Periprosthetic joint infections: Development of new therapies

Abstract

Summary Implants such as hip and knee prostheses have revolutionized healthcare by significantly improving quality of life for millions worldwide. However, along with these benefits come inherent risks, such as periprosthetic joint infection (PJI). These infections can occur in 1% to 2.5% of primary joint replacements and van rise as high as 16% in revision surgeries. In the Netherlands alone, approximately 60,000 hip and knee replacements were performed in 2019, a number expected to increase globally due to demographic shifts towards aging populations. Projections for the United States suggest a rise to 2.8 million procedures by 2030 and 4.8 million by 2040, highlighting the growing challenge of managing PJI in the future. Staphylococcus aureus is a common pathogen implicated in implant-related infections, particularly notable for its ability to form biofilms. These biofilms protect bacteria from the host immune system and antibiotics, complicating treatment and contributing to persistent infections. Despite advancements in treatment strategies such as antibiotics and surgical interventions like debridement, antibiotics, and implant retention (DAIR), followed by one or two-stage revisions, outcomes vary significantly. Short-term mortality rates range from 2.6% to 10.6%, rising to approximately 21% over five years, influenced by factors including bacterial resistance, patient age, and comorbidities. In response to the challenges posed by traditional treatments, alternative therapeutic approaches such as monoclonal antibodies (mAbs), radio-immunotherapy (RIT), and photo-immunotherapy (PIAT) must be explored. mAbs show promise in targeting specific pathogens like S. aureus and disrupting biofilms, either by enhancing immune responses or delivering antimicrobial payloads such as radionuclides or photosensitizers directly to infection sites. RIT involves the use of antibodies conjugated with radionuclides that emit ionizing radiation, selectively targeting bacterial cells while minimizing damage to surrounding healthy tissue. PIAT utilizes antibodies linked to photosensitizers activated by near-infrared light, generating reactive oxygen species to eradicate bacterial infections effectively. Research conducted at UMC Utrecht has provided critical insights into the effectiveness of current PJI treatments over a 13-year period, revealing variable success rates. While DAIR showed promising outcomes, revision surgeries demonstrated higher failure rates, particularly in patients with complex medical histories or prior unsuccessful treatments. For these cases, long-term antibiotic therapy, surgical procedures like the Girdlestone technique, or in severe cases, limb amputation may be necessary, significantly impacting patient quality of life. Looking ahead, optimizing antibody selection, exploring innovative radionuclides such as 225Ac and 177Lu for enhanced therapeutic efficacy in RIT, and refining PIAT for broader clinical applications are essential research priorities. Integrating these advanced therapies with conventional treatments offers a promising strategy for managing challenging PJI cases effectively, aiming to improve patient outcomes and alleviate the growing burden on healthcare systems globally.