Streptokinase Treatment Reverses Biofilm-Associated Antibiotic Resistance in Staphylococcus aureus

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.

Intrapleural Fibrinolytic Therapy for Empyema and Pleural Loculation: Knowns and Unknowns

“…Fibrinolysins can degrade cross-linked fibrin and decrease viscosity of purulent fluids, which uPA has been reported to efficiently do (15). Biofilms produced by infectious organisms incorporate fibrin as well as DNA, and expedited degradation by fibrinolysins supplementing antibiotics has also been reported (16). It is also plausible that activity of intrapleural tPA is affected when combined with DNase, because the size and quality of DNA fragments can alter tPA activity or that of uPA (17).…”

Tranexamic acid decreases the risk of revision for acute and delayed periprosthetic joint infection after total knee replacement

“…In an experimental animal study, Kwiecinski et al [19] found that precoating of the surface of indwelling medical devices with plasminogen activators resulted in less fibrin deposition on the implant surface which reduced the attachment of free-floating bacteria with subsequent biofilm formation. Similarly, Jørgensen et al [20] and Hogan et al [21] detected that biofilm dispersal fibrinolytic agents increase the penetration and effect of antibiotics in biofilm-related infections. Since TA has an anti-fibrinolytic effect, in the context of previously mentioned studies, TA administration should be associated with a higher risk of biofilm formation and subsequent acute and delayed PJI.…”

New developments and future challenges in prevention, diagnosis, and treatment of prosthetic joint infection

“…Converting biofilm bacteria to their planktonic form may increase bacterial cell susceptibility to commonly used systemic antibiotics. Some examples that target the matrix components of biofilm include enzymatic treatments such as trypsin, dispersin B, lysostaphin, and DNases 142–144 . Additionally, fibrinolytics like streptokinase or nattokinase break down the fibrin matrix within biofilm and decrease the MBEC of available systemic antibiotics 143,144 .…”

“…Another strategy for triggering biofilm dispersal includes targeting the quorum sensing system. For example, treatment in vitro with autoinducing peptide type I, a critical component of the quorum sensing system, was able to trigger dispersal of MRSA on titanium discs 144 . RNAIII‐inhibiting peptide (RIP) is another peptide that targets the quorum sensing system in S. aureus by competing with RNAIII‐activating peptide which results in decreased cell adhesion and agr activation and has been investigated to reduce S. aureus adhesion to foreign materials 145 .…”

“…One major concern about dispersal agents is that planktonic bacteria cells disassembled from their biofilms may be capable of exacerbating systemic infection. Therefore, dispersal agents must be used in combination with systemic therapies such as antibiotics 143,144,152 . These treatments remain in the preclinical stages in the treatment of musculoskeletal infection.…”