Intravascular catheters, from peripheral intravenous lines to central venous lines, intra-arterial lines or even long-term ports, provide incredible benefits in the modern management of a vast majority of hospitalised patients. The multiple different benefits of catheters have led to millions of these catheters in use every day. Yet there are risks. Intravascular catheters can lead to sepsis in 0.36 patients per 1000 catheter days (Ruiz-Giardin et al, 2019). In burn units this number can reach as high as 4% to 12% of patients during their stay (King at al, 2007). In the USA there are more than 250 000 cases of catheter-related bloodstream infections (CRBSIs) each year, with a mortality rate from this of around 12–25% (Maki et al, 2006). CRBSIs are the number one cause of sepsis in the hospital, which leads to increased cost, morbidity and death. Perhaps the use of intravascular catheters should be limited as much as possible; however, since these catheters provide such a great benefit, it is more realistic to prevent or mitigate complications. For the health professional to limit these bloodstream infections, it is necessary to understand the underlying microbiology that produces these complications.
Careful attention to detail and the adherence to procedure guidelines when inserting and managing intravascular catheters has decreased the incidence of CRBSI. This is especially true for central venous catheters, which are 64 times more likely to cause sepsis than peripheral catheters (Cicalini et al, 2003). That is, what we do in the management of intravascular catheters directly effects outcomes. This has led to the proposal of using the incidence of the development of sepsis with intravascular catheters as a quality measure (Hallam et al, 2018; Javeri et al, 2020). Health professionals can be much more effective in preventing catheter complications and improving outcomes by employing multiple methods to suppress biofilm.
The nature of biofilm
Biofilm can explain the clinical findings most often seen with CRBSIs, yet biofilm is poorly understood within medicine. In the early 1980s, the name biofilm was given to observations of bacteria growing in communities of different species (polymicrobial) attached to solid surfaces and protected by a self-secreted matrix (Costerton et al, 1978; 1999). It was observed that biofilm is the dominant mode of growth of bacteria in the world and these communities were of great interest to engineers because it was these masses of biological (bacterial) material that were corroding pipes, clogging water systems and fouling cooling towers (Costerton and Stewart, 2001). Researchers found that the individual bacterial cells of these communities had different gene expressions (phenotypes) than those found in the individual bacteria (planktonic) that health professionals learn about in microbiology classes. A common number of genes for a bacterial species is 3000–4500 genes. When a given bacterial cell is planktonic and free-floating, roughly one-third of the genes are upregulated to produce flagella and secretory molecules necessary for life as an individual cell. Whereas when the bacterial cell is in the community attached to a surface (such as a catheter), those genes are downregulated and approximately 700 different genes are expressed for the production of different secretory molecules, matrix polymers and mechanisms for increased horizontal gene transfer (Cornforth et al, 2018). The phenotypic transformation of free-floating planktonic bacteria to a dense community of bacterial cells expressing biofilm gene function is much like a caterpillar metamorphosing into a butterfly. The bacterial cell in both situations has the same exact genome but the genes that are expressed out of that genome make the planktonic and biofilm phenotype bacteria radically different (Sauer et al, 2002)
Biofilms cause chronic infections (Høiby et al, 2015). It is accepted science that bacteria growing on solid surfaces such as a catheter are predominantly in biofilm phenotype; because all chronic infections are caused by biofilm most chronic infections have similar behaviours (Høiby et al, 2015). We can look to other chronic infections such as hard-to-heal wounds (James et al, 2008), osteomyelitis (Brady et al, 2008). and cystic fibrosis pneumonia (Høiby, 2011) to better understand how catheters develop biofilm that leads to CRBSI. Bacteria adhere to the solid surface and upregulate a group of genes that allow the cells to be tolerant to antiseptics and antibiotics while producing a self-secreted protective matrix, which is made up of polymeric sugars, extracellular DNA, bacterial secreted proteins, host components (mainly fibrin) and many other substances (Bjarnsholt et al, 2013) From within the matrix bacterial cells secrete quorum sensing molecules, which are cytokines that direct the gene expression of the bacteria within the community (Rumbaugh et al, 2012). The different species cooperate to form a three-dimensional cluster of bacterial cells on the surface of the catheter. For the biofilm to be successful it must be able to secrete small molecules, usually effector proteins from the type 3 and type 6 secretory systems, which commandeer host immunity (Kim et al, 2010). When the biofilm is fully mature, the individual bacterial cells within the matrix are protected from host white blood cells, complement and other host defences (Costerton and Stewart, 2001). Once the biofilm evades host immunity the community can then spread across the catheter. During the first 10 days most biofilm is found on the extrinsic surface of catheters; whereas after 10 days, the lumen has the most biomass of biofilm. Unlike our caterpillar/butterfly analogy, biofilm is continually seeding the environment with fragments of biofilm as well as individual bacterial cells in planktonic phenotype (seeding dispersal) (Stoodley et al, 2001; Purevdorj-Gage et al, 2005). So both modes of growth, biofilm and planktonic, challenge the host in and around the catheter.
