Every year, millions of hospitalised patients worldwide develop a healthcare-associated infection (HAI). While many of these infections can be treated easily, a non-negligible proportion prove to be serious or even fatal. Around 90,000 annual deaths in the EU, and 100,000 in the US, can be attributed to an HAI. A leading culprit is the urinary catheter. These are essential medical devices by anyone’s standards, required by around 20% of patients in NHS hospitals. At the same time, they’re unusually conducive to infection. According to one 2019 study, around 12% of US patients who have a catheter inserted for 30 days will develop an HAI.
These infections can be classed as ‘catheterassociated urinary tract infections’ (CAUTI), or else the more serious ‘catheter-associated bloodstream infections’ (CABSI). While the latter is rarer, its reported mortality rate stands as high as 25%. Clearly, then, this is a huge problem for the affected patients, who may be looking at an extended hospital stay and a drop in their quality of life. It poses a burden for healthcare systems too: in the UK, CAUTI and CABSI are estimated to cost the NHS more than £200m a year, whereas US data puts the figure at up to $10,197 per patient. Globally, that cost extends to billions of dollars.
Why CAUTI are so common
Whatever the challenges, solutions to urinary catheter infections aren’t always available. The good news is that about half of catheter-associated infections are thought to be preventable, essentially by applying the right kinds of infection control measures or by eliminating the unnecessary use of catheters. But that leaves the many millions that occur through no fault of the medical team.
“The normal flora, which are bacteria that live on the body, are easily transmitted into the urethra during insertion of a catheter,” explains Dr Tim Nichol, a microbiology and biosciences lecturer at Sheffield Hallam University. “Insertion can also cause tissue damage and an immune reaction. But even if everything goes really well, the very fact that you’ve got this foreign object inside the body disrupts the normal balance of things.”
Fundamentally, this is down to basic biology. When the human body encounters a foreign object, it responds to the intrusion by laying down a protein coat onto the surface of the material. Once bacteria start adhering to that protein coat, an infection can easily take root.
“The bacteria involved in urinary tract infections are often things like E. coli, which have adhesins that can attach to the epithelial cells that line the urethra,” says Nichol. “So they bind to the cells, they bind to the surface of the catheter itself, and they are able to form biofilms – communities of bacteria that are physically protected from the immune system.”
Biofilms, for their part, are notoriously hard to eradicate, not least because of the presence of ‘persister cells’ – dormant bacteria that shut down their metabolic processes and become invulnerable to antibiotics. This means that antimicrobial coatings, a solution sometimes attempted, may prove ineffective.
Add in the fact that some bacteria can invade the cells themselves, residing in the tissue that lines the urethra, and it’s easy to see how recurrent infections might occur even once the condition has notionally been treated.
£142
The amount of money that can be saved for each catheter prevented.
Science Direct
“The other thing is the status of the patients themselves,” Nichol adds. “So if you have very ill or old patients, they can have reduced immune responses. That’s also the case for patients who are on antibiotic regimes for infections elsewhere – taking antibiotics can disrupt their normal flora and allow for more pathogenic organisms to take hold.”
A range of research avenues
Although their research is still in its early stages, Nichol, along with Prof Thomas Smith and others at Sheffield Hallam, have a potential solution in mind. They have been working on a new type of catheter coating that could prevent biofilms from forming on its surface. If their coating proves effective, it could lead to a significant reduction in catheter-associated infections.
3.5 million
The number of healthcareassociated infections that take place in the EU every year. European Centre for Disease Prevention and Control
Their technology is based on sol-gel chemistry, which involves taking liquid precursors and adding an acid catalyst. The liquids start to react together, forming a kind of network within a liquid solvent. As Nichol explains, the end product looks a little bit like nail varnish.
“Because it’s a liquid, we can dip it, we can paint it, we can spray it,” the academic says. “It can be applied onto surfaces very easily, where it sets as an ultra-thin coating. But the important thing is that it’s porous. We can incorporate different antimicrobials into that, and we can alter the formulation to control the release of those products.”
