Introduction to the Urinary Tract

Figure 1. The urinary system, consisting of kidneys, ureters, a bladder and a urethra.

It consists of four main features: two kidneys, two ureters, a bladder and a urethra [1], Fig.1. These components normally work synergistically to process and excrete urine, however when there is a problem with this process, a urinary catheter may be put in place.

Catheterisations and the Causes

• There are two main types of urinary catheters, the first type being intermittent catheters, where the device is inserted when the bladder needs to be emptied, and then removed [2]. This is repeated for each time the bladder is full. The second type are indwelling catheters, which remain in place for days to weeks[11]. The latter are preferred due to them being more comfortable for patients as there are less repeated insertions [2]. If they need to be in place for a month or longer, then it is considered long-term catheterisation [3], and chances of bacterial contamination severely increases [4].
• The Foley catheter is a prevalent type of indwelling urinary catheter [5], its main characteristic being a fluid-filled balloon at the top to hold it in place in the urethra, Fig. 2.

Figure 2. Diagram depicting the components of a Foley catheter, which is one of the most common urinary catheters used in the healthcare setting [5]. Adapted from [6] and [12]

Estimates state that between 15%-25% of hospitalised patients may have urinary catheters during their stay [3]. Urinary catheters are considered for a wide range of problems with the urinary system, which could be caused by a variety of causes such as urinary retention, urinary incontinence, or surgery, that all lead to inefficient voiding (urination) [2]. Here are the main causes:

• Urinary retention: The urine is not completely emptied from the bladder, which can be caused by a physical blockage e.g. an enlarged prostate. A catheter would provide the bladder with rest after a period of urinary retention [8].
• Chronic urinary incontinence: The lack of control on pelvic floor muscles and urethral sphincter leads to the accidental passing of urine [9].
• Surgery: General surgeries require indwelling catheters during the procedure, as a patient who is fully anesthetised would not be able to control urination, but to also monitor urine output [10]. However, procedures concerning places such as the bladder and bowel would also require it after for recovery, meaning that the catheter can be situated from several days to several weeks [10].
• Conditions affecting the nervous system: This includes strokes, multiple sclerosis, or a spinal injury [5].

Biofilm Formation

Catheter-associated urinary tract infections (CAUTIs) are caused by pathogen entry into the urinary tract, where bacteria may form biofilms leading to persistent infections.

Entry of Pathogens:

• Introduction of microorganisms can be endogenous, meaning they were already residing on the host (e.g. on the meatal, rectal, vaginal region etc.), or exogenous, indicating that the source is from the outside [12]. Exogenous entry could occur when there is contamination during the catheter insertion.
• In addition to their source, the pathogens can enter the urinary tract through an extraluminal route (migrating along the area between the catheter and urethra), or through an intraluminal route (travelling along the inside of the catheter) [13]. Intraluminal entry indicates a contamination from the catheter itself, like the urine collection bag or catheter-drainage tube junction.
• Extraluminal entry dominates the cause of CAUTIs [4], at 66% (intraluminal at 34%) [14], hence why our project will be targeting the outside of the catheter, through the creation of a coating and spray.

Bacteriuria:

• The risk of the presence of bacteria in urine (bacteriuria) increases by approximately 5% per day the catheter is in place [15]. After 30 days, this risk approaches 100%, which happens to be the boundary between short and long-term catheterisation [4].
• Bacteriuria doesn’t necessarily cause problems, as it can be asymptomatic, but the risk of an infection increases proportionally. Therefore, for long-term catheterisations, it is inevitable that that bacterial colonisation will occur.

