Tissue Plasminogen Activator Coating on Implant Surfaces Reduces Staphylococcus aureus Biofilm Formation

Abstract

cStaphylococcus aureus biofilm infections of indwelling medical devices are a major medical challenge because of their high prevalence and antibiotic resistance. As fibrin plays an important role in S. aureus biofilm formation, we hypothesize that coating of the implant surface with fibrinolytic agents can be used as a new method of antibiofilm prophylaxis. The effect of tissue plasminogen activator (tPA) coating on S. aureus biofilm formation was tested with in vitro microplate biofilm assays and an in vivo mouse model of biofilm infection. tPA coating efficiently inhibited biofilm formation by various S. aureus strains. The effect was dependent on plasminogen activation by tPA, leading to subsequent local fibrin cleavage. A tPA coating on implant surfaces prevented both early adhesion and later biomass accumulation. Furthermore, tPA coating increased the susceptibility of biofilm infections to antibiotics. In vivo, significantly fewer bacteria were detected on the surfaces of implants coated with tPA than on control implants from mice treated with cloxacillin. Fibrinolytic coatings (e.g., with tPA) reduce S. aureus biofilm formation both in vitro and in vivo, suggesting a novel way to prevent bacterial biofilm infections of indwelling medical devices.

Untangling the Diverse and Redundant Mechanisms of Staphylococcus aureus Biofilm Formation

“…Fibrin-mediated biofilms can be eradicated by plasmin and other fibrinolytic enzymes such as nattokinase or serrapeptase [ 20 ]. Kwiecisnki et al demonstrated that increasing levels of staphylokinase, which activates plasminogen, inhibited biofilm in a mouse catheter infection model [ 32 ], whereas pre-coating catheter surfaces with tissue plasminogen activator also inhibited adhesion and biomass accumulation in the same in vivo model [ 33 ]. The drug dabigatran (a pharmacological inhibitor of both staphylothrombin and thrombin) inhibited fibrin-mediated biofilm by blocking the interaction between Coa/vWbp and prothrombin both in vitro and in a murine central venous catheter model [ 23 ].…”

Streptokinase Treatment Reverses Biofilm-Associated Antibiotic Resistance in Staphylococcus aureus

“…This was shown by preventing S. aureus -mediated coagulation by adding a thrombin inhibitor to jugular vein catheters in mice [ 34 ], or by adding human plasminogen to a staphylokinase-overexpressing S. aureus strain, which led to fibrin dissolution as a result of staphylokinase-mediated activation of plasminogen [ 20 ]. Biofilm formation was also reduced by coating implant surfaces with the human tissue plasminogen activator (tPA), and the biofilms that did form were more susceptible to antibiotics [ 35 ]. These are encouraging results for the possibility of preventing biofilm formation to avoid acute infections on new implants.…”

Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection

“…In terms of S. aureus biofilm infection, some models utilize a large infectious inoculum or introduce implants that are precoated with bacteria (30)(31)(32)(33)(34)(35)(36). A high-challenge dose, particularly in a confined space such as the joint/bone, would be predicted to elicit a vigorous proinflammatory cascade that could likely alter the course of the resultant immune response and bacterial survival.…”