Efficacy and pharmacokinetics of site-specific cefazolin delivery using biodegradable implants in the prevention of post-operative wound infections.

Abstract

The study objective was to evaluate the efficacy and pharmacokinetics of cefazolin delivered locally as a glyceryl monostearate (GMS) based biocompatible implant for prevention of post-operative wound infection in Sprague Dawley rats subcutaneously inoculated with Staphylococcus aureus. For the efficacy and pharmacokinetic studies, 18 rats were subcutaneously inoculated with 4.5 x 10(7) CFU of S. aureus on the dorsum (6 per rat), and randomly assigned into three group of 6 rats each: (1) the control group, in which rats did not receive antibiotics, (2) the intermittent i.m. treatment group, in which rats received i.m. injections of 10 mg/kg cefazolin every 4 hr (total of 180 mg/kg in 3 days), and (3) the implant treatment group, in which rats were implanted subcutaneously with four Cefazolin-GMS implants in the vicinity of the inoculations. The implants were designed to deliver 180 mg/kg cefazolin over a 3 day period. For efficacy evaluation, the rats were euthanized one week post-inoculation and abscess count, weight and size were determined. Rats in the control group had developed 21 abscesses out of the 36 inoculations, indicating validity of the infection model. The local delivery of cefazolin resulted in complete eradication of the infection, since no abscesses formed in the rats in the implant group. In the IM treatment group, only one abscess was formed and no significant difference in efficacy between the two treatment groups was observed. The GMS implants sustained the release of cefazolin for a period of three days with only 3-fold fluctuations in plasma concentration (5.5-17.5 micrograms/ml). However, plasma concentrations after the intermittent IM administration of cefazolin fluctuated 110-fold between 44-0.4 micrograms/ml every 4 hr. The release rate of cefazolin from the implants was nearly zero order for the entire duration. Bioerosion of the implants was determined by examining the condition of the implants six weeks post-implantation. Two of the 12 implants had completely disappeared and the remaining implants were in a pasty form and had lost 20-80% of their weight. Absence of irritation or inflammation around the implants indicated biocompatibility of the GMS implants. Implantable system that provided a prolonged delivery of cefazolin was found to be effective against S. aureus infection, and demonstrated suitable pharmacokinetics and biocompatibility with significant bioerosion.