Title: Infection-responsive theranostic coatings for prevention of catheter blockage.
Funder: Dunhill Medical Trust

Abstract: Urethral catheterisation is commonly used to manage a range of conditions in older people, but blockage is a common complication that has serious consequences for patient health [1-3]. Blockage is mainly due to infection by Proteus mirabilis which forms extensive crystalline biofilms on catheter surfaces. This is driven by the potent urease activity of P. mirabilis, which generates ammonia and elevates urine pH. Under these alkaline conditions, components of urine precipitate and form crystals that become embedded in growing biofilms. Ultimately, this leads to extensive encrustation and catheter blockage [4-8]. Blockage can occur rapidly and without warning, often leading to pyelonephritis, septicaemia and shock. Currently all available catheter types (including those with conventional antimicrobial coatings) are vulnerable to encrustation by P. mirabilis, and there is no reliable way to predict or prevent blockage [2,3,9]. We have recently demonstrated two distinct technologies that together could provide a solution to this unmet clinical need [4-6,10-12]. Firstly, we have shown that a range of drugs already licensed for use in humans have anti-biofilm activity and can inhibit catheter blockage by P. mirabilis. These work through inhibition of efflux systems important for bacterial biofilm formation [4-6], and highlights the potential to repurpose existing medicines to help combat catheter infection and blockage [Fig 1 & 2; 4]. In parallel, we have also developed a novel infection-responsive surface coating that can automatically release agents in response to P. mirabilis infection [10-12]. This dual-layer system utilises a hydrogel basement layer as a reservoir for agents to be delivered, which is sealed with a pH responsive Eudragit polymer. When urine pH is elevated to alkaline levels by P. mirabilis infection the Eudragit layer erodes releasing the cargo molecules in the hydrogel reservoir [Fig 3; 10,11]. This proposal now seeks to unite these research themes to develop an encrustation-resistant “theranostic” coating for urethral catheters. This coating will be able to provide both early warning of the potential for blockage through a simple colour change, and automatically deliver anti-biofilm drugs to combat the infection and prevent blockage. Using a representative in vitro model of the catheterised urinary tract available in our laboratories, we will evaluate the performance of our theranostic coatings in terms of drug delivery and ability to prevent catheter blockage. This will include exploring the potential for this approach to deliver a combination of drugs that can simultaneously inhibit multiple targets required for P. mirabilis biofilm formation.

Lay abstract: Long-term catheterisation (LTC) is commonly used to manage incontinence or urine retention in older people. However, benefits from LTC are frequently undermined by infection. The bacterial species Proteus mirabilis is a particular problem in this regard, and causes blockage of catheters leading to serious complications. P. mirabilis is able to block catheters by attaching to catheter surfaces and forming layers of cells covered in a protective slime called a biofilm. P. mirabilis is also able to breakdown components of urine, which makes urine more alkaline. Making the urine more alkaline leads to the formation of crystals which become trapped within the biofilm, where they are able to grow further in size. Ultimately this results in hard encrustations forming on catheters which blocks urine flow. Blockage can occur rapidly and without warning, and can lead to serious conditions such as kidney infections, and bloodstream infections (septicaemia). Presently, there are no approaches that adequately control or predict blockage, and effective strategies are urgently needed. We have recently demonstrated two new strategies to prevent catheter encrustation and blockage. Each approach shows potential on its own, but we believe that combining these strategies could provide a solution to catheter blockage. The first strategy is the identification of drugs that can inhibit biofilm formation to control blockage. We have shown that a number of drugs, already used in human medicine for other purposes, also have anti-biofilm activity and can inhibit catheter blockage by P. mirabilis. However, these drugs are mostly likely to work best if they can be delivered directly to the site of infection when required. The second strategy is a coating for catheters that detects P. mirabilis infection, and can warn patients before blockage occurs by releasing a dye to change the colour of urine collecting in the drainage bag. This coating can also be used to deliver drugs directly to the urinary tract in response to infection. Therefore, the aim of this project is to now combine these two promising approaches to develop coatings for catheters that can both control blockage and prevent the resulting harm to people living with urethral catheters. The proposed coating will be able to provide an early warning to patients and carers that catheters are at risk of blockage. At the same time it will release anti-biofilm agents to actively prevent encrustation and blockage.

Research activity codes: 5.3 MEDICAL DEVICES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION