Development of IE requires circulating organisms, usually bacteria. In a 2016 study, Delahaye and colleagues successfully identified the portal of entry or source of infection in 74% of the 318 patients presenting with IE. The most frequent entry was cutaneous, 40%, either healthcare-related or injection drug use. The source was oral or dental in 29% (tooth infection in 59% and procedure in only 2%). The source was gastrointestinal in 18% of the patients (upper 9%, lower 91%: 48% colon polyps, 27% sigmoid diverticulitis, 14% rectal adenocarcinomas).

Wyssokowitch and Orth in 1886 demonstrated that aortic cusp injury predisposed to development of IE. ^, The first event was later suggested to be development of nonbacterial thrombotic endocarditis (NBTE). ^, A recent PubMed search for NBTE talks about NBTE as a disease of its own—Libman-Sacks, marantic, thrombotic, or verrucous endocarditis—with no discussion of NBTE being the cause or implicated in the development of IE. Understood this way, NBTE is associated with hypercoagulability and malignancies, treated with anticoagulation, associated with embolic complications and significant mortality, and is a differential diagnosis of IE, in particular of culture-negative IE. ^, Garrison, Freedman, and Perlman (1970–1971) produced endocarditis in rabbits by inserting catheters filled with a Staph. aureus culture on the right or the left side of the heart. ^, Animals with infected catheters developed bacterial vegetations with resemblance to human IE. Rabbits with sterile catheters still developed vegetations from the catheter trauma and, by the authors, referred to as marantic endocarditis. Durack and Beeson, in 1972, used the same model to confirm colonization of NBTE lesions by Strep. viridans. This model remains the principal experimental paradigm for the mechanical basis of IE. In addition to direct trauma, endocardial injury more often is the result of preexisting valve disease or jet and other lesions caused by blood turbulence, such as patent ductus arteriosus or restrictive VSD, mitral valve prolapse, or bicuspid aortic valve (BAV).

Rodbard put forward another persuasive hypothesis, the Venturi effect hypothesis for the pathogenesis of IE. Basically, high-velocity jets form at a narrow orifice when blood under high pressure enters a low-pressure sink and result in mechanical endocardial erosion and deposition of platelets and thrombin. The maximal deposition of bacteria is immediately beyond the orifice ( Fig. 14.1 ). These conditions exist beyond stenotic valves, on the pulmonary artery side of a patent ductus arteriosus ( Fig. 14.2 ), and on the left atrial aspect of a regurgitant mitral valve. The fact that most IE lesions of the aortic valve are on the ventricular aspect suggests a role for valvar regurgitation in pathogenesis. Numerous cardiac malformations are associated with increased turbulence and abnormal endothelial surfaces to become a substrate for bacterial adherence and infection.

Flow through a stenotic tube. High-pressure source drives fluid through an orifice into a low-pressure sink. Curved arrows leaving the stream entering wall in upstream segment represent normal perfusion of lining layer. Velocity is maximal and perfusing pressure is low immediately beyond orifice, where momentum of stream converges streamlines to form a vena contracta. Low pressure in this segment results in reduced perfusion and may cause retrograde flow from deeper layers of vessel into the flowing stream. It is at the vena contracta that bacteria and other formed elements in blood accumulate.

(From Rodbard S. Blood velocity and endocarditis. Circulation . 1963,27:18.)

Representation of infective endocarditis at a patent ductus arteriosus. Vegetations are deposited on pulmonary artery wall opposite a high-velocity jet through an open ductus.

The most common sites of cardiac infection are on the line of closure of a valve, typically on the atrial side of atrioventricular valves and on the ventricular surface of semilunar valves. Bacterial adhesion is mediated via specific virulence factors, adhesion proteins like fibronectin and staphylococcal clumping factors. Prosthetic valves are more prone to infection than native valves. Staph. aureus binds to porcine valvar endothelial cells by a mechanism that is specific and receptor-mediated. This most likely represents a specific physiochemical interaction between microbial adhesins and a host-cell receptor that involves fibronectin lipoteichoic acid.

Once bacteria attach to the surface, vegetations develop through cycles of bacterial proliferation and fibrin and platelet deposition, monocyte recruitment, and inflammatory response. A hallmark of the microorganisms commonly causing IE, including staphylococci, streptococci, and enterococci but also less common pathogens such as Candida species and Pseudomonas aeruginosa , is capacity for biofilm production ( Fig. 14.3 ). ^, Bacterial populations live embedded in a self-produced extracellular polysaccharide slime-like matrix. Quorum sensing is a chemical cell-to-cell communication mechanism that synchronizes gene expression and activates assembly and maturation of the biofilm. Once established, biofilm protects organisms from host immune defenses and impedes antimicrobial efficacy, dramatically reducing the ability of medical therapy alone to eradicate the infection.

