Demand for vascular access devices (VADs) to meet the clinical needs of patients has increased dramatically in recent years, with a disproportionate increase in the numbers of patients requiring a central venous access device (CVAD) (Gabriel, 2015; Ray-Barruel and Rickard, 2015). This increase is linked not only to the ageing population and associated comorbidities that come with longevity, but also to the increasing range of parenteral therapies available to support patients, as well as the improved range and quality of CVADs (Ray-Barruel and Rickard, 2015; NHS England and NHS Improvement, 2019).
The insertion of a CVAD will require the skin to be punctured/cut. Once the skin is broken, an entry point for pathogens into the body is created. If that broken skin is part of a tract into a blood vessel, ie a cannulation site, bacteria can gain direct entry into the patient's bloodstream (Gabriel, 2015). Infections can also result from biofilm, which develops on the material of CVADs, with the potential to lead to catheter-related bloodstream infections (CRBSIs) (Srejic, 2016). The challenge of parenteral therapy is to minimise the risk of infusion-related infections for patients. Prevention is the key, not relying on antibiotics to solve the problem that treatment has initiated.
CRBSIs are a significant concern for all patients who are recipients of a CVAD, owing to their frequency and associated morbidity and mortality (Pironi et al, 2016; Lal et al, 2018). Estimates vary in relation to the occurrence of CRBSIs, with ranges of between 0.38 and 4.58 per 1000 catheter days in 2012, compared with 0.31 to 11.5 per 1000 catheter days in more recent study reviews (Lal et al, 2018).
Although by no means underestimating the emotional cost and discomfort of a CRBSI for an individual patient, the financial cost of CRBSI is significant. It has been estimated as around £15 000 per episode, excluding the additional length of stay for the patient (Lal et al, 2018). Scott, writing in 2009, estimated the annual cost of CRBSIs to the US health system as US$2.68 billion. In 2013, Zhang et al estimated the cost per episode of care in the USA as approximately US$25 000 without any additional length of stay included. This figure is not too dissimilar to the costs identified by Cai et al (2019) given inflation and current exchange rates.
The aim of this article is to increase awareness of the role biofilm can play in the development of CRBSIs. It will discuss the different lock solutions that are available to minimise the potential for CRBSIs based on a range of published evidence/guidelines, including those from groups such as the European Society for Clinical Nutrition and Metabolism (ESPEN) and British Intestinal Failure Alliance (BIFA) (Pironi et al, 2016; Lal et al, 2018).
Central venous access devices
The tips of CVADs terminate in the central venous system (lower third of the superior vena cava or right atrium). They are used for a range of therapies including vesicants, high-volume fluids, blood products and parenteral nutrition (PN). CVADs can have between one and five lumens, with each lumen being managed as if it were a separate CVAD for the purposes of occlusion prevention (Royal College of Nursing (RCN), 2016).
For patients requiring longer-term vascular access, a tunnelled or implantable CVAD would be preferable. This is because the tunnelling process creates an additional barrier to minimise the potential for infection, as well as reducing the risk of catheter migration due to the ingrowth of tissue around the Dacron cuff. This cuff is an integral part of the catheter, residing in the skin tunnel (Gabriel, 2008). The injection port of an implantable CVAD is buried in a subcutaneous pocket, with the catheter then being tunnelled to the desired venous insertion site (Gabriel, 2008). Some CVADs also have non-return valves incorporated into their design, which prevents the reflux of blood into the lumen of the device. These are referred to as ‘valved CVADs’ (Gabriel, 2008; RCN, 2016). However, all CVADs have the potential for biofilm development and its associated risk of CRBSIs (Srejic, 2016).
Catheter-related bloodstream infections
A CRBSI is defined as a bloodstream infection that arises from a CVAD when there is no other source of infection present (RCN, 2016; Kleinman Sween, 2017). Proof that the CVAD is the cause of infection is confirmed by growing the same organism from a peripheral blood sample taken at the same time as blood is aspirated from the CVAD, or from the catheter tip culture if the CVAD has been removed. The cultures are then compared and, if the same organisms are identified, this confirms a CRBSI (RCN, 2016; Kleinman Sween, 2017). Individuals who are seriously ill, particularly those who are also immunocompromised, are more susceptible to CRBSIs (Zhang et al, 2013).
