Infective endocarditis is a lethal disease that carries an in-hospital mortality of 20% . Descriptions of infective endocarditis date back to the 1880s, by William Osler, but it was not until almost a century later in 1961 that Kay et al.  reported the first surgical cure of a patient with medically resistant infective endocarditis. In 1965 Wallace et al.  reported successful valve replacement in active infective endocarditis. These documented accounts of success in active infective endocarditis led to a revolution and paradigm shift to surgical management of complicated infective endocarditis. With this focused review, we hope to improve the evolving management of this challenging and sometimes convoluted disease process.
Infective endocarditis has an incidence of 3–10 per 100,000 patient-years [1, 4] and can arise from both native valves and prosthetic valves, resulting in varied disease presentations. Risk factors include older age, diabetes, hemodialysis, intravenous drug abuse, rheumatic disease, and cardiac device/prosthetic valve instrumentation . Historically the causative organisms for infective endocarditis were microorganisms originating in the oral pharynx leading to rheumatic disease, but that is a rare cause today in most developed countries. This decrease in the incidence of rheumatic heart disease along with increases in the incidence of degenerative heart disease, prosthetic valve implantation, intravenous drug abuse, and hemodialysis has resulted in more virulent Staphylococcus species surpassing streptococci as the commonest cause of infective endocarditis [5, 6]. In developed nations, the major risk factor is prior instrumentation with a prosthetic valve (50 times higher) and/or intracardiac devices (i.e., pacer and implantable cardioverter-defibrillator leads) [5, 7]. Approximately 25% of cases of infective endocarditis are secondary to a hospital- or health care–acquired cause; hospital-acquired infective endocarditis has been defined as either infective endocarditis with onset of symptoms 72 hours or more after hospitalization or infective endocarditis occurring within up to 6 months after discharge, particularly if an invasive procedure was performed during hospitalization. [4, 5, 7–9]. In the United States there has been an increase in the number of hospitalizations for infective endocarditis in the past decade, almost doubling from 29,820 cases in 2000 to 47,134 cases in 2011 . While staphylococci and streptococci account for 80% of cases of infective endocarditis , the increase was seen across all types of pathogens: Staphylococcus, Streptococcus, Gram-negative bacteria, and fungi . The rates of valve replacement for infective endocarditis increased significantly from 2000 to 2007 (30 versus 14 valve replacements per 1000 infective endocarditis cases, P=0.03), but the rate has since stabilized [4, 8, 10]. The subsequent plateau has been postulated to be due to increased awareness and better diagnostic tools, both of which enable earlier detection of infective endocarditis.
With 10 years of experience from 2005 to 2015, large registry data cite the incidence of infective endocarditis in the transcatheter aortic valve replacement (TAVR) population to be 1.1% per person-year (250 cases of infective endocarditis in 20,006 patients after TAVR), with a mean time from TAVR to infective endocarditis of 5.3 months . This population has a higher in-hospital mortality rate of 36% and a 2-year mortality rate of 66.7% when infective endocarditis is diagnosed . Given the exponential rise in transcatheter caseload, this population will invariably account for a substantial number of total future infective endocarditis cases.
Health care–associated infections have been the target of several preventative strategies since the 1870s, with the scientific contributions of Robert Koch, Charles Chamberland, and Gustav Adolf Neuber. Basic hand hygiene, aseptic technique, and perioperative administration of antibiotics have been cornerstones in successful surgery. The timeless challenge, however, has been increasing adherence to these ideals, and decreasing breaches in aseptic technique [13, 14].
Antibiotic prophylaxis guidelines for prevention of infective endocarditis differ slightly by the organization providing the recommendation. Widely adopted guidelines have been provided by the American Dental Association, the European Society of Cardiology (ESC), the American Heart Association (AHA), and the National Institute for Health and Care Excellence (NICE). The American Dental Association and the ESC recommend prophylaxis for dental procedures in individuals with a prosthetic valve, prior orthotopic heart transplant with valvulopathy, or a history of infective endocarditis, work on gingival tissue, and congenital cases including unrepaired cyanotic congenital heart disease (palliative shunts and conduits), repaired congenital heart defect with prosthetic material or device for the first 6 months, and repaired congenital heart defect with residual defect [10, 15, 16]. From class 3, level C evidence, antibiotic prophylaxis is not recommended for local anesthetic injections in uninfected tissue, removal of sutures, dental X-rays, placement or adjustment of removable prosthodontic or orthodontic appliances or braces, following the shedding of deciduous teeth, or in the case of trauma to the lips and oral mucosa. Moreover, for respiratory tract procedures, including bronchoscopy, laryngoscopy, and transnasal or endotracheal intubation, antibiotic prophylaxis is not recommended. In addition, during gastrointestinal or urogenital procedures such as gastroscopy, colonoscopy, sigmoidoscopy, cystoscopy, or transesophageal echocardiography, no antibiotic prophylaxis is recommended. Similarly, the AHA recommends antibiotic prophylaxis for those at risk and undergoing dental or upper respiratory tract procedures, but not for genitourinary (cystoscopy) or gastrointestinal (sigmoidoscopy or colonoscopy) procedures [15, 16].
