Bioerodible polyanhydrides for antibiotic drug delivery: In vivo osteomyelitis treatment in a rat model system

Abstract

Acute and chronic osteomyelitis can be difficult to treat by conventional means. Current methods of treatment involve the use of systemic antibiotics, the local implantation of non-degradable drug carriers, and surgical débridement. Each method has specific drawbacks. We report on the use of a new controlled release system utilizing gentamicin and bioerodible, biocompatible polymers (polyanhydrides) designed for drug delivery applications for the treatment of clinical osteomyelitis. We compared this system's ability to reduce bacterial levels in infected bone with that of conventional non-degradable delivery systems based on polymethylmethacrylate (PMMA) and gentamicin. Polyanhydride copolymers of bis-carboxyphenoxypropane and sebacic acid P loaded with gentamicin sulfate and PMMA/gentamicin matrices were implanted in the long bones of Sprague-Dawley rats infected with a strain of Staphylococcus aureus. After 3 weeks of implantation, the polymeric delivery devices were removed and quantitative cultures were used to determine bacterial levels in bone. The polyanhydride/gentamicin matrices demonstrated significant degradation over the 3 week implantation period. Levels of bacteria, measured in colony forming units, were significantly lower in bone implanted with the polyanhydride/gentamicin release system than in long bones of control animals without an implant (p < 0.01), of animals with a polyanhydride polymer implant alone (p < 0.01), and of animals with a PMMA/gentamicin implant (p = 0.03). Bioerodible polyanhydrides show promise as a new treatment modality for infections in bone.

A new model of implant‐related osteomyelitis in rats

“…40 Others induced local osteonecrosis by either application of sclerosing agents (sodium morrhuate) 10,22,41 or thermally, by use of high speed carbide burrs. 21,39,42 In contrast to other rat models of osteomyelitis 10,21,22,40 no other manipulations except dilatation of the medullary cavity and insertion of a titanium Kirschner wire were undertaken to reliably induce destructive acute osteomyelitis. In most models bone wax or dental gypsum are applied to seal the site of application in order to prevent bacterial leakage into the surrounding tissue.…”

“…Besides the inoculation of pathogens, other authors have described the need for additional tissue manipulation in order to achieve onset of infection. These manip- ulations include the incorporation of foreign bodies (steel, methylmethacrylate) 38,39 or fibrin glue. 40 Others induced local osteonecrosis by either application of sclerosing agents (sodium morrhuate) 10,22,41 or thermally, by use of high speed carbide burrs.…”

Local Delivery of Vancomycin for the Prophylaxis of Prosthetic Device-Related Infections

“…However in most cases, due to poor vasculature of the wound site, conventional route of delivery fails to achieve optimal concentration of the antibiotics at the implantation site with unnecessary exposure of other organs in the body to high concentration of antibiotics (12). Attempts to overcome this problem have made use of local delivery systems, which deliver antibiotics at the site of implantation where they are most needed (13)(14)(15)(16)(17)(18). High concentrations of antibiotics are achieved locally with minimal exposure to other organs in the body thus minimizing problems due to drug toxicity.…”

Gatifloxacine-loaded PLGA and β-tricalcium phosphate composite for treating osteomyelitis

“…The effectiveness of local antibiotic delivery using biodegradable polymers has been substantiated by in vitro and in vivo studies. The biodegradable polymers that have been studied include poly(D,L-lactic acid) 6,7) , polylactide-co-glycolide [8][9][10][11] , copolymers of L-lactide and DL-lactide 12) , polyanhydrides of bis-carboxyphenoxypropane and sebacic acid 13) , polycaprolactone [14][15][16] , and polyhydroxyalkanoate 17) . These antibiotic biodegradable polymers released antibiotics for several hours to 40 weeks in vitro and were effective for several weeks in vivo 18,19) .…”