Native and Prosthetic Aortic Valve Endocarditis

1.1 Definitions Infective endocarditis (IE) is an endovascular, microbial infection of intracardiac structures facing the blood, including infections of the large intrathoracic vessels and of intracardiac foreign bodies. The early characteristic lesion is a variably sized vegetation, although destruction, ulceration, or abscess formation may be seen earlier by echocardiography (Habib et al, 2009). Prosthetic valve endocarditis (PVE) is classified as early or late, depending on when infection is diagnosed: early PVE (within 12 months after surgery) and late PVE (12 months or more after surgery). Nosocomial IE is defined as an infection occurring > 72 h after admission to the hospital or IE acquired in association with a significant invasive procedure performed during a recent hospitalization ≤ 8 weeks before the onset of symptoms. Persistent infection is defined as a repeat episode of IE caused by the same microorganism developing < 1 year after the first episode (Hill et al, 2007).

Endothelial damage may result from mechanical lesions induced by turbulent blood flow, electrodes or catheters, inflammation, as in rheumatic carditis, or, in the elderly, degenerative changes associated with inflammation, micro-ulcers, and microthrombi. Endothelial inflammation without valve lesions may also promote IE. Local inflammation triggers endothelial cells to express integrins of the b1 family (very late antigen). Integrins are transmembrane proteins that can connect extracellular determinants to the cellular cytoskeleton. Integrins of the b1 family bind circulating fibronectin to the endothelial surface while S. aureus and some other IE pathogens carry fibronectin-binding proteins on their surface. Hence, when activated endothelial cells bind fibronectin, they provide an adhesive surface for circulating staphylococci. Once adherent, S. aureus trigger their active internalization into valve endothelial cells, where they can either persist and escape host defenses and antibiotics, or multiply and spread to distant organs. Thus, there are at least two scenarios for primary valve infection: one involving a physically damaged endothelium, favoring infection by most types of organism, and one occurring on physically undamaged endothelium, promoting IE due to S. aureus and other potential intracellular pathogens. The role of bacteremia has been studied in animals with catheter-induced NBTE. Both the magnitude of bacteremia and the ability of the pathogen to attach to damaged valves are important. Of note, bacteremia does not occur only after invasive procedures, but also as a consequence of chewing and tooth brushing. Such spontaneous bacteremia is low-grade and of short duration. Classical IE pathogens (S. aureus, Streptococcus spp., and Enterococcus spp.) share the ability to adhere to damaged valves, trigger local procoagulant activity, and nurture infected vegetations in which they can survive. They are equipped with numerous surface determinants that mediate adherence to host matrix molecules present on damaged valves (e.g. fibrinogen, fibronectin, platelet proteins) and trigger platelet activation. Following colonization, adherent bacteria must escape host defenses. Gram-positive bacteria are resistant to complement. However, they may be the target of platelet microbicidal proteins (PMPs), which are produced by activated platelets and kill microbes by disturbing their plasma membrane. Bacteria recovered from patients with IE are consistently resistant to PMP-induced killing, whereas similar bacteria recovered from patients with other types of infection are susceptible. Thus, escaping PMP-induced killing is a typical characteristic of IE-causing pathogens (Habib et al, 2009).

Diagnosis
The diagnosis of IE remains a continuous challenge. It must be suspected in the presence of a new regurgitant heart murmur, embolic events of unknown origin, sepsis of unknown cause, and fever. IE should be suspected if fever is associated with intracardiac prosthetic material, a previous history of IE, previous valvular or congenital heart disease, and other predisposition or conditions for IE (immunocompromised state, evidence of congestive heart failure, conduction disturbance, vascular or immunologic phenomena, unexplained focal or non-specific neurological symptoms and signs, etc.). Echocardiography (transthoracic, transesophageal) and microbiological diagnosis confirm the diagnosis. When diagnosing IE, molecular biology techniques such as PCR are rapid and reliably detect fastidious and nonculturable agents in patients, but they have inherent limitations, such as they cannot be reliably applied to whole blood samples, they risk contamination, they yield false-negatives because of PCR inhibitors in clinical samples, they are unable to provide information about bacterial sensitivity to antimicrobial agents, and they are persistently positive despite clinical remission. The variability in the clinical presentation of IE requires a diagnostic strategy that is both sensitive for disease detection and specific for its exclusion across all forms of the disease. In 1994, a diagnostic schema, termed the Duke criteria, was proposed. It stratified patients with suspected IE into 3 categories: "definite" cases, identified either clinically or pathologically (IE proved at surgery or autopsy); "possible" cases (not meeting the criteria for definite IE); and "rejected" cases (no pathological evidence of IE at autopsy or surgery, rapid resolution of the clinical syndrome with either no treatment or short-term antibiotic therapy, or a firm alternative diagnosis) (Durack et al, 1994;Baddour et al, 2005). The revised Duke Clinical Diagnostic Criteria for IE were published in 2000, and included the following changes: the category "possible IE" was defined as having at least 1 major criterion and 1 minor criterion or 3 minor criteria; the minor criterion "echocardiogram consistent with IE but not meeting major criterion" was eliminated, given the widespread use of transesophageal echocardiography (TEE); bacteremia because of S. aureus was considered a major criterion, regardless of whether the infection was nosocomially acquired or whether a removable source of infection was present; and positive Q-fever serology was changed to a major criterion (Li et al, 2000).

