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Proposed scenario of interaction between the host and pathogens in infective endocarditis (IE). The formation of valve vegetations is induced by the damaged and infected endothelium. Platelets aggregate to the injured endothelial cells followed by accumulation of innate immune cells and upregulation of tissue factor, fibrinogen, fibrin, and cytokines. O2 consumption in the valve vegetations (biofilm) and by the activated neutrophils may prevent appropriate O2 in the tissue. Increased IL-8, interaction between activated platelets and neutrophils trigger the formation of neutrophil extracellular traps (NETs). Many bacteria exhibit virulence mechanisms to survive the NET formation. Deep-seated bacteria are less metabolically active, consequently reducing the efficacy of oxygen-dependent antibiotics. In the local tissue of the valve vegetations, key inflammatory markers of progression are elevated, for example, G-CSF, IL-1β, IL-6, IL-8 (analog to KC in rodents), IL-17, IFN-γ, and VEGF (Moser et al., 2017) (with permission from the editor of APMIS and authors).
Source publication
Infective endocarditis (IE) is a life-threatening infective disease with increasing incidence worldwide. From early on, in the antibiotic era, it was recognized that high-dose and long-term antibiotic therapy was correlated to improved outcome. In addition, for several of the common microbial IE etiologies, the use of combination antibiotic therapy...
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Citations
... Given the above, the question that arises is whether it would be necessary to explore new strategies for the treatment of Enterococcus spp. IE in patients with prosthetic valves and when surgery is not indicated, such as antibiofilm treatments (51,52), or to consider the RelA-alarmone system as a new potential target for new treatment development. ...
Infective endocarditis (IE) caused by Enterococcus spp. represents the third most common cause of IE, with high rates of relapse compared with other bacteria. Interestingly, late relapses (>6 months) have only been described in Enterococcus faecalis, but here we describe the first reported IE relapse with Enterococcus faecium more than a year (17 months) after the initial endocarditis episode. Firstly, by multi locus sequence typing (MLST), we demonstrated that both isolates (EF646 and EF641) belong to the same sequence type (ST117). Considering that EF641 was able to overcome starvation and antibiotic treatment conditions surviving for a long period of time, we performed bioinformatic analysis in identifying potential genes involved in virulence and stringent response. Our results showed a 13-nucleotide duplication (positions 1638–1650) in the gene relA, resulting in a premature stop codon, with a loss of 167 amino acids from the C-terminal domains of the RelA enzyme. RelA mediates the stringent response in bacteria, modulating levels of the alarmone guanosine tetraphosphate (ppGpp). The relA mutant (EF641) was associated with lower growth capacity, the presence of small colony variants, and higher capacity to produce biofilms (compared with the strain EF646), but without differences in antimicrobial susceptibility patterns according to standard procedures during planktonic growth. Instead, EF641 demonstrated tolerance to high doses of teicoplanin when growing in a biofilm. We conclude that all these events would be closely related to the long-term survival of the E. faecium and the late relapse of the IE. These data represent the first clinical evidence of mutations in the stringent response (relA gene) related with E. faecium IE relapse.
... We performed ceftriaxone time-kill curves with two different inocula to test this idea. A 10 5 CFU/mL inoculum, typical of a urinary tract infection and higher than most blood stream infection (24,25), and a 10 8 CFU/mL inoculum that replicates the high local concentration of bacteria that might occur on a prosthetic device or in a heart valve vegetation (26) were tested. We used experimen tal ceftriaxone concentrations of 10 µg/mL and 100 µg/mL that are well above the MICs of both organisms, and would approximate achievable in vivo trough and peak concentrations, respectively (23). ...
The chromosomally encoded AmpC beta-lactamase is widely distributed throughout the Enterobacterales. When expressed at high levels through transient induction or stable de-repression, resistance to ceftriaxone, a commonly used antibiotic, can develop. Recent clinical guidance suggests, based on limited evidence, that resistance may be less likely to develop in Serratia marcescens compared to the better-studied Enterobacter cloacae and recommends that ceftriaxone may be used if the clinical isolate tests susceptible. We sought to generate additional data relevant to this recommendation. AmpC de-repression occurs predominantly because of mutation in the ampD peptidoglycan amidohydrolase. We find that, in contrast to E. cloacae , where deletion of ampD results in high-level ceftriaxone resistance (with ceftriaxone MIC = 96 µg/mL), in S. marcescens deletion of two amidohydrolases ( ampD and amiD2 ) is necessary for AmpC de-repression, and the resulting ceftriaxone MIC is 1 µg/mL. Two mechanisms for this difference were identified. We find both a higher relative increase in ampC transcript level in E. cloacae Δ ampD compared to S. marcescens ΔampDΔamiD2 , as well as higher in vivo efficiency of ceftriaxone hydrolysis by the E. cloacae AmpC enzyme compared to the S. marcescens AmpC enzyme. We also observed higher relative levels of transient AmpC induction in E. cloacae vs S. marcescens when exposed to ceftriaxone. In time-kill curves, this difference translates into the survival of E. cloacae but not S. marcescens at clinically relevant ceftriaxone concentrations. In summary, our findings can explain the decreased propensity for on-treatment ceftriaxone resistance development in S. marcescens , thereby supporting recently issued clinical guidance.
