Local Antimicrobial Potential of Bupivacaine and Tolfenamic Acid-Loaded Ultra-High Molecular Weight Polyethylene (UHMWPE) for Orthopedic Infection

Peri-prosthetic joint infection (PJI) is a major post-arthroplasty complication that warrants alternative antibacterial approaches to improve prophylaxis and treatment outcomes. Local administration of analgesics post-surgery is common. Recent studies have demonstrated the antimicrobial potential of analgesics and the feasibility of dual drug-eluting ultra-high molecular weight polyethylene (UHMWPE) for local antibacterial applications. However, the antibacterial mechanism of action is poorly understood, and the translational value of antimicrobial dual drug-loaded UHMWPE has not been evaluated. In this study, we utilized the Laurdan assay and gene expression analysis to demonstrate the antibacterial action of bupivacaine hydrochloride (BP) and tolfenamic acid (TA) against <i>Staphylococcus aureus.</i> Furthermore, we incorporated BP and TA into UHMWPE at different weight concentrations and studied their longitudinal drug release and real-time antibacterial properties. The analgesics showed a significant effect on the bacterial membrane properties comparable to known antibiotics and regulated bacterial gene expression. For the dual drug-loaded UHMWPE, the drug release rate from BP/TA combinations was interestingly not a direct function of the loaded drug weight percent, potentially due to the hydrophobicity of TA and the interactions between the two drugs. Combinations of BP and TA at the higher total drug concentration (10 and 20%) showed a prolonged antibacterial effect against <i>S. aureus</i>, with great potential for prophylactic use.