It is unclear whether it is planktonic seeding or small fragments of biofilm breaking off into the bloodstream that eventually results in the acute infection that we see as CRBSI. Catheter-related biofilm is parasitic in nature and achieves its nutrition from host inflammation, which does not usually necrose host cells (Bjarnsholt et al, 2013). On the other hand, planktonic bacteria cause a predatory-type infection (acute infection) that kills host cells and uses the cell debris for nutrition and propagation (Bjarnsholt, 2013). This acute infection can harm and sometimes kill the host. Therefore, an important goal of catheter management is to suppress the biofilm on all catheters to such a level that it prevents any significant seeding that will overwhelm host defences and lead to sepsis.
The literature identifies four routes for microbes to adhere on a catheter and start biofilm formation (Gahlot et al, 2014). The first is catheter contact with any fomite, skin of the patient (or health professional) and even airborne microbes transferred to the catheter surface prior to insertion. Following national guidelines (eg in the USA this would include guidance from the Healthcare Infection Control Practices Advisory Committee (HICPAC) (O'Grady et al, 2017)), general infection control practices and a well-planned, focused insertion limiting total time reduces all of these risks.
The second is adherence of microbes during catheter insertion. The majority of microbial species causing CRBSIs are from the skin. These microbes include coagulase-negative Staphylococcus species, Corynebacterium, anaerobic bacteria such as Propionibacterium, Anaerococcus, Peptoniphilus, Bacteroides and others. In some local areas, such as the groin for femoral catheters, Candida species may predominate. It is critical to understand that biofilm is polymicrobial by nature and culture methods have demonstrated that 48% of intravascular catheters have polymicrobial species of microbes present on their surface. (Almuneef et al, 2006). Recent work with urinary catheters using molecular methods to identify microbes showed that almost 100% of the catheters have polymicrobial biofilms on their surface (Yu et al, 2019). These biofilm principles probably hold true for intravascular catheters, also. It is important to keep the adherence of any skin microbes to the catheter at a minimum during the insertion, and this can only be done by meticulous preparation of the insertion site with a clear strategy to suppress biofilm. The most effective management strategy for reducing the amount of biofilm phenotype bacteria in the area of insertion is skin preparation including scrubbing (Wolcott et al, 2010). Physically removing the keratin and loose epidermal cells greatly reduces the number of microbial cells. Skin commensals reside deep within the dermis and hair follicles, and although scrubbing with surfactants and antiseptics will reduce their number, this will not eradicate all microbes. It should also be remembered that commensals are in a very special environment, and there is crosstalk between host cells and the microbes using specific cytokines that exert great control on commensal microorganisms (Scharschmidt et al, 2017). However, below the skin in the subcutaneous tissues and even the blood, these host control mechanisms no longer exist and this is a permissive environment for commensals to produce host infections such as the chronic infection of the catheter and the acute infection of sepsis.
Third, and probably the most dominant vector for biofilm development on catheters, is catheter management. This includes redressing the catheter site, manipulating the connections in the line (such as bag attachment, extension tubing, connections to the hub, etc) and the fluids and/or devices connected to or running through the catheter. There are numerous guidelines for catheter management, commonly cited are the guidelines from the Infectious Diseases Society of America (IDSA) (Mermel et al, 2009), the HICPAC guidelines (O'Grady et al, 2017) and the standards from the Infusion Nurses Society (Gorski et al, 2016). However, the sheer repetitiveness of such tasks along with time constraints make fully adhering to these guidelines very difficult. There are significant risks associated with catheter use (25% mortality with sepsis), so it is important to follow national and institutional guidelines.
The fourth area where bacteria can adhere to catheters is non-catheter-related sources. Bacteria in the blood that seed the catheter make up one possible source (Uitto et al, 2012). The bacteria in the blood are from well-documented seeding of blood from oral, gastrointestinal or other sources that we all continually experience. The microbes that find their way into the blood are usually neutralised by complement and/or white blood cells (mainly neutrophils and macrophages). This conglomeration of bacteria and host products is cleared by the Kupffer cells in the liver. However, if any of the bacteria that find their way into the blood are in biofilm phenotype, the protected bacterial cells can evade this host response and attach to foreign bodies such as the solid surface of the catheter. Once attached, these small seeds can establish a formal biofilm. Other non-catheter sources are infections near or around the insertion site, which spread to the catheter or through the lymphatic system to the catheter.
Diagnosis
CRBSI should be suspected clinically with early signs being malaise, nausea or even mild mental status changes. Once fever, chills and unexplained hypotension emerges the patient is far along the road of sepsis. The mortality rate of sepsis defined by these clinical signs is 12–25% (Maki et al, 2006). The earlier in the course the bloodstream infection can be identified, the better the outcomes. The microbiological diagnosis is currently made through culture methods and there are several methods outlined in the 2009 IDSA guidelines (Mermel et al, 2009) One method is a blood draw from a peripheral vein that is blood culture positive and then a culture from the tip of the catheter that demonstrates the same organism. For central venous catheters, there is a method of paired cultures whereby a sample for culture is drawn from the central venous catheter at the same time as a blood draw from a peripheral vein. If the central venous catheter culture is positive, showing the same organism but at 3–5 times the abundance, the infection is confirmed to be coming from the central venous catheter. A newer test relies on differential time; whereas the central venous catheter and peripheral blood are drawn at the same time and if the central venous catheter shows positive 2 hours earlier than the peripheral draw, then the central venous catheter is the source of the sepsis (Ruiz-Giardin et al, 2019). DNA-based identification and quantification methods of microbes in blood and on the catheter are emerging methods to help understand the complete microbiological reality of the catheter-related complications (Rudkjøbing et al, 2016; Wolcott et al, 2013).