... S. aureus has the ability to form biofilms on medical devices, mostly on heart implants, catheters and prosthetics which made the bacteria most notorious [2,3]. A recent report showed that staphylococcal biofilm gives rise to life-threatening infectious diseases such as infective endocarditis, defined as a heart infection that can be found on implanted cardiac devices [4]. Biofilm formation offers bacteria to tolerate harsh environments and an advanced defence system against antimicrobial agents, thereby limiting treatment opportunities [5,6]. ...
Staphylococcus aureus is a highly infectious pathogen that represents a significant burden on the current health-care system. Bacterial attachment to medical implants and host tissue, and the establishment of a mature biofilm, play an important role in chronic diseases such as endocarditis, osteomyelitis and wound infections. These biofilms decrease bacterial susceptibility to antibiotics and immune defences, making the infections challenging to treatment. S. aureus produces numerous exotoxins that contribute to the pathogenesis of the bacteria. In this study, we have identified a novel function of staphylococcal superantigen-like protein 10 (SSL10) in enhancing the formation of staphylococcal biofilms. Biofilm biomass is significantly increased when SSL10 is added exogenously to bacterial cultures, whereas SSL2 and SSL12 are found to be less active. Exogenously added SSL10 mask the surface charge of the bacterial cells and lowers their zeta potential, leading to the aggregation of the cells. Moreover, the biofilm formation by SSL10 is governed by amyloid aggregation, as evident from spectroscopic and microscopic studies. These findings thereby give the first overview of the SSL-mediated amyloid-based biofilm formation and further drive the future research in identifying potential molecules for developing new antibacterial therapies against Staphylococcus aureus.
... Infections resulting from pathogenic bacteria have become one of the main causes of human morbidity and death. It is reported that up to 1 million people fall ill or die from biofilm infections each year, and more than 60% of human pathogenic infections and 80% of chronic diseases are attributed to biofilm [1,2], such as chronic tonsillitis [3], otitis media [4], cystic fibrosis and endocarditis [5,6]. About 40-80% of bacteria in nature can form a biofilm [7], which is a microbial community formed by bacteria or fungi adsorbed on the surface of tissues or materials and wrapped in extracellular polymeric substances (EPS) such as polysaccharides, proteins and nucleic acids. ...
... The eradication rate of S. aureus biofilm was 99%. NO/PDT/PTT [53] ICG&CO@G3KBPY ICG, CO precursor MnBr(CO) 5 and nanogel G3KBPY. ...
A biofilm is a microbial community formed by bacteria that adsorb on the surface of tissues or materials and is wrapped in extracellular polymeric substances (EPS) such as polysaccharides, proteins and nucleic acids. As a protective barrier, the EPS can not only prevent the penetration of antibiotics and other antibacterial agents into the biofilm, but also protect the bacteria in the biofilm from the attacks of the human immune system, making it difficult to eradicate biofilm-related infections and posing a serious threat to public health. Therefore, there is an urgent need to develop new and efficient antibiofilm drugs. Although natural enzymes (lysozyme, peroxidase, etc.) and antimicrobial peptides have excellent bactericidal activity, their low stability in the physiological environment and poor permeability in biofilms limit their application in antibiofilms. With the development of materials science, more and more nanomaterials are being designed to be utilized for antimicrobial and antibiofilm applications. Nanomaterials have great application prospects in antibiofilm because of their good biocompati-bility, unique physical and chemical properties, adjustable nanostructure, high permeability and non-proneness to induce bacterial resistance. In this review, with the application of composite nanomaterials in antibiofilms as the theme, we summarize the research progress of three types of composite nanomaterials, including organic composite materials, inorganic materials and organic–inorganic hybrid materials, used as antibiofilms with non-phototherapy and phototherapy modes of action. At the same time, the challenges and development directions of these composite nanomaterials in antibiofilm therapy are also discussed. It is expected we will provide new ideas for the design of safe and efficient antibiofilm materials.
