Development of a physiologically relevant platform to inform clinical practice and limit antimicrobial resistance in orthopaedic implants

Project Outline

Antibiotics are a cornerstone of modern medicine, and as well as treating infections, are crucial for clinical success in many operations including orthopaedic implants. However, antimicrobial resistance is a growing global health emergency. The World Health Organisation’s “Global Action Plan (GAP) on Antimicrobial Resistance” emphases awareness, education, and prevention, as well as the need for optimisation of current antimicrobial therapies. As such, informing clinical practice of optimal dosing regimes, concentrations and combinations of existing antibiotics as well as novel antimicrobial strategies is a strategic area of focus [1].

Nonetheless, the available literature has been focused on single molecules or combinations of well-known antibiotics without fully recognising the long-term effect of new bactericidal elements (e.g. silver) in conventional regimes. Novel antimicrobials such as silver or copper are arising across healthcare applications to tackle AMR, however, recent studies have shown that combinations of these elements and current antibiotic practices can result in increased resistance development in vitro [2]. This disregard of novel technologies is further compounded by the limitations inherent to most used methods available to evaluate antimicrobial effectiveness. Only recently has the microbiology community recognised the critical role fluid flow and surface mechanics play in the survival of bacteria in natural environments [3]. Thus, static microtiter assays lack clinical relevance, increasing the potential for antibiotic misappropriation. Considering this, utilising bioreactors has the potential to provide more physiologically relevant and accurate infection models, improving the predictive value of current practices. Consequently, immediate actions against AMR should be focused on optimising antibiotic and antimicrobial treatments through clinically relevant models.

This PhD will develop a physiologically relevant platform to inform orthopaedic clinical practise with the aim of limiting AMR. For this purpose, the experimental plan will be focused in four principal areas:

Ascertain the effectiveness of antibiotic and antimicrobial mixtures, dosing and regimes on the short term and long-term resistance development of an array of clinical and laboratory strains of both Gram positive and negative bacteria typically associated with orthopaedic implant infections.

Unravel the phenotypic and genetic mechanisms behind the observed changes in resistance.

Modification of an existing bioreactor set up to create a physiologically relevant infection model for both planktonic bacteria and orthopaedic device surfaces colonised with early-stage attached bacteria and fully formed biofilms.

Engage with healthcare experts and regulators to optimise current practices.

References

1. Hall, T. J. et al. (2020). A call for action to the biomaterial community to tackle antimicrobial resistance. Biomaterials Science, 8(18), 4951-4974.
2. Villapún, V. M. et al. (2021). Repeated exposure of nosocomial pathogens to silver does not select for silver resistance but does impact ciprofloxacin susceptibility. Acta Biomaterialia, 134, 760-773.
3. Persat, A. et al. (2015). The mechanical world of bacteria. Cell, 161(5), 988-997.

Techniques

• Bacterial culture.
• Bioinformatics.
• Confocal microscopy.
• Flow cytometry.
• Surface analysis.
• Bioreactor.