Vegetation proteome and its origins. Native or bioprosthetic valves are infiltrated directly following bacteremia, or valvular damage, exposing prothrombogenic components to create a platelet-rich nidus. The vegetation grows via layering of components starting with opsonization of pathogens by circulating immunoglobins, complement, and other factors of the innate immune system in response to pathogen virulence factors. Circulating fibrin and fibronectin trap red blood cells and recruit additional platelets as they bind to the nidus. The accumulated platelets provoke additional fibrin deposition in the region. Neutrophils invade the site of infection. Inaccessible pathogens within the valve mediate persistent neutrophil chemotaxis via degranulation and NETosis, releasing citrullinated DNA and proteases. NETosis and platelet degranulation further stimulates cellular and protein deposition. Vegetations are thus a conglomerate of multiple proteomes whose respective percentage contributions can vary widely between vegetations. Pathogen and host protease-mediated vegetation turnover may destabilize the vegetation, which, when combined with turbulent valve function, could promote embolization, leading to cerebral or peripheral abscesses, infarcts, and mycotic aneurysms. Human as well as microbial proteases can contribute to protein turnover in vegetations. TAILS analysis suggested extensive turnover of extracellular proteins, with fibrin and fibronectin among the top proteins modified by proteolysis.

(Reprinted with permission, Cleveland Clinic Foundation ©2025. All Rights Reserved.)

In several studies, one-quarter of IE cases occurred on normal valves. ^, Likely organisms are those that have increased adhesion molecules noted on dextran polymerization, namely Staphylococci, Strep. viridans , and Enterococci. Common risk factors are intravenous (IV) drug abuse, overwhelming sepsis, resuscitation from shock, use of long-term indwelling catheters, and fungemia associated with prolonged antibiotic therapy. However, among patients with catheter sepsis, only about 5% develop IE. Persons who inject drugs (PWID) often use dirty syringes and needles and inject huge numbers of bacteria to infect their normal valves. Today, more than a quarter of patients with IE are PWID. IE in PWID involves the tricuspid valve in about half the cases, aortic or mitral valves in the remainder, and is often associated with more than one valve. PWID not only have less predisposing structural heart disease than non-drug-using patients, but tend to be younger and have fewer comorbidities.

Bacteremia and iatrogenic IE occurs most often in patients on chronic hemodialysis (HD) who have frequent episodes of staphylococcal bacteremia and are more likely to have sclerotic aortic or mitral valves. However, iatrogenic IE may occur in any patient with a peripherally or centrally inserted indwelling catheter or who is undergoing an invasive procedure.

Histopathologic examination of vegetations or embolic material remains the gold standard for diagnosis of IE. Histologic criteria for the diagnosis of active endocarditis are infected vegetations and valvular inflammatory reaction. In the acute phase of infection, vegetations are composed of fibrin, platelets, inflammatory cells, necrotic debris, and microbial colonies. Microbial colonies are unevenly distributed within vegetations. Inflammatory infiltrates are predominantly neutrophilic, with an admixture of lymphocytes and histiocytes. Histopathologic analysis helps differentiate infectious versus noninfectious causes of valve pathology. Osler’s original descriptions of the endocarditis pathology were very accurate and still worth reading. ^,

Left-sided IE accounts for 90% of IE cases, and right-sided IE accounts for 10% of IE cases. Right-sided IE usually occurs in the setting of IV drug abuse and affects the tricuspid valve in 90% and the pulmonary valve in 10%. Most of our understanding of the pathology of endocarditis comes from autopsies and surgical findings, in both situations primarily reflecting advanced stages of the disease.

Native valve endocarditis (NVE).

Usual sites for IE found at operation in patients with NVE not related to IV drug use are shown in Fig. 14.4 . Vegetations and erosive lesions are on the ventricular aspect of the aortic valve cusps and at the base of the atrial aspect of the mitral valve leaflets. Vegetations develop through successive cycles of colony growth and thrombus deposition and are predominantly composed of fibrin, platelets, neutrophils, and microbial colonies. Vegetations are destructive lesions, causing disintegration of underlying tissue. The progression of the pathology is decided by the virulence factors produced by the organisms. Toxins and enzymes produced by the organism cause tissue disintegration and invasion, resulting in valve regurgitation, fistulas, paravalvular abscesses, and heart block. Host neutrophil proteases mediate additional tissue destruction, explaining why antibiotics alone are sometimes insufficient to prevent further destruction.

