an aseptic nontouch technique for connecting the catheter hub to the PN infusion “giving set,” use of 2% chlorhexidine + 70% ethanol as CVC hub antiseptic. Appropriate cleaning and dressing of the catheter exit site on the chest wall was routinely performed once per week. Parents were initially taught to instill heparin solution (10 U/mL), or, after consenting to the routine use of 0.7 to 1.0 mL taurolidine solution into the catheter at the completion of the PN infusion on a daily basis. The heparin or taurolidine was left within the CVC for at least 12 hours until the next infusion was connected to the catheter, when taurolidine was flushed into the bloodstream. In some children who were less dependent on PN and did not require an infusion every night, the taurolidine would have been left in situ for 36 hours or longer until the next infusion.
The period of surveillance of CRBSI was 1 year before the use of taurolidine lock (or from the start of the first CVC if that was less than 1 year) and up to October 2010 or until discontinuation of taurolidine lock. The median pretaurolidine surveillance duration was 11.5 to 12 months in 15 patients and 8 to 11 months in 4 patients. This accounted for a cumulative duration of 6630 pretreatment catheter days. The average duration of taurolidine lock usage was 16.5 months, ranging from 2 to 33 months. This added up to a cumulative duration of 9520 posttreatment catheter days for comparison. The incidence of CRBSI was calculated as the number of episodes per 1000 catheter days.
Information on the episodes of CRBSI was obtained and verified in 2 ways: all blood culture reports in the child's name from the microbiology departments of the child's local hospital and our tertiary children's hospital and clinical notes documented by the medical team caring for the patient. A sample of venous blood was taken from the CVC for microbiological examination if the child was unwell with a fever of 38°C or higher, rigors (particularly after connecting the intravenous PN infusion), unusual lethargy, neurological changes, acute worsening of gastrointestinal losses, or other symptoms suggestive of infection. An episode of CRBSI was defined as a laboratory-confirmed bloodstream infection that was not secondary to an infection at another body site and was associated with a central venous line, which was in place at the time of, or within 48 hours before, onset of the infection (17). This episode of bloodstream infection also had to meet 1 of the following criteria:
1. A recognized pathogen (eg, Staphylococcus aureus, Enterococcus spp, Escherichia coli, Pseudomonas spp, Klebsiella spp, Canidida spp) was cultured from 1 or more blood cultures that was not related to an infection at another site.
2. Common skin contaminants (ie, diptheroids [Corynebacterium spp], Bacillus [not B anthracis] spp, Propionibacterium spp, coagulase-negative staphylococci [including S epidermis], viridans group streptococci, Aerococcus spp, Micrococcus spp) were cultured from 2 or more blood cultures, with the same organism found in the blood cultures, drawn on separate occasions within 2 days of each other.
A second positive culture was considered a new infection after a previous culture if a new organism was grown or if the culture was positive at least 2 weeks after the completion of the antibiotic course. Mixed CRBSI was defined as positive growth of a combination of 2 or more different classes of organisms, such as Gram-positive bacteria, Gram-negative bacteria, and/or fungi.
Statistical analyses were performed using SPSS, version 11.0 for Windows (SPSS Inc, Chicago, IL). We determined the significance of the difference between the pre- and post-taurolidine incidences of CRBSI using the Wilcoxon signed rank test. All P values were based on 2-tailed tests (level of significance, P < 0.05).
There was a statistically significant overall reduction in the rates of CRBSI among these 19 patients after starting on taurolidine line lock. There were a total of 57 episodes of CRBSI during the pretreatment surveillance period, accounting for an incidence of 8.6 episodes of CRBSI per 1000 catheter days. After using taurolidine lock, there were only 10 episodes of CRBSI documented among all of the 19 patients, giving rise to only 1.1 episodes per 1000 catheter days (P = 0.003) (Fig. 1). A total of 14 (74%) of the 19 patients did not have any further episode of CRBSI after starting taurolidine treatment. The mean length of infection-free duration was 16.4 months, with the longest period of up to 33 months. Five children (ie, 2 of 8 cases of enteropathy, 1 of 7 cases of short bowel syndrome, and 2 of 4 cases of gastrointestinal dysmotility) had further episodes of CRBSI after taurolidine lock. Their home PN regimens were similar to the rest of the cohort, including the type of central lines, PN preparation, and infusing/cycling duration. Their mean overall rate of CRBSI was 3.9 episodes per 1000 catheter days in the posttaurolidine period as compared to 6.7 episodes per 1000 catheter days before starting taurolidine (P = 0.500).
