S. aureus endocarditis: Clinical aspects and experimental approaches

International Journal of Medical Microbiology 308 (2018) 640–652

Contents lists available at ScienceDirect

International Journal of Medical Microbiology journal homepage: www.elsevier.com/locate/ijmm

S. aureus endocarditis: Clinical aspects and experimental approaches a,⁎

b

c

d

e

f

d

T b

V. Hoerr , M. Franz , M.W. Pletz , M. Diab , S. Niemann , C. Faber , T. Doenst , P.C. Schulze , S. Deinhardt-Emmera, B. Löfflera a

Institute of Medical Microbiology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany Department of Internal Medicine I, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany Institute for Infectious Diseases and Infection Control, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany d Department of Cardiothoracic Surgery, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany e Institute of Medical Microbiology, University Hospital Münster, Domagkstr. 10, 48149 Münster, Germany f Department of Clinical Radiology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A16, 48149 Münster, Germany b c

A R T I C L E I N F O

A B S T R A C T

Keywords: S. aureus infective endocarditis Pathophysiological mechanisms Clinical management Diagnostic regimens Therapeutic treatment and surgical intervention Experimental models

Infective endocarditis (IE) is a life-threatening disease, caused by septic vegetations and inflammatory foci on the surface of the endothelium and the valves. Due to its complex and often indecisive presentation the mortality rate is still about 30%. Most frequently bacterial microorganisms entering the bloodstream are the underlying origin of the intracardiac infection. While the disease was primarily restricted to younger patients suffering from rheumatic heart streptococci infections, new at risk categories for Staphylococcus (S.) aureus infections arose over the last years. Rising patient age, increasing drug resistance, intensive treatment conditions such as renal hemodialysis, immunosuppression and long term indwelling central venous catheters but also the application of modern cardiac device implants and valve prosthesis have led to emerging incidences of S. aureus IE in health care settings and community. The aetiologic change has impact on the pathophysiology of IE, the clinical presentation and the overall patient management. Despite intensive research on appropriate in vitro and in vivo models of IE and gained knowledge about the fundamental mechanisms in the formation of bacterial vegetations and extracardiac complications, improved understanding of relevant bacterial virulence factors and triggered host immune responses is required to help developing novel antipathogenic treatment strategies and pathogen specific diagnostic markers. In this review, we summarize and discuss the two main areas affected by the changing patient demographics and provide first, recent knowledge about the pathogenic strategies of S. aureus in the induction of IE, including available experimental models of IE used to study host-pathogen interactions and diagnostic and therapeutic targets. In a second focus we present diagnostic (imaging) regimens for patients with S. aureus IE according to current guidelines as well as treatment strategies and surgical recommendations.

1. Introduction Infective Endocarditis (IE) is a complex and heterogeneous disorder associated with high mortality rates up to 30% (Habib et al., 2009; Habib et al., 2015). The most frequent aetiology of IE is microbial with bacteria as the predominant microorganisms − the incidence is 3–10 per 100000 per year (Habib et al., 2015; Hoen et al., 2002). In this context, it has to be mentioned that up to 30% of IE cases are healthcare-associated (Selton-Suty et al., 2012). Thus, the strict adherence to hygiene regulations and aseptic handling during interventional procedures is mandatory and has evolved into a crucial component of IE prophylaxis (Habib et al., 2009; Habib et al., 2015). The poor outcome of patients acquiring an IE is, among others, due to the non-specific

⁎

clinical presentation and the absence of typical laboratory parameters detecting the disease (Habib et al., 2015; Heiro et al., 2006). As a consequence, there is a significant diagnostic latency of 29 ± 35 days and a mean hospital stay of 42 ± 29 days (Habib et al., 2015). Once IE is diagnosed, prognosis of patients is determined by the occurrence of complications, in particular liver failure, as one of the most important organ failures that is associated with in-hospital mortality (Diab et al., 2017), heart failure resulting in cardiogenic shock or locally uncontrolled infection with abscess formation leading to sepsis. These patients have to be transferred to an Intensive Care Unit (ICU) immediately and emergency or urgent surgery is required in the majority of cases (Habib et al., 2015). Karth and co-workers could identify severe heart failure (64%), septic shock (21%) and neurological complications

Corresponding author at: Institute of Medical Microbiology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. E-mail address: [email protected] (V. Hoerr).

https://doi.org/10.1016/j.ijmm.2018.02.004 Received 9 August 2017; Received in revised form 18 February 2018; Accepted 20 February 2018

1438-4221/ © 2018 Elsevier GmbH. All rights reserved.

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

represent an ideal surface to interact with circulating bacteria which consequently bind to the coagulum, colonize the endothelium and form vegetations (Moreillon et al., 2002). The adherent bacteria further attract immune cells such as monocytes and trigger the release of tissue factor and cytokines (Veltrop et al., 2000; Werdan et al., 2014). Subsequent interaction between bacteria, platelets and white blood cells follow which regulates growth, inhibition and disappearance of the infected vegetation through pro- and anti-inflammatory cytokines (Deviri and Glenville, 2007). Fibrin clots activated by the coagulation system through the expression of tissue factor, play a key role in the formation of vegetations (Bancsi et al., 1996; Veltrop et al., 2000). Tissue factor activity is primarily induced in infected endothelial cells, as well as in monocytes mediated through fibronectin receptors upon the adhesion of monocytes to the vegetation. It is up and down regulated by pro- and anti-inflammatory cytokines (Bancsi et al., 1996; Deviri and Glenville, 2007). A second important pathway is initiated by activated endothelial cells in inflammatory endothelial lesions (Fig. 2), often associated with degeneration processes, arteriosclerosis-like microulcerations and contaminated injections by drug users (McKinsey et al., 1987; Stehbens et al., 2000; Werdan et al., 2014). The activation promotes the expression of various molecules, including integrins, facilitating the adhesion of bacteria to the extracellular matrix by the deposition of fibrin and fibrinogen (Hemler et al., 1990). Thus, adherence and invasion of bacteria in endothelial cells occur and result in cytotoxic and tissue damaging effects fostering the formation of vegetations (Hemler et al., 1990). A further important trigger of IE is a prosthetic heart valve. The pathogenesis of prosthetic valve endocarditis (PVE) is classified in early and late PVE, as its occurrence is considered time-dependent (Habib et al., 2015). In early PVE, developed within 1 year of surgery microorganisms infect the valve prosthesis by peri-operative contamination during surgery or by intensive-care procedures during the initial days after surgery. Beyond 1 year of surgery, late PVE occurs and the root of infection is similar to that of native valves, resulting frequently in infectious foci on the leaflets of the prosthesis (Habib et al., 2015). As in the early time window prosthesis-tissue interference including valve sewing ring, cardiac annulus and sutures, are not yet endothelialized, damaged tissue and foreign material are often coated with platelets, fibronectin, fibrinogen-fibrin and plasma proteins, which form an ideal seeding ground for microorganisms. In different retrospective studies of early PVE patients, staphylococci were identified as the major pathogens. Especially in peri-operative early PVE severe disease courses are observed, leading to heart or renal failure and persistent bacteremia (Nonaka et al., 2013). In late PVE, besides staphylococci, the infection is also associated with streptococci and enterococci as the most frequent causes (Nonaka et al., 2013; Rivas et al., 2005; Wang et al., 2007). The essential first step in the development of a cardiac valve infection is the interaction of the pathogen with the endothelial layer. Especially S. aureus induces a strong adherence to damaged and inflamed tissue and the extracellular matrix, due to its huge variety of different adhesive proteins (adhesins), which are either covalently bound to the cell wall (microbial surface components reorganizing adhesive matrix molecules, MSCRAMMs) (Foster and Hook, 1998) or secreted and rebound to the cell surface (secretable expanded repertoire adhesive molecules, SERAMs) (Chavakis et al., 2005). In the group of MSCRAMMs the role of fibronectin-binding proteins (FnBPs) and fibrinogen-binding protein clumping factor A (ClfA) is already well established in the pathogenesis of IE (Claes et al., 2017; Heying et al., 2007; Hienz et al., 1996). While FnBPs seem to promote adhesion of S. aureus to still undamaged endothelial cells by binding to integrin α5β1 via fibronectin (Heying et al., 2007; Que et al., 2005; Sinha et al., 1999), the complex formation of ClfA and secreted staphylococcal von Willebrand factor-binding protein (vWbp) was identified to bind to von Willebrand factor (vWF) to mediate the anchoring of S. aureus to inflamed and damaged endothelium under shear stress

(15%) as the three main reasons for ICU admission in IE patients. Patients requiring transfer to an ICU show increased mortality with rates between 35–84% (Habib et al., 2015; Karth et al., 2002; Mourvillier et al., 2004). Thus, complicated courses of IE have to be considered as cardiovascular emergencies. In the last two decades, the percentage of complicated courses has continuously increased and the overall presentation of IE has changed considerably (Seckeler and Hoke, 2011; Slipczuk et al., 2013). In the past, IE mainly affected younger patients and was a clearly defined disease showing classic clinical features such as Osler’s node and splenomegaly (Murdoch et al., 2009). The most common predisposing conditions were rheumatic heart valve alterations and the main causative microorganisms were streptococci leading to sub-acute courses known as endocarditis lenta (Habib et al., 2015; Selton-Suty et al., 2012). Today, patients in the western world are significantly older and there are a variety of novel risk factors like the presence of heart valve prosthesis, degenerative heart valve disease, e.g., aortic stenosis or mitral regurgitation, intravenous drug abuse, the growing number of invasive procedures, e.g., cardiac device implantation, etc. (Thuny et al., 2012). With respect to the causative microorganisms, streptococci have been overtaken by staphylococci, in particular Staphylococcus (S.) aureus, which is the predominant bacterium leading to IE in developed countries (Cahill et al., 2017a; Habib et al., 2015; Moreillon and Que, 2004). In 16 countries S. aureus was identified as the major cause (Fowler et al., 2005). It is involved in 15–40% of all IE cases (Asgeirsson et al., 2017), showing highest numbers in the US, Australia, New Zealand and South Africa (Federspiel et al., 2012; Hoen, 2006; Muñoz et al., 2015; Thalme et al., 2007). In a recently published French study on the microbiological background of IE, 497 patients were investigated and S. aureus was identified in 26.6% of all cases compared to coagulase-negative staphylococci (9.7%), oral streptococci (18.7%) and non-oral streptococci (17.5%) (Selton-Suty et al., 2012). In line, a pooled analysis from 5 prospective studies comprising 3395 adult patients with S. aureus-bacteremia (SAB) described a nonfocus stratified 90 days mortality of 29.2% (range 22.2%–39.9%). In this analysis, endocarditis was diagnosed in 8.3% of all cases, ranging from 5.7% reported in the UK to 11.6% in an US study. Mortality was dependent of the focus of bacteraemia with the highest rates in patients with pneumonia, followed by patients in whom the focus could not be identified and patients with endocarditis. Lower mortality was associated with central and peripheral venous catheter-related infection, skin and soft tissue infection, and osteoarticular infection (Kaasch et al., 2014). The current presentation of IE is characterized as an aggressive disease often associated with acute fulminant courses and limited prognosis (Cahill et al., 2017a; Habib et al., 2009; Habib et al., 2015; Plicht et al., 2010). Thereby S. aureus has been identified as independent predictor of poor outcome in IE (Diab et al., 2016; Remadi et al., 2007). Fig. 1 summarizes some well-established parameters for prognosis prediction in an IE patient (Habib et al., 2015). In the following, we describe the pathophysiology and experimental research of S. aureus endocarditis as well as its consequences for clinical management, diagnosis, therapeutic treatment and surgical interventions. 2. Pathophysiology of S. aureus endocarditis The underlying reason for the occurrence and development of IE (Fig. 2) is often a diseased heart valve and damaged endothelial layer by previous disease, trauma or turbulent blood flow at these sites (Holland et al., 2016; Que and Moreillon, 2011; Tong et al., 2015). In consequence, the underlying matrix proteins are exposed to blood resulting in a rapid fibrinogen-fibrin network, fibronectin, plasma proteins and platelet deposition (Werdan et al., 2014). These plateletprotein aggregates, also called ‘nonbacterial thrombotic endocarditis’ 641

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

Fig. 1. Prognostic predictors in IE. (Adapted from current guidelines, (Habib et al., 2009; Habib et al., 2015))

immune responses and antibiotic treatment (Donlan and Costerton, 2002; Oyama et al., 2016; Zhu et al., 2009). However, S. aureus can also enter into endothelial cells, leading to varying post-invasion events, such as stimulation of the host cell and the intracellular release of multiple pro-inflammatory and cytotoxic staphylococcal compounds leading to tissue destruction (Strobel et al., 2016) and invasion of S. aureus deep inside the tissue. In addition, S. aureus can persist inside host cells, well protected against the immune system and antibiotic treatment. Main players in the uptake process of S. aureus into host cells are FnBPs, fibronectin and the integrin α5β1 on host cell side (Sinha et al., 1999). The importance of fibrinogen and fibronectin as bridging molecules in IE development has previously been demonstrated in animal models (Piroth et al., 2008; Que et al., 2005). It is well known, that 25–30% of the adult human population are S. aureus carriers, and thus have an increased risk in developing a severe invasive S. aureus infection such as IE. Recently, differences in the virulence gene expression of S. aureus isolates have been investigated in suitable animal models during the commensal-to-pathogen transition identifying especially shifts and upregulation of the protein gens of serine-aspartate repeat protein C (sdrc), fnbpA, ferric siderophore binding protein (fhuD), ferrated catecholamines and catechol siderophore binding protein (sstD) and alpha-toxin (hla) in invasive pathogens (Jenkins et al., 2015). As the number of S. aureus strains recognized to be involved in the induction of IE increases continuously, intensified efforts have also been made to investigate correlations between specific virulence factor and the induction of IE (Oprea et al., 2014). So far, no relevant differences in the genetic background based on virulence profiles including adhesins, exotoxins, superantigens and biofilm determinants, could be identified between S. aureus strains leading to IE and those isolated from other infections. However, there is increasing evidence that clinical S. aureus isolates from IE are strongly associated with clonal complex 30 (CC30), facilitating hematogenous complications and infection severity (Nienaber et al., 2011; Sharma-Kuinkel et al., 2015). In a rabbit endocarditis model, it could further been shown that the probability to induce endocarditis is higher with CC30 S. aureus strains compared to other clinically relevant strains (Spaulding et al., 2012). Yet, there is still a controversial discussion about the effect of different groups of CC (King et al., 2016). For example, CC30 lineages are also described as low-cytotoxicity strains with less virulence (Jones et al., 2014; King et al., 2016; Rose et al., 2015), which has also been found in mouse sepsis models (DeLeo et al., 2011; Sharma-Kuinkel et al., 2015), suggesting that attenuated virulence in mouse models of infection might occur.

