Title: Investigating the role of bacterial genomic adaptation in orthopaedic infection
Funder: The Academy of Medical Sciences

Abstract: Orthopaedic infections, including Prosthetic joint infection (PJI), osteomyelitis and fracture site infections are a growing problem with significant morbidity. Even with expert surgical revision and systemic anti-microbials, recurrent infection is common. I propose an investigation of the role for bacterial persistence and adaptation, compared with re-infection, in bacterial orthopaedic infection. In collaboration with the Bone Infection Unit, a major national centre for orthopaedic infection, I will prospectively study bacteria found in orthopaedic infection in the clinical microbiology laboratory of Oxford University Hospitals NHS Trust. For cases of recurrent PJI with the same bacterial species, we will use high throughput sequencing to identify bacterial genomic changes occurring between index and repeat infection, allowing distinction of recurrence due to persistent infection from new infection. In recurrent PJI and haematogenous osteomyelitis, genomic sequencing will be used to identify changes accumulating in persistent infection, identifying the evolution of antimicrobial resistance and other adaptive mutations arising with bones and prosthetic joints. Results of this study will inform design and funding applications for a multi-site prospective study of relapse in PJI quantifying the importance of bacterial persistence and re-infection, and identifying bacterial changes favouring persistence in orthopaedic infection. Knowledge of the processes underlying these difficult infections will have far-ranging implications for surgical and medical treatment of orthopaedic infection. This information could also shape the development of new treatment strategies, including the development of implantable devices that combat the adaptive strategies of bacteria and the evolution of antimicrobial resistance to help prevent PJI.

Lay abstract: Orthopaedic surgery is a critically important treatment for arthritis and fractures, relieving pain and improving movement, function and quality of life. However, infection is a difficult complication of surgery with implanted prosthetic devices. Approximately one in fifty people who has their hip or knee replaced will develop an infection, usually bacterial. These are difficult to treat, requiring surgery and long courses of antibiotics. After surgery for one infection, the risk of another infection becomes even higher. This study aims to understand how bacteria change to allow them better to infect bones and joints. By studying the genetic code of infecting bacteria from prosthetic joint infection, we will be able to say how often further infection is due to the same bacteria being able to persist in the joint despite surgery and antibiotics, and how often it is due to new bacteria causing infection after the first has been treated. Where we see the same bacteria persisting, we will study in depth the mutations accumulated over time. We will also study the mutations that accumulate in bone infection with bacteria that have spread from the bloodstream. In doing so we will be able to identify any changes in the genetic code occurring over time, which may help the bacteria persist, including those which enable them to become resistant to antibiotics, or become better at attaching to the joint or avoiding the body’s immune system. This information will help us understand what treatments are likely to succeed in reducing prosthetic joint infections.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;MUSCULOSKELETAL