The use of bone cement for the localized, controlled release of the antibiotics vancomycin, linezolid, or fusidic acid: effect of additives on drug release rates and mechanical strength

Abstract

Bone cement containing antibiotics is commonly used to treat orthopedic related infections. However, effective treatment (especially of resistant bacteria, methacillin-resistant Staphylococcus aureus (MRSA)) is compromised by very low levels of drug release so that typically less than 10% of loaded drug is released over a 6-week period. The objective of this study was to investigate the effect of incorporation of water soluble excipients (polyethylene glycol, sodium chloride, or dextran) into antibiotic-loaded cement on mechanical strength and drug release properties. Poly(methyl methylacrylate) cement implants containing various amounts of drug (vancomycin, linezolid or fusidic acid (all MRSA active)) and excipients were cast in the form of beads or films and characterized using differential scanning calorimetry. Mechanical strength as assessed by Young's modulus was determined by thermo-mechanical analysis. Drug release was measured by incubation in phosphate buffered saline with analysis by HPLC methods. The inclusion of sodium chloride up to 20% w/w caused only minor reductions in Young's modulus. Vancomycin and linezolid released very slowly from unmodified bone cement beads (less than 3% released by 4 weeks) whereas fusidic acid released more quickly (approximately 8% released by 4 weeks). The inclusion of sodium chloride or dextran in bone cement resulted in major increases in the release rate of vancomycin, linezolid and fusidic acid. These studies support the inclusion of sodium chloride and dextran in bone cement to increase the release rate of vancomycin, linezolid, or fusidic acid without compromising the mechanical strength of the composite material.

The application of layered double hydroxide clay (LDH)-poly(lactide-co-glycolic acid) (PLGA) film composites for the controlled release of antibiotics

“…Because DOX and 5FU only released small amounts of drug from the LDH clay, these LDH/drug complexes were not included in film studies. VAN and SF only bound weakly to the LDH clays, but these drugs are particularly effective against drug-resistant bacteria, which represent a increasing problem in hospital settings [17]. By incorporating these drugs in LDH claypolymer film formulations, we have demonstrated that antimicrobial activity can be preserved over longer durations (Table 1).…”

“…We have previously reported that the drugs VAN, SF, and ASO are stable for extended periods in aqueous environments [17,23] whereas commonly used antibiotics erythromycin, cefazolin and TET are rapidly degraded in water. In this study TET was retained in the non-degraded form when bound to clay, despite prolonged incubation in water.…”

“…Counter measures include the local application of antibiotics at the time of catheter deployment or antimicrobial coating incorporated directly into film coatings on the catheter [14][15][16]. Similarly, implantable formulations of antibiotics may be surgically placed near the infected site to release drug locally and maintain antimicrobial concentrations for extended periods to combat or prevent infection [17,18].…”

Controlled release drug delivery systems to improve post-operative pharmacotherapy

“…Similarly, options of adding additives to improve antibiotic release without compromising the mechanical strength of bone cement have been reported. Jackson et al demonstrated that the addition of sodium chloride and dextran into bone cement improved drug release while maintaining mechanical strength [58].…”

RNA therapeutics targeting osteoclast-mediated excessive bone resorption

“…Polymethylmethacrylate (PMMA) bone cements used clinically for implant fixation, kyphoplasty, [266] and bone augmentation, [267] exhibit very poor control over entrapped dose release kinetics, often leaving up to 40% of the drug trapped in PMMA. [268,269] Injectable CPC exhibits several unique properties for bone drug delivery, including peri-operative preparation and drug loading, liquid-solid setting in situ, intrinsic osteoconductivity (degradable by osteoclasts), osteoinductivity (infiltrated by osteoblasts and replaced with new bone), and acceptable biocompatibility. [270][271][272] CPC's self-setting ability at ambient or body temperature within the bone cavity [273] enables injectable formulation, largely expanding its therapeutic utility.…”