In 2007 the AHA narrowed the guideline indications for bacterial infective endocarditis regarding dental prophylaxis . Recent studies speculated that decrease in the use of antibiotic prophylaxis for infective endocarditis since 2007 is related to the rise in the incidence of Streptococcus infective endocarditis . However, there was no significant difference in the rates of valve replacement before and after the release of the new guidelines in 2007 in the National Inpatient Sample database . In parallel, in the United Kingdom, after the NICE recommendations in March 2008, there was complete cessation of antibiotic prophylaxis before dental and other invasive procedures. Thornhill et al., cited that while there was a large (78.6%) and rapid decrease in prescribed antibiotic prophylaxis for infective endocarditis, there was no corresponding increase in the incidence of infective endocarditis or deaths in the 2 years after the guideline was introduced [16, 17].
However, Dayer et al.  went on to perform a secular trend study, to investigate the effect of antibiotic prophylaxis versus no prophylaxis on the incidence of infective endocarditis in England. While the number of prescriptions of antibiotic prophylaxis for the prevention of infective endocarditis fell substantially after the introduction of the NICE guidance (mean 10,900 prescriptions per month from January 1, 2004, to March 31, 2008, vs. 2236 prescriptions per month from April 1, 2008, to March 31, 2013; P<0.0001), starting in March 2008, the number of cases of infective endocarditis increased significantly above the projected historical trend, by 0.11 cases per 10 million people per month (95% confidence interval 0.05–0.16, P<0.0001). By March 2013, 35 more cases per month were reported than would have been expected had the previous trend continued. This increase in the incidence of infective endocarditis was significant for both individuals at high risk of infective endocarditis (defined according to AHA and ESC criteria) and those at lower risk. Although the data did not establish a causal association, since the introduction of the 2008 NICE guidelines, the number of prescriptions of antibiotic prophylaxis has fallen substantially, while the incidence of infective endocarditis has increased significantly . This suggests that while previously there was likely rampant overprescription of antibiotics for infective endocarditis prophylaxis, the pendulum has swung completely in the opposite direction.
Diagnostic perioperative workup for infective endocarditis is centered on multimodality imaging. It is recommended to start with transthoracic echocardiography, and progress to transesophageal echocardiography as necessary to gauge the extent of valvular disease and dysfunction. Computed tomography (CT) and magnetic resonance imaging and can be helpful in complicated cases of infective endocarditis for defining anatomical landmarks as well as more detailed insight regarding abscess erosion, prosthetic valve infective endocarditis, splenic infarcts, or infected intracranial aneurysms (IIA). The addition of positron emission tomography to CT has shown value for diagnosis of prosthetic valve infective endocarditis and cardiac device infection by highlighting foci of increased fluorodeoxyglucose uptake and metabolic activity [16, 19, 20].
With regard to diagnostic criteria, the modified Duke criteria are the most used measure for diagnosing infective endocarditis. The clinical criteria required for infective endocarditis are two major criteria, or one major criterion and three minor criteria, or five minor criteria [19, 21]. The major criteria include (1) blood cultures positive for typical microorganisms (Streptococcus viridians, Streptococcus bovis, Haemophilus influenzae, Acinetobacter, Cardiobacterium, Eikenella, Kingella [HACEK organisms], Staphylococcus aureus) or community-acquired enterococci, in the absence of a primary focus, or at least two blood cultures positive for less common organisms, or (2) evidence on echocardiogram, including typical vegetation or supporting structures, abscess, new partial dehiscence of prosthetic valve, and/or new valvular regurgitation. The minor criteria include (1) predisposition, predisposing heart condition, or intravenous drug abuse, (2) fever (temperature greater than 38 °C), (3) vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions, (4) immunologic phenomena (glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor), and (5) microbiological evidence (positive blood culture findings but that do not meet a major criterion as noted above; excludes single cultures positive for coagulase-negative staphylococci and organisms that do not cause infective endocarditis) or serologic evidence of active infection with an organism consistent with infective endocarditis. In the instances where the criteria are not met, evidence of possible infective endocarditis can be included with one major criterion and one minor criterion, or three minor criteria. Diagnosis of infective endocarditis should be rejected if there is a firm alternative diagnosis explaining the presence of infective endocarditis, resolution of infective endocarditis syndrome with antibiotic therapy for less than 4 days, no histopathologic evidence of infective endocarditis at surgery or autopsy (if applicable) following antibiotic therapy for less than 4 days, or the patient does not meet the criteria for possible infective endocarditis as listed above [19, 21]. Pathologic criteria, the gold standard for diagnosis of infective endocarditis at the time of surgery or autopsy, include microorganisms by as evidenced by culture or histology of vegetation, vegetation emboli, intracardiac abscess, or histopathologic lesions, and vegetation or intracardiac abscess confirmed by histology showing active endocarditis [19, 21].
