Project Grant R21AR084167

USE OF BACTERIAL BIOFILM DISRUPTING ANTIBODIES TO PREVENT AND TREAT PERIPROSTHETIC JOINT INFECTION - PROJECT SUMMARY.................................................................................................................. PERIPROSTHETIC JOINT INFECTION (PJI) DESCRIBES INFECTION ON AND AROUND AN ORTHOPEDIC IMPLANT USED FOR JOINT REPLACEMENT. PJI IS THE MOST COMMON DEVASTATING COMPLICATION FOLLOWING JOINT REPLACEMENT SURGERY. TREATMENT OF PJI OFTEN INVOLVES MULTIPLE REVISION SURGERIES AS WELL AS MONTHS TO OVER A YEAR OF ANTIBIOTICS. CURRENT PJI TREATMENT STRATEGIES CAN HAVE HIGH FAILURE RATES, AND FURTHER ADVERSE OUTCOMES FROM PJI INCLUDE AMPUTATION OR DEATH, WITH MORTALITY IN PATIENTS WITH PJI OFTEN OVER 10%. THERE IS A CRITICAL NEED FOR ENHANCED METHODS TO PREVENT PJI AND ERADICATE PJI ONCE IT HAS OCCURRED. THE MOST PROBLEMATIC UNADDRESSED FEATURE OF PJI IS BACTERIAL BIOFILM FORMATION, WHICH IS A COMPOSITION OF SUBSTANCES SECRETED OUTSIDE THE BACTERIAL CELL THAT PROVIDES A PROTECTIVE BARRIER AGAINST ANTIBIOTICS AND THE HOST IMMUNE RESPONSE. BACTERIAL BIOFILM FORMATION, AND ITS INFLUENCE ON ANTIBIOTIC AND IMMUNE MEDIATED BACTERIAL CLEARANCE, OCCURS AS EARLY AS HOURS FOLLOWING INFECTION. OUTSIDE THE CONTEXT OF THE ORTHOPEDIC SETTING AND PJI, A NOVEL BIOFILM DISRUPTING ANTIBODY (ANTI-DNABII MONOCLONAL ANTIBODY) HAS BEEN DEVELOPED. VALIDATION OF THE EFFICACY OF THIS ANTIBODY HAS BEEN RIGOROUSLY TESTED IN VITRO, AS WELL AS ANIMAL MODELS OF OTITIS MEDIA (MIDDLE EAR INFECTION) AND PNEUMONIA AND HAS BEEN DEMONSTRATED TO DIMINISH BACTERIAL BIOFILM BIOMASS BY OVER 90% AND ENHANCE CLEARANCE OF INFECTION IN VIVO. THIS ANTI-DNABII ANTIBODY IS CURRENTLY UNDERGOING PHASE 1 CLINICAL TRIALS IN PATIENTS WITH BACTERIAL PNEUMONIA. IN THIS INVESTIGATION, WE WILL TEST ANTI-DNABII ANTIBODY IN A MOUSE MODEL OF PJI USING THE MOST COMMON CLINICAL CAUSE OF PJI, STAPHYLOCOCCUS AUREUS (S. AUREUS). AIM 1 WILL DETERMINE IF IMPLANTS COATED WITH ANTI-DNABII ANTIBODY CAN PREVENT IMPLANT BIOFILM IN A MOUSE MODEL OF PJI. WE HYPOTHESIZE THAT LOCALIZATION OF ANTI-DNABII ANTIBODY TO THE IMPLANT, AT THE TIME OF IMPLANT SURGERY AND BACTERIAL INOCULATION, WILL SUBSTANTIALLY DIMINISH S. AUREUS BACTERIAL BIOFILM FORMATION ON THE IMPLANT IN THE MOUSE PJI MODEL. AIM 2 WILL DETERMINE IF ANTI-DNABII ANTIBODY ERADICATES PERSISTENT S. AUREUS INFECTION IN A MOUSE MODEL OF PJI. WE HYPOTHESIZE LOCALIZED DELIVERY OF ANTI-DNABII ANTIBODY THROUGH INTRA-ARTICULAR INJECTION TO THE INFECTED SURGICAL SITE, STARTING AT DAY 7 FOLLOWING IMPLANT PLACEMENT AND S. AUREUS INOCULATION, WILL RESULT IN COLLAPSE AND DISINTEGRATION OF THE BACTERIAL BIOFILM AND ALLOW COMPLETE ERADICATION OF INFECTION IN COMBINATION WITH ANTIBIOTIC TREATMENT IN THE MOUSE PJI MODEL. DATA GENERATED FROM THIS INVESTIGATION WILL INFORM FUTURE PRE-CLINICAL AS WELL AS CLINICAL STUDIES TO INVESTIGATE THE ABILITY OF ANTI-DNABII ANTIBODY TO ERADICATE OR PREVENT PJI.