As for the etiology of the 57 episodes of CRBSI during the pretaurolidine surveillance period, more than half (56%) of these episodes were entirely because of Gram-negative bacteria (Fig. 1). Twenty-eight percent of the episodes were caused by Gram-positive bacteria, and 9% were caused by fungal infections. The remaining 4 episodes were mixed CRBSI: 2 episodes of combined Gram-positive and Gram-negative bacterial infection and 2 episodes of combined Gram-negative bacterial and fungal infection. The most common Gram-negative bacteria causing CRBSI was Klebsiella pneumoniae (Table 1). Unusual organisms isolated as the definite etiology for individual cases of CRBSI from persistent blood cultures were Ochrobactrum anthropi, Raoultella ornithinolytica, Sphingobacterium, Escherichia hermannii, Achromobacter xylosoxidans, Paenibacillus, Streptococcus parasanguinis, Kocuria kristinae, and Microbacterium paraoxydans.
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During the posttaurolidine surveillance period, Gram-negative bacterial infection also accounted for the majority of the cases (70%), with only 3 cases of Gram-positive bacterial infection. None of the patients had fungal infection. Of note, the sensitivities of the isolates in the positive blood cultures were reviewed and there were no multiresistant bacteria strains grown. None of the children had an associated urinary tract infection or other focus of infections when septicemic.
There were no deaths during the study and no patients reported any adverse effects while taurolidine was in situ within the lumen of the CVC. Only the parent of a single patient reported cloudy aspirates when blood was withdrawn from the catheter for laboratory testing.
Our study has demonstrated that using taurolidine as an indwelling catheter solution after disconnecting each overnight PN infusion is associated with a decreased incidence of CRBSI, from 8.6 to 1.1 episodes per 1000 catheter days. The incidences of all types of infection—Gram-positive, Gram-negative, or fungal—were reduced without inducing antibiotic resistance. The fact that almost 3 of 4 patients actually remained infection free after using taurolidine is also encouraging, with up to 33 months of infection-free period documented. This is the largest report so far of a cohort of children treated with PN who were given taurolidine line locks.
Taurolidine was first discovered as an antiseptic agent for infections such as peritonitis (18) and empyema (19). The subsequent development of TauroLock by the incorporation of taurolidine into a catheter lock solution has indeed increased its usage, particularly in patients on hemodialysis (20,21) and with oncological diseases (22,23). The outcomes in these patients have consistently been a definite decrease in the rate of CRBSI after the application of taurolidine lock.
Surprisingly, the use of taurolidine lock in home PN patients has not gained as much acceptance as expected, despite the similarity to oncology and home dialysis patients of having the presence of a long-term CVC. To our knowledge, the idea of having taurolidine as an additive in parenteral solutions (24) was first reported in 1987 when its safety and lack of pharmacological interaction with commonly used PN fluids including lipid emulsions were reported. Subsequently, the first published report of taurolidine use in a patient with a catheter for PN was in 1993 (25), when the authors described a young adult with Crohn disease experiencing recurrent episodes of bacterial and fungal CRBSI. After using taurolidine, he had no further infections for 12 months until he discontinued it, when he developed another episode of septicemia within 2 weeks of stopping. Since then, he was on taurolidine prophylaxis and had remained well. A similar case report was published in 1998 (26) on a patient with short bowel syndrome from massive bowel resection for ulcerative colitis and superior mesenteric artery thrombus. His infection rate fell from 8.5 to 1.5 episodes per 1000 days since he was started on taurolidine lock. In 2005, a small case series of 7 pediatric patients on home PN was reported (27) in which the rate of CRBSI was decreased from 10.8 to 0.8 episodes per 1000 catheter days after treatment with daily taurolidine lock. Only 1 randomized controlled trial on the use of taurolidine lock in home PN patients was found (9)—it was a crossover study involving 30 patients with intestinal failure randomized to taurolidine or heparin lock. The mean infection-free duration was 175 days for the heparin arm as compared to 641 days for the taurolidine arm.