Major Criteria
Two positive blood cultures for organisms typical of endocarditis Three positive blood cultures for organisms consistent with endocarditis Serologic evidence of Coxiella burnetii Echocardiographic evidence of endocardial involvement: oscillating intracardiac mass on a heart valve, on supporting structures, in the path of regurgitant jets, or on implanted material without another anatomic explanation, cardiac abscess, new dehiscence of prosthetic valve, new valvular regurgitation

Minor Criteria
Predisposing heart disorder, intravenous drug abuse, fever ≥ 38°C Vascular phenomena: arterial embolism, septic pulmonary embolism, mycotic aneurysm, intracranial hemorrhage, conjunctival petechiae, Janeway lesions Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth's spots, rheumatoid factor Microbiologic evidence of infection consistent with but not meeting major criteria Serologic evidence of infection with organisms consistent with endocarditis For definite clinical diagnosis: 2 major criteria or 1 major criterion and 3 minor criteria or 5 minor criteria For possible clinical diagnosis: 1 major criterion and 1 minor criterion or 3 minor criteria. For rejection of diagnosis: Firm alternative diagnosis explaining the findings of IE, resolution of symptoms and signs after antimicrobial therapy for ≤ 4 days, no pathologic evidence of infective endocarditis found during surgery or autopsy, or failure to meet the clinical criteria for possible endocarditis

Microbiological diagnosis 2.2.1 Blood cultures
Positive blood cultures remain the cornerstones of diagnosis and provide live bacteria for susceptibility testing. Three sets (including at least one aerobic and one anaerobic), each containing 10 ml of blood obtained from a peripheral vein using a meticulously sterile technique, is virtually always sufficient to identify the usual microorganisms-the diagnostic yield of repeated sampling thereafter is low. Sampling from central venous catheters should be avoided in view of the high risk of contaminants (false-positives, typically staphylococcal) and misleading findings (Habib et al, 2009). Although infective endocarditis secondary to anaerobic infection is uncommon, cultures should be sent for both aerobic and anaerobic incubation. No evidence suggests that cultures should be taken coincident with peaks of temperature, as bacteremia is constant (Beynon et al, 2006).

Culture-negative infective endocarditis and atypical organisms
Blood-culture negative IE (BCNIE) occurs in 2.5-31% of all cases of IE, often delaying diagnosis and the initiation of treatment, with profound impact on clinical outcome. BCNIE arises most commonly as a consequence of prior antibiotic administration, underlying the need for withdrawing antibiotics and repeating blood cultures in this situation. An increasingly common scenario is infection by fastidious organisms (including Legionella, Coxiella, the HACEK group and fungi such as Candida, Histoplasma, and Aspergillus species) with limited proliferation under conventional culture conditions, or requiring specialized tools for identification. These organisms may be particularly common in IE and affect patients with prosthetic valves, indwelling venous lines, pacemakers, renal failure, and immunocompromised states.

Histological/immunological techniques
Pathological examination of resected valvular tissue or embolic fragments remains the gold standard for diagnosing IE and may also guide antimicrobial treatment if the causative agent can be identified using special stains or immunohistological techniques. Electron microscopy is highly sensitive and may help characterize new microorganisms, but it is time consuming and expensive. Coxiella burnetii and Bartonella species may be easily detected using serological testing with indirect immunofluorescence or an enzyme-linked immunosorbent assay (ELISA), and recent data (Watkin et al, 2006) demonstrate similar utility for staphylococci. An immunological analysis of urine may allow the detection of microorganism degradation products, and ELISA detection of Legionella species has been described (Helbig et al, 2001). Incorporating these methods into accepted diagnostic criteria awaits prospective validation.

Molecular biology techniques
The polymerase chain reaction (PCR) allows rapid and reliable detection of fastidious and nonculturable agents in patients with IE. PCR uses nucleic acid target or signal amplification, alone or in combination with sequence analysis. The technique is particularly useful when negative cultures are caused by previous administration of antibiotics (as the technique is culture independent) or the presence of a fastidious organism and to identify the culprit organism in polymicrobial infection (Beynon et al, 2006).

Echocardiography
Echocardiography plays a key role in IE, concerning its diagnosis, the diagnosis of its complications, its follow-up under therapy and prognostic assessment. Echocardiography is particularly useful for the initial assessment of embolic risk and in decision-making in IE. Transesophageal echocardiography (TEE) plays a major role both before surgery and during surgery (intraoperative echocardiography). Echocardiographic results must be taken into consideration for both the decision to operate or not and the choice of the optimal timing for surgery. In all cases, however, the results of echocardiographic studies may be interpreted taking into account the clinical features of the patient ).