Biofilm Formation:

Colonisation of bacteria can result in biofilm formation on the catheter (Fig. 3). Here are the steps as to what happens:

1. Once the catheter has been inserted, it is naturally coated with proteins, electrolytes, and other organic molecules from the host’s urine, which provides a conditioned surface for microbial attachment [7]. The longer the catheter has been in place, the greater the accumulation of molecules, meaning that the chances of microbial attachment increases. This also occurs on the external catheter surface due to host-derived factors from the urogenital surface [13], meaning that both the outside and inside face of the catheter is susceptible to microbial attachment.
2. The bacteria attach by using ashesins, recognising the host cell receptors on the prepped catheter surface or on the host cells themselves [13]. Various factors are produced by the bacteria during the attachment phase to not only recognise surface cell types but to also evade host immune responses [13].
3. Once the bacteria have attached themselves to the catheter surface, phenotypical changes result in the expression of exopolysaccharides, to further anchor them to the abiotic surface. Soon microcolonies develop due to replication, which then form into persistent bacterial colonies [6].
4. The biofilm gradually matures, orchestrated by quorum sensing, which is dependent on a variety of genes expression relating to population [13].

Figure 3. The steps of bacterial colonisation and biofilm formation within a catheter. Possible entry points of bacteria are highlighted by the blue arrows. Adapted from [16] and [17].

Pathogenesis, and Subsequent Complications:

The Infection:

Significance of the catheter:

• Indwelling medical devices increase the chances of an infection occurring due to the introduction of a foreign surface allowing any opportunistic organisms to enter the body, which would otherwise not [18].
• Furthermore, the process of inserting a urinary catheter may damage the sensitive uroepithelial mucosa, hence resulting in the creation of more binding sites for pathogens [12].
• The presence of the catheter completely disrupts the natural host mechanical defences, i.e. incomplete voiding, hence resulting in residual urine leading to greater chances of microbial growth [12].

Once the biofilm is established:

• To obtain nutrients in the new environment, the bacteria may release degradative enzymes to break down the surrounding tissue [12].
• Certain uropathogens can use urea to their benefit (as it is a nitrogen source), to create crystalline biofilms (the precipitation of ions become incorporated with existing biofilms). Crystalline biofilms are a significant problem as they are more stubborn than conventional biofilms and must be removed from host to completely resolve the infection, and antimicrobial treatments are futile against them [12].
• To evade the host immune-system, gram negative pathogens produce capsules, various proteases (to degrade immunoglobulins), and lipopolysaccharides (LPSs). With the help of these they can overcome phagocytosis, bactericidal properties of human serum, and antimicrobial peptides [12]. The capsules aid in preventing the mature biofilm from desiccating and phage attack. LPSs in gram negatives can an illicit extreme powerful inflammatory response, and potential septic shock [12].
• Once the biofilm is matured, detachment and dispersion of planktonic bacteria occurs where gram negative bacteria use flagellum-mediated motility and type IV pilous-mediated motility to further spread the infection to new sites [12].

E.coli Specific Pathology

• The uropathogenic Escherichia coli (E. coli UPEC) strain is commensal (residing in the large intestine), however it is highly pathogenic in the urinary tract, accounting for 70-90% of causes for community acquired UTIs. Similarly, S. epidermidis, being commensal bacteria, are less virulent, however the process of catheterisation facilitates entry into the urinary tract [12].
• Cytotoxic Necrotizing Fractor 1 (CNF1) is a toxin, produced by the UPEC strain, that induces apoptosis in bladder epithelial cells, resulting in the bladder shedding in vivo and exposing underlying tissue for bacterial invasion [12].
• Furthermore, the UPEC strain can form biofilm structures called intracellular bacterial communities (IBCs) [12]. The E. coli cells attach and arrange themselves to be engulfed by the uroepithelial cell. Once internalised, rapid replication occurs leading to ‘pod-like’ protrusions forming on the host cell, which is the IBC. Similar to the final stages of biofilm formation, bacterial detachment occurs from the pods, releasing planktonic cells into the environment. E. coli, like UPEC, strains that can form IBCs could be a reason as to why some UTIs recur [4].
• Catheter materials like silicone may promote virulent UPEC biofilm formation, whereas materials like polystyrene and glass are better suited for asymptomatic bacteriuria [12]. Flexible materials like silicone are favoured, however, as a suitable catheter material due to it’s inert properties and flexibility for comfort.
• UPEC secretes several auto-transporters, which cells such as kidney epithelial cells during a sudden kidney infection (acute pyelonephritis), due to UTI [13].

