Abstract
Catheter-associated urinary tract infections (CAUTIs) attribute to almost 80% of nosocomial infections worldwide. One of the main difficulties associated with CAUTIs that make them problematic to treat is device encrustation. Encrustation occurs due to colonisation of the catheter surface by urease-producing bacteria, mainly Proteus mirabilis, and leads to catheter lumen blockage. Furthermore, many uropathogens have shown resistance to common antibiotics. Weak organic acids (WOAs) have been used as antifungal and antimicrobial preservatives in the food industry for centuries. WOAs are reported to exert their antimicrobial effect by the flow of unionised molecules through the cell membrane of the bacteria. The resulting decrease in intracellular pH due to accumulation of acidic anions and hydrogen ions causes cell damage and death.The central aim of this research was to develop antibiofouling and antiblocking catheter coating which could be used in the prevention of CAUTIs and catheter lumen blockages. This involved development of an anti-adherent coating loaded with antimicrobial agents providing dual action against CAUTIs. Initially, the antibacterial activity of a suite of WOAs (citric acid, malic acid, propionic acid, mandelic acid, lactic acid, benzoic acid, pyruvic acid and hippuric acid), was investigated against common nosocomial uropathogens (Proteus mirabilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa). All eight WOAs alone displayed inhibitory and biocidal activities against the four uropathogens in their planktonic and biofilm modes of growth. Importantly, the citric and propionic acids in combination were shown to have more rapid kill kinetics than the acids alone. Identified synergistic activity between the WOAs and BKZ shown MIC values reduced up to 250-fold when the acids were used in combination.
Following on from the antimicrobial activity of the WOAs, the efficacy of inhibiting the swarming motility and urease production of P. mirabilis was determined. Citric acid, malic acid, propionic acid, mandelic acid, lactic acid and pyruvic acid exhibited promising inhibitory effects on swarming motility. Furthermore, significant decreases in urease activity at sub inhibitory concentrations (0.5 x MIC), were observed. Next, the efficacy of selected WOAs, citric acid and propionic acid, alone and in combination, on the prevention of P. mirabilis crystalline biofilm formation and catheter blockages in in vitro static and flow models was investigated. The rate of encrustation around the catheter eyeholes was reduced in the presence of the citric acid and propionic acid combination resulting in a threefold longer time to blockage.
The findings from the chapters 2 – 4 were exploited in the development of candidate hydrogel catheter coatings. A range of hydrogel coatings consisting of hydroxyethyl methacrylate, methyl methacrylate and polymethyl methacrylate were formulated. WOAs were physically loaded into the coatings and surface properties were characterised. Increased surface wettability and hydrophilicity of the hydrogel coatings in comparison to uncoated silicone gave promising indications of biocompatibility and improved anti-adherent properties. A wide spectrum of activity and significant reductions in bacterial adherence was observed on WOA-loaded hydrogel coated silicone relative to controls.
Lastly, the developed WOA-loaded hydrogel coatings were translated to urinary catheter substrates. In vitro catheter bridge swarming models and bladder models were used to assess the efficacy of WOA-loaded-hydrogel coatings in preventing swarming and migration of P. mirabilis, resistance to bacterial colonisation and lumen blockages. However, the catheter coatings did not inhibit P. mirabilis swarming motility and no significant differences were found between the coated and uncoated catheters time to blockage.
The multi-mechanistic, infection-resistant WOA-loaded hydrogel coatings identified herein represent promising alternatives to antibiotic impregnated catheters to combat common uropathogens for the prevention of CAUTIs and catheter blockages.
Thesis is embargoed until 31 July 2028.
| Date of Award | Jul 2023 |
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| Original language | English |
| Awarding Institution |
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| Sponsors | Healthcare Infection Society |
| Supervisor | Colin McCoy (Supervisor) & Louise Carson (Supervisor) |