The main drawback of all these diagnostic methods is that microorganisms must be grown. The hallmark of the biofilm phenotype mode of growth is that bacteria expressing these genes are viable but they are not culturable by routine clinical culture methods (Fux et al, 2005). Therefore, many samples obtained from catheter tips or blood draws through catheters in which biofilm phenotype microbes predominate may not grow in routine clinical cultures. This greatly underreports catheters as a source of sepsis. A second important point is that many microorganisms, especially anaerobic bacteria, are not culturable regardless of phenotype. Therefore, for blood draws through the catheter suspected as the source of infection many of the important bacterial species producing catheter-related complications cannot be cultured. These two situations alone demonstrate that the microbiological data used to diagnose CRBSI only show us a partial picture and, therefore, decisions must be made on a clinical basis.
Once the diagnosis has been made that the catheter is producing bloodstream infections or other complications, the management becomes somewhat difficult. It seems most prudent to remove the catheter suspected as the source of infection and reinsert another at a different site. National guidelines offer several insights on when to salvage and when to remove a catheter (Gorski et al, 2016; O'Grady et al, 2017). For many patients removal is not an option and their catheter is their only hope for survival. In this case, salvaging the catheter becomes very important and antibiofilm strategies for suppression of biofilm on the catheter become paramount. For long-term catheters (greater than 10 days) most of the biofilm mass will be intraluminal. Suppression of biofilm can be accomplished through high-dose antibiotic regimens with a long duration dwell time. This is often called an antibiotic lock where high doses of specific antibiotics targeting the microbes identified are instilled in the hub and lumen of the catheter and allowed to dwell (antibiotic lock) for hours (Justo and Bookstaver, 2014) It should be pointed out that microbes growing in biofilm phenotype require 1000 times the concentrations for minimum inhibitory concentration (MIC) and even then only provide 1-1.5 log reduction in the number of bacterial constituents within the biofilm. To put it another way, this antibiotic lock procedure does not eradicate the biofilm. Many agents can be included with the antibiotic that will allow it to be more effective such as quorum sensing inhibitors (acetylsalicylic acid/aspirin, hamamelitannin, farnesol), surfactants such as benzalkonium chloride and/or antiseptics such as ethanol, iodine or silver can be included in the antibiotic lock solution.
Conclusion
CRBSIs cost the healthcare system billions of dollars. Considering central venous catheters alone, in the USA the Centers for Disease Control and Prevention (CDC) received 18 009 reports of central-line associated bloodstream infections in 2019 (CDC, 2021). The pathogenesis of CRBSI is that bacteria come in contact with the catheter, forming biofilm and a local chronic infection involving the intravascular catheter. The biofilm reproduces, seeding the environment with fragments of biofilm and planktonic bacteria. Since intravascular catheters directly contact the bloodstream, inevitably bloodstream infections develop in some of these patients with intravascular catheters. It is imperative that early diagnosis of sepsis be made on clinical grounds and confirmed by current microbiological methods (Mermel et al, 2009). The presence of biofilm phenotype bacteria residing on catheters is best identified using molecular methods such as PCR and/or sequencing, which is available through major clinical laboratories. Treatment is removal and reinsertion of the catheter in a different site when possible. However, antibiofilm strategies can be employed to try to salvage the catheter. The use of high-dose (greater than 1000 times MIC) antibiotics for long durations inside the catheter and hub (antibiotic/antiseptic lock) can suppress biofilm enough to reduce the seeding of the blood below a level that the patient's immune system can prevent sepsis. The addition of antibiofilm agents such as surfactants, quorum sensing inhibitors and biocides, in combination with high-dose antibiotics, may be the most effective next step in the management of CRBSIs.
KEY POINTS
- Biofilm is a protected mode of growth that is very different from planktonic growth
- Biofilm defences make the biofilm community tolerant of antibiotics and antiseptics
- Biofilm is the cause of chronic infections, which includes all catheter infections
- Although chronic infections are associated with long duration to develop (4–6 weeks), biofilm usually forms on a catheter in 24 hours
CPD reflective questions
- Consider the reasons why central venous catheters are much more likely to cause bloodstream infections and sepsis than peripheral vascular catheters
- Why would removal of an intravascular catheter not be an option for some patients? What impact might a suspected CRBSI have on such a patient?
- The incidence of catheter-related bloodstream infections is used in several healthcare systems as a marker of care quality. Are you aware of how and where this is tracked and reported for your place of work?