Feature Article

Defences under attack
The urinary tract poses a real challenge for biomaterial and catheter manufacturers in the development of materials and devices that can resist bacterial colonisation, while draining urine effectively from the bladder. Materials used for urological devices include latex coated products, silicones and poly vinyl chlorines. The manufacturing process can be crude resulting in rough surfaces especially around the eyehole regions, thus making these devices vulnerable to colonisation and infection by bacteria.

Biofilm related infections are the major cause of urological device failure despite much research targeted at their prevention and eradication. The range of strategies aimed at improving device design, bio-material composition, surface characteristics and drug delivery have in the most part been thwarted by microbes and their range of attachment, host evasion, antimicrobial resistance and survival strategies. Biofilm formation is a natural part of the lifecycle of microorganisms and is an important strategy that has helped them survive on the planet for billions of years.¹ The fact that biofilms develop on biomaterials that are placed in the body is simply an extension of their natural tendency to adhere to surfaces and to some extent explains why they are so difficult to control. In addition, the majority of organisms that colonise urological devices originate from the skin and gastrointestinal tract and are, therefore, well adapted to dealing with our immune defence system.

The normal human urinary tract has a number of defence mechanisms to protect it against infection, including the regular flushing of the urinary tract with sterile urine, the presence of beneficial bacteria such as lactobacilli, which prevent colonisation by pathogenic bacteria² and a smooth epithelial lining known as the urothelium. The failure of any of these host defences through ageing, pathologic processes or the insertion of a medical device will result in the individual being more susceptible to colonisation and infection by pathogenic bacteria. This fact is well demonstrated with the Foley catheter, which is used to drain urine from the bladder. The use of a catheter undermines the cyclic filling and emptying that normally ensures that any bacteria contaminating the urine are washed out. The presence of the balloon to hold the catheter in place and eyeholes above the balloon result in a stagnant sump of urine in the bladder of approximately 100 mL,³ which acts as a nutrient source for contaminating organisms and allows their growth and proliferation. Urine drains though the eyeholes of the catheter as a continuous dribble that provides contaminating organisms with a constant source of nutrients. The Foley catheter acts as a constant threat to the integrity of the bladder and upper urinary tract. 

The design specification
Calvin Kunin, in his editorial in the New England Journal of Medicine asked the question: “Can we build a better catheter?”⁴ The huge challenge for device manufacturers is to produce a device that allows the urinary tract to retain its normal physiological and mechanical characteristics. Kunin suggested that this requires the design of a thin-walled, continuously lubricated, collapsible catheter so that the integrity of the urethra is maintained. In addition, the retention balloon needs to be replaced with a mechanism that holds the device in place without allowing a sump of urine to collect, and allows regular, intermittent, complete emptying of the bladder. Novel devices like these will be more difficult to manufacture and therefore more expensive, but if they reduce the incidence of catheter associated urinary tract infection (CAUTI) and maintain the integrity of the urinary tract, they would be worth the investment.

Size of the market
In North America alone more than 100 million urinary tract devices including urethral catheters, ureteral stents and penile prostheses are inserted each year, which results in millions of device-related infections and billions of dollars in additional healthcare expenditure each year.⁵ These devices provide novel, nonhost surfaces on which bacteria can colonise and form biofilms. Short term use of urethral catheters, for example, during surgery to monitor urinary output, does not typically result in urinary tract infections, because there is insufficient time for the bacteria to colonise the catheter and form a biofilm. However, in patients undergoing long-term catheterisation because of urine retention or incontinence, recurrent urinary tract infections are common. The risk of infection is related to the length of time the catheter is in situ. This rate has been calculated at 3% per day⁶ and in practice, even with meticulous nursing care, all patients undergoing catheterisation for >28 days will develop urinary tract infections.⁷ The major bacterial species involved in long term catheter and stent infections are Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, Staphylococcus epidermidis, Enterococcus faecalis and Staphylococcus aureus. These organisms are commonly isolated from the patient’s gastrointestinal tract, thus providing a constant source of bacteria for reinfection if a device is changed or the patient undergoes a course of antibiotics to clear the infection.

