Sonoran Biosciences, 3931 West Butler Street, Chandler, AZ, 85226, USA.
School of Biological and Health Systems Engineering, Center for Interventional Biomaterials, Arizona State University, PO Box 879709, Tempe, AZ, 85287-9709, USA.
Drug Deliv Transl Res. 2019 Aug;9(4):802-815. doi: 10.1007/s13346-019-00630-5.
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.
局部抗菌药物递送是一种很有前途的策略，可以通过消除手术清创后残留在伤口或其边缘周围的细菌来改善深部手术部位感染（SSI）的治疗效果。消除生物膜细菌可能需要持续暴露于高浓度的抗菌药物（我们估计持续 24 小时需要 100-1000μg/mL），而这远远超过全身给药所能提供的浓度。我们之前报道了基于聚（N-异丙基丙烯酰胺-co-二甲基丁酸内酯丙烯酰胺-co-Jeffamine M-1000 丙烯酰胺）（PNDJ）的温度响应水凝胶的开发，该水凝胶在体外具有持续的抗菌药物释放能力，并且在手术清创后灌注时可有效治疗兔骨髓炎模型。在这项工作中，我们试图测量 PNDJ 水凝胶的体内抗菌药物释放情况以及相邻组织中的抗菌药物浓度。在兔的四个给药部位（股骨髓腔内、股四头肌软组织缺损、半腱肌肌肉内注射和膝关节内关节内注射）中给予含有妥布霉素和万古霉素的 PNDJ 水凝胶。在给药后 72 小时内收集凝胶和组织，并分析药物水平。体内抗菌药物释放（72 小时后 43-95%）明显快于体外释放。药物水平因给药部位而异，但与所测试的聚合物配方无关。值得注意的是，所有给药部位相邻组织中的总抗菌药物浓度至少在 24 小时内维持在估计的可消除生物膜的水平（24 小时时为 461-3161μg/mL）。这些结果表明，载抗菌药物的 PNDJ 水凝胶有望改善生物膜相关 SSI 的治疗效果。