Usual sites of native valve infective endocarditis. (A) Aortic valve with vegetation on noncoronary cusp and partial destruction of left coronary cusp. (B) Aortic valve with vegetation between noncoronary and right coronary cusps extending as an anular abscess. (C) Leaflet vegetation and ring abscess of posterior medial aspect of mitral valve. (D) Mitral valve with drop lesion of anterior leaflet. LCA, Left coronary artery; RCA, right coronary artery.

The invasive pathology develops in stages, from superficial erosion to cellulitis to abscess to pseudoaneurysm. Disease stage at diagnosis is related to the aggressiveness of the pathogen and the duration of the disease. The rate of progression is organism-specific with Staph. aureus being most aggressive. NVE invasion is local, preferentially occurring in one or more locations underneath a commissure or by the raphe of a bicuspid valve. Pressure drives invasion, and therefore, invasion occurs most frequently with aortic valve IE and least commonly, if at all, with right-sided endocarditis ( Fig. 14.5 ). For the same reason, invasive disease is more frequently associated with aortic than with mitral IE; two-thirds of surgical aortic valve cases have invasive disease compared to one-third of mitral valve cases. Once a mitral valve IE lesion is depressurized toward the atrium, no further progression of invasion occurs. By transesophageal echocardiography (TEE), about one-third of all cases have cavitary lesions, abscess cavities, or pseudoaneurysm, and in these cases, Staph. aureus is the predominant organism. Atrioventricular block is usually associated with aortic valve endocarditis and caused by the infection invading from the aortic root into the floor of the right atrium, into the Koch triangle, to destroy the upper end of the bundle of His and the atrioventricular node.

Invasive disease distribution. (A) By involved valve. Right-sided IE was rarely invasive, and aortic valve IE was more invasive than mitral valve IE. (B) By invasive disease stage. Invasion was greater in both type and degree in aortic than mitral valve IE. (C) By native versus prosthetic valve IE. Invasive disease on the left side was more common in prosthetic valve IE, but more so for aortic than mitral valve IE. AV , aortic valve; MV , mitral valve; NVE , native valve endocarditis; PVE , prosthetic valve endocarditis; RS , Right sided.

(From Hussain ST, Shrestha NK, Witten J, et al. Rarity of invasiveness in right-sided infective endocarditis. J Thorac Cardiovasc Surg . 2018;155(1):54-61.e1.)

Aortic valve.

Vegetations usually develop on the ventricular surface of the cusps. Vegetations cause cusp perforations and tears. Invasion most often starts in one of the triangles beneath the commissures, most frequently the triangle beneath the left-noncoronary commissure or along the base of a cusp. Tissue destruction, disintegration, and weakening allow the infection to spread outside the aorta, in the space around the root. Conduction problems and heart block appear when infection invades the right atrium and the Koch triangle, and destroys the atrioventricular node and His bundle. The early stage of invasion, the cellulitis stage of invasive IE, is characterized by necrosis of infected, indurated, and inflamed adipose tissue invaded by inflammatory cells forming microabscesses. With continued activity of proteolytic enzymes, this process develops into the suppurative abscess stage, macroscopic collections of pus. When such an abscess ruptures and empties, the result is an abscess cavity visible as a cavity on TEE. Continued irrigation by the blood eventually transforms this cavity into a pseudoaneurysm. Rupture of an abscess into the pericardial space leading to purulent pericarditis and cardiac tamponade is very rare. Invasion of the infection under the left and right commissure results in an extra aortic abscess, often extending underneath the pulmonary artery. Invasion under the right-non-coronary commissure down to the membranous portion of the interventricular septum can lead to the formation of a fistula between the aortic root/left ventricular outflow tract and the right ventricle and right atrium, referred to as an acquired Gerbode defect, resulting in intracardiac shunting. Also in this setting, involvement of the bundle of His, as it travels at the lower border of the membranous septum, with conduction abnormalities is possible. ^,

Mitral valve.