(Claes et al., 2017). In apparently intact endothelial-layers ultralarge von Willebrand factor fibers were further found to contribute to the endothelial adhesion of S. aureus (Pappelbaum et al., 2013). Other wall components, such as wall teichoic acid (WTA), but not staphylococcal protein A (SpA), have also been identified to participate in the bacterial adhesion (Pappelbaum et al., 2013; Weidenmaier et al., 2005). In contrast, the role of ClfB is rather limited, even though (Entenza et al., 2000) it has the ability to aggregate platelets (Miajlovic et al., 2007). The collagen-binding adhesin (CNA) and the binding of S. aureus to collagen is not considered essential to initiate the infection either. However, the binding is supposed to promote bacterial survival, leading to increased bacterial counts on infected valves (Hienz et al., 1996). The binding of S. aureus to platelets is promoted by proteins such as fibrinogen/fibrin, thrombospondin-1, vWF or fibronectin as well as the MSCRAMMs ClfA, FnBPs and SpA (Hamzeh-Cognasse et al., 2015; Niemann et al., 2004). Adherence can also lead to activation and finally to platelet aggregation resulting in an enlargement of the vegetation. In this process IgGs, the platelet Fc receptor FcγRIIa, and the platelet integrin αIIbβ3 are additionally engaged (Arman et al., 2014; Fitzgerald et al., 2006). In comparison to the MSCRAMMs, SERAMs, such as extracellular adherence protein (Eap), extracellular matrix binding protein (Emp), vWbp or coagulase (coa), are less investigated in the pathogenesis of IE. Eap can activate platelets by involved stimulation of thiol isomerases (Bertling et al., 2012) and was identified to bind to peripheral blood mononuclear cells and to trigger the release of proinflammatory TNF-α, which promotes the attachment of S. aureus to endothelial cells via involvement of SpA (Edwards et al., 2012). Coa and vWbp, promote IE development by fibrin formation since both molecules are able to bind to prothrombin and form the enzymatically active staphylothrombin complex (Panizzi et al., 2011; Vanassche et al., 2012). Superantigens, such as enterotoxin C or toxic shock syndrome toxin1 (TSST-1) have in addition to their superantigenicity a stimulating effect on cells, which leads to cytokine release by endothelial cells, T cells, B cells, macrophages and dendritic cells (Chung et al., 2014; Krogman et al., 2017; Salgado-Pabón et al., 2013). High cytokine levels enhance disease severity substantially, leading to large vegetations and bacterial counts and can result in lethal progression and complication of IE such as heart failure, stroke and metastatic infections. Once the superantigens and cytokine storm reach the blood stream toxic shock syndrome along with fever and capillary leakage occur (Salgado-Pabón et al., 2013; Stach et al., 2016). Upon adhesion to endothelial cells S. aureus can proliferate and form biofilms (Werdan et al., 2014) facilitating the escape from 642

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

Fig. 2. Development of IE. Pathway 1: Heart valve colonisation initiated by mechanical damage of the endothelial layer A. Non-bacterial thrombotic endocarditis as a consequence of mechanical damage of the heart valve endothelium. B. S. aureus binds to coagulum during transient bacteremia, colonizes the endothelium and infects the cells. More platelets are attracted and become activated by S. aureus. C. Adherent bacteria attract and activate immune cells, which increase the inflammatory process by inducing high levels of tissue factor and cytokines, leading to an enlargement of the vegetation. Pathway 2: Heart valve colonisation initiated by activated endothelial cells A. Inflammatory processes lead to an activation of endothelial cells. The cells release cytokines and the increased expression of various molecules, such as integrins, facilitates the deposition of proteins (e.g., fibrinogen and fibronectin). B. S. aureus adheres to proteins and can be internalized by endothelial cells, which further promotes the release of cytokines. These attract and activate immune cells, such as monocytes and neutrophils. Platelets become activated and adhere to proteins. The vegetation grows. C. Bacterial products as well as inflammatory processes damage endothelial cells, leading to destruction of the heart valve tissue. The vegetation is enlarged by these processes even more.

643

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

artery on anesthetized animals. 24 h to 72 h post catheterization − depending on the model − a bacterial dose in the range of 105 to 106 colony forming units (CFUs) is usually injected intravenously, which results in the formation of septic vegetations and bacterial coagulum. These aggregates consist of a matrix of fibrin and platelets as well as bacterial aggregates and mimic the clinical situation. It could be clearly shown that catheterization leads to fibrin layers and areas of necrosis on the aortic valves and activated macrophages and fibroblasts in the adventitia (Gibson et al., 2007). Once the injured and traumatized tissue is challenged with the injected bacteria, bacterial vegetations in bacteriaplatelet thrombi form along the aortic valve, which are approximately 3–4 orders of magnitude larger in the bacterial load than on valves of non-catheterized but infected animals (Gibson et al., 2007; Ring et al., 2014). For the induction of IE, the adhesion of bacteria to the endothelial layer of the cardiac valves under shear stress conditions is essential. Thus physiological flow conditions, as present on the cardiac valves in vivo or in mesenteric perfusion models (Fig. 3b) (Claes et al., 2017) are necessary to investigate and identify bacterial and host factors involved and responsible for the induction of IE. To study the impact of specific bacterial and host factors on the adhesive interaction, also in vitro flow chamber models are in use. They consist of a perfusion chamber placed on a coverslip coated with collagen or endothelial cells and connected to an infusion pump to allow for the generation of different flow rates (Fig. 3c) (Claes et al., 2015). Yet, in vivo models are required, especially when host immune responses are studied, even though they are not without limitations. There is increasing evidence that especially S. aureus superantigens and exotoxins such as Panton-Valentine leukocidin (PVL), and adhesins such as FnBP, serine-aspartate repeat protein G (SdrG) and iron-regulated surface determinant B (IsdB), display high specificity towards their human targets, questioning how well infectious disease mouse models actually mimic the human inflammatory stress response (Parker, 2017; Seok et al., 2013; Warren et al., 2015) and advancing the development and use of humanized mice to study infectious diseases (Brehm et al., 2014; Shultz et al., 2012).

3. Experimental models To improve the understanding of the underlying pathogeneses and to address the urgent need for improved diagnosis and therapeutic treatment regimens, several experimental models of S. aureus endocarditis have been established. Already in the 19th century, the first investigations on S. aureus endocarditis have been performed in animal models (Zak and Sande, 1999). In the early days mainly large animals have been used, which however required extensive surgical interventions to induce valve trauma and subsequent bacterial colonisation (Highman et al., 1959) questioning reliability. In the early 1970s catheter-related models were first described by Garrison and Freedman (Garrison and Freedman, 1970) and bacterial endocarditis in rats (Baddour et al., 1984) and rabbits (Durack and Beeson 1972; Durack et al., 1973) has been induced in experimental studies (Sande and Johnson, 1985). In these animals, bacterial vegetations could be detected easily macroscopically on the cardiac valves and could be removed for further investigations. However the large body size implied also the application of high amounts of drug candidates which often led to experimental limitations. Nowadays, investigations on IE, especially S. aureus endocarditis, are also performed on a mouse model of endocarditis introduced by Gibson et al., in 2007. Mice have several advantages over bigger animals including small body size, economic housing and rapid reproduction. In addition, they are similar to humans with respect to the nervous, cardiovascular and endocrine system (Buer and Balling, 2003; Parker, 2017; Perlman, 2016; Rosenthal and Brown, 2007) and several knock-out and knock-in mutants have been generated, to study host immune factors involved in the infection. The majority of investigations on potential drugs and pathogenesis pathways, however, are still performed on rats (Gupta et al., 2013; Li et al., 2016) and rabbits (Abdelhady et al., 2017; Sullam et al., 1996) especially as the immune and cardiovascular system of rabbits is more similar to humans (Salgado-Pabon and Schlievert, 2014). All animal models of IE utilize comparable surgical interventions and route of infection (Fig. 3a): Valve trauma is first induced by placing a polyethylene catheter across the aortic valve, via the right carotid

Fig. 3. Experimental models. Overview about different experimental models to study pathogenic mechanisms underlying IE. (A) in vivo animal model: Valve trauma is induced by placing a catheter via the right carotid artery to the aortic root, followed by i.v. administration of a bacterial suspension. (B) in vivo perfusion model: Mesenteric arteriolar and venular circulation allowing the microscopic visualization of the vascular adhesion of labeled bacteria to the extracellular matrix and endothelial cells. (C) in vitro flow chamber consisting of a perfusion chamber and a cover slip coated with collagen or endothelial cells to study adhesive interactions between specific bacterial and host factors.

644

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

4. Clinical management and future perspectives

Definite IE is defined by the presence of 2 major criteria, 1 major and 3 minor or 5 minor criteria. In contrast, possible IE is defined by at least 1 major and 1 minor or 3 minor criteria (Habib et al., 2015; Li et al., 2000). Especially with respect to imaging in IE, also in the current guidelines transthoracic (TTE) and TEE remain the gold standards (Fig. 4). There are three main findings in echocardiography considered as major criteria for IE: typical vegetation, abscess formation or novel valve dehiscence. Sensitivity of TEE is superior compared to TTE. Thus, although a TTE should be primarily performed in each patient suspicious for IE, the current guidelines recommend a TEE in all patients with negative or non-conclusive TTE findings. If prosthetic heart valves or intra cardiac devices, e.g. pacemaker, are in place, a TEE should be performed as first choice. The only situation in which TTE is equal to TEE with respect to sensitivity of IE detection is right heart endocarditis in patients with good acoustic window (Habib et al., 2015). Since specificity is relatively low for both, TTE and TEE, echocardiography is not recommended as a screening method but should be applied in preselected patients presenting with symptoms and clinical findings highly suspicious for IE (Habib et al., 2009, Habib et al., 2015). In addition, novel modalities have been introduced, in particular white blood cell (WBC) single-photon emission CT (SPECT)/CT and 18F-FDG positron emission tomography (PET)/CT. These novel methods are recommended for complex clinical situations, e.g. patients suspicious for prosthetic valve IE, in addition to echocardiography (Habib et al., 2015). In addition to image-based diagnostics, rapid detection and identification of the causative pathogen is decisive for a timely and targeted therapy. Of crucial importance is the correct extraction of three blood cultures (aerobic and anaerobic) before initiation of an antimicrobial treatment. Notably, despite correct puncture of a peripheral vein after sufficient disinfection, in up to 35% of the cases blood cultures remain negative (Subedi et al., 2017). The main cause of negative blood cultures is treatment with antibiotic agents prior to blood culture collection. Another explanation for a negative blood culture could be the presence of difficult-to-cultivate microorganisms. This includes the following pathogens: Fungi, Bartonella spp., Coxiella spp. and members of the HACEK group (Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodes, and Kingella species). Therefore, it is essential that clinicians and ID specialists discuss the suspected diagnosis of IE prior to blood collection to ensure an adequate microbiological procedure. Detection of S. aureus via blood culture is often associated with a brief time-to-positivity, commonly below 20 h. S. aureus identification of the bacteria is usually confirmed by a Staphaurex latex agglutination test on subcultures as a rapid first diagnosis followed by several identification systems such as MALDITOF and adjunctive antimicrobial susceptibility testing. A challenge in

