Infective endocarditis is a challenging disease with a high mortality and morbidity rate. Antibiotic prophylaxis is currently recommended in high-risk infective endocarditis patients. However, the use of antibiotics faces the challenge of a low efficacy and contributes further to the emerging infection rate by antibiotic-resistant strains, emphasizing the need for new therapeutic strategies. Platelets are essential in the initial phase of infective endocarditis, acting as first-line immune responders. During the first phase of disease, bacteria can interact with platelets and counteract platelet antimicrobial activities. Mechanistic in vitro and animal studies on the effect of aspirin on bacteria-platelet interactions and the prevention of vegetation development showed promising results. However, data from clinical studies on the outcome of infective endocarditis patients who were receiving medically indicated aspirin therapy remain controversial. Therefore, the benefit of antiplatelet agents in infective endocarditis prevention has been questioned. Besides aspirin, it has been discovered that the platelet P2Y12 receptor antagonist ticagrelor has antibacterial properties in addition to its potent antiplatelet activity. Furthermore, a recent study in mice and a case report remarkably indicated the ability of this drug to eradicate Staphylococcus aureus bacteremia. This review will focus on current knowledge on antibacterial activity of ticagrelor, compared to aspirin, pointing out main unanswered questions. The goal is to provide food for thought as to whether a prior ticagrelor therapy might be beneficial for the prevention of infective endocarditis.
Background: Pulmonary valve replacement is performed with excellent resultant hemodynamics in patients that have underlying congenital or acquired heart valve defects.Despite recent advancements in right ventricular outflow tract reconstruction, an increased risk of developing infective endocarditis remains, which has a more common occurrence for conduits of bovine jugular vein origin compared to cryopreserved homografts. The reason for this is unclear albeit it is hypothesized to be associated with an aberrant phenotypic state of cells that reendothelialize the graft tissue post implantation. The aim of this study was to develop an in vitro model that enables the analysis of endothelial cell attachment to cardiac graft tissues under flow.Experiment: Endothelial cell attachment was optimized on bovine pericardium patch using HUVECs. Different biological coatings, namely gelatin, fibronectin, plasma or a combination of fibronectin and plasma were tested. After cell adaptation, graft tissues were exposed to laminar flow in a parallel-plate flow chamber. Cell retention to the tissue was analyzed after nuclear staining with YO-PRO-1 and a membranous localization of VE-cadherin.Results: Combined coating with fibronectin and blood plasma together with a two-phased shear pattern resulted in a relevant cell monolayer on bovine pericardium patch and cryopreserved homograft. For bovine jugular vein tissue, no adherent cells under both static and shear conditions were initially observed. Conclusion:Having established the new flow chamber system we could obtain endothelial cell layers on the surface of bovine pericardium patch and cryopreserved pulmonary homograft tissues. The presented in vitro system can serve as a competent model to study cell phenotypes on cardiac grafts in the close-to-physiologic environment. Moreover, this approach allows broad applications and enables further development by testing more complex conditions.
Daptomycin is a last-resort antibiotic used for the treatment of infections caused by Gram-positive antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Treatment failure is commonly linked to accumulation of point mutations; however, the contribution of single mutations to resistance and the mechanisms underlying resistance remain incompletely understood. Here, we show that a single nucleotide polymorphism (SNP) selected during daptomycin therapy inactivates the highly conserved ClpP protease and is causing reduced susceptibility of MRSA to daptomycin, vancomycin, and β-lactam antibiotics as well as decreased expression of virulence factors.
Objective: Infective endocarditis remains a severe complication associated with a high morbidity and mortality in patients after heart valve replacement. Exploration of the pathogenesis is of high demand and we, therefore, present a competent model that allows studying bacterial adherence and the role of plasma fibrinogen in this process using a new in-house designed low-volume flow chamber. Three cardiac graft tissues used for pulmonary valve replacement have been tested under shear conditions to investigate the impact of surface composition on the adhesion events. Methods: Tissue pieces of cryopreserved homograft (non-decellularised), decellularised homograft and bovine pericardium patch were investigated for fibrinogen binding. Adherence of Staphylococcus aureus to these graft tissues was studied quantitatively under flow conditions in our newly fabricated chamber based on a parallel plates’ modality. The method of counting colony-forming units was reliable and reproducible to assess the propensity of different graft materials for bacterial attachment under shear. Results: Bacterial perfusions over all plasma-precoated tissues identified cryopreserved homograft with the lowest affinity for S. aureus compared to decellularised homograft presenting a significantly higher bacterial adhesion (p < 0.05), which was linked to a more avid fibrinogen binding (p < 0.01). Bovine pericardial patch, as a reference tissue in this study, was confirmed to be the most susceptible tissue graft for the bacterial adhesion, which was in line with our previous work. Conclusion: The two studied homograft tissues showed different levels of bacterial attachment, which might be postulated by the involvement of fibrinogen in the adhesion mechanism(s) shown previously for bovine tissues.
Daptomycin is a last-resort antibiotic used for treatment of infections caused by Gram-positive antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). Treatment failure is commonly linked to accumulation of point mutations, however, the contribution of single mutations to resistance and the mechanisms underlying resistance remain incompletely understood. Here we show that a single nucleotide polymorphism (SNP) selected during daptomycin therapy inactivates the highly conserved ClpP protease and is causing reduced susceptibility of MRSA to daptomycin, vancomycin, and β-lactam antibiotics as well as decreased expression of virulence factors. Super-resolution microscopy demonstrated that the improved survival of the clpP mutant strain during daptomycin treatment was associated with reduced binding of daptomycin to the septal site and diminished membrane damage. In both the parental strain and the clpP strain, daptomycin inhibited the inward progression of septum synthesis eventually leading to lysis and death of the parental strain while surviving clpP cells were able to continue synthesis of the peripheral cell wall in the presence of 10 × MIC daptomycin resulting in a rod-shaped morphology. To our knowledge, this is the first demonstration that synthesis of the outer cell wall continues in the presence of daptomycin. Collectively, our data provide novel insight into the mechanisms behind bacterial killing and resistance to this important antibiotic. Also, the study emphasizes that treatment with last-line antibiotics is selective for mutations that, like the SNP in clpP, favor antibiotic resistance over virulence gene expression.
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