Transthoracic echocardiography
Transthoracic echocardiography (TTE) is the initial technique of choice for investigating IE. In low-risk patients, a normal transthoracic echocardiogram provides confirmation that endocarditis is unlikely and suggests that investigations should be directed elsewhere (Beynon et al, 2006). If the clinical suspicion is high, TEE should be used. The sensitivity of TTE ranges from 40% to 63%. There is no better technique for noninvasive visualization of vegetations than echocardiography. Overall, the TTE detection rate for vegetations in patients with a clinical suspicion of endocarditis averages around 50%. The diagnostic yield of the technique in detecting vegetations is influenced by several factors: image quality; echogenicity and vegetation size; vegetation location; presence of previous valvular disease or valvular prosthesis; experience and skill of the examiner; and pretest probability of endocarditis (Evangelista & Gonzalez-Alujas, 2004).

Transesophageal echocardiography
In most cases, TTE is sufficient. TEE is indicated when mechanical prosthetic valves are present, to detect right-sided lesions and to visualize myocardial abscesses. TEE may be considered an invasive procedure, but it is only modestly uncomfortable to the patient, can be rapidly done, and is low-risk. It is more sensitive than conventional TTE for detecting valvular vegetations. Furthermore, it may detect an unsuspected paravalvular abscess, and it correlates well with surgical and pathologic findings. The sensitivity of TEE ranges from 90% to 100%. In high-risk groups, TEE, with its higher sensitivity and specificity, may be needed if the TTE is normal and suspicion of IE remains high. TEE is also used to investigate potential complications of IE (Beynon et al, 2006). TEE is particularly useful in patients with prosthetic valves and for evaluating myocardial invasion. Negative TEE has a negative predictive value of over 92% for IE (Mylonakis & Calderwood, 2001).

Other imaging technologies
Other advances in imaging technology have had minimal impact in routine clinical practice. Using harmonic imaging has improved study quality, while three-dimensional echocardiography and other alternative modes of imaging-computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and radionuclide scanning-have yet to be evaluated in IE. Multislice CT has recently been shown to give better results than does TEE when evaluating IE-associated valvular abnormalities, particularly when assessing the perivalvular extent of abscesses and pseudoaneurysms (Habib et al, 2009).

Other tests
Blood and urine studies: Complete blood count (CBC), electrolytes, creatinine, blood urea nitrogen (BUN), glucose, and coagulation panel. Erythrocyte sedimentation rate (ESR), while not specific, is elevated in more than 90% of cases. Proteinuria and microscopic hematuria are present in approximately 50% of cases. Chest X-ray: This has a limited value, although it may demonstrate signs of congestive heart failure. Multiple embolic pyogenic abscesses may be visualized. Electrocardiography: This may help detect the 10% of patients who develop a conduction delay during IE by documenting an increased P-R interval. Nonspecific changes are common. A first-degree atrioventricular (AV) block and new interventricular conduction delays may signal septal involvement in aortic valve disease; both are poor prognostic signs. Coronary angiography: This is recommended pre-surgery according to the ESC Guidelines on the Management of Valvular Heart Disease in men over 40 years, in post-menopausal women, and in patients with at least one cardiovascular risk factor or a history of coronary artery disease. Exceptions arise when there are large aortic vegetations that may be dislodged during catheterization, or when emergency surgery is necessary. In these situations, high-resolution CT may be used to rule out significant coronary artery disease.

Treatment
The major goals of therapy for IE are to eradicate the infectious agent from the thrombus and to address the complications of valvular infection. The latter includes both the intracardiac and extracardiac consequences of IE. Some of the effects of IE require surgical intervention.

Medical treatment
Successful treatment of IE relies on microbe eradication by antimicrobial drugs. Surgery contributes by removing infected material and draining abscesses. Host defenses are of little help. This explains why bactericidal regimens are more effective than bacteriostatic therapy, both in animal experiments and in humans. Aminoglycosides synergize with cell wall inhibitors (i.e. b-lactams and glycopeptides) for bactericidal activity and are useful for shortening the duration of therapy (e.g. oral streptococci) and eradicate problematic organisms (e.g. Enterococcus spp.). One major hindrance to drug-induced killing is bacterial antibiotic tolerance. Tolerant microbes are not resistant, i.e. they are still susceptible to growth inhibition by the drug, but escape drug-induced killing and may resume growth after treatment discontinuation. Slow-growing and dormant microbes display phenotypic tolerance towards most antimicrobials (except rifampin to some extent). They are present in vegetations and biofilms, e.g. in PVE, and justify the need for prolonged therapy (6 weeks) to sterilize infected heart valves fully. Some bacteria carry mutations rendering them tolerant during both active growth and stationary (dormant) phases. Bactericidal drug combinations are preferred to monotherapy against tolerant organisms. Drug treatment for PVE should last longer (at least 6 weeks) than that for native-valve endocarditis (NVE) (2-6 weeks), but is otherwise similar, except for staphylococcal PVE, for which the regimen should include rifampin whenever the strain is susceptible.
In NVE needing a valve to be replaced by a prosthesis during antibiotic therapy, the postoperative antibiotic regimen should be that recommended for NVE, not for PVE. In both NVE and PVE, the duration of treatment is based on the first day of effective antibiotic therapy, not on the day of surgery. After surgery, a new full course of treatment should start only if valve cultures are positive, and the choice of antibiotic should be based on the susceptibility of the latest recovered bacterial isolate (Habib et al, 2009 Table 2. Proposed antibiotic regimens for initial empirical treatment of IE (before or without pathogen identification) (Adapted from Habib et al, 2009)