To face the current challenges in IE, the following issues have to be resolved: diagnostic latency and complex patient management, which is difficult to implement in daily clinical practice and therefore deficient (Cahill et al., 2017b; Thuny et al., 2012). The current guidelines of the European Society of Cardiology (ESC), published in 2015, tried to address these problems by implementing some novel aspects concerning overall patient management, diagnosis and therapy. Guideline adherence was proven to be useful in terms of mortality reduction in IE in a very small but interesting study 15 years ago (Gonzalez De Molina et al., 2002). Management of IE patients should be realized in an interdisciplinary team approach, the so-called endocarditis team consisting of cardiologists, cardiac surgeons, microbiologists, infectious diseases (ID) physicians, neurologists, anesthesists and − with special importance for both, initial diagnosis and follow-up care − the general practitioner (Cahill et al., 2017a; Thuny et al., 2012). Such a team approach has been evidenced to improve patients’ outcome and survival (BotelhoNevers et al., 2009; Chirillo et al., 2013). In the guidelines, the team approach is described in detail and recommended as class IIa level of evidence B. Moreover, the requirements for specialized hospitals, so called endocarditis centres, are clearly defined (Habib et al., 2015). The idea of an infective endocarditis team is not restricted to European guidelines but is well accepted in the international community and has been excellently summarized by an international working group in 2014 (Chambers et al., 2014). Recently, SAB has been recognized as a promising entity for infectious disease consultations, since the involvement of an ID physician can decrease mortality by up to 60% according to retrospective studies (Vogel et al., 2016). This success may also partly be explained by a higher rate of transesophageal echocardiography (TEE) in order to detect underlying endocarditis. Currently, the first randomized controlled trial (RCT) is on-going aiming to proof a decrease in SAB mortality by unsolicited ID telephone consultations (Weis et al., 2017). 5. Diagnosis Diagnosis of IE is based on the four columns clinical presentation/ symptoms; laboratory parameters; imaging; and microbiology which mainly follow the major and minor modified Duke criteria such as predisposing heart condition, heart murmur, fever, Osler nodes, Janeway’s lesions, microbiological evidence (minor criteria) as well as detection of circulating bacteria of S. aureus in blood cultures and positive imaging findings (major criteria) (Baddour et al., 2005; Habib et al., 2015). The Duke criteria have been modified several times. The current version of the European Guidelines still entails 2 major and 5 minor criteria.

Fig. 4. Diagnostic echocardiography. Echocardiographic findings in a patient suffering from severe prosthetic aortic valve endocarditis (biological prosthesis) due to S. aureus (transesophageal echocardiography). a) long-axis view showing the prosthetic valve in aortic position (AV) with a paravalvular abscess formation (green arrow). b) short-axis view showing the large abscess formation (green arrows) and an additional vegetation in the right atrium (RA, green circle). (LA, left atrium; Ao, aorta; LV, left ventricle; RV, right ventricle; MV, mitral valve; TV, tricuspid valve; IAS, interatrial septum)

645

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

Fig. 5. MRI in a mouse model of endocarditis. In vivo MRI-UTE (ultra-short echo time) images over the full cardiac cycle of a mouse heart, catheterized and infected with S. aureus, showing bacterial vegetation and bacterial coagulum on the aortic valve (arrows).

diagnostic procedures (Habets et al., 2014). Especially its high-resolution images of anatomical structures complement well the information about function and extracardiac complications obtained by 18F-FDG PET/CT. Statistics reveal that already the additional application of 18FFDG PET/CT to routine diagnostic regimens has led to changes in the therapeutic treatment in 35% of the cases (Orvin et al., 2015). However, antimicrobial therapeutic treatment or elevated blood glucose concentration might also cause false negative results and the high sensitivity of the detection of accumulated 18F-FDG might lead to false positive findings caused by recent cardiac events such as thrombi, surgical interventions or malignant and inflammatory events (Gomes et al., 2017; Scholtens et al., 2017). Therefore, the combination of the complementary imaging modalities of 18F-FDG PET and MDCTA provides highest diagnostic accuracy (Balmforth et al., 2016; Pizzi et al., 2015; Roque et al., 2017). In contrast, WBC scintigraphy using SPECT/CT is rather specific for an infection, as it detects granulocytes in an inflamed holosphere around the cardiac valves and is thus strongly correlated with high inflammatory activity (Borst et al., 1993). Until today, a defined application of magnetic resonance imaging (MRI) in the diagnosis of IE is still controversial. The recommendations are currently restricted to complications of IE such as myocarditis, pericarditis and cerebral consequences (Habib et al., 2015; von Knobelsdorff-Brenkenhoff and Schulz-Menger, 2016; Snygg-Martin et al., 2008). Even though the technique provides good anatomical and structural resolution and is potentially a beneficial diagnostic adjunct, current image quality of human cardiac valves often suffers from flow artifacts and have to be improved until a substantial role can be defined for MRI (Gomes et al., 2017). To this end, a novel 2D cinematic selfgated ultra-short echo time (UTE) technique was developed recently at a 9.4 T small animal scanner (Hoerr et al., 2013) and was applied on a mouse model of S. aureus endocarditis (Ring et al., 2014). The new technique allowed for an artifact-free visualization of the aortic valves over the full cardiac cycle and enabled the detection of valve thickening, vegetations and additional structures (Fig. 5). Notwithstanding these results, its clinical value has to be proven. However, the increasing availability of high magnetic field scanners for patient examinations and the great advances in detector technology and acquisition as well as post processing methods make MRI a promising method for clinical investigations. Near-microscopic resolution, depicting the valves and tiniest structures with excellent contrast may provide a diagnostic tool with added value compared to the established methods. Besides technical developments, also different approaches in the field of molecular imaging have been pursued over the last years, addressing the limited sensitivity and missing pathogen specificity in the current diagnostic tools of IE. None of the so far proposed technologies are pathogen specific nor do they enable the distinction between infection and inflammation. First attempts have been made already in 1988 when first imaging labels were developed based on fibrin-targeted antibodies

diagnosis and treatment of IE is given by a particular S. aureus phenotype called small colony variants (SCVs). This subpopulation presents with a decreased metabolic activity along with a deficiency in the electron transport, is thus resistant to aminoglycosides and cell wall inhibitors, leading to a persistent and indolent clinical picture of IE (Bhattacharyya et al., 2012; Tuchscherr et al., 2011; Tuchscherr et al., 2016). Yet, microbiological culture is to date the most sensitive and bestvalued method for detection of microbial organisms. As a primary diagnostic tool, every blood culture bottle is incubated with a fully automated blood culture system (e.g. BacT/Alert, Organon Teknika Corp., Durham, N.C.). When growth is detected, blood is dyed using gram staining and microscopically examined. Simultaneously, the sample is spread across a petri dish containing a growth medium. Different nutrient and complex agars are available which allows a wide range of microbial cultivation. Moreover, modern culture-independent serological and molecular methods of identification are available and became of interest over the last years for differential diagnosis.

6. Diagnostic imaging As described above, the use of imaging modalities gains increasing importance in the diagnosis and clinical management of IE. Even though TEE improves accurate diagnoses in patients with infected prosthestic heart valves, both TTE and TEE miss IE and relevant sequelae in 30% of patients (Gomes et al., 2017; Habib et al., 2015; Hill et al., 2007). Especially in patients with intracardiac prosthetic material, perivalvular extensions such as aneurysms and abscesses, or extracardiac complications, mainly based on systemic embolism and infectious metastasis, remain frequently unnoticed, demanding for novel imaging approaches (Gomes et al., 2017; Iung et al., 2014). Investigations by using WBC SPECT/CT (Erba et al., 2012; Erba et al., 2013; Hyafil et al., 2013) and 18F-FDG PET/CT (Asmar et al., 2014; Yan et al., 2016; Gomes et al., 2016) have already been included in current guidelines to diagnose IE, especially in difficult-to-diagnose cases (Habib et al., 2015). However, in several studies and assessments also Electrocardiogram (ECG)-gated multidetector CT angiography (MDCTA) is currently suggested and superior in indecisive situations (Fagman et al., 2012; Fagman et al., 2016; Feuchtner et al., 2009; Gomes et al., 2017; Habets et al., 2014; Wong et al., 2016). MDCTA is an imaging modality which provides detailed anatomical information but also insight into vascular system, aerodigestive structures and soft tissue, and is applicable both in native and prosthetic valve endocarditis (Entrikin et al., 2012; Feuchtner et al., 2009). In several studies, adjunctive value to the application of TEE was achieved, mainly due to its benefit in the detection of perivalvular extension of IE presented as abscesses and aneurysms, besides valve perforations and vegetations. It could be shown that the treatment strategy was changed in 25% of the patients upon the adjunctive application of MDCTA to the standard 646

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

7.3. Which antibiotic for methicillin-resistant S. aureus (MRSA)?

coupled with 111Indium (In) or 99Technetium (Tc) (Knight et al., 1988, Yokota et al., 2001). Also labeled annexin V was used successfully to detect apoptotic cells and activated platelets by 99Tc SPECT (Rouzet et al., 2008). With the aim to foster specificity, 99Tc labeled antistaphylococcal antibodies were proposed (Huang et al., 1980), however only minor accumulation was achieved. The application of modified antibiotics followed and antibiotics of different classes such as ciprofloxacin, vancomycin or spiromycin were labeled with fluorochromes, iron oxide nanoparticles or manipulated for autoradiographic detection (Cremieux et al., 1988; Lee et al., 2008; van Oosten et al., 2013). Recently, prothrombin analogues coupled to fluorescence and copper-64-PET-tracers could be generated successfully, facilitating specific binding to staphylocoagulase and intercalation into the bacterial coagulum (Panizzi et al., 2011). Other approaches could show in a S. aureus endocarditis model the promising application of fluorescent carbon nanotubes functionalized by using M13 bacteriophage. These nanotubes confer the distinction between F'-positive and F'-negative bacterial strains and can be modified with anti-bacterial antibodies, offering possibility to detect deep tissue infections with high specificity and sensitivity (Bardhan et al., 2014).

Despite serious limitations regarding tissue penetration, efficacy and toxicity, vancomycin is still considered to be the gold standard for MRSA endocarditis by the ESC guideline (IB). However, daptomycin is an alternative with better in vitro efficacy and a more favourable safety profile but with a currently smaller body of evidence. Both ESC and AHA rank daptomycin with a IIB recommendation. The optimal dose of daptomycin is an issue of debate. It was licensed for right-sided endocarditis based on a RCT using a dosage of 6 mg/kg (Fowler et al., 2006). The ESC recommends 10 mg/kg and the AHA ≥ 8 mg/kg. However, a study in healthy volunteers and case reports have shown that 14 days of 12 mg/kg of daptomycin is safe (Benvenuto et al., 2006; Schrenk et al., 2016). In the 2011 IDSA guideline on MRSA infections, 10 mg/kg are suggested for salvage therapy of MRSA bacteremia. Rare but severe side effects of daptomycin are rhabdomyelysis and eosinophilic pneumonia that can be detected early by monitoring creatinine kinase levels and the differential blood count. Daptomycin is inactivated by surfactant and thus ineffective in S. aureus pneumonia acquired via the aspiration route. However, in the RCT mentioned above daptomycin was effective against septic pulmonary emboli caused by S. aureus (Fowler et al., 2006).

7. Treatment 7.4. Combination therapy in native valve endocarditis (NVE) 7.1. Antibiotic treatment– current guidelines and controversies The combination with gentamicin, initially recommended because of a possible in vitro synergism, is now discouraged by both guidelines for NVE because of relatively high rates of intrinsic gentamicin resistance, a lack of clinical efficacy, and toxicity. Further, the in vivo efficacy of rifampin in combination with other antibiotics is highly variable. Rifampin as adjunct therapy for S. aureus NVE was associated with higher rates of adverse events (primarily hepatotoxicity) and a significantly lower survival rate in a retrospective cohort study (Riedel et al., 2008). Thus, routine use of rifampin is not recommended for treatment of staphylococcal NVE by both guidelines.

There are 2 current (2015) major international guidelines for the treatment of IE issued by the ESC (Habib et al., 2015) and the American Heart Association (AHA) (Baddour et al., 2015), respectively. Furthermore, there is an older (2011) Infectious Disease Society of America (IDSA) guideline for methicillin-resistant S. aureus (MRSA) infections including bacteremia and endocarditis (Liu et al., 2011). However, a guideline explicitly for S. aureus bacteremia is missing and currently under preparation by the IDSA. Yet, as outlined above, there is a substantial overlap as literally all S. aureus IE are also SAB by definition and 10–15% of all SAB-patients exhibit endocarditis. In consequence, most studies reporting on SAB include a substantial proportion of patients with SAB endocarditis.

