199. A novel and scalable antimicrobial surface modification technology to prevent and mitigate implant related surgical site infections: an in-vivo safety and efficacy study

Abstract

<h3>BACKGROUND CONTEXT</h3> Despite significant technological advancements in material science, a high level of hand-hygiene and systematic use of antiseptics and antibiotics, surgical site infections (SSI) are still to date the number one complication seen after surgery in the United States. Methicillin-resistant Staphylococcus aureus (MRSA) is the largest purveyor of health care-acquired infections (HCAI) and is responsible for significant morbidity and mortality. <h3>PURPOSE</h3> This study aimed to demonstrate the in-vivo safety and antibacterial efficacy of non-eluting titanium implants covalently bound with a novel broad-spectrum biocidal quaternary ammonium compound (DBG21) against MRSA biofilm. <h3>STUDY DESIGN/SETTING</h3> Subcutaneous MRSA infection mouse model comparing the antimicrobial efficacy of untreatedversusDBG21-treated titanium alloy discs. A separate comparative safety study was performed in the absence of infection. <h3>PATIENT SAMPLE</h3> Sixty-five 11-week-old balb/c mice. <h3>OUTCOME MEASURES</h3> Efficacy study: Number of adherent bacteria on implants (CFU) and in the surrounding tissue (CFU/g) at days 7 and 14. Safety study: systemic and subacute toxicity (clinical tolerance, blood tests and histology). <h3>METHODS</h3> Efficacy Study: TiAl6V4 discs, 6mm ø, 0.5 mm thick, were activated, dip-coated in a polymer solution, and baked to produce covalently bound DBG21-treated discs. Untreated TiAl6V4 discs were used as controls. All discs underwent subsequent sterilization by 25kGy gamma-irradiation, were implanted either untreated for control mice or DBG21-treated for treated mice, and were challenged with a high-bacterial inoculum of MRSA (ATCC43300) in a well-established subcutaneous infection mouse model (11-week-old balb/c) in the absence of antibiotics. A veterinary ethics committee validated the protocol. Sixty-five mice (33 controls, 32 treated) were included in an antibacterial efficacy study. After implantation of one disc in a posterior subcutaneous pocket and closure of the skin for each mouse, 7 log10CFU (colony forming units) of MRSA were injected through a catheter into the operating site. Mice were sacrificed after either 7 days (18 treated, 18 controls) or 14 days (15 controls, 14 treated) to determine the number of adherent bacteria (biofilm) on implants and in the peri-implant surrounding tissues. Results were expressed respectively as median log10CFU reduction on implants and median log10CFU/g reduction in tissue compared with untreated control mice. The statistical significance (p) was determined using Mann-Whitney tests. Safety Study: Ten mice implanted with either control (5 mice) or DBG-21 treated (5 mice) discs were assessed in a safety study in the absence of infection (ISO 10993-11:2017 for systemic and subacute toxicity including clinical tolerance, blood tests and local histology). <h3>RESULTS</h3> Efficacy Study: At both 7 and 14 days, DBG21-treated implants yielded a significant decrease in MRSA biofilm (respectively 3.6 median log10CFU (99.97%) reduction (p < 0.001) and 1.9 median log10CFU (98.7%) reduction (p = 0.037)) and peri-implant surrounding tissues (respectively 2.7 median log10CFU/g (99.8%) reduction (p < 0.001) and 5.6 median log10CFU/g (99.9997%) reduction (p < 0.001)). At day 7, three treated mice (16.6%) were completely sterilized on both tissue and implant. At day 14, 10 treated mice (71.4%) had sterile peri-implant tissue. Safety Study: There were no significant differences between control and treated mice in terms of clinical scores, blood tests and local histology after up to 11 days from implantation. <h3>CONCLUSIONS</h3> Preventing biofilm formation has been recognized as a key element of SSI prevention. Yet, no biofilm-resistant titanium implants are available in clinical practice to prevent and mitigate the burden of SSIs. This small animal safety and efficacy trial suggests that DBG-21 is a promising candidate for antimicrobial surface modification of titanium implants. <h3>FDA DEVICE/DRUG STATUS</h3> DBG21 antimicrobial surface modification (Not approved for this indication).