Penicillin-susceptible oral streptococci and group D streptococci
The cure rate is expected to be > 95%. In uncomplicated cases, short-term (2-week) therapy can be administered by combining penicillin or ceftriaxone with gentamicin or netilmicin. Ceftriaxone alone or combined with gentamicin or netilmicin given once a day is particularly convenient for outpatient therapy. Patients allergic to b-lactams should receive vancomycin. Teicoplanin has been proposed as an alternative and requires loading doses (6 mg/kg/12 h for 3 days) followed by 6-10 mg/kg/day. Loading is critical because the drug is highly bound to serum proteins and penetrates slowly into vegetations.

Penicillin-resistant oral streptococci and group D streptococci
Such resistant streptococci are increasing. Antibiotic therapy for penicillin-resistant and penicillin-susceptible oral streptococci is qualitatively similar. However, in penicillinresistant cases, aminoglycoside treatment may be prolonged to 3-4 weeks, and short-term therapy regimens are not recommended. Little experience exists with highly resistant isolates (MIC > 4 mg/L)-vancomycin might be preferred in such circumstances.

Streptococcus pneumoniae, b-hemolytic streptococci (groups A, B, C, and G)
IE due to S. pneumoniae has become rare since the introduction of antibiotics. It is associated with meningitis in up to 30% of cases, which requires special consideration in penicillinresistant cases. Treatment is similar to that of oral streptococci, except for the use of shortterm (2-week) therapy, which has not been formally investigated. In cases with meningitis, penicillin must be avoided because it poorly penetrates the cerebrospinal fluid, and should be replaced with ceftriaxone or cefotaxime alone or cefotaxime combined with vancomycin. IE due to group A, B, C, or G streptococci-including the S. milleri group (S. constellatus, S. anginosus, and S. intermedius)-is relatively rare. Group A streptococci are uniformly susceptible to b-lactams, whereas other serogroups may display resistance. IE due to group B streptococci was once associated with the peripartum period, but now occurs in adults, especially the elderly. Group B, C, and G streptococci and S. milleri produce abscesses and thus may require adjunctive surgery. The mortality of group B PVE is very high, and cardiac surgery is recommended. Antibiotic treatment is similar to that of oral streptococci, except that short-term therapy is not recommended.

Nutritionally variant streptococci
Nutritionally variant streptococci produce IE with a protracted course, which is associated with higher rates of complications and treatment failure (up to 40%), possibly due to delayed diagnosis and treatment. Antibiotic recommendations include penicillin, ceftriaxone, or vancomycin for 6 weeks, combined with an aminoglycoside for at least the first 2 weeks.

S. aureus and coagulase-negative staphylococci
S. aureus is usually responsible for acute and destructive IE, whereas CNS produce more protracted valve infections (except S. lugdunensis and some cases of S. capitis). S. aureus PVE carries a very high risk of mortality (> 45%) and often requires early valve replacement. Other differences in comparison with NVE include the overall duration of therapy, prolonged additional use of aminoglycosides, and the addition of rifampin. Although the level of evidence is poor, adding rifampin in the treatment of staphylococcal PVE is standard practice, although treatment may be associated with microbial resistance, hepatotoxicity, and drug interactions.  Table 3. Antibiotic treatment of IE due to Staphylococcus spp. (Habib et al, 2009) www.intechopen.com

Methicillin-resistant and vancomycin-resistant staphylococci
MRSA produce low-affinity plasma-binding protein (PBP) 2A, which confers crossresistance to most b-lactams. They are usually resistant to multiple antibiotics, leaving only vancomycin to treat severe infections. However, vancomycin-intermediate S. aureus (VISA) (MIC 4-16 mg/L) and hetero-VISA (MIC ≤ 2 mg/L, but with subpopulations growing at higher concentrations) have emerged worldwide, and are associated with IE treatment failures (Howden et al, 2006). Moreover, some highly vancomycin-resistant S. aureus have been isolated from infected patients in recent years, requiring new approaches to treatment. New lipopeptide daptomycin (6 mg/kg/day i.v.) was recently approved for S. aureus bacteremia and right-sided IE (Fowler et al, 2006). Observational studies suggest that daptomycin might also be considered in left-sided IE and may overcome methicillin and vancomycin resistance (Levine & Lamp, 2007). Importantly, daptomycin needs to be administered in appropriate doses to avoid further resistance. Other choices include newer b-lactams with relatively good PBP2A affinity, quinupristin-dalfopristin with or without blactams, b-lactams plus oxazolidinones, and b-lactams plus vancomycin. Such cases warrant collaborative management with an infectious diseases specialist.

