Title: Characterisation, commercialisation and clinical studies of a longterm antimicrobial urinary catheter
Funder: Department of Health and Social Care

Abstract: The research will consist of production and sterilization of antimicrobial Foley catheters, investigation of processed catheters surface characteristics and mineral crystallization prevention studies, studies of their activity against a panel of CAUTI pathogens including longterm studies in a multi-challenge flow model, and a short safety study and feasibility study. The experimental plan will begin with studies on the ability of the antimicrobial impregnated catheter to prevent encrustation. This will consist of an initial period of microbiological characterization of the urease-producing (UP) and urease-negative (UN) control bacteria to be used in these studies (2 months). The three isolates, Proteus mirabilis (UP), Staphylococcus saprophyticus (UP), and E. coli (UN) will be fully characterized and their antimicrobial susceptibilities determined. The isolates will then be used in four experiments to investigate the ability of the processed catheter to affect attachment of UP organisms and crystal mineralization (TK100 Assay), the effect of processing and exposure to urine on surface characteristics of the catheter (which could affect nucleation sites and therefore encrustation) (Atomic force microscopy studies on pore characteristics of the catheter material), the effect of processing on time until encrustation and if encrustation, mineral characteristics (Static model in artificial urine), the effect of processing on time until encrustation under flow conditions (Perfusion model). Crystal characteristics will be examined by light microscopy and a representative sample further characterised by scanning electron microscopy, electron probe microanalysis, and x-ray diffraction. (1 year) Previous studies have shown 80-100 days activity of the antimicrobial catheter against Klebsiella pneumoniae, P. mirabilis, E. coli, Staphylococcus epidermidis, and Staphylococcus aureus. For the studies further characterising the antimicrobial activity of the impregnated catheter against multi-resistant strains, this will also begin with a period of characterization of the isolates used in these experiments, which will include extended-spectrum beta-lactamase producing E. coli, methicillin-resistant S. epidermidis, Staphylococcus saprophyticus, New-Delhi metallo-beta-lactamase-1 producing E. coli, methicillin-resistant S. aureus, and an additional strain of methicillin-sensitive S. aureus (2 months). The antimicrobial activity will be assessed by a TK100 assay differing from the above as the main goal of this experiment is to determine the length of time needed to kill 100% of each attached bacteria, and by an in vitro challenge model. In this model bacteria will be inoculated into a flow model (see Supplementary Documentation Figure 1) and challenged weekly to determine the ability of the catheter to withstand repeated bacterial challenge (10 months). At the end of Year 2, Ethics and R&D applications will be completed and patient focus groups contacted in readiness for the safety clinical study of 20+20 patients. Prior to submission of the study to the IRAS and Ethics, the focus groups and several project management meetings will take place to design patient leaflets, consent forms, and questionnaires. The safety study and the in-built feasibility study will take place in the remaining 6-8 months of the grant period (6 months). These studies are not necessarily consecutive and some tasks will run concurrently (See Gantt Chart). The design of the clinical studies has been discussed with the Nottingham Clinical Trials Unit. Both of these clinical studies will be single-centre. This information will inform a future randomized, multi-centre efficacy clinical trial.

Lay abstract: Urinary tract infection is a major problem in longterm users of urinary catheters such as those with spinal injuries or stroke. It requires repeated catheter removal and courses of antibiotics, and has been described as &ldquo;a misery&rdquo; by catheter users. Infection also usually leads to obstruction by urinary minerals (encrustation). Pain, illness, hospital visits, side-effects of antibiotics and sometimes more serious complications are seen, particularly in the elderly. Use of antibiotics in urinary infections is a powerful driver of antibiotic resistance in hospitals and the community. No antimicrobial catheter is currently available with the required long duration of activity, as existing ones lose activity after a few days. Our patented process is not a coating, but introduces antimicrobials into the catheter material in such a way that they can migrate to the surface to constantly replenish that which is removed by urine flow. In this way a duration of activity of 80-100 days is achieved. The antimicrobials are chosen for activity against the causative bacteria, but they are also selected to avoid resistance. The Dual Drug Principle shows that if more than one carefully chosen antimicrobial is used, bacteria are thousands of times less likely to be able to mutate to resistance. Also, the amount of antimicrobial released from the catheter is not sufficient to select for resistant strains, and lastly, reduction of antibiotic use to prevent and treat catheter infections also reduces the risk of resistance. Here we propose to consolidate our pilot research by extending the range of test bacteria, ensuring no resistance development, and studying the surface properties of the catheters which might be linked to mineral encrustation. We will then conduct a safety trial and a feasibility study in patients. The results will then underpin a randomized multicentre efficacy trial and the commercialization process.

Research activity codes: 6.3 MEDICAL DEVICES;5.3 MEDICAL DEVICES
Health categories: INFECTION