The common pathogens responsible for CRBSIs are (Zhang et al, 2013; Gahlot et al, 2014):
These pathogens can either enter the bloodstream via the lumen (intraluminal infections), for example through a contaminated infusate, or as extraluminal infections, such as a pathogen migrating along the cannulation tract adhering to the external wall of the CVAD and thereby commencing the biofilm development process. Biofilm formation can play a pivotal role in contributing to CRBSIs. Any indwelling medical device can be affected, such as heart valves, urinary catheters, prosthetic joints, contact lenses and CVADs (Srejic, 2016). A CVAD that has been in situ for as little as 3 days (Donlan and Costerton, 2002) will begin to show evidence of biofilm formation. This is a process whereby microorganisms will irreversibly adhere to the surface of the CVAD, creating a film. Some of the common organisms associated with biofilms are also responsible for CRBSIs (see above) (Srejic, 2016). Over time, the biofilm builds, developing its own life-support system by delivering nutrients and oxygen to the growing cells. These cells can eventually detach from the biofilm and travel into the wider blood circulation system, causing infection in its host (ie the patient) (Srejic, 2016). The microorganisms developing the biofilm have a low susceptibility to antimicrobials, creating a challenge to manage this phenomenon, which can lead to a CRBSI.
Maintenance of CVAD locks
Prevention of biofilm formation can play a significant role in decreasing CRBSIs (Clark et al, 2019). To minimise the potential for biofilm development, together with the associated risk of intraluminal occlusion as the biofilm thickens, a number of lock solutions have been used following aspiration/infusion via the CVAD as part of recommended routine CVAD management (Pironi et al, 2016; RCN, 2016; Lal et al, 2018). These solutions include ethanol and antibiotics, with heparin and 0.9% sodium chloride being the two solutions most commonly used (Gabriel, 2008; RCN, 2016; Lopez-Briz et al, 2018; Dang et al, 2019). The volume of the lock solution should be equal to the amount of the prime solution for the lumen of the CVAD. If the CVAD has more than one lumen, each lumen should be managed as if it were a separate catheter in terms of ‘routine’ care. The more lumens, the greater the potential for infection (Gabriel, 2008; Olthof et al, 2014; RCN, 2016).
Heparinised saline had for many years been the preferred lock solution for open-ended CVADs; that is, devices that do not have an integral valve that automatically remains closed in the absence of negative or positive pressure (Gabriel, 2008). However, studies have identified a link between heparinised saline and the formation of biofilm, which in turn increases the potential for CRBSIs (Pironi et al, 2016). Therefore, ESPEN no longer recommends heparinised saline for the prevention of catheter-related infections. Valved catheters are more commonly ‘locked’ with 0.9% sodium chloride (RCN, 2016). Table 1 summarises commonly used lock solutions for CVADs, as well as their potential disadvantages/complications.
| Lock solution | Advantages | Complications/disadvantages |
|---|---|---|
| 0.9% sodium chloride | Low cost |
|
| Heparinised saline | Low cost |
|
| Ethanol | Low cost |
|
| Antibiotics |
|
|
| TauroSept (taurolidine 2% monotherapy) |
|
|
| TauroLock (taurolidine 1.34% + citrate 4%) |
|
|
CVAD=central venous access device; CRBSI=catheter-related bloodstream infection; MRSA= meticillin-resistant Staphylococcus aureus; VISA=vancomycin-intermediate Staphylococcus aureus; VRE=vancomycin-resistant Enterococci; ESPEN=European Society for Clinical Nutrition and Metabolism; HIT=heparin-induced thrombocytopenia
Taurolidine
Taurolidine is a non-toxic agent derived from the amino acid taurine. Taurine has the following properties (Bisseling et al, 2010):
Its proven antimicrobial activity is against Gram-positive and Gram-negative bacteria as well as fungi. Because it acts as an antiseptic it does not lead to the development of antibiotic resistance (Gudiol et al, 2018). These properties play a crucial role in diminishing the development of biofilm within the lumen of CVADs when taurolidine is used as a catheter lock. Its broad spectrum of activity against fungal and bacterial pathogens has lead to a decrease in the incidence of CRBSIs (Gudiol et al, 2018; Clark et al, 2019). The avoidance of antibiotics in the lock solution also reduces the potential for antibiotic resistance in its host, which is becoming an ever-increasing challenge for health care today (NHS England and NHS Improvement, 2019).
In 2010 Bisseling et al published their research comparing the efficacy of heparinised saline and TauroSept (taurolidine 2% solution) as preventive locks against developing CRBSIs in a group of 30 individuals. All 30 patients were considered high risk in that they had previously experienced a CRBSI and were receiving PN. The patients were randomised into two groups. One group received heparinised saline as their lock solution (the control group) and the other group received taurolidine. In the control group, 10 new CRBSIs were observed, compared with only 1 in the taurolidine group. Bisseling et al (2010) concluded from this study of high-risk patients that the use of taurolidine significantly decreased CRBSIs compared with the use of heparinised saline as a CVAD lock with ports and tunnelled catheters (peripherally inserted central catheters (PICCs) were excluded from the study). This has been supported by a more recent study by Wouters et al (2018) who saw a reduction in CRBSIs when using TauroSept compared with sodium chloride in their double-blind multi-centre study.