Enterococcus spp.
Enterococcal IE is primarily caused by E. faecalis (90% of cases) and, more rarely, by E. faecium or other species. They pose two major problems. First, enterococci are highly tolerant to antibiotic-induced killing, and eradication requires prolonged administration (up to 6 weeks) of synergistic bactericidal combinations of cell-wall inhibitors with aminoglycosides. Secondly, they may be resistant to multiple drugs, including aminoglycosides, b-lactams (via PBP5 modification and sometimes b-lactamases), and vancomycin. Fully penicillinsusceptible strains (penicillin MIC ≤ 8 mg/L) are treated with penicillin or ampicillin (or amoxicillin) combined with gentamicin. Ampicillin (or amoxicillin) might be preferred since MICs are 2-4 times lower. Prolonged courses of gentamicin require regular monitoring of serum drug levels and renal and vestibular function. One study reported success with shortcourse administration of aminoglycosides (2-3 weeks) in 74 (81%) of 91 episodes of enterococcal IE (Olaison & Schadewitz, 2002). This option might be considered in cases where prolonged treatment is limited by toxicity. High-level gentamicin resistance is frequent in both E. faecalis and E. faecium. An aminoglycoside MIC > 500 mg/L is associated with the loss of bactericidal synergism with cell-wall inhibitors, and aminoglycosides should not be used in such conditions. Streptomycin may remain active in such cases and is a useful alternative. An additional recently described (Gavalda et al, 2007) option against gentamicin-resistant E. faecalis is the combination of ampicillin and ceftriaxone, which synergize by inhibiting complementary PBPs. Otherwise, more prolonged courses of b-lactams or vancomycin should be considered. B-Lactam and vancomycin resistance are observed primarily in E. faecium. Since dual resistance is rare, b-lactam might be used against vancomycin-resistant strains, and vice versa. Varying results have been reported with quinupristin-dalfopristin, linezolid, daptomycin, and tigecycline. Again, these situations require the expertise of an infectious diseases specialist.  interpret. Some HACEK group bacilli produce b-lactamases, and ampicillin is therefore no longer the first-line option. Conversely, they are susceptible to ceftriaxone, other thirdgeneration cephalosporins, and quinolones-the standard treatment is ceftriaxone 2 g/day for 4 weeks. If they do not produce b-lactamase, intravenous ampicillin (12 g/day i.v. in four or six doses) plus gentamicin (3 mg/kg/day in two or three doses) for 4 weeks is an option. Ciprofloxacin (2 x 400 mg/day i.v. or 1000 mg/day orally) is a less well-validated option (Das et al, 1997). Non-HACEK species: Recommended treatment is early surgery plus long-term (≥ 6 weeks) therapy with bactericidal combinations of b-lactams and aminoglycosides, sometimes with additional quinolones or cotrimoxazole. In vitro bactericidal tests and monitoring serum antibiotic concentrations may be helpful. Because of their rarity and severity, these conditions should be managed with the input of an infectious diseases specialist (Habib et al, 2009).

Blood culture-negative IE
Due to the lack of large series, the optimal duration of the treatment of IE due to these pathogens is unknown. The presented durations are based on selected case reports. Treating Whipple IE remains highly empirical. Successes have been reported with long-term (> 1 year) cotrimoxazole therapy. -Interferon is protective in intracellular infections and has been proposed as adjuvant therapy in Whipple's disease.

Fungi
Fungi are most frequently observed in PVE and in IE affecting IVDAs and immunocompromised patients. Candida and Aspergillus spp. predominate, the latter resulting in BCNIE. Mortality is very high (> 50%), and treatment necessitates dual antifungal administration and valve replacement. Most cases are treated with various forms of amphotericin B with or without azoles, although recent case reports describe successful therapy with the new echinocandin caspofungin (Garzoni et al, 2007;Lye et al, 2005). Suppressive treatment with oral azoles is often maintained long term and sometimes for life.

Surgical treatment
Surgery has an established role in the management of IE across a wide range of patients, a role that appears poised to increase as the complexity of patients with this difficult condition rises and the benefits of earlier surgery emerge. Contemporary data in Europe indicate that surgical treatment is used in approximately half of patients with IE because of severe complications. Reasons to consider early surgery in the active phase, i.e. while the patient is still receiving antibiotic treatment, are to avoid progressive heart failure (HF) and irreversible structural damage caused by severe infection and to prevent systemic embolisms. On the other hand, surgical therapy during the active phase of the disease is associated with significant risk. Surgery performed very early may improve survival in patients with the most severely complicated IE. However, a greater risk of relapses and postoperative valvular dysfunctions should be expected with very early surgery (Thuny et al, 2009).  (Prendergast & Tornos, 2010). The three main indications for early surgery in IE are: HF, uncontrolled infection, and prevention of embolic events.