7.5. Combination therapy in prosthetic valve endocarditis (PVE) S. aureus PVE is associated with high mortality. Both guidelines recommend therefore a combination antimicrobial therapy even if there are no RCTs to support this approach. However, in animal studies, rifampin appears to be key in the complete sterilization of foreign bodies infected by MRSA (Chuard et al., 1991; Lucet et al., 1990). For infection caused by MSSA, nafcillin or oxacillin together with rifampin is suggested; with MRSA, vancomycin and rifampin should be used. Gentamicin should be administered for the initial 2 weeks of therapy with either beta-lactam or vancomycin-containing regimens. Recently, two studies analyzing a limited number of S. aureus isolates reported an antagonism of daptomycin and rifampin questioning the benefit of this combination (Khasawneh et al., 2008; Miró et al., 2009). However, a large analysis including 9 clinical MSSA and 49 MRSA isolates found mainly additive effects and did not confirm this observation (Stein et al., 2016). According to the AHA guideline, the usefulness of empirical combination therapy with vancomycin plus an antistaphylococcal betalactam antibiotic in patients with S. aureus bacteremia – until oxacillin susceptibility is known – is uncertain (Class IIb; level of evidence B).

7.2. Which antibiotics for methicillin-susceptible S. aureus (MSSA)? Beta-Lactams are the cornerstone of treatment for MSSA. Despite the fact that MSSA strains are commonly susceptible in vitro against all beta-lactam/beta-lactamase inhibitor combinations, cephalosporins (except ceftolozan and ceftazidime) and carbapenems, only antistaphylococcal penicillins (i.e. flucloxacillin, dicloxacillin, oxacillin, nafcillin) and first generation cephalosporins are considered adequate treatment choices. Several large cohort studies have revealed an excess mortality for other beta-lactams compared to cefazolin or antistaphylococcal penicillins e.g. for cefuroxime, ceftriaxone or piperacillin/tazobactam (Nissen et al., 2013; Paul et al., 2011). While the ESC endocarditis guideline suggests preference of antistaphylococcal penicillins due to higher dosages and a slightly better in vitro activity, a large recent cohort study reported decreased mortality in patients receiving cefazolin compared to antistaphylococcal penicillins (McDanel et al., 2017). Due to the retrospective nature of that study, a bias by indication, i.e. patients with severe SAB will probably receive less frequently cefazolin, cannot be excluded. However, the lower mortality associated with the use of cefazolin may also be explained by a more favourable safety profile (i.e. less hepatotoxicity). While the 2015 ESC guideline recommends only oxacillin or nafcillin (IB), the 2015 AHA/ IDSA guideline ranks nafcillin/oxacillin 12 g/24 h (IC) lower than cefazolin 6 g/24 h (IB). In case of concomitant brain abscesses, cefazolin should be preferred due to better penetration according to the AHA guideline.

7.6. Oral therapy for IE There is broad consensus that despite the long treatment duration of 4–6 weeks, oralisation is not an option for IE. In the 2015 ESC guideline, for the first time a cotrimoxazol/clindamycin combination administered for 1 week intravenously and followed by 5 weeks of high dose (Sulfamethoxazole 4800 mg/day and Trimethoprim 960 mg/day) cotrimaxoazol intake has been recommended as alternative for 647

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

8.2. IE affecting cardiac implantable electronic devices (CIEDs)

uncomplicated right-sided native valve MSSA with a level IIb recommendation. However, this recommendation is an issue of debate and has not been adopted by a number of national societies and their recommendations. The level of the supporting evidence is poor (Cashin, 1990; Mzabi et al., 2016).

Infection of CIEDs is an increasing issue which is also associated with high mortality (Baddour et al., 2003). Staphylococci account for 60–80% of the cases. Medical therapy alone has been associated with high mortality and risk of recurrence (Rodriguez et al., 2012; Rundström et al., 2004). Therefore, CIED removal is recommended in all cases of proven cardiac device-related IE (CDRIE) (Class I; level of evidence C) and should also be considered if CDRIE is only suspected in cases of occult infection without any apparent source other than the device (Class II; level of evidence C) (Habib et al., 2015).

8. Surgical intervention 8.1. Left-sided IE Despite optimal medical treatment, more than 50% of IE patients require surgery (Tornos et al., 2005). The number of patients operated on during the active phase of IE has been increased during the last two decades from 30% to 60% (Hoen et al., 2002). The most frequent indications are congestive heart failure, prevention of embolic complications and uncontrolled infection (Habib et al., 2015). The risk of embolism is highest within the first 14 days after initiation of antibiotic therapy (Di Salvo et al., 2001; García-Cabrera et al., 2013; Thuny et al., 2005; Vilacosta et al., 2002). The timing of surgery for IE remains controversial. To date only one randomized trial has been performed to examine the effect of early surgery for IE on outcome. The authors defined early surgery as surgery within 48 h after admission, whereas late surgery as surgery ( > 48 h) during the initial hospitalization. It could be shown that early surgery reduced the composite end point of death from any cause and embolic events by effectively decreasing the risk of systemic embolism. Most importantly, early surgery was not associated with higher incidence of recurrence of IE (Kang et al., 2012). Recent guidelines depend mostly on data from observational studies to make recommendations on the indications and timing of surgery for IE (Baddour et al., 2015; Habib et al., 2015). However, there are some discrepancies between the ESC (Habib et al., 2015) guidelines and AHA guidelines (Baddour et al., 2015). While the ESC guidelines consider PVE, caused by staphylococci, an indication for urgent/elective surgery (class IIa; level of evidence C), AHA guidelines do not mention staphylococcal PVE as an indication for surgery. This recommendation from AHA guidelines is based on data from the international collaboration on endocarditis (ICE). It contains the largest prospective international register of patients with IE which did not show any beneficial effect of early surgery in patients with PVE caused by S. aureus (Chirouze et al., 2015). However, in an earlier report the same group showed a beneficial effect of early surgery on mortality in patients with native IE (Lalani et al., 2010). The authors of the ICE register defined early surgery as surgery during initial hospitalization (Kiefer et al., 2011; Lalani et al., 2010). This definition might be misleading as it includes patients which might be operated on within the first few days or in the first few weeks after admission. Reasons to consider early surgery in the active phase of IE are to avoid progressive heart failure and irreversible structural damage caused by severe infection and to prevent systemic embolism (Habib et al., 2015). Especially S. aureus is well known to cause tissue destruction and deep invasion inside tissues (Piroth et al., 2008; Que et al., 2005), and is therefore associated with a high incidence of periannular extension (abscess, false aneurysm, or fistula) (Fernicola and Roberts, 1993) which represents an indication for urgent (within a few days, < 7 days) surgery (Class I; level of evidence B) (Habib et al., 2015). In consequence, surgery in cases of S. aureus IE must not be delayed in order to prevent periannular extension. In addition, S. aureus is associated with a high incidence of cerebral embolism (Diab et al., 2016; García-Cabrera et al., 2013), which underlines the benefit of early surgery by reducing the risk of embolism in the case of S. aureus IE (Kang et al., 2012). Finally, S. aureus IE is characterized by an aggressive clinical course associated with valvular damage causing congestive heart failure which is the most common indication for emergent (within 24 h) or urgent surgery (Habib et al., 2015).

9. Conclusion Despite the progress in preclinical and clinical investigations and in line with the current guidelines, management of IE still exhibits many deficiencies, which have to be overcome in the future to improve the outcomes of our patients. In detail, the improvements should focus on prevention, e.g., reduction of health-care associated IE, adequate antibiotic prophylaxis in high-risk patients etc.; diagnosis, e.g., increased attention by all involved physicians in case of clinical suspicion for IE, patients’ education, rapid and adequate imaging and microbiological diagnosis in high-risk patients and optimized overall management, e.g., development of endocarditis teams and infrastructure for early collaboration with endocarditis centres, individual-adjusted antimicrobial therapy, adequate/early timing of surgery and structured follow-up in cooperation with general practitioners (Cahill et al., 2017a,b; Habib et al., 2015). Especially the presence of S. aureus bacteremia has crucial impact on the diagnostic algorithm of IE since it could be clearly shown that high-risk patients, e.g., prosthetic valve or pacemaker carries, definitely benefit from TEE, which is strongly recommended in these patients. In contrast, even promising clinical prediction rules for IE are currently not safe enough in this special entity and must undergo validation in further studies (Bai et al., 2017; Salvador et al., 2017). Concluding, one has to state that, despite recent advancements, the body of evidence in IE is not satisfying yet and there is an urgent need for large, prospective, randomized trials addressing unsolved problems in the field. In addition, further preclinical and fundamental research is necessary both in vivo and in vitro to improve the understanding of the clinical manifestation, the underlying pathomechanism and to identify the role of relevant virulence factors, which is essential to advance diagnostic regimens and to disclose and develop novel antipathogenic strategies. Acknowledgements This work was supported by the German Research Foundation, SFTR34 projects C12 and C14 (BL, VH and CF). MWP was supported by a grant of the German Ministry for Science and Education (01KI1501). References Abdelhady, W., Bayer, A.S., Gonzales, R., Li, L., Xiong, Y.Q., 2017. Telavancin is active against experimental aortic valve endocarditis caused by daptomycin- and methicillin-resistant staphylococcus aureus strains. Antimicrob. Agents Chemother. 61 (pii16-e01877). Arman, M., Krauel, K., Tilley, D.O., Weber, C., Cox, D., Greinacher, A., Kerrigan, S.W., Watson, S.P., 2014. Amplification of bacteria-induced platelet activation is triggered by FcgammaRIIA, integrin alphaIIbbeta3, and platelet factor 4. Blood 123, 3166–3174. Asgeirsson, H., Thalme, A., Weiland, O., 2017. Staphylococcus aureus bacteraemia and endocarditis – epidemiology and outcome: a review. Infect. Dis. (Lond). 6, 1–18. Asmar, A., Ozcan, C., Diederichsen, A.C., Thomassen, A., Gill, S., 2014. Clinical impact of 18F-FDG-PET/CT in the extra cardiac work-up of patients with infective endocarditis. Eur. Heart J. Cardiovasc. Imaging 15, 1013–1019. Baddour, L.M., Christensen, G.D., Hester, M.G., Bisno, A.L., 1984. Production of experimental endocarditis by coagulase-negative staphylococci: variability in species virulence. J. Infect. Dis. 150, 721–727.