The result of our study concurs with the above: taurolidine lock indeed decreases the rate of CRBSI, with a statistically significant reduction from 8.6 to 1.1 episodes per 1000 catheter days. The decision to calculate an overall rate using the absolute number of episodes of CRBSI during the total number of catheter days under surveillance was based on 2 reasons: first, we had adequate numbers of pre- and posttreatment days to make reasonable comparisons, which is also the strength of our study; and second, the majority of the patients actually remained infection free completely after using taurolidine lock, and so a calculation using an infection rate per patient and then a mean would have given an falsely higher estimate. Also, a single-center recruitment of patients limited the possibility that variation in other aspects of management may bias the results. All of the patients and parents adhered to the same protocols for home PN training and administration remained consistent.
Our definition of CRBSI was adopted from the Centers for Disease Control and Prevention (17), based on our patient population, which consisted mainly of young children. Other studies looking at CRBSI in pediatric patients had also used similar definitions, for instance, a set of 2 blood cultures taken peripherally and via the CVC (27) or at least 2 blood cultures positive for organisms such as coagulase-negative Staphylococcus or Streptococcus epidermidis(23), so as to prevent overreporting of possible contamination of blood cultures. Despite the strict definition of CRBSI for reporting purposes, we still recommend to give an empirical course of broad-spectrum antibiotic therapy with adequate Gram-positive and Gram-negative coverage for any patient with a CVC for a possible line infection, even if the blood cultures did not fulfill the definition, as long as the patient is symptomatic and is at risk for a serious infection and to only discontinue the treatment when the blood cultures are negative at 48 hours.
Among the 5 patients who continued to develop infections after the use of taurolidine lock, their combined incidence of CRBSI was lower at 3.9 episodes per 1000 catheter days as compared to 6.7 episodes per 1000 catheter days in the pretreatment period. Although this was not statistically significant (P = 0.500), there is still a suggestion that taurolidine does help to decrease the risk of CRBSI. There was only 1 patient who had a concomitant IgG subclass deficiency and she continued to have infections after using taurolidine lock, which suggests that the benefit of taurolidine lock may not be adequate in the presence of an underlying immunodeficiency.
There is also a major economic benefit in using taurolidine to reduce the rate of CRBSI. The financial burden of CRBSI for the United Kingdom health care system is extremely considerable, with an estimated additional cost of £2949 to £6209 per CRBSI-related intensive care unit admission and an annual cost related to CRBSI of £19.1 to £36.2 million (28). In contrast, taurolidine infusion only costs about £8 per day. The regular use in all of the patients with a CVC who have a history of CRBSI and are “cycling” infusions could have a significant effect by reducing the incidence of CRBSI.
None of our patients on taurolidine lock reported any significant adverse effects during our study. Taurolidine is nontoxic for humans (29) and is rapidly metabolized into taurine, carbon dioxide, and water, which explains its excellent safety profile. Only 1 study (23) had reported mild adverse effects. One patient experienced severe local pain following accidental administration via peripheral cannulae, which was resolved immediately on flushing with normal saline. Few other patients in the same study described an unusual taste in the mouth directly after the injection of taurolidine; however, none of the patients discontinued taurolidine because of this. There were also no cases of catheter thrombosis in our study, supporting the adequacy of the citrate component of TauroLock in preventing clot formation as compared to the conventional heparin lock. Taurolidine itself has been reported to inhibit clotting-activating substances such as bacterial coagulase (30). In addition, from the review of the positive blood cultures after the use of taurolidine lock, there were no multiresistant bacterial strains, which supports the concept that taurolidine does not induce bacterial resistance despite its good bactericidal properties. All of these features contribute to making taurolidine a worthwhile catheter lock solution in terms of both antimicrobial and antithrombotic functions.
In conclusion, our study has shown that taurolidine lock is associated with a reduced incidence of CRBSI in pediatric home PN patients, without the risk of inducing bacterial resistance or any other adverse effects. This evidence leads us to suggest a recommendation for taurolidine lock in all children on cyclical treatment with PN who have recurrent episodes of septicemia. Larger studies, particularly randomized double-blind trials, should be conducted to gather more supporting evidence to allow implementation of taurolidine lock as a standard practice for all home PN patients in the years to come.
We thank Venetia Horn and the nutrition pharmacy team at Great Ormond Street Hospital for facilitating the use of taurolidine in our patients.
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