3. Staphylococcus aureus

S. aureus is a Gram-positive coccus with a diameter of 0.5–1.5 μm, grouped as single cells, in pairs, tetrads, short chains, or forming a conglomerate in a cluster of grapes. This microorganism was first described in the year 1880, in Aberdeen, Scotland, by the surgeon Alexander Ágoston. The name comes from the Greek σταφυλόκοκκος, which is composed of the terms "staphylé," meaning cluster, and coccus, meaning grain or grape, and from the Latin "aureus" which means golden, that is to say "cluster of golden grapes."

They are non-motile bacteria, not sporulated, with no capsule (although there are some strains that develop a slime capsule); they are facultative anaerobes. Most staphylococci produce catalase (enzyme capable of dismutating hydrogen peroxide in H2O+O2), characteristic that is used to differentiate its sort from others like Streptococcus and Enterococcus. In 1961, the first report was made on the existence of a methicillin-resistant Staphylococcus aureus [18].

### 3.1 Staphylococcus aureus and endothelial cell

S. aureus is a pathogen that causes significant morbidity and mortality worldwide [2]. It is the leading pathogen associated with life-threatening bloodstream infections [19].

Although S. aureus is mainly known as an extracellular pathogen, it has been shown to invade and survive within endothelial cells, both within vacuoles and free in the cytoplasm, which implies that the bacteria can escape from the phagolysosome. S. aureus tends to infect endovascular tissue. It is believed that this ability contributes to causing a persistent endovascular infection with endothelial destruction.

#### 3.2 Endothelial cell and Staphylococcus aureus ingestion

On the other hand, the death of endothelial cells after the invasion of S. aureus occurs at least in part by apoptosis, as demonstrated by DNA fragmentation and changes in nuclear morphology. Apoptotic changes are observed as early as 1 h after infection of endothelial cells [18]; they are considered to function as nonprofessional phagocytes, being able to ingest S. aureus [20, 21] following the adhesion of this to endothelial cell monolayers; invasion can occur through ingestion by endothelial cells.

For the internalization of S. aureus, adherence seems to be necessary, since the use of the phagocytosis inhibitor cytochalasin D prevented apoptosis. Studies show that living intracellular S. aureus induces apoptosis of endothelial cells and that this depends on a factor associated with viable organisms, since dead S. aureus (by ultraviolet light) also internalized does not induce it [18]. The process has been observed through electron transmission micrographs of bovine aortic endothelial cell monolayers infected with S. aureus, showing phagocytosis following a sequence of events: (I) adhesion of S. aureus to the endothelial cell, (II) formation of cupshaped processes on the surface of the endothelial cell underlying the adherent bacteria, and (III) elongation of the cup and engulfment of bacteria within a phagosome [19].

### 3.3 Heme prosthetic group and Staphylococcus aureus

To colonize a vertebrate host, S. aureus requires numerous nutrients, such as the prosthetic group heme. The requirement can be met through two distinct mechanisms: importing exogenous heme through dedicated machinery or synthesizing endogenous heme from own metabolic precursors. These two mechanisms are necessary for a complete virulence of S. aureus [22, 23]. Once acquired, heme is used for several cell processes. The intact heme is used as a cofactor for enzymes [24], including cytochromes in the electron transport chain, catalase for the detoxification of reactive oxygen species, and bacterial nitric oxide synthase (bNOS).

Although the S. aureus requires heme, its excess is toxic to the germ, so it has a mechanism for hem detoxification through a hem sensor system (HssRS) that induces the expression of a hem regulator transporter (hrtAB) [25]. The suppression of the components of this route affects the virulence of S. aureus. This ability to detoxify heme is critical to survive in the host. Also, the synthesis of nitric oxide is important for the bacteria to survive. Bacteria encode genes similar to nitric oxide synthetase in mammals, which leads to the characterization of the nitric oxide synthase hemoprotein (bNOS) [26].

#### 3.4 Staphylococcus aureus as a pro-inflammatory agent

The S. aureus contains molecules such as peptidoglycan and lipoteichoic acid, potent stimulants for the production of cytosines such as TNF-α, IL-4, IL-6, IL-8, IL-12, IL-1be, growth-regulated oncogene (GRO) alpha, and regulated upon activation, normal T-cell expressed, and secreted (RANTES). RANTES has a chemotactic function to perform leukocyte recruitment to areas of infection in addition to inducing tumor necrosis factor alpha and interleukin 1. Elevated levels can persist for 7–14 days [27]. As we can observe, S. aureus activates in a very important way the process of inflammation.

#### 3.5 Staphylococcus aureus and blood stream infections in infective endocarditis

Circulatory blood stream infections (positive blood cultures) occur in patients with intravascular prosthetic devices as the most common source of infections related to health care [28]. MRSA was the most frequent pathogen in these types of infections with a consistent increase in the isolates of MRSA [29–31]. In the EU, epidemiological surveillance data on bloodstream infections show a marked variability among the member countries that make up a proportion of S. aureus that is resistant to methicillin, ranging from less than 1% to more than 50%. In addition to infections associated with health care, new MRSA strains have emerged in their communities as human pathogens associated with livestock [32].