Limited performance
Urinary tract infections can also affect the performance of the medical device. A major complication in the care of patients undergoing long-term indwelling bladder catheterisation is the deposition of crystalline bacterial biofilm on the catheter. This encrustation causes trauma to the bladder mucosa and can obstruct the flow of urine through the catheter with potentially disastrous consequences to the patient.⁸ The problem stems from infection of the catheterised urinary tract by urease producing bacteria, particularly Proteus mirabilis. These organisms colonise the catheter surfaces and form biofilm communities embedded in a polysaccharide matrix. The bacterial urease generates ammonia from urea and elevates the pH of the urine and biofilm. Under these alkaline conditions, crystals of magnesium ammonium phosphate (struvite) and calcium phosphate (hydroxyapatite) are formed and become trapped in the organic matrix that surrounds the cells. The continued development of this crystalline material eventually blocks the catheter lumen.⁹ Laboratory experiments have shown that all currently available catheters are vulnerable to encrustation and blockage by Proteus mirabilis biofilms irrespective of the material from which the catheter is manufactured.¹⁰

Coating strategies
The prevention and treatment of biofilms on urological devices has focused on the surface properties of the biomaterial itself or the development and application of surface coatings to interfere with the bacterial attachment to the biomaterial. The most studied surface coating in urology is the silver-coated urethral catheter, which has been in use for more than 20 years. The broad spectrum antimicrobial effects of silver have been known for many years and studies have shown that it acts on bacteria by blocking multiple enzymatic processes¹¹ and through membrane destabilisation.¹² Some studies claim that silver alloy, not silver oxide-coated devices, is effective in reducing CAUTI rates by up to 45%,^13,11 but it is difficult to find studies with good statistical data. Therefore, it still remains unclear whether silver coated urethral catheters are effective at reducing CAUTI.⁵

A wide range of antimicrobial agents have been coated onto urological devices in a bid to reduce bacterial colonisation, including gentamicin, cefazolin and nitrofurazone.^14,15,16,17 Clinical studies have produced variable results and this, combined with short elution periods and concern about antimicrobial resistance has limited this line of research. Triclosan, a board spectrum antimicrobial that is used extensively in numerous consumer and medical products interferes with bacterial fatty acid biosynthesis and results in membrane destabilisation. Ureteral stents and urinary catheters impregnated with triclosan have been studied, and it has been found that Proteus mirabilis, the most common cause of crystalline biofilms, is particularly sensitive to this antimicrobial. Using laboratory models of the catheterised bladder demonstrated that triclosan¹⁸ can diffuse through the balloons of all silicone catheters to significantly reduce the number of viable bacterial cells in the urine, prevent the rise in urinary pH and inhibit crystalline biofilm formation on catheters. This strategy of delivering agents directly to the bladder via the catheter balloon does not disturb the closed drainage system, does not require the manufacture of new catheters and delivers the active agent directly to the bladder and the foci of infection. Clinical studies are now needed to confirm the effectiveness of triclosan in patients who suffer repeatedly with problems associated with infection and encrustation with Proteus mirabilis.

A complete redesign
Research and development is essential to overcome many of the complications associated with current urological devices. The morbidity caused to patients and the costs to healthcare systems resulting from the use of long term indwelling urinary catheters is unacceptable. Simply applying antimicrobial compounds or coatings that inhibit bacterial adhesion are unlikely to have any long term effect on bacterial colonisation. The basic design of the catheter needs to be studied; smoother surfaces, better eyeholes and wider internal lumens will improve the performance of the catheter. A redesign of the device is required to enable complete emptying of the bladder and prevention of the sump of urine, and the introduction of mechanisms to maintain the normal cyclical filling and emptying of the bladder. This is a huge challenge in an area of medicine that is often neglected.
 

References

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