Periprosthetic infections are life-threatening complications that occur in about 6% of medical device insertions. Stringent sterile techniques have reduced the incidence of infections, but many implant patients are at high risk for infection, especially the elderly, diabetic, and immune compromised. Moreover, because of low vascularity at the site of the new implant, antibiotic prophylaxis is often not effective. To address this problem, we designed a covalent modification to titanium implant surfaces to render them bactericidal. Specifically, we aminopropylated titanium, a widely used implant material and extended a tether by solid phase coupling of ethylene glycol linkers, followed by solid phase coupling of vancomycin. Vancomycin covalently attached to titanium still bound soluble bacterial peptidoglycan, reduced Staphylococcus aureus colony-forming units by 88% +/- 16% over 2 hr, and retained antibacterial activity upon a repeated challenge.

Periprosthetic infection is a devastating consequence of implant insertion and can arise from hematogenous sources or surgical contamination. Microbes can preferentially colonize the implant surface and, by forming a biofilm, escape immune surveillance. We hypothesized that if an antibiotic can be tethered to a titanium alloy (Ti) surface, it will inhibit bacterial colonization, prevent biofilm formation, and avert late-stage infection. To test this hypothesis, a Ti rod was covalently derivatized with vancomycin. Reaction efficiencies were evaluated by colorimetric and spectrophotometric measurements. The vancomycin-modified surface was stable in aqueous solutions over extended time periods and maintained antibiotic coverage, even after pressfit insertion into a cadaverous rat femora. When evaluated using fluorescently labeled bacteria, or by direct colony counts, the surface-bound antibiotic prevented bacterial colonization in vitro after: (1) exposure to high levels of S. aureus; (2) extended incubation in physiological buffers; and (3) repeated bacterial challenges. Importantly, whereas the vancomycin-derivitized pins prevented bacterial colonization, S. aureus adhered to control pins, even in the presence of concentrations of vancomycin that exceeded the strain MIC. These results demonstrate that we have effectively engineered a stable, bactericidal Ti surface. This new surface holds great promise in terms of mitigating or preventing periprosthetic infection. ß

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Four isolates of Staphylococcus aureus from patients with endocarditis and bacteremia were capable of secreting high-molecular-weight soluble peptidoglycans when grown in a minimal cell wall medium containing penicillin G. Vancomycin was not able to substitute for penicillin G in triggering this secretion. Secretion reflected de novo synthesis of soluble peptidoglycan and was strongly dependent on time of incubation (30 to 60 min), and number of bacteria (2 x 108 to 5 x 108 colony-forming units per ml), but not on penicillin G concentration (10 to 250 ,ug/ml). The incorporation of alanine into the peptidoglycans secreted in vitro by these isolates incubated in the presence of penicillin G under optimal conditions was variable. The least incorporation of alanine into peptidoglycan occurred with an isolate from a patient treated with nafcillin who had no detectable antipeptidoglycan titer.