Among the manifestations of infective endocarditis, systemic embolisms to the spleen, kidney, liver, or CNS are an uncommon but potentially serious complication. Splenic emboli and infarction occur in up to 47% of left-sided infective endocarditis, and lead to splenic abscesses in 5% of these patients . In those patients with evidence of abscess rupture or large persistent abscesses, splenectomy is considered . Our institutional practice has been to screen all of our infective endocarditis patients for splenic infarction, and we have a documented rate of 2.5% for splenic abscesses. Logically, the organisms isolated from splenic abscesses mirror the underlying infection, and so Staphylococcus aureus, Streptococcus viridians, Enterococcus, and aerobic Gram-negative bacilli and fungi account for 40, 40, 15, and less than 5% of cases respectively [23, 24]. Akhyari et al.  examined whether prophylactic splenectomy could be of benefit. They documented a cohort of 202 infective endocarditis patients, of which 184 had no splenic lesions but underwent simultaneous prophylactic splenectomy, and noted mortality of 12.5% and a 180-day survival rate of 67.9%, compared with 18 patients with splenic lesions on CT, who had mortality of 0% and a 180-day survival rate of 94% (P=0.016). This suggested that in the absence of splenic abscess or overt rupture, prophylactic splenectomy for infective endocarditis is not indicated.
In patients with infective endocarditis, intracranial hemorrhage is the second commonest neurologic complication [26–29]. While there is a 1–10% risk of IIA [25–28] in a patient with diagnosed infective endocarditis, the AHA/American College of Cardiology (ACC) guidelines recommend no screening for IIA in the absence of neurologic signs or symptoms [17, 19]. Moreover, infectious emboli may be asymptomatic, and thus IIA may remain entirely asymptomatic before rupture. Singla et al.  reviewed the National Inpatient Sample, and found there was a significant preference toward conservative management of IIA in infective endocarditis patients. Of the total 393 patients, 73 underwent coiling/clipping, 72 underwent cardiac procedures, and only six patients (or 1.5%) underwent both procedures. This corresponded to a significant mortality difference, with mortality of 26.7% in the conservative management group, compared with 15.1% in the clipping or embolism group (P<0.001) . By contrast, in our institution we have been more aggressive, intervening at a rate of 72.7% with combined coiling and cardiac procedures with success.
Treatment algorithms supported by the AHA, the ACC, and the Society of Thoracic Surgeons (STS) direct clinical treatment in even the most complicated cases of infective endocarditis by using the model of a multidisciplinary team. This team includes specialists in cardiology, cardiothoracic Surgery, infectious disease, oral Surgery, neurosurgery, general surgery, anesthesia, and critical care [19, 31, 32]. Guidelines have advocated for a multidisciplinary team approach for management of infective endocarditis in major hospital centers , and some studies have even shown a greater than 50% reduction of in-hospital mortality secondary to infective endocarditis after team implementation .
The clinical management options for infective endocarditis include medical treatment alone, early surgery, delayed surgery, palliative care, and hospice care, or any combination thereof. Primary management of infective endocarditis revolves around a full course (4–6 weeks) of parenteral antibiotic therapy in an attempt to eradicate the infection. However, medical management alone is unsuccessful in approximately 50% of infective endocarditis cases . Evidence of persistent systemic infection, valvular dysfunction, new conduction abnormalities, or annular abscesses/fistulae indicates failure of medical therapy and warrants surgical intervention. The decision to proceed with surgery should be made with good communication within the multidisciplinary team [19, 32]. Predictive models for cardiothoracic procedures have been created with use of registry databases, and are summarized by the STS and EUROSCORE II risk calculators. These models calculate patient risk, and provide an objective data point for the multidisciplinary team to determine the best treatment plan.