Timing of surgery -
Emergency surgery (within 24 hours): NVE or PVE and severe congestive HF or cardiogenic shock caused by: acute valvular regurgitation, severe prosthetic dysfunction (dehiscence or obstruction), fistula into a cardiac chamber or the pericardial space -Urgent surgery (within days): NVE with persistent congestive HF, signs of poor hemodynamic tolerance, or abscess; PVE with persistent congestive heart failure, signs of poor hemodynamic tolerance, or abscess; PVE caused by staphylococci or Gramnegative organisms, large vegetation (> 10 mm) with an embolic event, large vegetation (> 10 mm) with other predictors of a complicated course, very large vegetation (> 15 mm), especially if conservative surgery is available, large abscess or periannular involvement with uncontrolled infection; -Early elective surgery (during the in-hospital stay): Severe aortic regurgitation with congestive HF and good response to medical therapy, PVE with valvular dehiscence or congestive heart failure and good response to medical therapy, presence of abscess or periannular extension, persistent infection when extracardiac focus has been excluded, fungal or other infections resistant to medical cure (Prendergast & Tornos, 2010).

Surgical approach and techniques
The two primary objectives of surgery are the total removal of infected tissue and the reconstruction of cardiac morphology, including repair or replacement of the affected valve. The mode of surgery (replacement versus repair) or type of prosthesis used (mechanical versus biological) has no influence on operative mortality, although repair techniques, when applicable, offer long-term advantages, including a reduced risk of late complications (notably, recurrent IE) and obviate the need for lifelong anticoagulation medication. Homografts offer a reduced risk of recurrent infection in aortic IE, although their use remains controversial owing to a higher risk of late complications. Cardiac transplantation may be considered in extreme cases with recurrent PVE (Pavie, 2006). Where infection is confined to the valve cusps or leaflets, any method of repairing or replacing the valve may be used. However, valve repair is favored whenever possible. Perforations in a single valve cusp or leaflet may be repaired with an autologous glutaraldehyde-treated or bovine pericardial patch. In complex cases with locally uncontrolled infection, total excision of infected and devitalized tissue should be followed by valve replacement and repair of associated defects to secure valve fixation. Mechanical and biological prostheses have similar operative mortality (Edwards et al, 1998). The use of foreign material should be kept to a minimum. Small abscesses can be closed directly. Radical resection of the abscess is essential. The general consensus is that an aortic valve homograft is the ideal conduit for an aortic root abscess, but that it is not a substitute for radical extirpation of the abscess and all inflamed tissue . In aortic IE, replacing the aortic valve with a mechanical or biological prosthesis is the technique of choice. Using cryopreserved or sterilized homografts has been suggested to reduce the risk of persistent or recurrent infection (Lopes et al, 2007). However, mechanical prostheses and xenografts compare favorably, and with improved durability. Homografts or stentless xenografts may be preferred in PVE or in cases where there is extensive aortic root destruction with aorto-ventricular discontinuity (Sabik et al, 2002). A tailored tubular Dacron graft to concomitantly reconstruct the left ventricular outflow tract and replace the aortic root is a useful and safe operative technique for patients with destroyed aortoventricular junction. A monoblock aorto-mitral homograft has been suggested as a surgical option for extensive bivalvular IE (Obadia et al, 2006).

Operative mortality and morbidity
Perioperative mortality and morbidity vary according to the type of infective agent, the extent of destruction of cardiac structures, the degree of left ventricular dysfunction, and the patient's hemodynamic condition at the time of surgery. Currently, operative mortality in IE lies between 5% and 15%. The outcomes of PVE are worse than those of NVE. The main reason the operative mortality for PVE is higher than that for NVE is the complexity of the operation and the fact that it is often associated with a paravalvular abscess (David et al, 2006). When surgery must be done within the first week of antimicrobial therapy, a recent study showed that in-hospital mortality is 15%, with risks of recurrence and non-infective postoperative valvular dysfunction of 12% and 7%, respectively (Thuny et al, 2008).
In less complex cases, where disease is limited to the valve structures alone allowing complete excision of the infected tissue, mortality should be similar to routine valve surgery.
The cause of death is often multifactorial, but the main reasons are multiorgan failure, HF, intractable sepsis, coagulopathy, and stroke.

Postoperative complications
Immediate postoperative complications are relatively common. Among the most frequent are severe coagulopathy requiring treatment with clotting factors, re-exploration of the chest for bleeding or tamponade, acute renal failure requiring hemodialysis, stroke, low cardiac output syndrome, pneumonia, and atrioventricular block following radical resection of an a o r t i c r o o t a b s c e s s w i t h a n e e d f o r p a cemaker implantation. A preoperative ECG demonstrating left bundle branch block predicts the need for a postoperative permanent pacemaker.