648

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

Chuard, C., Herrmann, M., Vaudaux, P., Waldvogel, F.A., Lew, D.P., 1991. Successful therapy of experimental chronic foreign-body infection due to methicillin-resistant Staphylococcus aureus by antimicrobial combinations. Antimicrob. Agents Chemother. 35, 2611–2616. Chung, J.W., Karau, M.J., Greenwood-Quaintance, K.E., Ballard, A.D., Tilahun, A., Khaleghi, S.R., David, C.S., Patel, R., Rajagopalan, G., 2014. Superantigen profiling of Staphylococcus aureus infective endocarditis isolates. Diagn. Microbiol. Infect. Dis. 79, 119–124. Claes, J., Liesenborghs, L., Lox, M., Verhamme, P., Vanassche, T., Peetermans, M., 2015. in vitro and in vivo model to study bacterial adhesion to the vessel wall under flow conditions. J. Vis. Exp. 100, e52862. Claes, J., Liesenborghs, L., Peetermans, M., Veloso, T.R., Missiakas, D., Schneewind, O., Mancini, S., Entenza, J.M., Hoylaerts, M.F., Heying, R., Verhamme, P., Vanassche, T., 2017. Clumping factor A, von Willebrand factor-binding protein and von Willebrand factor anchor Staphylococcus aureus to the vessel wall. J. Thromb. Haemost. 15, 1009–1019. Cremieux, A.C., Vallois, J.M., Maziere, B., Ottaviani, M., Bouvet, A., Carbon, C., Pocidalo, J.J., 1988. 3H-spiramycin penetration into fibrin vegetations in an experimental model of streptococcal endocarditis. J. Antimicrob. Chemother. 22 (Suppl B), 127–133. DeLeo, F.R., Kennedy, A.D., Chen, L., Bubeck Wardenburg, J., Kobayashi, S.D., Mathema, B., Braughton, K.R., Whitney, A.R., Villaruz, A.E., Martens, C.A., Porcella, S.F., McGavin, M.J., Otto, M., Musser, J.M., Kreiswirth, B.N., 2011. Molecular differentiation of historic phage-type 80/81 and contemporary epidemic Staphylococcus aureus. Proc. Natl. Acad. Sci. U. S. A. 108, 18091–18096. Deviri, E., Glenville, B.E., 2007. Inflammatory response in infective endocarditis. Eur J Inflamm. 5, 57–63. Di Salvo, G., Habib, G., Pergola, V., Avierinos, J.F., Philip, E., Casalta, J.P., Vailloud, J.M., Derumeaux, G., Gouvernet, J., Ambrosi, P., Lambert, M., Ferracci, A., Raoult, D., Luccioni, R., 2001. Echocardiography predicts embolic events in infective endocarditis. J. Am. Coll. Cardiol. 37, 1069–1076. Diab, M., Guenther, A., Sponholz, C., Lehmann, T., Faerber, G., Matz, A., Franz, M., Witte, O.W., Pletz, M.W., Doenst, T., 2016. Pre-operative stroke and neurological disability do not independently affect short- and long-term mortality in infective endocarditis patients. Clin. Res. Cardiol. 105, 847–857. Diab, M., Sponholz, C., von Loeffelholz, C., Scheffel, P., Bauer, M., Kortgen, A., Lehmann, T., Färber, G., Pletz, M.W., Doenst, T., 2017. Impact of perioperative liver dysfunction on in-hospital mortality and long-term survival in infective endocarditis patients. Infection 45, 857–866. Donlan, R.M., Costerton, J.W., 2002. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin. Microbiol. Rev. 15, 167–193. Durack, D.T., Beeson, P.B., 1972. Experimental bacterial endocarditis: i. Colonization of a sterile vegetation. Br. J. Exp. Pathol. 53, 44–49. Durack, D.T., Beeson, P.B., Petersdorf, R.G., 1973. Experimental bacterial endocarditis. 3. Production and progress of the disease in rabbits. Br. J. Exp. Pathol. 54, 142–151. Edwards, A.M., Bowden, M.G., Brown, E.L., Laabei, M., Massey, R.C., 2012. Staphylococcus aureus extracellular adherence protein triggers TNFα release promoting attachment to endothelial cells via protein A. PLoS One. 7, e43046. Entenza, J.M., Foster, T.J., Ni Eidhin, D., Vaudaux, P., Francioli, P., Moreillon, P., 2000. Contribution of clumping factor B to pathogenesis of experimental endocarditis due to Staphylococcus aureus. Infect. Immun. 68, 5443–5446. Entrikin, D.W., Gupta, P., Kon, N.D., Carr, J.J., 2012. Imaging of infective endocarditis with cardiac CT angiography. J. Cardiovasc. Comput. Tomogr. 6, 399–405. Erba, P.A., Conti, U., Lazzeri, E., Sollini, M., Doria, R., De Tommasi, S.M., Bandera, F., Tascini, C., Menichetti, F., Dierckx, R.A., Signore, A., Mariani, G., 2012. Added value of 99mTc-HMPAO-labeled leukocyte SPECT/CT in the characterization and management of patients with infectious endocarditis. J. Nucl. Med. 53, 1235–1243. Erba, P.A., Sollini, M., Conti, U., Bandera, F., Tascini, C., De Tommasi, S.M., Zucchelli, G., Doria, R., Menichetti, F., Bongiorni, M.G., Lazzeri, E., Mariani, G., 2013. Radiolabeled WBC scintigraphy in the diagnostic workup of patients with suspected device-related infections. JACC Cardiovasc. Imaging 6, 1075–1086. Fagman, E., Perrotta, S., Bech-Hanssen, O., Flinck, A., Lamm, C., Olaison, L., Svensson, G., 2012. ECG-gated computed tomography: a new role for patients with suspected aortic prosthetic valve endocarditis. Eur. Radiol. 22, 2407–2414. Fagman, E., Flinck, A., Snygg-Martin, U., Olaison, L., Bech-Hanssen, O., Svensson, G., 2016. Surgical decision-making in aortic prosthetic valve endocarditis: the influence of electrocardiogram-gated computed tomography. Eur. J. Cardiothorac. Surg. 50, 1165–1171. Federspiel, J.J., Stearns, S.C., Peppercorn, A.F., Chu, V.H., Fowler Jr., V.G., 2012. Increasing US rates of endocarditis with Staphylococcus aureus: 1999–2008. Arch. Intern. Med. 172, 363–365. Fernicola, D.J., Roberts, W.C., 1993. Frequency of ring abscess and cuspal infection in active infective endocarditis involving bioprosthetic valves. Am. J. Cardiol. 72, 314–323. Feuchtner, G.M., Stolzmann, P., Dichtl, W., Schertler, T., Bonatti, J., Scheffel, H., Mueller, S., Plass, A., Mueller, L., Bartel, T., Wolf, F., Alkadhi, H., 2009. Multislice computed tomography in infective endocarditis: comparison with transesophageal echocardiography and intraoperative findings. J. Am. Coll. Cardiol. 53, 436–444. Fitzgerald, J.R., Loughman, A., Keane, F., Brennan, M., Knobel, M., Higgins, J., Visai, L., Speziale, P., Cox, D., Foster, T.J., 2006. Fibronectin-binding proteins of Staphylococcus aureus mediate activation of human platelets via fibrinogen and fibronectin bridges to integrin GPIIb/IIIa and IgG binding to the FcgammaRIIa receptor. Mol. Microbiol. 59, 212–230. Foster, T.J., Hook, M., 1998. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 6, 484–488. Fowler Jr, V.G., Miro, J.M., Hoen, B., Cabell, C.H., Abrutyn, E., Rubinstein, E., Corey,

Baddour, L.M., Bettmann, M.A., Bolger, A.F., Epstein, A.E., Ferrieri, P., Gerber, M.A., Gewitz, M.H., Jacobs, A.K., Levison, M.E., Newburger, J.W., Pallasch, T.J., Wilson, W.R., Baltimore, R.S., Falace, D.A., Shulman, S.T., Tani, L.Y., Taubert, K.A., 2003. Nonvalvular cardiovascular device-related infections. Circulation 108, 2015–2031. Baddour, L.M., Wilson, W.R., Bayer, A.S., Fowler Jr., V.G., Bolger, A.F., Levison, M.E., Ferrieri, P., Gerber, M.A., Tani, L.Y., Gewitz, M.H., Tong, D.C., Steckelberg, J.M., Baltimore, R.S., Shulman, S.T., Burns, J.C., Falace, D.A., Newburger, J.W., Pallasch, T.J., Takahashi, M., Taubert, K.A., 2005. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 111, e394–e434 (Erratum in: Circulation. 2008, 118, e497. Circulation. 2007, 115, e408. Circulation. 2005, 112, 2373. Circulation. 2007, 116, e547.). Baddour, L.M., Wilson, W.R., Bayer, A.S., Fowler Jr, V.G., Tleyjeh, I.M., Rybak, M.J., Barsic, B., Lockhart, P.B., Gewitz, M.H., Levison, M.E., Bolger, A.F., Steckelberg, J.M., Baltimore, R.S., Fink, A.M., O'Gara, P., Taubert, K.A., 2015. American Heart Association Committee on rheumatic fever, endocarditis, and kawasaki disease of the Council on cardiovascular disease in the young, Council on clinical cardiology, Council on cardiovascular surgery and anesthesia, and stroke Council. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 132, 1435–1486. Bai, A.D., Agarwal, A., Steinberg, M., Showler, A., Burry, L., Tomlinson, G.A., Bell, C.M., Morris, A.M., 2017. Clinical predictors and clinical prediction rules to estimate initial patient risk for infective endocarditis in Staphylococcus aureus bacteremia: a systematic review and meta-analysis. Clin. Microbiol. Infect pii: S1198-743X(17) 30236-7. Balmforth, D., Chacko, J., Uppal, R., 2016. Does positron emission tomography/computed tomography aid the diagnosis of prosthetic valve infective endocarditis? Interact Cardiovasc. Thorac. Surg. 23, 648–652. Bancsi, M.J., Veltrop, M.H., Bertina, R.M., Thompson, J., 1996. Role of phagocytosis in activation of the coagulation system in Streptococcus sanguis endocarditis. Infect. Immun. 64, 5166–5170. Bardhan, N.M., Ghosh, D., Belcher, A.M., 2014. Carbon nanotubes as in vivo bacterial probes. Nat. Commun. 5, 4918. Benvenuto, M., Benziger, D.P., Yankelev, S., Vigliani, G., 2006. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob. Agents Chemother. 50, 3245–3249. Bertling, A., Niemann, S., Hussain, M., Holbrook, L., Stanley, R.G., Brodde, M.F., Pohl, S., Schifferdecker, T., Roth, J., Jurk, K., Muller, A., Lahav, J., Peters, G., Heilmann, C., Gibbins, J.M., Kehrel, B.E., 2012. Staphylococcal extracellular adherence protein induces platelet activation by stimulation of thiol isomerases. Arterioscler. Thromb. Vasc. Biol. 32, 1979–1990. Bhattacharyya, S., Roy, S., Mukhopadhyay, P., Rit, K., Dey, J., Ganguly, U., Ray, R., 2012. Small Colony variants of Staphylococcus aureus isolated from a patient with infective endocarditis: a case report and review of the literature. Iran J. Microbiol. 4, 98–99. Borst, U., Becker, W., Maisch, B., Börner, W., Kochsiek, K., 1993. Clinical and prognostic effect of a positive granulocyte scan in infective endocarditis. Clin. Nucl. Med. 18, 35–39. Botelho-Nevers, E., Thuny, F., Casalta, J.P., Richet, H., Gouriet, F., Collart, F., Riberi, A., Habib, G., Raoult, D., 2009. Dramatic reduction in infective endocarditis-related mortality with a management-based approach. Arch. Intern. Med. 169, 1290–1298. Brehm, M.A., Wiles, M.V., Greiner, D.L., Shultz, L.D., 2014. Generation of improved humanized mouse models for human infectious diseases. J. Immunol. Methods 410, 3–17. Buer, J., Balling, R., 2003. Mice, microbes and models of infection. Nat. Rev. Genet. 4, 195–205. Cahill, T.J., Baddour, L.M., Habib, G., Hoen, B., Salaun, E., Pettersson, G.B., Schäfers, H.J., Prendergast, B.D., 2017a. Challenges in infective endocarditis. J. Am. Coll. Cardiol. 69, 325–344. Cahill, T.J., Harrison, J.L., Jewell, P., Onakpoya, I., Chambers, J.B., Dayer, M., Lockhart, P., Roberts, N., Shanson, D., Thornhill, M., Heneghan, C.J., Prendergast, B.D., 2017b. Antibiotic prophylaxis for infective endocarditis: a systematic review and metaanalysis. Heart 103, 937–944. Cashin, P.J., 1990. Osteoarthritis–clinical aspects. Biochem. Soc. Trans. 18, 212–214. Chambers, J., Sandoe, J., Ray, S., Prendergast, B., Taggart, D., Westaby, S., Arden, C., Grothier, L., Wilson, J., Campbell, B., Gohlke-Bärwolf, C., Mestres, C.A., Rosenhek, R., Pibarot, P., Otto, C., 2014. The infective endocarditis team: recommendations from an international working group. Heart 100, 524–527. Chavakis, T., Wiechmann, K., Preissner, K.T., Herrmann, M., 2005. Staphylococcus aureus interactions with the endothelium: the role of bacterial secretable expanded repertoire adhesive molecules (SERAM) in disturbing host defense systems. Thromb. Haemost. 94, 278–285. Chirillo, F., Scotton, P., Rocco, F., Rigoli, R., Borsatto, F., Pedrocco, A., De Leo, A., Minniti, G., Polesel, E., Olivari, Z., 2013. Impact of a multidisciplinary management strategy on the outcome of patients with native valve infective endocarditis. Am. J. Cardiol. 112, 1171–1176. Chirouze, C., Alla, F., Fowler Jr, V.G., Sexton, D.J., Corey, G.R., Chu, V.H., Wang, A., Erpelding, M.L., Durante-Mangoni, E., Fernández-Hidalgo, N., Giannitsioti, E., Hannan, M.M., Lejko-Zupanc, T., Miró, J.M., Muñoz, P., Murdoch, D.R., Tattevin, P., Tribouilloy, C., Hoen, B., ICE Prospective Investigators, 2015. Impact of early valve surgery on outcome of Staphylococcus aureus prosthetic valve infective endocarditis: analysis in the International Collaboration of Endocarditis-Prospective Cohort Study. Clin. Infect. Dis. 60, 741–774.

