We demonstrate that coating calcium sulfate with deacetylated chitosan enhances the elution profile of daptomycin by prolonging the period during which high concentrations of antibiotic are released. Coatings reduced initial bolus release of daptomycin by a factor of 10 to approximately 1000 μg/ml, and levels remained above 100 μg/ml for up to 10 days. Chitosan-coated and uncoated calcium sulfate implants with and without 15% daptomycin were evaluated in an experimental model of staphylococcal osteomyelitis through bacteriology scores, radiology, histopathology, and Gram staining. Significant reduction in bacteriology scores was observed for implants containing daptomycin and coated with chitosan compared with all the other groups. We confirm that the use of chitosan-coated calcium sulfate beads for local antibiotic delivery can be correlated with an improved therapeutic outcome following surgical debridement in the treatment of chronic osteomyelitis.

The growing infection rate by methicillin-resistant Staphylococcus aureus, especially with bone fracture fixation implants, is a major concern in extremity musculoskeletal wound treatment. This preliminary investigation evaluates the ability of chitosan film to be loaded with daptomycin and vancomycin in the operating room, in situ loading, and applied to musculoskeletal fixation devices to lessen or prevent infection. Films with 61, 71, and 80% degrees of deacetylation (DDA) made using lactic or acetic acid solvents were analyzed for their antibiotic uptake, elution, and activity along with film swelling ratio, ultimate tensile strength, Young’s modulus, adhesive strength, and degradation. Chitosan films after 1 min of rehydration were able in a simulated, clinical setting to maintain mechanical integrity and adhesive strength to be applied to bone fracture fixation devices or implant surfaces. The film percent degradation increased with DDA increasing from 61 to 80%, but film degradation rate decreased in the presence of antibiotics. Eighty percent DDA chitosan films were optimal for absorbing and eluting antibiotics. Antibiotics eluted by the films were active against Staphylococcus aureus. These findings indicate that an 80% DDA chitosan film is potentially advantageous as a clinically adjunctive treatment in musculoskeletal injuries to lessen or prevent infections.

e Using a rabbit model of postsurgical osteomyelitis, we demonstrate that incorporation of xylitol into polymethylmethacrylate (PMMA) bone cement enhances the elution of daptomycin under in vivo conditions. We also demonstrate that this can be correlated with an improved therapeutic outcome in the treatment of a chronic bone infection following surgical debridement.

Background Although bacterial antibiotic resistance is increasing, fewer new antibiotics are being developed to compensate. Localized delivery of synergistic antiseptics and antibiotics with a chitosan sponge device may offer an alternative infection treatment. Questions/purposes In this pilot study, we asked whether antiseptic and antibiotic combinations provided in vitro synergism against Staphylococcus aureus, whether synergism reduces cell viability, and whether their combination releases drugs at inhibitory levels. Methods To investigate the pharmacodynamics among three combinations of the antiseptic chlorhexidine digluconate (CHX) with the antibiotics amikacin, daptomycin, and vancomycin (VAN) (n = 1), we determined the fractional inhibitory concentration (FIC) index against S aureus Cowan I. The determined synergistic combination of CHX and VAN was evaluated for cell compatibility using NIH/3T3 fibroblasts (n = 3) and the drug release profile from a chitosan sponge device (n = 5). Results With an FIC index \ 0.5, the combination of CHX + VAN exhibited synergism against S aureus. CHX concentrations C 3.91 lg/mL resulted in fibroblast viability decrease, whereas the combination of CHX + VAN did not decrease fibroblast viability until their concentrations reached C 7.81 lg/mL. The CHX and VAN release profile, both individually and in combination, was an initial bolus with no difference between eluate concentrations after Day 5. Conclusions CHX + VAN combination may be delivered locally by a chitosan sponge that synergistically inhibits S aureus growth. Clinical Relevance The use of synergism between combined antibiotic and antiseptics delivered at high local concentrations with an implanted chitosan sponge may provide a useful alternative infection treatment option.

Background Local drug delivery has substantial potential to prevent infections compared with systemic delivery. Although calcium sulfate (CaSO 4 ) has been studied for local drug delivery and two types are commercially available, it is unknown whether they differentially release antibiotics. Questions/purposes We determined the differences between two sources of CaSO 4 and the K 2 SO 4 catalyst's presence on the degradation, daptomycin elution, and activity against Staphylococcus aureus. Methods We formed pellets from synthetic and naturally sourced (from gypsum) CaSO 4 and loaded with 5% daptomycin and 3% or 0% K 2 SO 4 . We used in vitro experiments to determine the daptomycin concentration and degradation profiles over 10 days. Turbidity assays were used to evaluate the activity of the daptomycin eluates against S. aureus.

Polymicrobial biofilm-associated implant infections present a challenging clinical problem. Through modifications of lyophilized chitosan sponges, degradable drug delivery devices for antibiotic solution have been fabricated for prevention and treatment of contaminated musculoskeletal wounds. Elution of amikacin, vancomycin, or a combination of both follows a burst release pattern with vancomycin released above minimum inhibitory concentration for Staphylococcus aureus for 72 h and amikacin released above inhibitory concentrations for Pseudomonas aeruginosa for 3 h. Delivery of a vancomycin, amikacin, or a combination of both reduces biofilm formation on polytetrafluoroethylene catheters in an in vivo model of contamination. Release of dual antibiotics from sponges is more effective at preventing biofilm formation than single-loaded chitosan sponges. Treatment of pre-formed biofilm with high-dose antibiotic release from chitosan sponges shows minimal reduction after 48 h. These results demonstrate infection-preventive efficacy for antibiotic-loaded sponges, as well as the need for modifications in the development of advanced materials to enhance treatment efficacy in removing established biofilm.

Chitosan sponges were developed for adjunctive local antibiotic delivery to reduce bacteria in wounds. There is a need to increase sponge degradation for rapid clearance from the wound site during initial wound care. This work examined the effect of using 0.25 M sodium acetate buffers, at pH 4.6 or 5.6, to fabricate sponges with an amorphous chitosan polymer structure. Sponges were evaluated for their crystallinity, thermal, spectroscopic, and morphological properties, in addition to in vitro degradation, and cytocompatibility analysis using normal human dermal fibroblasts. In vivo degradation and biocompatibility were also examined after 4 and 10 days in rat intramuscular tissues. Both buffered chitosan sponge variations exhibited decreases in crystallinity and thermal decomposition temperatures, and increases in surface roughness, which resulted in over 40% increases in degradation over 10 days in vitro compared to the neutral sponges. There were no significant differences between sponges during in vivo degradation over 10 days with respect to histomorphometric analysis of the recovered sponges. These results demonstrated that the acetate buffer did change characteristic chitosan sponge material properties, and increasing the in vivo sponge degradation rate will require balancing material characteristics and processing.

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