Crystalline Biofilms and Encrustation of the Catheter:

As mentioned earlier, certain uropathogens could use the components in urine for their advantage and strengthen their biofilm by creating crystalline biofilms:

• Encrustation on the catheter, although commonly believed to be formed by sedimentation of urine, can be facilitated by organisms residing in biofilms: especially those which can hydrolyse urea, to release ammonia, which is basic. That creates a high pH environment, (further propagating more pathogenic bacteria) and precipitation of minerals. The species which have this ability are the Proteus species, Pseudomonas aeruginosa, Klebsiella pneumoniae [16].
• This introduces the idea that genetic variation, leading to metabolic variation, can result in different probabilities of catheter crystallisation. Those who produce more alkaline urine, calcium, protein, and mucin are more likely to experience repeated blocked catheters. This is further supported by the fact that patients with blocked catheters are also significantly more often colonised with the said species above, especially Proteus mirabilis. Currently, none of available types of indwelling urethral catheters are capable of preventing encrustation by P. mirabilis biofilms [16].
• A study indicated that 62% of patients suffering from recurrent encrustation and blockage of their catheters had bladder stones: which seemed to harbour P. mirabilis and can rapidly recolonise fresh replacement catheters with crystalline biofilms. Removal of stones through flexible cystoscopy is a viable treatment [16].

Current Treatments and Related Shortcomings

Shortcomings in diagnosing CAUTIs:

• Current diagnosis of a UTI by Infectious Diseases Society of America: “the presence of symptoms or signs compatible with UTI with no other identified source of infection along with 10³ colony-forming units / mL”, coinciding with the symptoms “new onset or worsening of fever, rigors, altered mental status, malaise, or lethargy with no other identified cause; flank pain; costovertebral angle tenderness; acute hematuria; pelvic discomfort.” [6] The diagnosis is unspecific due to there being little to no symptoms relating to the urinary system. This means that the infection is most likely caught when it has progressed to the point where systemic symptoms arise i.e. fever.
• Furthermore, microbiology laboratory results based on urine only account for planktonic bacteria, disregarding the sessile bacteria present in a biofilm [16]. This means that the amount, and the species variety of the pathogenic bacteria can be severely underestimated using this method of testing.

Current Treatments:

• Current measures focus on delaying the onset of bacteriuria [13], through methods like avoiding unnecessary catheterisation, selecting alternative catheterisation procedures, maintain a closed drainage system (preventing introduction of bacteria), and eliminating bacterial colonisation of the meatus, through periodic cleansing of the area [13].
• Catheters are recommended to be replaced with new ones every 8 to 10 days, and drainage bags should be emptied at a minimum of 4-6 hours to avoid bacteria entering the catheter lumen [13].
• Exploration of cleaning the meatus of bacteria has been explored, however it has proved itself to be futile, same with irrigating the bladder with antibiotics that made no difference to the incidences of CAUTIs [19].
• Once patient is believed to have CAUTI, the catheter is removed as soon as possible, due to the high rate of the infection returning (relapse). Once the new catheter has been inserted, organism concentrations decrease significantly [15], however that does not mean that the pathogenic bacteria have been omitted, as mentioned above. Most patients then go through with antimicrobial therapy for 10-14 days, but parenteral nutrition (nutrients provided through IV) therapy is usually initiated in severely ill patients, and then switched to oral treatment after improvement [13].

Medical Significance of Biofilms:

• Biofilms are difficult to treat through antibiotics as they are less susceptible to external drugs attacking them. The reasons are that the biofilm results in slower diffusion of antimicrobial agents, and even if it does enter, the microenvironment of the biofilm impairs the activity of the agent [16].
• The bacterial cells are in close proximity in the biofilm, that enhances plasmid exchange [16]. This means that there are far greater chances of antimicrobial resistance occurring within a biofilm compared to bacteria residing in a planktonic state.
• As mentioned earlier, results from the clinical laboratory can be misleading, due to the tests seeming to rely on planktonic bacteria. This is a shortcoming, which can impact how the severity of the reaction is perceived.

References

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