Using ultrasound and microbubbles to augment antibiotic efficacy against periprosthetic joint infections - Project Summary/Abstract In the >1,000,000 joint arthroplasties performed annually in the United States, ~5% will experience periprosthetic joint infection (PJI), with a 5 year mortality rate above 11%, (exceeding that of breast cancer, melanoma, and Hodgkin’s lymphoma). To prevent PJI, surgeons maintain stringent sterility in the operating theater, initiate prophylactic intravenous (IV) antibiotics at least 1 hour prior to surgery, ensure joint sterility with antiseptic lavage, and, depending on the center, may place 1-2 g of powdered vancomycin in the wound during closure. Bacterial survival and the ensuing potential for infection are attributed to formation of implant-adherent bacterial biofilms. These antibiotic-tolerant bacterial aggregates are formed by bacteria most commonly responsible for PJI, including Staphylococcus aureus (S. aureus), methicillin-resistant S. aureus (MRSA), and Staphylococcus epidermidis (S. epidermidis). Once PJI is present, the surgeon may attempt a “debridement with antibiotics and implant retention” (DAIR) procedure, which currently has an ~50% re-infection rate in the United States. Otherwise, a one- or two stage exchange revision arthroplasty, which relies on implant removal, local antibiotic treatment and re-implantation, is undertaken; these have an ~25% re-infection rate. We hypothesize that failure of the infection treatment is at least partially caused by the continued presence of the floating and tissue-adherent bacterial aggregates. To that end, we have shown that bacterial aggregates can be sensitized to antibiotics in vitro and in vivo using a combination of antibiotics and ultrasound-triggered microbubble destruction (UTMD). In this application, we propose that an adjunct treatment of local antibiotics + UTMD will increase antibiotic efficacy in the joint space, thus lowering infection recurrence rates compared to clinical standard of care of surgery and antibiotics alone. We will investigate this adjunct therapy for each of the two main surgical treatments for PJI, in forty-eight (48) patients undergoing the DAIR procedure and in forty-eight (48) patients undergoing a one- or two-stage exchange arthroplasty revision for infection. The primary outcome of the study will be to compare time to reinfection between the experimental group (n = 24) and the control group receiving clinical standard of care (n = 24) for both procedures. In addition, as part of the insonation, we will develop quantitative ultrasound (i.e., H-scan) for prediction of infection-associated bone changes to determine any correlation with chronic PJI. We aim to determine the efficacy of this adjunct therapy, and to develop an immediately clinically-adaptable therapy to tackle the significant challenge of PJI. We expect that the combination of local antibiotics and UTMD will be broadly applicable to preventing surgical site infections, and ultimately decrease the incidence of PJI in primary and revision arthroplasty.
