Development of Strategies for the Treatment of Biofilm Infections in Indwelling Medical Devices

Biofilms are evolutionary adaptations that allow bacteria to aggregate together and undergo physiological and morphological changes, altered gene regulation and generation of extracellular polymeric substance (EPS). EPS acts as a glue that effectively adheres the biofilm to almost any surface, but it also allows for the release of extracellular DNA, proteins and many more cofactors that encourage resistance and tolerance of antimicrobials. Bacterial biofilms are found in diverse environments from water pipes to indwelling medical devices such as catheters. Biofilm infections can be challenging to diagnose in vivo and difficult to eradicate. Once established, the EPS protects the bacteria against fluid flow and mass transport resulting in a matrix highly resistant to antibiotics and immune cells. This is due to many factors associated with the biofilm community; various cells within the polymicrobial ecosystem communicate via quorum sensing and may confer antimicrobial resistance genes from cell to cell. It has been estimated that the levels of antibiotics required to eliminate bacteria in biofilms can be up to a thousand times higher than for planktonic cells, this may due to lack of effective perfusion of the drugs through the biofilm EPS or it could indicate drug binding, which may result in unwanted side-effects. This project will involve the collection of experimental data for the time-resolved characterisation of biofilm formation and treatment of biofilm infections using state-of-the-art equipment within the Sheffield Centre for Antimicrobial Resistance and Biofilms (SCARAB), recently funded by InnovateUK.

There is an increasing need for strategies that involve the treatment of bacteria in biofilms without administering antibiotics, thus limiting the development of antimicrobial resistance and tolerance within biofilms. There is evidence to suggest that 80% of human bacterial infections are biofilm related (Roberts et al., 2015) and therefore a need for new treatments is ever more urgent. Alternative strategies include the development of material coatings that prevent adherence of bacteria to surfaces, and hence biofilm formation, or dynamic antibacterial coatings that deliver novel therapeutics in response to certain types of bacteria. However, biofilms typically consist of polymicrobial communities, the make-up of which is country-specific. Therefore, effective treatment of biofilm related infections is a complex problem where the synergistic or antagonistic effects of the microorganisms may have an impact on treatment that has not been greatly explored.

Catheter-associated urinary tract infections (CAUTIS) are one of the most common nosocomial infections and can be both dangerous to the patient, resulting in life-threatening conditions such as sepsis and represent a large financial burden to hospitals and healthcare facilities. A lab-based model system for CAUTIs will be developed involving communities of clinically relevant bacteria: Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis and Proteus mirabilis. This research will explore mechanisms of polymicrobial biofilm growth in a flow environment designed to mimic that of catheters and test the community response to emerging strategies for treatment. This may include the prevention of adhesion using coated materials and antifouling materials or employing novel technologies for the treatment of biofilms which could include antibiofilm peptides.
We will collaborate with colleagues in the Faculty of Medicine, Dentistry and Health as well as work with stakeholders: Devices for Dignity, an NHS healthcare technology co-operative, to ensure that strategies developed are relevant to healthcare providers.

References
Roberts, A., Kragh, K., Bjarnsholt, T. and Diggle, S. (2015). The Limitations of In Vitro Experimentation in Understanding Biofilms and Chronic Infection. Journal of Molecular Biology, 427(23), pp.3646-3661.