... Several novel approaches have been described in pre-clinical models to tackle the problem of biofilm formation in infective endocarditis. These include non-antibiotic strategies such as the administration of anti-thrombotic agents, hyperbaric oxygen therapy, and agents which potentially disrupt the gene regulation of bacteria during biofilm formation [45]. The use of novel extra-cellular matrix patches for mitral valve as well as tricuspid valve reconstruction has also been reported [46,47]. ...
Infective endocarditis carries a heavy disease burden with a high in-patient mortality. Surgery is the mainstay of treatment in 50% of patients diagnosed with infective endocarditis. Surgery for infective endocarditis can be challenging; a detailed understanding of surgical anatomy is essential and several fundamental principles need to be taken into consideration including optimal timing, radical debridement, decision to repair versus replace as well as the optimal choice for reconstruction. Outcomes of surgery depend on several factors including patient characteristics, the valve (s) involved, the virulence of the organism, and the extent of invasion of the infective process. Despite recent advances in treatment and improved outcomes, there remains areas for potential research including the ideal valve prosthesis/substitute and the optimal material for reconstruction. In this chapter, we will discuss the technical challenges and pitfalls in the surgical treatment of infective endocarditis, the predictors of outcome as well as novel strategies in treatment.
... This leads to the activation of endothelial cells, the release of cytokines, and other inflammatory markers, eventually forming biofilm. [1][2][3] The incidence of IE has been increasing with time, reaching more than 1 million, with 66,320 deaths in 2019 and 12.7 hospitalizations per 100,000 in the United States alone. 4,5 Additionally, IE is associated with excessive length of stay, increased cost of hospitalization, and mortality in 14.5% of admitted patients in the United States. ...
Infective endocarditis is a complex heterogeneous condition involving the infection of the endocardium and heart valves, leading to severe complications, including death. Surgery is often indicated in patients with infective endocarditis but is associated with elevated risk compared with other forms of cardiac surgery. Risk models play an important role in many cardiac surgeries as they can help inform clinicians and patients regarding procedural risk, decision-making to proceed or not, and influence perioperative management; however, they remain under-utilized in the infective endocarditis settings. Another crucial role of such risk models is to assess predicted versus found mortality, thereby allowing an assessment of institutional performance in infective endocarditis surgery. Traditionally, general cardiac surgery risk models such as European System for Cardiac Operative Risk Evaluation (EuroSCORE), EuroSCORE II, and Society of Thoracic Surgeon's score have been applied to endocarditis surgery. However, there has been the development of many endocarditis surgery-specific scores over the last decade. This review aims to discuss clinical characteristics and applications of all contemporary risk scores in the setting of surgical treatment of infective endocarditis.
... Inhibition of SCG-induced fibrin formation by neutralizing antibodies in murine septic models also improved survival rates (43). Targeting infective endocarditis in in vivo animal models, adjunctive dabigatran therapy has indeed reduced valve vegetation size, bacterial load in aortic valves, and proinflammatory markers, which supports the latest anti-biofilm approach to improve the outcome in S. aureus infections (44,45). ...
Background
Staphylocoagulase (SCG) is a virulence factor of Staphylococcus aureus, one of the most lethal pathogens of our times. The complex of SCG with prothrombin (SCG/ProT) can clot fibrinogen, and SCG/ProT-induced fibrin and plasma clots have been described to show decreased mechanical and lytic resistance, which may contribute to septic emboli from infected cardiac vegetations. At infection sites, neutrophils can release DNA and histones, as parts of neutrophil extracellular traps (NETs), which in turn favor thrombosis, inhibit fibrinolysis and strengthen clot structure.
Objectives
To characterize the combined effects of major NET-components (DNA, histone H1 and H3) on SCG/ProT-induced clot structure, mechanical and lytic stability.
Methods
Recombinant SCG was used to clot purified fibrinogen and plasma. The kinetics of formation and lysis of fibrin and plasma clots containing H1 or core histones+/-DNA were followed by turbidimetry. Fibrin structure and mechanical stability were characterized with scanning electron microscopy, pressure-driven permeation, and oscillation rheometry.
Results
Histones and DNA favored the formation of thicker fibrin fibers and a more heterogeneous clot structure including high porosity with H1 histone, whereas low porosity with core histones and DNA. As opposed to previous observations with thrombin-induced clots, SCG/ProT-induced fibrin was not mechanically stabilized by histones. Similarly to thrombin-induced clots, the DNA-histone complexes prolonged fibrinolysis with tissue-type plasminogen activator (up to 2-fold). The anti-fibrinolytic effect of the DNA and DNA-H3 complex was observed in plasma clots too. Heparin (low molecular weight) accelerated the lysis of SCG/ProT-clots from plasma, even if DNA and histones were also present.
