Modulating Micrococcal Nuclease-Triggered Antibiotic Releases for One-Stage Revisions of Staphylococcus...

Periprosthetic joint infections caused by Staphylococcus aureus (S. aureus) 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 S. aureus. When these pins were implanted in S. aureus-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 S. aureus-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 S. aureus 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.