Infection is a major complication of implantable medical devices, which provide a scaffold for biofilm formation, thereby reducing susceptibility to antibiotics and complicating treatment. ...Hematogenous implant-related infections following bacteremia are particularly problematic because they can occur at any time in a previously stable implant. Herein, we developed a model of hematogenous infection in which an orthopedic titanium implant was surgically placed in the legs of mice followed 3 wk later by an i.v. exposure to Staphylococcus aureus. This procedure resulted in a marked propensity for a hematogenous implant-related infection comprised of septic arthritis, osteomyelitis, and biofilm formation on the implants in the surgical legs compared with sham-operated surgical legs without implant placement and with contralateral nonoperated normal legs. Neutralizing human monoclonal antibodies against α-toxin (AT) and clumping factor A (ClfA), especially in combination, inhibited biofilm formation in vitro and the hematogenous implant-related infection in vivo. Our findings suggest that AT and ClfA are pathogenic factors that could be therapeutically targeted against S. aureus hematogenous implant-related infections.
Abstract
Infection is a major impediment to the long-term success of implantable medical devices. Treatment of these infections is complicated by bacteria biofilms, which form on the implants and ...block penetration of immune cells and antibiotics. Hematogenous implant-related infections following a transient bacteremia are particularly problematic because they can occur at any time in a previously stable implant. To evaluate alternative targeted immune-based therapies against these infections, we developed a hematogenous infection model in which an orthopaedic titanium implant was surgically placed in the legs of mice followed by an intravenous injection of Staphylococcus aureus 21 days later. This resulted in a marked propensity for a hematogenous implant-related infection comprised of septic arthritis, osteomyelitis with neutrophil abscess formation in the bone and biofilm formation on the implants in the surgical legs compared with sham surgical legs without implant placement or contralateral nonsurgical normal legs. Prophylaxis with two neutralizing human monoclonal antibodies directed against S. aureus virulence factors, secreted alpha-toxin (AT) and surface expressed clumping factor A (ClfA) inhibited biofilm formation in vitro and the hematogenous implant-related infection in vivo. Our findings suggest that AT and ClfA are important pathogenic factors that could be targeted as a novel immunotherapeutic against S. aureus hematogenous implant-related infections.
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