Early surgery for infective endocarditis is defined by surgical intervention before the completion of a full course (within 48 hours to less than 20 days). Supported by class I, level b evidence, it is implemented when infective endocarditis has led to heart failure, heart block through an annular abscess, persistent fever and bacteremia more than 5 days after therapy, and/or embolic events with vegetations despite antibiotic therapy [16, 32–34]. In addition, in cases of large vegetations (>10 mm) even without emboli, or those with characteristically resistant causative organisms (Staphylococcus aureus, fungi, and HACEK organisms), early surgery is preferred [16, 32–35]. Kang et al.  compared early surgery with conventional treatment in stable patients with native valve infective endocarditis, and found that the early surgery group had a significant reduction in a composite end point of in-hospital death or embolism. A subsequent review and meta-analysis by Narayanan et al.  in 2016 reported a similar benefit for early surgery. The analysis showed the odds ratio of all-cause mortality for early surgery was 0.61 (95% confidence interval 0.50–0.74, P<0.001) in unmatched groups and 0.41 (95% confidence interval 0.31–0.54, P<0.001) in the propensity-matched groups. Furthermore, there was no significant difference in in-hospital mortality, the rate embolization, the rate of heart failure, and the rate of recurrence of endocarditis between the overall unmatched cohorts, suggesting that early surgical intervention is associated with significantly lower risk of death in patients with infective endocarditis . In prosthetic valve infective endocarditis, early surgery is advocated for cases of relapsing infection, any evidence of annular dehiscence or prosthetic valve instability, or annular abscess . In 2015 Sorabella et al.  found that patients with infective endocarditis and embolic stroke more commonly had annular abscesses (52 vs. 27%, P<0.001), and these were more frequently caused by Staphylococcus aureus (39 vs. 21%, P=0.004). Furthermore, with no significant difference in postoperative 30-day mortality (P=0.57) or rates of new postoperative stroke, they concluded that most patients can safely undergo valve surgery for infective endocarditis in the early period after embolic stroke.
Delayed surgery is surgery postponed for more than 4 weeks, and should be considered if there is any evidence of major ischemic or hemorrhagic stroke. Given the necessity of systemic anticoagulation with cardiopulmonary bypass, this allows recovery for the acute neurologic process. As neurologic complications occur in in 20–40% of patients with infective endocarditis , this is commonly used strategy. In our institution, we reimage the patient to confirm no ischemic/hemorrhagic evolution, and obtain reevaluation by neurology and neurosurgery before surgery.
Once the patient has been taken to the operating theater, the intraoperative algorithm is determined by the extent of disease. Mechanical or bioprosthetic valves and cryopreserved homografts have comparable rates of recurrent infective endocarditis if the infection is limited to the valve/annulus . As in cases of routine valve replacement, the type of valve chosen depends on various factors, including patient age, life expectancy, history of drug abuse, and adherence. If any radical debridement is required, reconstruction with a bovine pericardial patch is usually necessary. With concern regarding cerebral events, we default to use of tissue valves to avoid anticoagulation. A homograft is considered in cases with extensive destruction of the annulus and aortic root. For infective endocarditis secondary to intravenous drug abuse, use of a homograft may have a lower risk of reinfection given the lack of a cloth sewing ring; however, many surgeons may be concerned about durability in younger patients and the technical challenges of implantation and difficult reoperation following homografts. To combat the questionable durability in these cases as well as potential patient adherence issues, we have used biological valve conduits, although others have advocated the use of decellularized homografts, which have shown some success in 10-year follow-up data . In 10–25% of patients with infective endocarditis there is advanced disease with multiple valve involvement, and the STS guidelines state repair is recommended when feasible for mitral and tricuspid valves. Mitral valve repair can be achieved with pericardial patch and anatomical reconstruction, with preservation of chordae and ring annuloplasty, all of which serve to aid left ventricular function and invariably improve patient survival .
Infectious endocarditis is a challenging multifaceted disease that can involve any vascularized system. Our approach to infective endocarditis adheres to the AHA, ACC, STS, and ESC guidelines, although our institutional bias is to aggressively screen patients for and intervene in cases of IIA and splenic disease. Multimodality imaging is invaluable to provide a comprehensive diagnosis. With rapidly increasing transcatheter valve implantation, we expect an increased caseload of infective endocarditis from this population and the technical challenges it may bring. Beyond patients with hemorrhagic strokes, we advocate for early surgery for infective endocarditis if medical management has failed. A multidisciplinary team approach is imperative in infective endocarditis, and clear communication reduces the time to diagnosis and definitive treatment for this challenging patient population.