#### 3.6 Endocardial endothelium and myocardial capillary endothelium

The anatomical and physiological barriers of cardiac protection such as the endothelium can be compromised in its structure when areas of turbulence and injury are generated, producing an area exposed to infection. The intracardiac cavities have a cell layer called endocardial endothelium (EE) that covers the endocardium of the atria, ventricles, and all their anatomical components (papillary muscles, chordae tendineae, and heart valves). The EE acts as an active mechanism of biological heart-blood barrier, since it interacts dynamically with cardiomyocytes allowing direct communication and signaling between both types of cells. This

Infective Endocarditis: Inflammatory Response, Genetic Susceptibility, Oxidative Stress… DOI: http://dx.doi.org/10.5772/intechopen.84908

electrochemical communication between the cells of the EE and the cardiomyocytes allows a rapid intracellular electrochemical propagation and amplification of the functional properties of the EE.

Signaling between cardiac endothelial cells (EE and myocardial capillary endothelium) and cardiomyocytes influences cardiac growth, contractile performance, and rhythmicity. The network of Purkinje fibers and the subendocardial neural plexus (parasympathetic nervous system) is immediately below the endocardial endothelium (EE) and participates in the endothelial control of cardiac rhythm. Endothelin-1 (Et-1), nitric oxide (ON), prostaglandins (PGI2), prostacyclin (AI and AII), angiotensin I and II, and vascular endothelial growth factor (VEGF) are involved in these processes.

The endothelium that covers cardiac structures is at the vascular level, the myocardial capillary, and the endocardium; its activation includes changes in the endothelial phenotype as part of the physiological adaptive response to several possible injuries and stressors. The dysfunction of the endothelium implies a deregulated response that is not useful and that can be permanent.

One of the clinical disorders that selectively damage the endocardium and subendocardial interstitial tissue is endocarditis. This entity causes activation of the vascular and endocardial endothelial system, as well as poor adaptation or failure characterized by hemodynamic abnormalities, neurohormonal imbalance, cytokine expression, and endothelial dysfunction [33].

Infective endocarditis is an anatomoclinical entity characterized by microbial infection of the valvular or parietal endothelium or both; it is located predominantly on the left side of the heart, although it can also occur in the right (e.g., endovenous drug), which produces inflammation, exudation, and proliferation of the endocardium. The most characteristic lesion is the vegetation, constituted by an amorphous mass of platelets and fibrin, of variable size, which contains multiple microorganisms and scarce inflammatory cells (fibrinoplaquetary thrombus) [34]. This type of lesions generates metastatic infection in other anatomical territories, for example, the central nervous system, apostematous meningitis, myocarditis, pyelonephritis, and splenic abscesses which are at risk of rupture [35, 36].

#### 4. Clinical manifestations

The clinical manifestations of infective endocarditis are acute rapidly progressive or subacute; the pathophysiological processes of both are explained by immunological and vascular phenomena, such as inflammatory response, mediators of inflammation triggered by a maladaptive response to an infectious process, aggregation of immune complexes, infectious vasculitis, and peripheral microembolism [34, 37]. Depending on the affected cardiac cavity (right/left) or valvular system, the clinical manifestations will be due to the aforementioned processes [38] (Table 1).

#### 4.1 Anatomopathological changes

The anatomopathological changes due to the formation of vegetations in the valvular ring and/or in the leaflets cause an anatomical alteration. If this anatomical alteration generated by a vegetation prevents valvular closure, it will be expressed as a murmur of valvular insufficiency and in severe cases such as microembolisms septic and non-septic and cardiac failure [34, 37].


#### Table 1.

Clinical signs and complications of infective endocarditis.

#### 4.2 Considerations on the cardiac cavity affected by infective endocarditis

The standard reference to corroborate the clinical diagnosis of IE is transesophageal echocardiography since the transthoracic echocardiogram, even when limited to native valves, decreases the diagnostic probability of IE [39].

Right and left endocarditis are two distinct entities that require different clinical and surgical approaches. The diagnosis of endocarditis on the right side requires a high index of clinical suspicion. It can occur with a history of intravenous drug use, fever, and pulmonary infiltrates, although intravenous drug abuse is also a cause of IE on the left side of the heart [36]. The information provided by echocardiography is of prognostic and therapeutic value.

If the vegetation is <1.0 cm in diameter, it can be expected that antibiotic therapy will resolve the infection; if the size of the vegetation determined by echocardiography is ≥1.0 cm without response to treatment, surgical intervention should be considered [40].

Surgical treatment in IE on the left side of the heart, for example, the mitral valve, is indicated in patients with severe mitral regurgitation, even in the absence of congestive heart failure, with mitral annular abscess, large vegetation >10 mm, uncontrolled sepsis, and multiple embolisms [41]. Mitral valve (MV) replacement has traditionally been considered as the standard treatment for MV endocarditis that does not respond to antibiotic treatment.

However, the pioneering work of Dreyfus et al. surgery for repair of the mitral valve with IE can be performed safely and is often associated with a better outcome compared to mitral valve replacement [42, 43].
