Abstract
Biofilms formed by Staphylococcus aureus is a serious complication to the use of medical implants. A central part of the pathogenesis relies on S. aureus’ ability to adhere to host extracellular matrix proteins, which adsorb to medical implants and stimulate biofilm formation. Being coagulase positive, S. aureus furthermore induces formation of fibrin fibers from fibrinogen in the blood. Consequently, we hypothesized that fibrin is a key component of the extracellular matrix of S. aureus biofilms under in vivo conditions, and that the recalcitrance of biofilm infections can be overcome by combining antibiotic treatment with a fibrinolytic drug. We quantified S. aureus USA300 biofilms grown on peg-lids in brain heart infusion (BHI) broth with 0%–50% human plasma. Young (2 h) and mature (24 h) biofilms were then treated with streptokinase to determine if this lead to dispersal. Then, the minimal biofilm eradication concentration (MBEC) of 24 h old biofilms was measured for vancomycin and daptomycin alone or in combination with 10 µg/mL rifampicin in the presence or absence of streptokinase in the antibiotic treatment step. Finally, biofilms were visualized by confocal laser scanning microscopy. Addition of human plasma stimulated biofilm formation in BHI in a dose-dependent manner, and biofilms could be partially dispersed by streptokinase. The biofilms could be eradicated with physiologically relevant concentrations of streptokinase in combination with rifampicin and vancomycin or daptomycin, which are commonly used antibiotics for treatment of S. aureus infections. Fibronolytic drugs have been used to treat thromboembolic events for decades, and our findings suggest that their use against biofilm infections has the potential to improve the efficacy of antibiotics in treatment of S. aureus biofilm infections.
Highlights
A key aspect of pathogenesis by Staphylococcus aureus is the formation of biofilms [1] by interacting with mammalian extracellular matrix (ECM) molecules on ECM-covered surfaces in the body [2,3]
S. aureus biofilm infections are often localized to bones, soft tissues, heart valves [12,13,14], or implants which are quickly covered with ECM molecules following implantation [15,16,17]
This recalcitrance to antibiotic treatment is due to a combination of several factors, including the reduced penetration and lower diffusion coefficient of many antibiotics in the biofilm, which has been demonstrated for S. aureus biofilms with, for example, vancomycin, oxacillin, and cefotaxime [28,29]
Summary
A key aspect of pathogenesis by Staphylococcus aureus is the formation of biofilms [1] by interacting with mammalian extracellular matrix (ECM) molecules on ECM-covered surfaces in the body [2,3]. The antibiotic dosage required for eradication of a mature S. aureus biofilms in vitro are in the range of 256–2048 mg/L for vancomycin, daptomycin, and other relevant anti-staphylococcal drugs, which far exceeds the concentration that can be achieved in vivo [25,27] This recalcitrance to antibiotic treatment is due to a combination of several factors, including the reduced penetration and lower diffusion coefficient of many antibiotics in the biofilm, which has been demonstrated for S. aureus biofilms with, for example, vancomycin, oxacillin, and cefotaxime [28,29]. Confocal laser scanning microscopy visualized the biofilm architecture and viability
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