| Summary: | Background and Aims: Catheter-associated urinary tract infections (CAUTI) are a common and costly complication of indwelling urinary catheterisation. No commercial technology exists that protects against the major uropathogens for the lifetime of a long-term catheter. Silicone indwelling urinary catheters were impregnated with the antimicrobials (AUC) rifampicin, sparfloxacin, and triclosan to confer antimicrobial activity. With the overall aim of delivering this technology to urinary catheters users, this thesis aims to firstly, understand the profile of micoorganisms attached to indwelling urinary catheters. Secondly, using a combination of studies investigating the impregnated catheter surface and in vitro models, determine the ability of the AUC to resist mineral encrustation. Thirdly, this thesis will assess the protective activity of the AUC against multi-drug resistant organisms and Enterococcus spp. Finally, the safety and patient acceptability of this AUC will be assessed by a single-centre clinical trial. Methods: Urinary catheters were collected from patients at Nottingham University Hospitals NHS Trust (NUHT), and also over one year from one volunteer. General microbiological methods, including a new method of processing urinary catheters and MALDI-ToF were employed to identify and quantify attached microorganisms. Pulsed-field gel electrophoresis (PFGE) and similarity analysis determined the relationship between isolates of the same species isolated from catheters collected consecutively from the volunteer. The catheter surfaces were investigated after antimicrobial impregnation and soaking using atomic force microscopy and bacterial attachment assays. Reduction of mineral encrustation on the AUC was investigated in the presence and absence of bacteria. Spectrophotocolourimetry quantified phosphate deposition in a static and in vitro flow model. The protective duration of the AUC against Enterococcus spp. and multi-drug resistant bacteria was investigated in a clinically predictive in vitro model. A single-centre, non-randomised safety and patient acceptability study was conducted. The primary outcome measure was rate of adverse events attributable to antimicrobial impregnation. Secondary outcome measures included patient acceptability, withdrawal before the end of the trial, and microorganism colonisation of trial catheters. Results:Sixty-one urinary catheters were collected from patients at NUHT. E. coli and Enterococcus faecalis were the most commonly isolated organisms. A novel method was developed to isolate micoorganisms from the catheter lumens and balloons separately. Nine consecutive urinary catheters were collected from one volunteer over one year. Methicillin-susceptible Staphylococcus aureus, E. faecalis, Citrobacter koseri, and Pseudomonas aeruginosa were isolated from many of the nine catheters over the course of the year. PFGE revealed the isolates were indistinguishable, except for three P. aeruginosa isolates, which were closely related but differed by a 2-3 band difference by PFGE. Surface characteristics of silicone urinary catheters were not adversely affected by antimicrobial impregnation. The AUC prevented blockage and reduced phosphate deposition when challenged with Proteus mirabilis in static and flow models. The AUC was not able to consistently eradicate E. faecalis and E. faecium isolates. The AUC resisted colonisation by methicillin-resistant S. aureus, methicillin-resistant Staphylococcus epidermidis, MSSA, Staphylococcus saprophyticus, extended-spectrum beta-lactamase producing E. coli, New Delhi metallo-beta-lactamase producing E. coli for approximately 12 weeks. Thirty patients were recruited to the safety clinical trial, which demonstrated the AUC was safe and was acceptable to the majority of participants. Only one adverse event was reported that was ‘probably’ associated with antimicrobial impregnation of the catheters and it was mild and resolved within 48 hours. There were significantly less bacterial isolates attached to the balloons of trial catheters compared to the matched original catheters. Conclusions: The AUC is safe and effective technology for long-term catheter users. Next steps include a clinical trial of efficacy and commercialisation.
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