Modulating Micrococcal Nuclease-Triggered Antibiotic Releases for One-Stage Revisions of <i>Staphylococcus aureus</i> -Infected Prostheses

Periprosthetic joint infections caused by <i>Staphylococcus aureus</i> (<i>S. aureus</i>) pose significant health risks and economic burdens. Following revisions of infected arthroplasty prostheses, the reinfection rate can be as high as 30%. We previously developed hydrogel coatings for intramedullary metallic pins where vancomycin or ampicillin was covalently attached through an oligonucleotide linker cleavable by micrococcal nuclease secreted by <i>S. aureus</i>. When these pins were implanted in <i>S. aureus</i>-inoculated rat femoral canals, the on-demand release of antibiotics from the coating prevented infections from developing. Here, we test the hypothesis that a combination coating with rapid and more sustained <i>S. aureus</i>-triggered antibiotic releases could mitigate infections following one-stage revisions of previously infected prostheses. We implemented varying degrees of phosphorothioate modification of the oligonucleotide linker tethering ampicillin to the coating to achieve rapid and more sustained on-demand antibiotic releases. We first demonstrated that rat femoral infections, established by the inoculation of 200 CFU <i>S. aureus</i> at the time of uncoated primary intramedullary pin insertion, could not be resolved after one-stage revision without a proper pin coating, consistent with clinically observed challenges. However, bacterial burdens were significantly reduced following a one-stage revision with intramedullary pins coated with ampicillin-releasing coatings, with the combination of rapid and more sustained releases proving the most effective. When the combination coating was augmented with a single systemic vancomycin injection at the time of revision, infection was eradicated, outperforming local or systemic treatment alone and achieving unprecedented revision outcomes.