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Local Intramedullary Delivery of Vancomycin Can Prevent the Development of Long Bone Staphylococcus aureus Infection.

ABSTRACT: Current treatments for methicillin-resistant Staphylococcus aureus (MRSA) infections require intravenously delivered vancomycin; however, systemically delivered vancomycin has its problems. To determine the feasibility and safety of locally delivering vancomycin hydrochloride (~25 mg/Kg) to the medullary canal of long bones, we conducted a pharmacokinetics study using a rat tibia model. We found that administering the vancomycin intraosseously resulted in very low concentrations of vancomycin in the blood plasma and the muscle surrounding the tibia, reducing the risk for systemic toxicity, which is often seen with traditional intravenous administration of vancomycin. Additionally, we were able to inhibit the development of osteomyelitis in the tibia if the treatment was administered locally at the same time as a bacterial inoculum (i.e., Log10 7.82 CFU/mL or 6.62x107 CFU/mL), when compared to an untreated group. These findings suggest that local intramedullary vancomycin delivery can achieve sufficiently high local concentrations to prevent development of osteomyelitis while minimizing systemic toxicity.

SUBMITTER: Loc-Carrillo C

PROVIDER: S-EPMC4966941 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Preventing orthopedic implant-associated bacterial infections remains a critical challenge. Current practices of physically blending high-dose antibiotics with bone cements is known for cytotoxicity while covalently tethering antibiotics to implant surfaces is ineffective in eradicating bacteria from the periprosthetic tissue environment due to the short-range bactericidal actions, which are limited to the implant surface. Here, we covalently functionalize poly(ethylene glycol) dimethacrylate hydrogel coatings with vancomycin via an oligonucleotide linker sensitive to Staphylococcus aureus (S. aureus) micrococcal nuclease (MN) (PEGDMA-Oligo-Vanco). This design enables the timely release of vancomycin in the presence of S. aureus to kill the bacteria both on the implant surface and within the periprosthetic tissue environment. Ti6Al4V intramedullary (IM) pins surface-tethered with dopamine methacrylamide (DopaMA) and uniformly coated with PEGDMA-Oligo-Vanco effectively prevented periprosthetic infections in mouse femoral canals inoculated with bioluminescent S. aureus. Longitudinal bioluminescence monitoring, ?CT quantification of femoral bone changes, end point quantification of implant surface bacteria, and histological detection of S. aureus in the periprosthetic tissue environment confirmed rapid and sustained bacterial clearance by the PEGDMA-Oligo-Vanco coating. The observed eradication of bacteria was in stark contrast with the significant bacterial colonization on implants and osteomyelitis development found in the absence of the MN-sensitive bactericidal coating. The effective vancomycin tethering dose presented in this on-demand release strategy was >200 times lower than the typical prophylactic antibiotic contents used in bone cements and may be applied to medical implants and bone/dental cements to prevent periprosthetic infections in high-risk clinical scenarios. This study also supports the timely bactericidal action by MN-triggered release of antibiotics as an effective prophylactic method to bypass the notoriously harder to treat periprosthetic biofilms and osteomyelitis.

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Local Intramedullary Delivery of Vancomycin Can Prevent the Development of Long Bone Staphylococcus aureus Infection.

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