Conclusions
In the interplay of NETs and fibrin formed by SCG, DNA and histones promote structural heterogeneity in the clots, and fail to stabilize them against mechanical stress. The DNA-histone complexes render the SCG-fibrin more resistant to lysis and thereby less prone to embolization.
... Infective endocarditis is a life-threatening cardiovascular infection occurring on the endocardium, artificial valves, artificial implanted devices, and on the inner surface of the heart [107]. Cases of infective endocarditis have been on the rise in the past 3 decades, from 478,000 cases in 1990 to 1,090,530 cases in 2019, with about 25% mortality [108]. ...
Abstract: Biofilms are complex communities of microorganisms that grow on surfaces and are embedded in a matrix of extracellular polymeric substances. These are prevalent in various natural and man-made environments, ranging from industrial settings to medical devices, where they can have both positive and negative impacts. This review explores the diverse applications of microbial biofilms, their clinical consequences, and alternative therapies targeting these resilient structures. We have discussed beneficial applications of microbial biofilms, including their role in wastewater treatment, bioremediation, food industries, agriculture, and biotechnology. Additionally, we have highlighted the mechanisms of biofilm formation and clinical consequences of biofilms in the context of human health. We have also focused on the association of biofilms with antibiotic resistance, chronic infections, and medical device-related infections. To overcome these challenges, alternative therapeutic strategies are explored. The review examines the potential of various antimicrobial agents, such as antimicrobial peptides, quorum-sensing inhibitors, phytoextracts, and nanoparticles, in targeting biofilms. Furthermore, we highlight the future directions for research in this area and the potential of phytotherapy for the prevention and treatment of biofilm-related infections in clinical settings.
... 23 The most common bacterial genera responsible for the disease is Staphylococcus aureus and coagulase-negative staphylococci (CoNS), followed by viridans streptococci (i.e., Streptococcus mutans, S. sanguis, S. sanguinis, S. mitis, S. salivarius, and S. bovis. 24 Presence of vancomycin resistant Staphylococci has been established in a 70-year world IE patient in Korea. 25 Generally, S. aureus colonizes on native heart valves whereas CoNS colonizes on implants. ...
Biofilm is defined as a community of microorganisms that are adhered to living or non-living solid surfaces and embedded in a common, self-made matrix, comprising of exopolysaccharide material. The role of biofilm in chronic diseases deserves special importance as these extracellular polymeric materials developed with quorum sensing support both the primary criteria of infection development namely adhesion and colonisation. Due to their structural and physiological changes, microorganisms present in the biofilm are difficult to treat or eradicate. The presence of a protective layer of extracellular polymers, changes in metabolic activity or a high rate of mutation make them tolerant or resistant to conventional treatment. The persistence of pathogenic microorganisms mostly renders biofilm to be associated with several acute and chronic infections and various nosocomial or healthcare-related infections. Furthermore, cancer development may also result due to biofilm formation. Biofilm may contribute to inflammation. This study deals with molecular aspects of biofilm formation and its role in different disease formations.
... The most probable cause of the increasing prevalence of IE is the growing population of elderly, high-risk, multi-morbid patients who receive implantable devices containing artificial materials posing a risk for IE, e.g., vascular catheters, grafts, prosthetic heart valves, occluders, cardiac implantable electronic devices (CDIEs) and left ventricle assist devices (LVADs). The predominant IE etiology is Staphylococcus aureus on native heart valves and coagulase-negative staphylococci on artificial implants, followed by viridans streptococci [52,53]. ...
Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. For developing new therapies, a better understanding of the underlying pathology is required. Historically, such insights have been primarily derived from pathological studies. In the 21st century, thanks to the advent of cardiovascular positron emission tomography (PET), which depicts the presence and activity of pathophysiological processes, it is now feasible to assess disease activity in vivo. By targeting distinct biological pathways, PET elucidates the activity of the processes which drive disease progression, adverse outcomes or, on the contrary, those that can be considered as a healing response. Given the insights provided by PET, this non-invasive imaging technology lends itself to the development of new therapies, providing a hope for the emergence of strategies that could have a profound impact on patient outcomes. In this narrative review, we discuss recent advances in cardiovascular PET imaging which have greatly advanced our understanding of atherosclerosis, ischemia, infection, adverse myocardial remodeling and degenerative valvular heart disease.
