Objective: Staphylococcal infections involving biofilms represent a significant challenge in the treatment of patients with device-related infections. Staphylococcus aureus biofilms have been shown to be SaeRS-regulated and dependent on coagulase-catalysed conversion of fibrinogen into fibrin on surfaces coated with human plasma. Here we investigated the treatment of staphylococcal biofilm device-related infections by digesting the fibrin biofilm matrix with and without existing antimicrobials.
Methods: The fibrinolytic agents plasmin, streptokinase, nattokinase and the recombinant trypsin-like protease TrypLE™ were used to digest and treat S. aureus biofilms grown in vitro using in vivo like static biofilm assays with and without antimicrobials. Cytotoxicity, potential to induce a cytokine response in whole human blood and risk of induction of tolerance to fibrinolytic agents were investigated. A rat model of intravascular catheter infection was established to investigate the efficacy of selected fibrinolytic agents in vivo.
Results: Under biomimetic conditions the fibrinolytic agents effectively dispersed established S. aureus biofilms and in combination with common anti-staphylococcal antimicrobials effectively killed bacterial cells being released from the biofilm. These fibrinolytic agents were not cytotoxic and did not affect host immune response. The rat model of infection successfully demonstrated the activity of the selected fibrinolytic agents alone and in combination with antimicrobials on established biofilm in vivo.
Conclusion: TrypLE™ and nattokinase most successfully removed adherent cells from plasma-coated surfaces and significantly improved the efficacy of existing antimicrobials against S. aureus biofilms in vitro and in vivo. These biofilm dispersal agents represent a viable future treatment option for S. aureus device-related infections.
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