BackgroundPost-arthroplasty infections represent a devastating complication of total joint replacement surgery, resulting in multiple reoperations, prolonged antibiotic use, extended disability and worse clinical outcomes. As the number of arthroplasties in the U.S. will exceed 3.8 million surgeries per year by 2030, the number of post-arthroplasty infections is projected to increase to over 266,000 infections annually. The treatment of these infections will exhaust healthcare resources and dramatically increase medical costs.Methodology/Principal FindingsTo evaluate novel preventative therapeutic strategies against post-arthroplasty infections, a mouse model was developed in which a bioluminescent Staphylococcus aureus strain was inoculated into a knee joint containing an orthopaedic implant and advanced in vivo imaging was used to measure the bacterial burden in real-time. Mice inoculated with 5×103 and 5×104 CFUs developed increased bacterial counts with marked swelling of the affected leg, consistent with an acute joint infection. In contrast, mice inoculated with 5×102 CFUs developed a low-grade infection, resembling a more chronic infection. Ex vivo bacterial counts highly correlated with in vivo bioluminescence signals and EGFP-neutrophil fluorescence of LysEGFP mice was used to measure the infection-induced inflammation. Furthermore, biofilm formation on the implants was visualized at 7 and 14 postoperative days by variable-pressure scanning electron microscopy (VP-SEM). Using this model, a minocycline/rifampin-impregnated bioresorbable polymer implant coating was effective in reducing the infection, decreasing inflammation and preventing biofilm formation.Conclusions/SignificanceTaken together, this mouse model may represent an alternative pre-clinical screening tool to evaluate novel in vivo therapeutic strategies before studies in larger animals and in human subjects. Furthermore, the antibiotic-polymer implant coating evaluated in this study was clinically effective, suggesting the potential for this strategy as a therapeutic intervention to combat post-arthroplasty infections.

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MyD88 is an adapter molecule that is used by both IL-1R and TLR family members to initiate downstream signaling and promote immune responses. Given that IL-1β is induced after S. aureus infections and TLR2 is activated by S. aureus lipopeptides, we hypothesized that IL-1β and TLR2 contribute to MyD88-dependent protective immune responses against post-arthroplasty S. aureus infections. To test this hypothesis, we used a mouse model of a post-arthroplasty S. aureus infection to compare the bacterial burden, biofilm formation and neutrophil recruitment in IL-1β-deficient, TLR2-deficient and wildtype mice. By using in vivo bioluminescence imaging, we found that the bacterial burden in IL-1β-deficient mice was 26-fold higher at 1 day after infection and remained 3- to 10-fold greater than wildtype mice through day 42. In contrast, the bacterial burden in TLR2-deficient mice did not differ from wildtype mice. In addition, implants harvested from IL-1β-deficient mice had more biofilm formation and 14-fold higher adherent bacteria compared with those from wildtype mice. Finally, IL-1β-deficient mice had ~50% decreased neutrophil recruitment to the infected postoperative joints than wildtype mice. Taken together, these findings suggest a mechanism by which IL-1β induces neutrophil recruitment to help control the bacterial burden and the ensuing biofilm formation in a post-surgical joint.