Introduction: Antibiotic resistance has forced clinicians and researchers into a race to find antimicrobial alternative strategies to improve patient outcomes. Surgical site infections (SSIs) are particularly difficult due to treat and prevent due to the exposure to the non-sterile external environment. To address current antimicrobial needs, we propose to evaluate a novel and pharmacologically-predictable antimicrobial technology composed of a silver carboxylate eluting matrix of titanium dioxide (TiO2) and polydimethyl siloxane (PDMS). This antimicrobial formulation utilizes the multi-modal antimicrobial properties of silver to treat bacterial infections regardless of antibiotic resistance, without the toxicity of previous formulations. We hypothesize silver carboxylate will be efficacious against drug-resistant pathogens with no local toxicity to primary cell types involved in wound healing. Significance: The extensive use of implantable devices has accentuated the need for new technologies as periprosthetic infections cost billions of dollars to healthcare and significant patient disability. The rise in antibiotic resistance and lack of novel antibiotics create a significant worldwide problem. In contrast to the single mechanism of antibiotic action, silver has multiple antimicrobial mechanisms that are difficult for bacteria to counteract, thus limiting potential for resistance and providing a viable alternative to resistant strains. Innovation: The proposed chemistry shows improved penetration into the cell wall of bacteria, while controlling rate of release and bioavailability via the customizable TiO2/PDMS matrix. We hypothesize this new chemistry will decrease toxicity associated with unpredictable concentrations and prolonged presence of clinically used broad spectrum and ?last resort? antibiotics. Previous research on this technology has focused on prevention of bacterial adherence on spinal implants, prosthetic liners, and sutures. Over a dozen bacterial and fungal pathogens have been tested with considerable levels of antimicrobial activities from 24 to 72 hours. Research Plan: We propose 2 specific aims which will: 1) Provide Evidence of Silver Carboxylate?s Low Cytotoxicity in Primary Cell Lines Involved in Wound Healing using the cell metabolic activity assay MTT, LDH, Necrosis and Apoptosis. 2) Quantify Silver Carboxylate?s Potency against Commonly-Encountered Antibiotic-Resistant Pathogen via dose-response curves and Kirby Bauer Assays. Proposed aims will provide additional data on the efficacy of the chemistry against bacteria regardless of gram designation or antimicrobial resistance while showing low toxicity against cells involved in wound healing. This data will be utilized to pursue an R01 grant which will focus on determining the mechanism of action of silver carboxylate, penetrance into biofilms, as well as activity against biofilm persister cells.
Mitigation of antibiotic resistance has become a major priority in healthcare. The proposed study focuses on the antimicrobial and cytotoxic evaluation of a pharmacologically-predictable and antibiotic-independent silver carboxylate-eluting titanium dioxide/polydimethyl siloxane chemistry on primary musculoskeletal cells and antibiotic resistant nosocomial pathogens. With more than 2 million hospital acquired infections (HAI) per year in the United States alone (and projected to increase), the need for antibiotic-independent antimicrobial technologies is paramount for our society?s future.