TauroSept is a monotherapy indicated for the prevention and treatment of catheter infections in any patient with a CVAD, including those who are high-risk patients, such as those who are immunocompromised and those on PN (Health Research Authority, 2014; Pironi, 2016). It contains a 2% solution of taurolidine (Health Research Authority, 2014; Pironi et al, 2016). A study by Olthof et al (2015) demonstrated that in vitro TauroSept achieved improved antimicrobial activity when compared with TauroLock.
TauroLock preparations contain taurolidine with either citrate to support routine care for CVADs to maintain patency in-between therapies, or with heparin to improve patency (TauroLock – Hep 100 (100 iu/ml) or TauroLock – 500 (500 iu/ml) in patients who are not heparin intolerant (HIT). A further formulation of TauroLock has the addition of urokinase 25 000 iu/ml (TauroLock – U25 000). TauroLock is only licensed for prevention whereas TauroSept is licensed for prevention and treatment of catheter infections.
Work undertaken by Clark et al (2018) discussed how the antiadherence properties of taurolidine can contribute to impeding biofilm development. In turn they observed in their paediatric population receiving PN a reduction in CRBSIs, when compared with heparin lock solutions. This supports other studies, including the that of Bisseling et al 2010, who looked at the effectiveness of taurolidine in preventing CRBSIs in patients receiving PN.
The work of Bisseling et al (2010) also suggests that taurolidine can be effective in reducing the potential for catheter-related thrombosis. This is due to its ability to inhibit coagulation surand staphylocoagulase activity, as well as preventing surface activation of platelets (Bisseling et al, 2010; Olthof et al, 2014). The development of thrombosis can also lead to intraluminal and extraluminal occlusion in CVADs, which also increases the risk of infection (Gabriel, 2008; RCN, 2016).
Conclusion
Understanding the link between biofilm and the development of CRBSIs will have a significant impact on future CVAD management. There is a growing body of evidence to support the use of taurolidine in secondary prevention, but further research may well identify its role in primary prevention (Bisseling, 2010). Knowledge of how to minimise the risk of harm for recipients of CVADs is continually growing, with the development of new technologies and their application to healthcare products, and through research to inform future care delivery. With the increasing numbers of patients receiving parenteral therapies for a wide range of conditions, health professionals have a duty of care to do no harm (RCN, 2016). Prevention starts with the basics in ensuring that there is no other route than the parenteral one for the intended therapy. Placing the device and its ongoing management should adhere to a strict aseptic technique. This includes the use of catheter locks to prevent intraluminal occlusion and potential CRBSI for those individuals receiving intermittent therapies (Gahlot et al, 2014; Gabriel, 2015; RCN, 2016). Through understanding biofilm and taking steps to minimise its development, the CVADs can be left in place for longer, without having to resort to antibiotic therapies and their associated risks, including potential for antimicrobial resistance (Bisseling et al, 2010; Gudiol et al, 2018; Clark et al 2019). Lock solutions containing taurolidine support health professionals in getting back to the fundamentals in preventing infection. Understanding biofilm, and how its development can be prevented through the use of lock solutions containing antiseptics and antithrombolitics, will support the prevention of CRBSIs. This will reduce the number of severely ill patients who have developed a CRBSI—a costly complication of CVAD placements with an associated incidence of high mortality (Gahlot et al, 2014).
Prevention is better than cure and CRBSIs are no exception. With increasing numbers of individuals becoming recipients of CVADs globally each year, the associated incidence of CRBSIs is also increasing. There is evidence to demonstrate that antimicrobial resistance is also a global challenge (NHS England and NHS Improvement, 2019). The incidence of CRBSIs can be significantly reduced by selecting the most appropriate CVAD if parenteral therapy is required, ie not using a multi-lumen device if a single lumen will suffice, maintaining a strict aseptic technique when placing, dressing and accessing the catheter, and maintaining catheter patency. This must be carried out using the relevant guidelines, such as ESPEN and BIFA (Pironi et al, 2016; Lal et al, 2018). Understanding biofilm formation and maintaining CVAD patency with lock solutions, such as TauroSept, has not only the potential to significantly reduce the incidence of CRBSIs, but also reduce our use of antibiotics and improve outcomes for individual patients.