Therapeutic assessment of N-formyl-methionyl-leucyl-phenylalanine (fMLP) in reducing periprosthetic joint infection.

Abstract

Despite many preventive measures, including prophylactic antibiotics, periprosthetic joint infection (PJI) remains a devastating complication following arthroplasty, leading to pain, suffering, morbidity and substantial economic burden. Humans have a powerful innate immune system that can effectively control infections, if alerted quickly. Unfortunately, pathogens use many mechanisms to dampen innate immune responses. The study hypothesis was that immunomodulators that can jumpstart and direct innate immune responses (particularly neutrophils) at the surgical site of implant placement would boost immune responses and reduce PJI, even in the absence of antibiotics. To test this hypothesis, N-formyl-methionyl-leucyl-phenylalanine (fMLP) (a potent chemoattractant for phagocytic leukocytes including neutrophils) was used in a mouse model of PJI with Staphylococcus aureus (S. aureus). Mice receiving intramedullary femoral implants were divided into three groups: i) implant alone; ii) implant + S. aureus; iii) implant + fMLP + S. aureus. fMLP treatment reduced S. aureus infection levels by ~ 2-Log orders at day 3. Moreover, fMLP therapy reduced infection-induced peri-implant periosteal reaction, focal cortical loss and areas of inflammatory infiltrate in mice distal femora at day 10. Finally, fMLP treatment reduced pain behaviour and increased weight-bearing at the implant leg in infected mice at day 10. Data indicated that fMLP therapy is a promising novel approach for reducing PJI, if administered locally at surgical sites. Future work will be toward further enhancement and optimisation of an fMLP-based therapeutic approach through combination with antibiotics and/or implant coating with fMLP.