Daptomycin is a new antibiotic active against many resistant Gram-positive organisms and seems an appropriate candidate for local delivery for severe musculoskeletal infections. Calcium sulfate dihydrate as a delivery vehicle is readily resorbable, allows new bone formation, and can be combined with therapeutic agents. We compared the elution of daptomycin and tobramycin in calcium sulfate pellets over time and determined the dissolution rates of the pellets. Unlike other water-soluble antibiotics, daptomycin required special techniques to convert the calcium sulfate from a hemihydrate powder to a hardened dihydrate shape. The elution of daptomycin on day 1 (537 microg/mL/g) was greater than that from days 2, 3, 7, 10, 14, 21, and 28. The concentration fell to 153 microg/mL/g and 37 microg/mL/g on days 2 and 3, respectively, then remained at between 5 microg/mL/g and 7 microg/mL/g for the remainder of the study. The elution behavior of the daptomycin pellets differed from that of the tobramycin-containing pellets on days 1 through 3, but was similar from day 7 through day 28. Daptomycin-containing pellets dissolved more rapidly in vitro than tobramycin-containing pellets, although the importance of this more rapid dissolution in an in vivo situation is unknown. Using the techniques described in this paper, daptomycin can be incorporated within a calcium sulfate matrix.

Osteoinductive of demineralized bone matrix has been attributed to bone morphogenetic proteins (BMP). Other growth factors, including insulin-like growth factor-l (ICF-I) and transforming growth factor-ß1 (TGFßl), have also been detected in demineralized bone matrix. Success of bone graft substitutes containing demineralized bone matrix has been assumed to be closely associated with osteoinductivity of the demineralized bone matrix. Because of differences in bone characteristics between donors and tissue banks, confirmation and measurement of osteoinductivity may play a crucial role in predicting the success of the bone graft substitute. In the current studies, BMP-2, BMP-4, TGFβ1, and IGF-I were measured in demineralized bone matrix. A strong association was noted between BMP-2 and TGF-β1 levels. A strong association was also found between BMP-2 and new bone formation in an ectopic nude rat model.

We used a goat model of a contaminated musculoskeletal defect to determine the effectiveness of rapidly-resorbing calcium-sulphate pellets containing amikacin to reduce the local bacterial count. Our findings showed that this treatment eradicated the bacteria quickly, performed as well as standard polymethylmethacrylate mixed with an antibiotic and had many advantages over the latter. The pellets were prepared before surgery and absorbed completely. They released all of the antibiotic and did not require a subsequent operation for their removal. Our study indicated that locally administered antibiotics reduced bacteria within the wound rapidly. This method of treatment may have an important role in decreasing the rate of infection in contaminated wounds.

Despite the continuing advances in treatment of open fractures and musculoskeletal wounds, infection remains a serious complication. Current treatments to prevent infection utilize surgical debridement and irrigation, and high doses of systemic antimicrobial therapy. The aim of this work was to evaluate, in vitro, the potential of a fast-resorbing calcium sulfate pellet loaded with an antibiotic. The pellet could be used as an adjunctive therapy at the time of debridement and irrigation to reduce bacterial wound contamination. Small pellets containing a binder and calcium sulfate were engineered to resorb rapidly (within 24 h) and deliver high local doses of antibiotic (amikacin, gentamicin, or vancomycin) to the wound site while minimizing systemic effects. Results from dissolution, elution, and biological activity tests against P. aeruginosa and S. aureus were used to compare the performance of antibiotic-loaded, rapidly resorbing calcium sulfate pellets to antibiotic-loaded crushed conventional calcium sulfate pellets. Antibiotic-loaded rapidly resorbing pellets dissolved in vitro in deionized water in 12-16 h and released therapeutic antibiotic levels in phosphate buffered saline that were above the minimal inhibitory concentration for P. aeruginosa and S. aureus, completely inhibiting the growth of these bacteria for the life of the pellet. Crushed conventional calcium sulfate pellets dissolved over 4-6 days, but the eluates only contained sufficient antibiotic to inhibit growth for the first 4 h. These data indicate that fast-resorbing pellets can release antibiotics rapidly and at therapeutic levels. Adjunctive therapy with fast-acting pellets is promising and warrants further in vivo studies. ß