Prophylaxis for IE
The European Society of Cardiology Guideline proposes limiting antibiotic prophylaxis to patients with the highest risk of IE undergoing the highest risk dental procedures. Patients with the highest risk of IE are patients with a prosthetic valve or a prosthetic material used for cardiac valve repair, patients with previous IE, patients with congenital heart disease, in particular those with complex cyanotic heart disease and those who have postoperative palliative shunts, conduits, or other prostheses. Procedures at risk involve the manipulation of the gingival or periapical region of teeth or perforation of the oral mucosa, including scaling and root canal procedures. Good oral hygiene and regular dental review are very important for reducing the risk of IE. Aseptic measures are mandatory during venous catheter manipulation and during any invasive procedures in order to reduce the rate of healthcare-associated IE (Habib et al, 2009). The American Heart Association Guideline includes cardiac transplant recipients who develop cardiac valvulopathy on the list of patients with the highest risk of IE. It also recommends prophylaxis for procedures on respiratory tract or infected skin, skin structures, or musculoskeletal tissue only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from IE (Wilson et al, 2007). An antibiotic for prophylaxis should be given in a single dose 30-60 minutes before the procedure. Amoxicillin is the preferred choice for oral therapy because it is well absorbed in the GI tract and provides high and sustained serum concentrations. For individuals who are allergic to penicillin or amoxicillin, the use of cephalexin or another first-generation oral cephalosporin, clindamycin, azithromycin, or clarithromycin is recommended. Because of possible cross-reactions, a cephalosporin should not be given to patients with a history of anaphylaxis, angioedema, or urticaria after treatment with any form of penicillin, including ampicillin or amoxicillin (Habib et al, 2009;Wilson et al, 2007).

Heart failure
HF is the most frequent complication of IE and represents the most frequent indication for surgery in IE. HF is observed in 50-60% of cases overall and is more often present when IE affects the aortic (29%) rather than the mitral (20%) valve (Baddour et al, 2005). HF can be caused by severe aortic regurgitation, intracardiac fistulae, or, more rarely, by valve obstruction, when a large vegetation partially obstructs the valve orifice.
Clinical presentation of HF may include severe dyspnea, pulmonary edema, and cardiogenic shock. In addition to clinical findings, TTE is crucially important for the initial evaluation and follow-up. Echocardiography is also of more general value for hemodynamic assessment of valvular dysfunction, measurement of pulmonary artery pressure, and assessment and monitoring of left ventricular systolic function and left and right heart filling pressures. Brain natriuretic peptide (NT-proBNP) is potentially useful for diagnosing and monitoring HF in IE. HF may progress from mild to severe during treatment, and two-thirds of these cases occur during the active phase of the disease. Moderate-to-severe HF is the most important predictor of in-hospital and 6-month mortality (Baddour et al, 2005).

Uncontrolled infection
Uncontrolled infection is the second most frequent cause for surgery and encompasses persisting infection (> 7-10 days), infection due to resistant organisms, and locally uncontrolled infection. Uncontrolled infection is most frequently related to perivalvular extension (the most frequent cause, associated with a poor prognosis and a high likelihood of the need for surgery) or difficult-to-treat organisms, such as fungi, multiresistant organisms, e.g. MRSA or vancomycin-resistant enterococci, and also in the rare infections caused by Gramnegative bacteria. Signs of locally uncontrolled infection include increasing vegetation size, abscess formation, false aneurysms, or the creation of fistulae. Persistent fever is also usually present. Unless severe comorbidity exists, the presence of locally uncontrolled infection indicates early surgery in patients with NVE (Habib et al, 2009).

Systemic embolism
Embolic events are a frequent and life-threatening complication of IE related to the migration of cardiac vegetations. It has been reported to occur in 13% to 49% of cases. The brain and spleen are the most frequent sites of embolisms in aortic IE. Embolisms after adequate antimicrobial treatment are frequent, and most embolisms occur within the first two weeks of therapy. Embolisms before antimicrobial therapy are a risk factor for embolisms after antimicrobial therapy has begun. Controlling infection is important for preventing embolisms. The benefits of surgery to prevent embolisms are greatest during the first week of antibiotic therapy, when embolic risk peaks. Several factors are associated with increased risk of embolisms: the size and mobility of vegetations, the location of the vegetation, an increase or decrease in the size of the vegetation under antibiotic therapy, particular microorganisms (staphylococci, Streptococcus bovis, Candida spp.), previous embolisms, multivalvular IE, and biological markers. The risk of embolization seems to increase with increasing vegetation size, and this is particularly significant in staphylococcal endocarditis (Vilacosta et al, 2002). 112 or brain abscesses. More nonspecific neurologic manifestations associated with IE include headache, seizures, and toxic encephalopathy. Cerebral hemorrhage is the most dramatic, though fortunately rare, neurologic complication of IE. It can be caused by a rupture of a mycotic aneurysm even months to years after the IE has been cured. Neurologic manifestations of IE occur mainly before antimicrobial treatment has begun, thus reinforcing the belief that rapidly diagnosing and initiating antimicrobial therapy may still be the most effective means of preventing neurologic complications (Heiro et al, 2000). After a first neurological event, most patients still have an indication for surgery that is generally not contraindicated.

Infectious aneurysms
Infectious (mycotic) aneurysms (IAs) result from septic arterial embolisms to the intraluminal space or vasa vasorum, or from the subsequent spread of infection through the intimal vessels. An intracranial location is most frequent, and the reported frequency of 2-4% (Corr et al, 1995) is probably an underestimate since some IAs are clinically silent.
The most important sequelae of these aneurysms is bleeding, which can occur days, weeks, months, or, rarely, years after successful therapy for the underlying IE. Cerebral mycotic aneurysms tend to occur in the more distal portions of the middle cerebral artery near the surface of the brain involving the secondary and tertiary branches. This characteristic pattern helps to separate them clinically from berry aneurysms, which tend to occur near the base of the brain and the circle of Willis.

