Temperature-responsive PNDJ hydrogels provide high and sustained antimicrobial concentrations in surgical sites

Local antimicrobial delivery is a promising strategy for improving treatment of deep surgical site infections (SSIs) by eradicating bacteria that remain in the wound or around its margins after surgical debridement. Eradication of biofilm bacteria can require sustained exposure to high antimicrobial concentrations (we estimate 100-1000 μg/mL sustained for 24 h) which are far in excess of what can be provided by systemic administration. We have previously reported the development of temperature-responsive hydrogels based on poly(N-isopropylacrylamide-co-dimethylbutyrolactone acrylate-co-Jeffamine M-1000 acrylamide) (PNDJ) that provide sustained antimicrobial release in vitro and are effective in treating a rabbit model of osteomyelitis when instilled after surgical debridement. In this work, we sought to measure in vivo antimicrobial release from PNDJ hydrogels and the antimicrobial concentrations provided in adjacent tissues. PNDJ hydrogels containing tobramycin and vancomycin were administered in four dosing sites in rabbits (intramedullary in the femoral canal, soft tissue defect in the quadriceps, intramuscular injection in the hamstrings, and intra-articular injection in the knee). Gel and tissue were collected up to 72 h after dosing and drug levels were analyzed. In vivo antimicrobial release (43-95% after 72 h) was markedly faster than in vitro release. Drug levels varied significantly depending on the dosing site but not between polymer formulations tested. Notably, total antimicrobial concentrations in adjacent tissue in all dosing sites were sustained at estimated biofilm-eradicating levels for at least 24 h (461-3161 μg/mL at 24 h). These results suggest that antimicrobial-loaded PNDJ hydrogels are promising for improving the treatment of biofilm-based SSIs.