649

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

Hoen, B., Alla, F., Selton-Suty, C., Béguinot, I., Bouvet, A., Briançon, S., Casalta, J.P., Danchin, N., Delahaye, F., Etienne, J., Le Moing, V., Leport, C., Mainardi, J.L., Ruimy, R., Vandenesch, F., Association pour l'Etude et la Prévention de l'Endocardite Infectieuse (AEPEI) Study Group, 2002. Changing profile of infective endocarditis: results of a 1-year survey in France. JAMA 288, 75–81. Hoen, B., 2006. Epidemiology and antibiotic treatment of infective endocarditis: an update. Heart 92, 1694–1700. Hoerr, V., Nagelmann, N., Nauerth, A., Kuhlmann, M.T., Stypmann, J., Faber, C., 2013. Cardiac-respiratory self-gated cine ultra-short echo time (UTE) cardiovascular magnetic resonance for assessment of functional cardiac parameters at high magnetic fields. J. Cardiovasc. Magn. Reson. 15, 59. Holland, T.L., Baddour, L.M., Bayer, A.S., Hoen, B., Miro, J.M., Fowler, V.G. Jr., 2016. Infective endocarditis. Nat. Rev. Dis. Primers 2, 16059. Huang, J.T., Raiszadeh, M., Sakimura, I., Montgomerie, J.Z., Harwig, J.F., 1980. Detection of bacterial endocarditis with technetium-99m-labeled antistaphylococcal antibody. J. Nucl. Med. 21, 783–786. Hyafil, F., Rouzet, F., Lepage, L., Benali, K., Raffoul, R., Duval, X., Hvass, U., Iung, B., Nataf, P., Lebtahi, R., Vahanian, A., Le Guludec, D., 2013. Role of radiolabelled leucocyte scintigraphy in patients with a suspicion of prosthetic valve endocarditis and inconclusive echocardiography. Eur. Heart J. Cardiovasc. Imaging 14, 586–594. Iung, B., Erba, P.A., Petrosillo, N., Lazzeri, E., 2014. Common diagnostic flowcharts in infective endocarditis. Q. J. Nucl. Med. Mol. Imaging 58, 55–65. Jenkins, A., Diep, B.A., Mai, T.T., Vo, N.H., Warrener, P., Suzich, J., Stover, C.K., Sellman, B.R., 2015. Differential expression and roles of Staphylococcus aureus virulence determinants during colonization and disease. MBio 6, e02272–14. Jones, M.B., Montgomery, C.P., Boyle-Vavra, S., Shatzkes, K., Maybank, R., Frank, B.C., Peterson, S.N., Daum, R.S., 2014. Genomic and transcriptomic differences in community acquired methicillin resistant Staphylococcus aureus USA300 and USA400 strains. BMC Genom. 15, 1145. Kaasch, A.J., Barlow, G., Edgeworth, J.D., Fowler Jr, V.G., Hellmich, M., Hopkins, S., Kern, W.V., Llewelyn, M.J., Rieg, S., Rodriguez-Baño, J., Scarborough, M., Seifert, H., Soriano, A., Tilley, R., Tőrők, M.E., Weiß, V., Wilson, A.P., Thwaites, G.E., ISAC, SABG INSTINCT, UKCIRG, et al., 2014. Staphylococcus aureus bloodstream infection: a pooled analysis of five prospective, observational studies. J. Infect. 68, 242–251. Kang, D.H., Kim, Y.J., Kim, S.H., Sun, B.J., Kim, D.H., Yun, S.C., Song, J.M., Choo, S.J., Chung, C.H., Song, J.K., Lee, J.W., Sohn, D.W., 2012. Early surgery versus conventional treatment for infective endocarditis. N. Engl. J. Med. 366, 2466–2473. Karth, G., Koreny, M., Binder, T., Knapp, S., Zauner, C., Valentin, A., Honninger, R., Heinz, G., Siostrzonek, P., 2002. Complicated infective endocarditis necessitating ICU admission: clinical course and prognosis. Crit. Care 6, 149–154. Khasawneh, F.A., Ashcraft, D.S., Pankey, G.A., 2008. In vitro testing of daptomycin plus rifampin against methicillin-resistant Staphylococcus aureus resistant to rifampin. Saudi Med. J. 29, 1726–1729. Kiefer, T., Park, L., Tribouilloy, C., Cortes, C., Casillo, R., Chu, V., Delahaye, F., DuranteMangoni, E., Edathodu, J., Falces, C., Logar, M., Miró, J.M., Naber, C., Tripodi, M.F., Murdoch, D.R., Moreillon, P., Utili, R., Wang, A., 2011. Association between valvular surgery and mortality among patients with infective endocarditis complicated by heart failure. JAMA 306, 2239–2247. King, J.M., Kulhankova, K., Stach, C.S., Vu, B.G., Salgado-Pabón, W., 2016. Phenotypes and virulence among staphylococcus aureus US, USA200, USA300, USA400, and USA600 clonal lineages. mSphere 1 (pii: e00071-16). Knight, L.C., Maurer, A.H., Ammar, I.A., Shealy, D.J., Mattis, J.A., 1988. Evaluation of indium-111-labeled antifibrin antibody for imaging vascular thrombi. J. Nucl. Med. 29, 494–502. Krogman, A., Tilahun, A., David, C.S., Chowdhary, V.R., Alexander, M.P., Rajagopalan, G., 2017. HLA-DR polymorphisms influence in vivo responses to staphylococcal toxic shock syndrome toxin-1 in a transgenic mouse model. HLA 89, 20–28. Lalani, T., Cabell, C.H., Benjamin, D.K., Lasca, O., Naber, C., Fowler Jr., V.G., Corey, G.R., Chu, V.H., Fenely, M., Pachirat, O., Tan, R.S., Watkin, R., Ionac, A., Moreno, A., Mestres, C.A., Casabé, J., Chipigina, N., Eisen, D.P., Spelman, D., Delahaye, F., Peterson, G., Olaison, L., Wang, A., International Collaboration on EndocarditisProspective Cohort Study (ICE-PCS) Investigators, 2010. Analysis of the impact of early surgery on in-hospital mortality of native valve endocarditis: use of propensity score and instrumental variable methods to adjust for treatment-selection bias. Circulation 121, 1005–1013. Lee, H., Sun, E., Ham, D., Weissleder, R., 2008. Chip-NMR biosensor for detection and molecular analysis of cells. Nat. Med. 14, 869–874. Li, J.S., Sexton, D.J., Mick, N., Nettles, R., Fowler Jr., V.G., Ryan, T., Bashore, T., Corey, G.R., 2000. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin. Infect. Dis. 30, 633–638. Li, X., Wang, X., Thompson, C.D., Park, S., Park, W.B., Lee, J.C., 2016. Preclinical efficacy of clumping factor a in prevention of Staphylococcus aureus infection. MBio 7, e02232–15. Liu, C., Bayer, A., Cosgrove, S.E., Daum, R.S., Fridkin, S.K., Gorwitz, R.J., Kaplan, S.L., Karchmer, A.W., Levine, D.P., Murray, B.E., J Rybak, M., Talan, D.A., Chambers, H.F., Infectious Diseases Society of America, 2011. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin. Infect. Dis. 52, e18–e55. Lucet, J.C., Herrmann, M., Rohner, P., Auckenthaler, R., Waldvogel, F.A., Lew, D.P., 1990. Treatment of experimental foreign body infection caused by methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 34, 2312–2317. McDanel, J.S., Roghmann, M.C., Perencevich, E.N., Ohl, M.E., Goto, M., Livorsi, D.J., Jones, M., Albertson, J.P., Nair, R., O'Shea, A.M., Schweizer, M.L., 2017. Comparative effectiveness of cefazolin versus nafcillin or oxacillin for treatment of methicillinsusceptible Staphylococcus aureus infections complicated by bacteremia: a

G.R., Spelman, D., Bradley, S.F., Barsic, B., Pappas, P.A., Anstrom, K.J., Wray, D., Fortes, C.Q., Anguera, I., Athan, E., Jones, P., van der Meer, J.T., Elliott, T.S., Levine, D.P., Bayer, A.S., ICE Investigators, 2005. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 293, 3012–3021. Fowler Jr, V.G., Boucher, H.W., Corey, G.R., Abrutyn, E., Karchmer, A.W., Rupp, M.E., Levine, D.P., Chambers, H.F., Tally, F.P., Vigliani, G.A., Cabell, C.H., Link, A.S., DeMeyer, I., Filler, S.G., Zervos, M., Cook, P., Parsonnet, J., Bernstein, J.M., Price, C.S., Forrest, G.N., Fätkenheuer, G., Gareca, M., Rehm, S.J., Brodt, H.R., Tice, A., Cosgrove, S.E., S. aureus Endocarditis and Bacteremia Study Group, 2006. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N. Engl. J. Med. 355, 653–665. García-Cabrera, E., Fernández-Hidalgo, N., Almirante, B., Ivanova-Georgieva, R., Noureddine, M., Plata, A., Lomas, J.M., Gálvez-Acebal, J., Hidalgo-Tenorio, C., RuízMorales, J., Martínez-Marcos, F.J., Reguera, J.M., de la Torre-Lima, J., de Alarcón González, A., Group for the Study of Cardiovascular Infections of the Andalusian Society of Infectious Diseases Spanish Network for Research in Infectious Diseases, 2013. Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. Circulation 127, 2272–2284. Garrison, P.K., Freedman, L.R., 1970. Experimental endocarditis I. Staphylococcal endocarditis in rabbits resulting from placement of a polyethylene catheter in the right side of the heart. Yale J. Biol. Med. 42, 394–410. Gibson, G.W., Kreuser, S.C., Riley, J.M., Rosebury-Smith, W.S., Courtney, C.L., Juneau, P.L., Hollembaek, J.M., Zhu, T., Huband, M.D., Brammer, D.W., Brieland, J.K., Sulavik, M.C., 2007. Development of a mouse model of induced Staphylococcus aureus infective endocarditis. Comp. Med. 57, 563–569. Gomes, A., Slart, R.H., Sinha, B., Glaudemans, A.W., 2016. 18F-FDG PET/CT in the diagnostic workup of infective endocarditis and related intracardiac prosthetic material a clear message. J. Nucl. Med. 57, 1669–1671. Gomes, A., Glaudemans, A.W., Touw, D.J., van Melle, J.P., Willems, T.P., Maass, A.H., Natour, E., Prakken, N.H., Borra, R.J., van Geel, P.P., Slart, R.H., van Assen, S., Sinha, B., 2017. Diagnostic value of imaging in infective endocarditis: a systematic review. Lancet Infect. Dis. 17, e1–e14. Gonzalez De Molina, M., Fernandez-Guerrero, J.C., Azpitarte, J., 2002. Infectious endocarditis: degree of discordance between clinical guidelines recommendations and clinical practice. Rev. Esp. Cardiol. 55, 793–800. Gupta, R.K., Alba, J., Xiong, Y.Q., Bayer, A.S., Lee, C.Y., 2013. MgrA activates expression of capsule genes, but not the α-toxin gene in experimental Staphylococcus aureus endocarditis. J. Infect. Dis. 208, 1841–1848. Habets, J., Tanis, W., van Herwerden, L.A., van den Brink, R.B., Mali, W.P., de Mol, B.A., Chamuleau, S.A., Budde, R.P., 2014. Cardiac computed tomography angiography results in diagnostic and therapeutic change in prosthetic heart valve endocarditis. Int. J. Cardiovasc. Imaging 30, 377–387. Habib, G., Hoen, B., Tornos, P., Thuny, F., Prendergast, B., Vilacosta, I., Moreillon, P., de Jesus Antunes, M., Thilen, U., Lekakis, J., Lengyel, M., Müller, L., Naber, C.K., Nihoyannopoulos, P., Moritz, A., Zamorano, J.L., 2009. ESC Committee for Practice Guidelines, Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the task force on the prevention, diagnosis, and treatment of infective endocarditis of the European Society of Cardiology (ESC). endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur. Heart J. 30, 2369–2413. Habib, G., Lancellotti, P., Antunes, M.J., Bongiorni, M.G., Casalta, J.P., Del Zotti, F., Dulgheru, R., El Khoury, G., Erba, P.A., Iung, B., Miro, J.M., Mulder, B.J., PlonskaGosciniak, E., Price, S., Roos-Hesselink, J., Snygg-Martin, U., Thuny, F., Tornos Mas, P., Vilacosta, I., Zamorano, J.L., Document Reviewers, Erol Ç, Nihoyannopoulos, P., Aboyans, V., Agewall, S., Athanassopoulos, G., Aytekin, S., Benzer, W., Bueno, H., Broekhuizen, L., Carerj, S., Cosyns, B., De Backer, J., De Bonis, M., Dimopoulos, K., Donal, E., Drexel, H., Flachskampf, F.A., Hall, R., Halvorsen, S., Hoen, B., Kirchhof, P., Lainscak, M., Leite-Moreira, A.F., Lip, G.Y., Mestres, C.A., Piepoli, M.F., Punjabi, P.P., Rapezzi, C., Rosenhek, R., Siebens, K., Tamargo, J., Walker, D.M., 2015. 2015 ESC guidelines for the management of infective endocarditis: the task force for the management of infective endocarditis of the European Society of Cardiology (ESC). endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur. Heart J. 36, 3075–3128. Hamzeh-Cognasse, H., Damien, P., Chabert, A., Pozzetto, B., Cognasse, F., Garraud, O., 2015. Platelets and infections − complex interactions with bacteria. Front. Immunol. 6, 82. Heiro, M., Helenius, H., Mäkilä, S., Hohenthal, U., Savunen, T., Engblom, E., Nikoskelainen, J., Kotilainen, P., 2006. Infective endocarditis in a Finnish teaching hospital: a study on 326 episodes treated during 1980–2004. Heart 92, 1457–1462. Hemler, M.E., Elices, M.J., Parker, C., Takada, Y., 1990. Structure of the integrin VLA-4 and its cell–cell and cell-matrix adhesion functions. Immunol. Rev. 114, 45–65. Heying, R., van de Gevel, J., Que, Y.A., Moreillon, P., Beekhuizen, H., 2007. Fibronectinbinding proteins and clumping factor A in Staphylococcus aureus experimental endocarditis: FnBPA is sufficient to activate human endothelial cells. Thromb. Haemost. 97, 617–626. Hienz, S.A., Schennings, T., Heimdahl, A., Flock, J.I., 1996. Collagen binding of Staphylococcus aureus is a virulence factor in experimental endocarditis. J. Infect. Dis. 174, 83–88. Highman, B., Roshe, J., Altland, P.D., 1959. Production of endocarditis with Staphylococcus aureus and Streptococcus mitis in dogs with aortic insufficiency. Circ. Res. 4, 250–256. Hill, E.E., Herijgers, P., Claus, P., Vanderschueren, S., Peetermans, W.E., Herregods, M.C., 2007. Abscess in infective endocarditis: the value of transesophageal echocardiography and outcome: a 5-year study. Am. Heart J. 154, 923–928.

