Local delivery of vancomycin for the prophylaxis of prosthetic device-related infections using glycerylmonostearate-based implants.

摘要

Prosthetic device-related infections present a significant challenge to physicians as they are typically deep-rooted, recalcitrant and often result in systemic infection necessitating removal of the prosthetic device. Prophylactic antibiotics administered systemically at the time of implantation of the prosthetic device have failed to prevent these infections due to poor vasculature of the wound site resulting in sub-optimal local concentrations of the antibiotics. Local delivery at the site of implantation of the prosthetic device will maintain high local concentration of the antibiotics thus optimizing therapy and also preventing high systemic levels thus reducing toxicity associated with antibiotics such as vancomycin and gentamicin. Therefore, the overall objective of this research was to develop an implantable biodegradable delivery system of vancomycin with glycerylmonostearate (GMS) for the prophylaxis of prosthetic device-related infections. GMS matrices were prepared using the optimal GMS formulation developed by Allababidi et al. In vitro release kinetics of vancomycin from the matrices was evaluated and using compression coating, in vitro release was prolonged for a period of 5 days. The in vivo efficacy and pharmacokinetics of vancomycin were evaluated in an animal model by subcutaneously implanting a small piece of a polytetrafluoroethylene (PTFE) vascular graft and inoculating the surrounding area with 1.5 x 108 cfu/ml of Staphylococcus epidermidis to induce biofilm infection. Formation of purulent discharge (pus) and yellowish discoloration of the prosthetic device were used as indicators to evaluate the efficacy of the treatment groups in preventing infection at the wound site. Although the control group of animals that did not receive any antibiotics developed clear signs of infection, the group of animals that received GMS implants loaded with vancomycin failed to show evidence of infection. The wound site and the prosthetic device were devoid of any purulent discharge indicating that the local delivery of antibiotics from the GMS implants was successful in preventing infection. The in vivo efficacy was also evaluated in a group of animals that received 12 intramuscular (systemic) injections of vancomycin at a dose of 25 mg/kg once every six hours and infection was observed in 4 out of 6 rats indicating that the systemic delivery was only partially effective in preventing biofilm infection. Although the plasma concentrations in the IM group of animals fluctuated between 2 and 20 mug/ml, the concentrations were maintained at about 4.77 mug/ml in the implant group after an initial burst in release. Microbiological studies in the form of subcultures of the wound swabs and identification of the resulting microorganisms indicated that biofilm-causing organisms such as Staphylococcus epidermidis and Enterococcus faecalis were recovered in a higher number of animals in the control group compared to the IM and implant groups suggesting that the treatment groups were effective in preventing proliferation and growth of the bacteria at the wound site. A long-term bioerosion and biocompatibility study of the GMS implants was performed in a group of 6 animals and it was found that the implants lost about 40--50% of the initial weight in about six weeks indicating the bioerodibility of GMS. The animals were normal and healthy throughout the six weeks. Upon excision, the site of implantation was clear without any signs of infection or inflammation indicating the biocompatibility of the implants. Overall, a GMS based local delivery system was developed that successfully prevented biofilm infection.