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The current clinical standard for local antibiotic depot is polymethylmethacrylate (PMMA) beads. Unfortunately, these are not ideal and negative pressure wound therapy (NPWT) reduces their limited effectiveness. Recently, a chitosan sponge has been shown to be an effective carrier of antibiotics. Because it acts as a delivery vehicle with increased wound contact area instead of an antibiotic depot, it may be more effective. The objectives of this study were to determine if (1) a chitosan sponge would be more effective than PMMA beads as a local antibiotic delivery device and (2) the chitosan sponge remains an effective method of delivery when used in conjunction with NPWT.Contaminated musculoskeletal wounds were created on the proximal tibia of goats; the animals were assigned to 1 of 4 groups (bead pouch, beads with NPWT, sponge pouch, and sponge with NPWT). The animals were survived for 48 hours, and the bacteria in the wound were quantified. The antibiotic levels in the blood and within the NPWT canisters were measured throughout the study period.After treatment, there were significantly fewer bacteria in wounds treated with antibiotic chitosan sponge delivery than antibiotic PMMA bead depot (P < 0.05), and NPWT did not reduce the effectiveness of the chitosan sponge even though large amounts of vancomycin was found in the canisters. The peak serum levels of vancomycin were well below what is considered safe levels.Antibiotic delivery to the wound using a chitosan sponge is compatible with NPWT and is more effective than PMMA antibiotic depot. The chitosan sponge works in conjunction with NPWT and may improve the outcomes of open fracture wounds.