650

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

Pizzi, M.N., Roque, A., Fernández-Hidalgo, N., Cuéllar-Calabria, H., Ferreira-González, I., Gonzàlez-Alujas, M.T., Oristrell, G., Gracia-Sánchez, L., González, J.J., RodríguezPalomares, J., Galiñanes, M., Maisterra-Santos, O., Garcia-Dorado, D., Castell-Conesa, J., Almirante, B., Aguadé-Bruix, S., Tornos, P., 2015. Improving the diagnosis of infective endocarditis in prosthetic valves and intracardiac devices with 18FFluordeoxyglucose positron emission tomography/computed tomography angiography: initial results at an infective endocarditis referral center. Circulation 132, 1113–1126. Plicht, B., Jánosi, R.A., Buck, T., Erbel, R., 2010. Infective endocarditis as cardiovascular emergency. Internist (Berl). 51, 987–994. Que, Y.A., Moreillon, P., 2011. Infective endocarditis. Nat. Rev. Cardiol. 8, 322–336. Que, Y.A., Haefliger, J.A., Piroth, L., Francois, P., Widmer, E., Entenza, J.M., Sinha, B., Herrmann, M., Francioli, P., Vaudaux, P., Moreillon, P., 2005. Fibrinogen and fibronectin binding cooperate for valve infection and in-vasion in Staphylococcus aureus experimental endocarditis. J. Exp. Med. 201, 1627–1635. Remadi, J.P., Habib, G., Nadji, G., Brahim, A., Thuny, F., Casalta, J.P., Peltier, M., Tribouilloy, C., 2007. Predictors of death and impact of surgery in Staphylococcus aureus infective endocarditis. Ann. Thorac. Surg. 83, 1295–1302. Riedel, D.J., Weekes, E., Forrest, G.N., 2008. Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by Staphylococcus aureus. Antimicrob. Agents Chemother. 52, 2463–2467. Ring, J., Hoerr, V., Tuchscherr, L., Kuhlmann, M.T., Löffler, B., Faber, C., 2014. MRI visualization of Staphyloccocus aureus-induced infective endocarditis in mice. PLoS One 9, e107179. Rivas, P., Alonso, J., Moya, J., de Górgolas, M., Martinell, J., Fernández Guerrero, M.L., 2005. The impact of hospital-acquired infections on the microbial etiology and prognosis of late-onset prosthetic valve endocarditis. Chest 128, 764–771. Rodriguez, Y., Greenspon, A.J., Sohail, M.R., Carrillo, R.G., 2012. Cardiac device-related endocarditis complicated by spinal abscess. Pacing Clin. Electrophysiol. 35, 269–274. Roque, A., Pizzi, M.N., Cuéllar-Calàbria, H., Aguadé-Bruix, S., 2017. 18F-FDG-PET/CT angiography for the diagnosis of infective endocarditis. Curr. Cardiol. Rep. 19, 15. Rose, H.R., Holzman, R.S., Altman, D.R., Smyth, D.S., Wasserman, G.A., Kafer, J.M., Wible, M., Mendes, R.E., Torres, V.J., Shopsin, B., 2015. Cytotoxic virulence predicts mortality in nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus. J. Infect. Dis. 211, 1862–1874. Rosenthal, N., Brown, S., 2007. The mouse ascending: perspectives for human-disease models. Nat. Cell Biol. 9, 993–999. Rouzet, F., Hernandez, M.D., Hervatin, F., Sarda-Mantel, L., Lefort, A., Duval, X., Louedec, L., Fantin, B., Le Guludec, D., Michel, J.B., 2008. Technetium 99m- Labeled annexin V scintigraphy of platelet activation in vegetations of experimental endocarditis. Circulation 117, 781–789. Rundström, H., Kennergren, C., Andersson, R., Alestig, K., Hogevik, H., 2004. Pacemaker endocarditis during 18 years in Göteborg. Scand. J. Infect. Dis. 36, 674–679. Salgado-Pabón, W., Breshears, L., Spaulding, A.R., Merriman, J.A., Stach, C.S., Horswill, A.R., Peterson, M.L., Schlievert, P.M., 2013. Superantigens are critical for Staphylococcus aureus Infective endocarditis, sepsis, and acute kidney injury. MBio 4 (pii: e00494-13). Salgado-Pabon, W., Schlievert, P.M., 2014. Models matter: the search for an effective Staphylococcus aureus vaccine. Nat. Rev. Microbiol. 12, 585–591. Salvador, V.B., Chapagain, B., Joshi, A., Brennessel, D.J., 2017. Clinical risk factors for infective endocarditis in staphylococcus aureus bacteremia. Tex. Heart Inst. J. 44, 10–15. Sande, M.A., Johnson, M.L., 1985. Antimicrobial therapy of experimental endocarditis caused by Staphylococcus aureus. J. Infect. Dis. 131, 367–375. Scholtens, A.M., Swart, L.E., Verberne, H.J., Budde, R.P.J., Lam, M.G.E.H., 2017. Dualtime-point FDG PET/CT imaging in prosthetic heart valve endocarditis. J. Nucl. Cardiol. http://dx.doi.org/10.1007/s12350-017-0902-3. Schrenk, K.G., Frosinski, J., Scholl, S., Otto, S., La Rosée, P., Hochhaus, A., Pletz, M.W., 2016. Successful treatment of neutropenic MRSA bacteremia with septic superior vena cava thrombus and cerebral embolism using high-dose daptomycin. Ann. Hematol. 95, 355–357. Seckeler, M.D., Hoke, T.R., 2011. The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin. Epidemiol. 3, 67–84. Selton-Suty, C., Célard, M., Le Moing, V., Doco-Lecompte, T., Chirouze, C., Iung, B., Strady, C., Revest, M., Vandenesch, F., Bouvet, A., Delahaye, F., Alla, F., Duval, X., Hoen, B., AEPEI Study Group, 2012. Preeminence of Staphylococcus aureus in infective endocarditis: a 1-year population-based survey. Clin. Infect. Dis. 54, 1230–1239. Seok, J., Warren, H.S., Cuenca, A.G., Mindrinos, M.N., Baker, H.V., Xu, W., Richards, D.R., McDonald-Smith, G.P., Gao, H., Hennessy, L., Finnerty, C.C., López, C.M., Honari, S., Moore, E.E., Minei, J.P., Cuschieri, J., Bankey, P.E., Johnson, J.L., Sperry, J., Nathens, A.B., Billiar, T.R., West, M.A., Jeschke, M.G., Klein, M.B., Gamelli, R.L., Gibran, N.S., Brownstein, B.H., Miller-Graziano, C., Calvano, S.E., Mason, P.H., Cobb, J.P., Rahme, L.G., Lowry, S.F., Maier, R.V., Moldawer, L.L., Herndon, D.N., Davis, R.W., Xiao, W., Tompkins, R.G., 2013. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl. Acad. Sci. U. S. A. 110, 3507–3512. Sharma-Kuinkel, B.K., Mongodin, E.F., Myers, J.R., Vore, K.L., Canfield, G.S., Fraser, C.M., Rude, T.H., Fowler Jr., V.G., Gill, S.R., 2015. Potential influence of staphylococcus aureus clonal complex 30 genotype and transcriptome on hematogenous infections. Open Forum Infect. Dis. 2, ofv093. Shultz, L.D., Brehm, M.A., Garcia-Martinez, J.V., Greiner, D.L., 2012. Humanized mice for immune system investigation: progress, promise and challenges. Nat. Rev. Immunol. 12, 786–798. Sinha, B., Francois, P.P., Nusse, O., Foti, M., Hartford, O.M., Vaudaux, P., Foster, T.J., Lew, D.P., Herrmann, M., Krause, K.H., 1999. Fibronectin-binding protein acts as Staphylococcus aureus invasin via fibronectin bridging to integrin alpha5beta1. Cell.

nationwide cohort study. Clin. Infect. Dis. http://dx.doi.org/10.1093/cid/cix287. (Epub ahead of print). McKinsey, D.S., Ratts, T.E., Bisno, A.L., 1987. Underlying cardiac lesions in adults with infective endocarditis The changing spectrum. Am. J. Med. 82, 681–688. Miajlovic, H., Loughman, A., Brennan, M., Cox, D., Foster, T.J., 2007. Both complementand fibrinogen-dependent mechanisms contribute to platelet aggregation mediated by Staphylococcus aureus clumping factor B. Infect. Immun. 75, 3335–3343. Miró, J.M., García-de-la-Mària, C., Armero, Y., Soy, D., Moreno, A., del Río, A., Almela, M., Sarasa, M., Mestres, C.A., Gatell, J.M., Jiménez de Anta, M.T., Marco, F., Hospital Clinic Experimental Endocarditis Study Group, 2009. Addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 53, 4172–4177. Moreillon, P., Que, Y.A., 2004. Infective endocarditis. Lancet 363, 139–149. Moreillon, P., Que, Y.A., Bayer, A.S., 2002. Pathogenesis of streptococcal and staphylococcal endocarditis. Infect. Dis. Clin. North Am. 16, 297–318. Mourvillier, B., Trouillet, J.L., Timsit, J.F., Baudot, J., Chastre, J., Régnier, B., Gibert, C., Wolff, M., 2004. Infective endocarditis in the intensive care unit: clinical spectrum and prognostic factors in 228 consecutive patients. Intensive Care Med. 30, 2046–2052. Muñoz, P., Kestler, M., De Alarcon, A., Miro, J.M., Bermejo, J., Rodríguez-Abella, H., Fariñas, M.C., Cobo Belaustegui, M., Mestres, C., Llinares, P., Goenaga, M., Navas, E., Oteo, J.A., Tarabini, P., Bouza, E., Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en España (GAMES), 2015. Current epidemiology and outcome of infective endocarditis: a multicenter, prospective, cohort study. Medicine (Baltimore). 94, e1816. Murdoch, D.R., Corey, G.R., Hoen, B., Miró, J.M., Fowler Jr., V.G., Bayer, A.S., Karchmer, A.W., Olaison, L., Pappas, P.A., Moreillon, P., Chambers, S.T., Chu, V.H., Falcó, V., Holland, D.J., Jones, P., Klein, J.L., Raymond, N.J., Read, K.M., Tripodi, M.F., Utili, R., Wang, A., Woods, C.W., Cabell, C.H., International Collaboration on EndocarditisProspective Cohort Study (ICE-PCS) Investigators, 2009. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch. Intern. Med. 169, 463–473. Mzabi, A., Kernéis, S., Richaud, C., Podglajen, I., Fernandez-Gerlinger, M.P., Mainardi, J.L., 2016. Switch to oral antibiotics in the treatment of infective endocarditis is not associated with increased risk of mortality in non-severely ill patients. Clin. Microbiol. Infect. 22, 607–612. Niemann, S., Spehr, N., Van Aken, H., Morgenstern, E., Peters, G., Herrmann, M., Kehrel, B.E., 2004. Soluble fibrin is the main mediator of Staphylococcus aureus adhesion to platelets. Circulation 110, 193–200. Nienaber, J.J., Sharma Kuinkel, B.K., Clarke-Pearson, M., Lamlertthon, S., Park, L., Rude, T.H., Barriere, S., Woods, C.W., Chu, V.H., Marín, M., Bukovski, S., Garcia, P., Corey, G.R., Korman, T., Doco-Lecompte, T., Murdoch, D.R., Reller, L.B., Fowler Jr., V.G., 2011. Methicillin-susceptible Staphylococcus aureus endocarditis isolates are associated with clonal complex 30 genotype and a distinct repertoire of enterotoxins and adhesins. J. Infect. Dis. 204, 704–713. Nissen, J.L., Skov, R., Knudsen, J.D., Ostergaard, C., Schønheyder, H.C., Frimodt-Møller, N., Benfield, T., 2013. Effectiveness of penicillin, dicloxacillin and cefuroxime for penicillin-susceptible Staphylococcus aureus bacteraemia: a retrospective, propensity-score-adjusted case-control and cohort analysis. J. Antimicrob. Chemother. 68, 1894–1900. Nonaka, M., Kusuhara, T., An, K., Nakatsuka, D., Sekine, Y., Iwakura, A., Yamanaka, K., 2013. Comparison between early and late prosthetic valve endocarditis: clinical characteristics and outcomes. J. Heart Valve Dis. 22, 567–574. Oprea, M., Patriche, D.S., Străuţ, M., Antohe, F., 2014. Molecular characterization of Staphylococcus aureus strains isolated from infective endocarditis. Roum. Arch. Microbiol. Immunol. 73, 74–83. Orvin, K., Goldberg, E., Bernstine, H., Groshar, D., Sagie, A., Kornowski, R., Bishara, J., 2015. The role of FDG-PET/CT imaging in early detection of extra-cardiac complications of infective endocarditis. Clin. Microbiol. Infect. 21, 69–76. Oyama, T., Miyazaki, M., Yoshimura, M., Takata, T., Ohjimi, H., Jimi, S., 2016. Biofilmforming methicillin-resistant Staphylococcus aureus survive in kupffer cells and exhibit high virulence in mice. Toxins (Basel) 8. Panizzi, P., Nahrendorf, M., Figueiredo, J.L., Panizzi, J., Marinelli, B., Iwamoto, Y., Keliher, E., Maddur, A.A., Waterman, P., Kroh, H.K., Leuschner, F., Aikawa, E., Swirski, F.K., Pittet, M.J., Hackeng, T.M., Fuentes-Prior, P., Schneewind, O., Bock, P.E., Weissleder, R., 2011. In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation. Nat. Med. 17, 1142–1146. Pappelbaum, K.I., Gorzelanny, C., Grässle, S., Suckau, J., Laschke, M.W., Bischoff, M., Bauer, C., Schorpp-Kistner, M., Weidenmaier, C., Schneppenheim, R., Obser, T., Sinha, B., Schneider, S.W., 2013. Ultralarge von Willebrand factor fibers mediate luminal Staphylococcus aureus adhesion to an intact endothelial cell layer under shear stress. Circulation 128, 50–59. Parker, D., 2017. Humanized mouse models of Staphylococcus aureus infection. Front. Immunol. 8, 512. Paul, M., Zemer-Wassercug, N., Talker, O., Lishtzinsky, Y., Lev, B., Samra, Z., Leibovici, L., Bishara, J., 2011. Are all beta-lactams similarly effective in the treatment of methicillin-sensitive Staphylococcus aureus bacteraemia? Clin. Microbiol. Infect. 17, 1581–1586. Perlman, R.L., 2016. Mouse models of human disease: an evolutionary perspective. Evol. Med. Public Health 2016, 170–176. Piroth, L., Que, Y.A., Widmer, E., Panchaud, A., Piu, S., Entenza, J.M., Moreillon, P., 2008. The fibrinogen- and fibronectin-binding domains of Staphylococcus aureus fibronectin-binding protein. A synergistically promote endothelial invasion and experimental endocarditis. Infect. Immun. 76, 3824–3831.