Acute renal failure
Acute renal failure is a common complication of IE, which occurs in 30% of patients and predicts a poor prognosis. Causes of acute renal failure are often multifactorial and include the following: immune complex and vasculitic glomerulonephritis, renal infarction, hemodynamic impairment in cases with HF or severe sepsis, or, after cardiac surgery, antibiotic toxicity, notably related to aminoglycosides, vancomycin, and even high-dose penicillin, nephrotoxicity of contrast agents used for imaging (Majumdar et al, 2000). Hemodialysis may be required in some patients, but acute renal failure is often reversible.

Rheumatic complications
Musculoskeletal symptoms (arthralgia, myalgia, back pain) are frequent during IE, and rheumatic complications may be the first manifestations of the disease. Peripheral arthritis occurs in 14% and spondylodiscitis in 3-15% of cases. Vertebral osteomyelitis is a known but rare complication of IE, occurring most frequently in patients with S. aureus infection. Acute septic arthritis involving 2 or more joints should raise a suspicion of IE (Speechly-Dick & Swanton, 1994).

Splenic abscess
Although splenic emboli are common, splenic abscess is rare. Persistent or recurrent fever and bacteremia suggest the diagnosis, and these patients should be evaluated using abdominal CT, MRI, or ultrasound. Treatment consists of appropriate antibiotic regimens. A splenectomy may be considered for splenic rupture or large abscesses that respond poorly to antibiotics alone, and should be done before valvular surgery, unless the latter is urgent. Percutaneous drainage is an alternative for high-risk surgical candidates. (Chou et al, 1992)

Myocarditis, pericarditis
Cardiac failure may also be due to myocarditis, which is frequently associated with abscess formation. Regional myocardial infarction may be caused by coronary embolisms or compression. Ventricular arrhythmias may indicate myocardial involvement and imply a poor prognosis. Myocardial involvement is best assessed using TTE. Pericarditis may be associated with an abscess, myocarditis, or bacteremia, often as a result of S. aureus infection. Purulent pericarditis is rare and may necessitate surgical drainage. Rarely, ruptured pseudoaneurysms or fistulae may communicate with the pericardium, with dramatic and often fatal consequences (Sexton & Spelman, 2002).

Outcome and long-term prognosis
The prognosis of aortic valve endocarditis depends largely on when the disease is diagnosed, which microorganism is involved, and how promptly it is treated. Patients with PVE have a more serious prognosis than patients with NVE. Late complications occurring after the initial infection contribute to the poor prognosis of IE. Following in-hospital treatment, the main complications include a recurrence of infection, HF, a need for valve surgery, and death. The risk of recurrence among survivors of IE varies between 2.7% and 22.5%. There are two types of recurrence: relapse and reinfection. The term "relapse" refers to a repeat episode of IE caused by the same microorganism as the previous episode. In contrast, "reinfection" is used primarily to describe infection with a different microorganism (Chu et al, 2005).
Relapses are most often due to an insufficient duration of the original treatment, a suboptimal choice of initial antibiotics, and a persistent focus of infection (e.g. a periprosthetic abscess). Progressive HF can occur as a consequence of valve destruction, even when the infection is healed. After the completion of treatment, recommendations for surgery follow conventional guidelines.
Following the in-hospital phase, principal factors that determine long-term mortality are age, comorbidity, and HF, particularly when surgery has not been done, which suggests that long-term mortality is related to the underlying conditions rather than to the IE itself. A high early surgery rate is related to good long-term results and does not increase inhospital mortality. Medical treatment, however, also offers favorable long-term results in cases of responsive IE where poor prognostic factors are absent (Bishara et al, 2001). The IE prognosis is not uniform. Mortality is high during the initial phase, but after one year, the risk of dying is low, although still above that of the general population. Part of the risk is probably the direct consequence of IE, but part is due to the course of the underlying heart disease (Delahaye et al, 1995).

Conclusions
IE is a changing disease with predisposing risk factors, etiology, manifestations, and therapeutics in continuous evolution. Although modern antibiotic and surgical treatments have substantially improved outcomes in recent decades, IE remains a life-threatening disease. As mortality during the active phase of the infection has declined, long-term morbidity and mortality caused by late sequelae such as congestive HF, valve incompetence, and predisposition to recurrent IE are becoming more important. Moreover, the focus has shifted away from infections of native valves to endocarditis of prosthetic valves in the elderly and to endocarditis in users of injected drugs. Effective therapy has become progressively more difficult to achieve because of the proliferation of implanted biomechanical devices and the rise in the number of resistant organisms. Endocarditis has evolved into several variations, keeping it near the top of the list of diseases that must not be misdiagnosed or overlooked.

Acknowledgement
This paper is supported by the Sectoral Operational Programme Human Resources Development, financed from the European Social Fund and by the Romanian Government under the contract number POSDRU 89/1.5/S/64109