Depending on the application, the team might want something that releases the drug a little more quickly or slowly. For instance, orthopaedic surgeons often need a coating that will protect the implant during the operation itself, releasing its antibiotic payload within about a week. A catheter, for its part, needs to retain the antimicrobial on the surface, so that it isn’t flushed out when the patient urinates.
As well as exploring different medical applications, Nichol is working with his colleague Dr Sarah Forbes on incorporating something called ‘quorum sensing inhibitors’ (QSIs). Quorum sensing is a form of chemical communication between cells, which allows bacteria to coordinate their behaviours. Inhibiting this process can silence the so-called crosstalk, meaning biofilm communities are prevented from forming.
Kelly Capper-Parkin, one of Forbes’ doctoral students, examined various types of QSIs in her thesis. She found that cinnamaldehyde, a component of cinnamon essential oil, worked especially well to stop biofilm formation. The compound was paired with silver nitrate, a commonly used biocide, and incorporated into a sol-gel coating. This approach, she thinks, shows great potential for creating a truly anti-infective catheter.
Another PhD student is working on a bone culture cell model, which would enable orthopaedics researchers to investigate infections without needing to perform tests on animals. At the same time, microbiology lecturer Dr Keith Miller is investigating new antimicrobial agents derived from snake and scorpion venom.
30%
Urinary tract infections as a percentage of total infections reported in acute care hospitals.
Centers for Disease Control and Prevention
“He’s identified a number of different peptides,” says Nichol, “and he’s altered versions of those peptides. We’ve looked at putting those peptides into the coating as well.”
Addressing antimicrobial resistance
An especially promising avenue for the researchers is their collaboration with MetalloBio, a spin-out company from the University of Sheffield. MetalloBio is developing two new antimicrobial compounds – the first to emerge in nearly 40 years – while the Sheffield Hallam team are looking to integrate these compounds into their sol-gel coating.
“MetalloBio has a ruthenium-based antimicrobial that has shown some really promising results,” Nichol explains. “They’re interested in using it in a whole host of different applications, including a coating for catheters. So we applied for a grant together through the Medical Research Council, and we managed to get a postdoc doing the initial work.”
This research was put on hiatus for a while, owing to the sudden passing of Dr Kirsty Smitten, CEO and co-founder of MetalloBio, at the age of just 29. Nonetheless, the two groups are planning on continuing their collaboration, and are now looking for their next round of funding.
“I can’t say too much about it,” says Nichol, “but essentially we’ve got a coating that shows a very good activity against a broad range of bacterial species. It shows favourable, sustained protection of the coating, and it’s not toxic to the cells of the body. We’re interested in carrying that on.”
While clearly excited about future developments – he describes their initial work as “very, very promising” – Nichol adds the caveat that this was just a proof-of-concept, and further research is needed. The path from idea to clinic is rarely straightforward, and there are more steps to be taken before the work can enter clinical trials.
“Hopefully, we’ll be able to secure some more funding in order to develop that to a point where we can approach potential commercial partners,” the lecturer says. “They will be able to take that through the relevant legislation and the relevant testing technologies.”
Despite the challenges ahead, Nichol is optimistic about the long-term prospects. He hopes that, over time, his team’s product could lead to a reduction in catheter-associated urinary tract infections – as well as healthcare-associated infections more generally.
“The main aim is to improve the quality of life of patients,” he says. “That’s the best thing about my research – you have that goal of helping people, as well as significantly reducing the economic burden on the healthcare system.”
As antimicrobial resistance becomes more widespread, infections such as CAUTI could start to become more prevalent, not to mention harder to treat. New strategies will therefore be urgently needed. A new kind of catheter coating, impregnated with a new class of antimicrobial, could be exactly what makes the difference further down the line.