651

International Journal of Medical Microbiology 308 (2018) 640–652

V. Hoerr et al.

Hoylaerts, M.F., Verhamme, P., 2012. Fibrin formation by staphylothrombin facilitates Staphylococcus aureus-induced platelet aggregation. Thromb. Haemost. 107, 1107–1121. Veltrop, M.H., Bancsi, M.J., Bertina, R.M., Thompson, J., 2000. Role of monocytes in experimental Staphylococcus aureus endocarditis. Infect. Immun. 68, 4818–4821. Vilacosta, I., Graupner, C., San Román, J.A., Sarriá, C., Ronderos, R., Fernández, C., Mancini, L., Sanz, O., Sanmartín, J.V., Stoermann, W., 2002. Risk of embolization after institution of antibiotic therapy for infective endocarditis. J. Am. Coll. Cardiol. 39, 1489–1495. Vogel, M., Schmitz, R.P., Hagel, S., Pletz, M.W., Gagelmann, N., Scherag, A., Schlattmann, P., Brunkhorst, F.M., 2016. Infectious disease consultation for Staphylococcus aureus bacteremia–A systematic review and meta-analysis. J. Infect. 72, 19–28. Wang, A., Athan, E., Pappas, P.A., Fowler, V.G. Jr., Olaison, L., Paré, C., Almirante, B., Muñoz, P., Rizzi, M., Naber, C., Logar, M., Tattevin, P., Iarussi, D.L., Selton-Suty, C., Jones, S.B., Casabé, J., Morris, A., Corey, G.R., Cabell, C.H., International Collaboration on Endocarditis-Prospective Cohort Study Investigators, 2007. Contemporary clinical profile and outcome of prosthetic valve endocarditis. JAMA 297, 1354–1361. Warren, H.S., Tompkins, R.G., Moldawer, L.L., Seok, J., Xu, W., Mindrinos, M.N., Maier, R.V., Xiao, W., Davis, R.W., 2015. Mice are not men. Proc. Natl. Acad. Sci. U. S. A. 112, E345. Weidenmaier, C., Peschel, A., Xiong, Y.Q., Kristian, S.A., Dietz, K., Yeaman, M.R., Bayer, A.S., 2005. Lack of wall teichoic acids in Staphylococcus aureus leads to reduced interactions with endothelial cells and to attenuated virulence in a rabbit model of endocarditis. J. Infect. Dis. 191, 1771–1777. Weis, S., Hagel, S., Schmitz, R.P., Scherag, A., Brunkhorst, F.M., Forstner, C., Löffler, B., Pletz, M.W., 2017. Study on the utility of a statewide counselling programme for improving mortality outcomes of patients with Staphylococcus aureus bacteraemia in Thuringia (SUPPORT): a study protocol of a cluster-randomised crossover trial. BMJ Open 7, e013976. Werdan, K., Dietz, S., Löffler, B., Niemann, S., Bushnaq, H., Silber, R., Peters, G., MuellerWerdan, U., 2014. Mechanisms of infective endocarditis: pathogen-host interaction and risk states. Nat. Rev. Cardiol. 11, 35–50. Wong, D., Rubinshtein, R., Keynan, Y., 2016. Alternative cardiac imaging modalities to echocardiography for the diagnosis of infective endocarditis. Am. J. Cardiol. 118, 1410–1418. Yan, J., Zhang, C., Niu, Y., Yuan, R., Zeng, X., Ge, X., Yang, Y., Peng, X., 2016. The role of 18F-FDG PET/CT in infectious endocarditis: a systematic review and meta-analysis. Int. J. Clin. Pharmacol. Ther. 54, 337–342. Yokota, M., Basi, D.L., Herzberg, M.C., Meyer, M.W., 2001. Anti-fibrin antibody binding in valvular vegetations and kidney lesions during experimental endocarditis. Microbiol. Immunol. 45, 699–707. Zak, O., Sande, M.A., 1999. Handbook of Animal Models of Infection: Experimental Models in Antimicrobial Chemotherapy. Academic Press. Zhu, Y., Xiong, Y.Q., Sadykov, M.R., Fey, P.D., Lei, M.G., Lee, C.Y., Bayer, A.S., Somerville, G.A., 2009. Tricarboxylic acid cycle-dependent attenuation of Staphylococcus aureus in vivo virulence by selective inhibition of amino acid transport. Infect. Immun. 77, 4256–4264. van Oosten, M., Schäfer, T., Gazendam, J.A., Ohlsen, K., Tsompanidou, E., de Goffau, M.C., Harmsen, H.J., Crane, L.M., Lim, E., Francis, K.P., Cheung, L., Olive, M., Ntziachristos, V., van Dijl, J.M., van Dam, G.M., 2013. Realtime in vivo imaging of invasive- and biomaterial-associated bacterial infections usingfluorescently labelled vancomycin. Nat. Commun. 4, 2584. von Knobelsdorff-Brenkenhoff, F., Schulz-Menger, J., 2016. Role of cardiovascular magnetic resonance in the guidelines of the European Society of Cardiology. J. Cardiovasc. Magn. Reson. 18, 6.

Microbiol. 1, 101–117. Slipczuk, L., Codolosa, J.N., Davila, C.D., Romero-Corral, A., Yun, J., Pressman, G.S., Figueredo, V.M., 2013. Infective endocarditis epidemiology over five decades: a systematic review. PLoS One 8, e82665 (Erratum in: PLoS One. 2014, 9, e111564.). Snygg-Martin, U., Gustafsson, L., Rosengren, L., Alsiö, A., Ackerholm, P., Andersson, R., Olaison, L., 2008. Cerebrovascular complications in patients with left-sided infective endocarditis are common: a prospective study using magnetic resonance imaging and neurochemical brain damage markers. Clin. Infect. Dis. 47, 23–30. Spaulding, A.R., Satterwhite, E.A., Lin, Y.C., Chuang-Smith, O.N., Frank, K.L., Merriman, J.A., Schaefers, M.M., Yarwood, J.M., Peterson, M.L., Schlievert, P.M., 2012. Comparison of Staphylococcus aureus strains for ability to cause infective endocarditis and lethal sepsis in rabbits. Front. Cell. Infect. Microbiol. 2, 18. Stach, C.S., Vu, B.G., Merriman, J.A., Herrera, A., Cahill, M.P., Schlievert, P.M., SalgadoPabón, W., 2016. Novel tissue level effects of the Staphylococcus aureus enterotoxin gene cluster are essential for infective endocarditis. PLoS One. 11, e0154762. Stehbens, W.E., Delahunt, B., Zuccollo, J.M., 2000. The histopathology of endocardial sclerosis. Cardiovasc. Pathol. 9, 161–173. Stein, C., Makarewicz, O., Forstner, C., Weis, S., Hagel, S., Löffler, B., Pletz, M.W., 2016. Should daptomycin-rifampin combinations for MSSA/MRSA isolates be avoided because of antagonism? Infection 44, 499–504. Strobel, M., Pfortner, H., Tuchscherr, L., Volker, U., Schmidt, F., Kramko, N., Schnittler, H.J., Fraunholz, M.J., Loffler, B., Peters, G., Niemann, S., 2016. Post-invasion events after infection with Staphylococcus aureus are strongly dependent on both the host cell type and the infecting S. aureus strain. Clin. Microbiol. Infect. 22, 799–809. Subedi, S., Jennings, Z., Chen, S.C., 2017. laboratory approach to the diagnosis of culturenegative infective endocarditis. Heart Lung Circ pii: S1443-9506(17)30097-5. Sullam, P.M., Bayer, A.S., Foss, W.M., Cheung, A.L., 1996. Diminished platelet binding in vitro by Staphylococcus aureus is associated with reduced virulence in a rabbit model of infective endocarditis. Infect. Immun. 64, 4915–4921. Thalme, A., Westling, K., Julander, I., 2007. In-hospital and long-term mortality in infective endocarditis in injecting drug users compared to non-drug users: a retrospective study of 192 episodes. Scand. J. Infect. Dis. 39, 197–204. Thuny, F., Di Salvo, G., Belliard, O., Avierinos, J.F., Pergola, V., Rosenberg, V., Casalta, J.P., Gouvernet, J., Derumeaux, G., Iarussi, D., Ambrosi, P., Calabró, R., Riberi, A., Collart, F., Metras, D., Lepidi, H., Raoult, D., Harle, J.R., Weiller, P.J., Cohen, A., Habib, G., 2005. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Circulation 112, 69–75. Thuny, F., Grisoli, D., Collart, F., Habib, G., Raoult, D., 2012. Management of infective endocarditis: challenges and perspectives. Lancet 379, 965–975. Tong, S.Y., Davis, J.S., Eichenberger, E., Holland, T.L., Fowler Jr., V.G., 2015. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin. Microbiol. Rev. 28, 603–661. Tornos, P., Iung, B., Permanyer-Miralda, G., Baron, G., Delahaye, F., Gohlke-Bärwolf, E.G., Butchart, Ch., Ravaud, P., Vahanian, A., 2005. Infective endocarditis in Europe: lessons from the Euro heart survey. Heart 91, 571–575. Tuchscherr, L., Medina, E., Hussain, M., Völker, W., Heitmann, V., Niemann, S., Holzinger, D., Roth, J., Proctor, R.A., Becker, K., Peters, G., Löffler, B., 2011. Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection. EMBO Mol. Med. 3, 129–141. Tuchscherr, L., Kreis, C.A., Hoerr, V., Flint, L., Hachmeister, M., Geraci, J., Bremer-Streck, S., Kiehntopf, M., Medina, E., Kribus, M., Raschke, M., Pletz, M., Peters, G., Löffler, B., 2016. Staphylococcus aureus develops increased resistance to antibiotics by forming dynamic small colony variants during chronic osteomyelitis. J. Antimicrob. Chemother. 71, 438–448. Vanassche, T., Kauskot, A., Verhaegen, J., Peetermans, W.E., van Ryn, J., Schneewind, O.,

652