Native mitral valve endocarditis is either primary or caused by spread from aortic valve endocarditis, either as drop, kissing, or jet lesions on the anterior mitral leaflet (cusp) or as continuous spread through the intervalvular fibrosa. A kissing lesion often causes anterior leaflet aneurysm or perforation. Primary mitral valve IE affects leaflets and chordae. Rupture of undermined and weakened chords is common and leads to leaflet prolapse and mitral regurgitation. Mitral valve IE is less often invasive than aortic valve IE, the reason being the fact that once the infection communicates with the atrium, the infected area is depressurized, and the invasion is unlikely to become deeper. However, when invasion happens under the posterior leaflet, the infection invades the atrioventricular groove and may cause anular and atrioventricular groove abscesses that can be further complicated by fistula or pseudoaneurysm formation and atrioventricular separation. Presence of adhesive, suppurative, or hemorrhagic pericarditis is strong evidence of advanced invasive disease of either the aortic or mitral valves. Mitral anular calcification (MAC), in addition to being a nidus for infection, adds another level of technical challenge during surgery when aggressive debridement is required to reduce the risk of reinfection.

Right-sided endocarditis.

Right-sided endocarditis accounts for 5% to 10% of IE episodes and is mostly seen in PWID. In PWID, bacterial adherence has been suggested to be facilitated by damage to the endothelium of normal valves caused by injected particulate matter. In patients not using drugs, isolated right-sided endocarditis occurs primarily in those with structural tricuspid valve disease, congenital heart disease, pacemakers, defibrillators, resynchronization devices, arteriovenous fistulas for dialysis, or central venous catheters.

IE is a rare disease that affects 3 to 10 per 100,000 per year in the population at large, and epidemiologic studies suggest that incidence is rising. There are 40,000 to 50,000 new cases each year in the United States. The IE profile has changed over the past several decades. In the current era, IE is more frequently associated with invasive medical procedures and old age and Staph. aureus is the dominating organism. ^, HD, indwelling catheters, immunosuppression, and injection drug use are frequent sources of bacteremia. Prosthetic heart valves represent a strong risk factor for IE, and a Danish national registry study reported a cumulative risk of IE at 10 years of 5.2% after aortic or mitral valve replacement and reported the risk to be slightly higher in patients who had received bioprostheses. The risk of developing PVE is greater in patients operated on for NVE than in those undergoing valve replacement for other reasons ( Fig. 14.7 ). ^, Prosthetic valve reoperation is a greater hazard for development of PVE than primary valve replacement ( Fig. 14.8 ). In contrast to prosthetic heart valves, implanted anuloplasty rings, and permanent pacemaker leads, particularly epicardial leads, are infrequently disposed to IE. ^, From 1986 to 2000, only 22 patients (unknown denominator) were treated at Cleveland Clinic for endocarditis affecting a previously repaired mitral valve, 15 (68%) of those required repeat mitral valve operations.

Hazard function for prosthetic valve endocarditis (PVE) in patients with and without previous native valve endocarditis.

(From Ivert TS, Dismukes WE, Cobbs CG, Blackstone EH, Kirklin JW, Bergdahl LA. Prosthetic valve endocarditis. Circulation . 1984;69:223.)

Hazard functions for prosthetic valve endocarditis (PVE) after original valve replacement and after reoperation. Both have early peaking and constant phases.

(From Blackstone EH, Kirklin JW. Death and other time-related events after valve replacement. Circulation . 1985; 72:753.)

Implicated causes of early PVE include intraoperative surface contamination, introduction of contaminated blood or blood substitute, bacterial colonization of a member of the surgical team, bacterial aerosolization in ventilators, nasal colonization of the patient, and preexisting urosepsis. The Food and Drug Administration issued its first warning about heater–cooler-associated Mycobacterium chimaera infection risk after coronary bypass and other cardiovascular procedures in October 2015. ^, Manifestations of Mycobacterium chimaera infections include IE, sternal wound infections, or vascular graft infections, in addition to other extravascular manifestations, and patients have presented half a year or later after their cardiac operations.

The incidence of IE in children is lower than that in adults, with 0.43 cases per 100,000 children per year. However, some data show that the incidence of pediatric IE, although low, has been increasing over the past two decades. Among the pediatric population, IE most often occurs in patients with VSDs and valvar aortic stenosis. Incidence is still low (14.5 per 10,000 person-years) but 35 times that of the normal population. Surgical closure of a VSD reduces but does not eliminate the risk of IE. After previous cardiac surgery, IE in children occurs most often after aortic valvotomy, valve replacement, or use of right ventricular-pulmonary trunk conduits. In both pediatric and adult populations, mitral valve prolapse has emerged as a frequent preexisting malformation associated with IE, constituting 29% in McKinsey and colleagues’ series. Cumulative risk of IE before age 18 in patients with any congenital heart disease is 0.61%.

Healthcare–associated organisms have increasingly defined the contemporary microbiology of IE. Staph. aureus predominates as the infecting organism in the majority of hospital-acquired and drug-related IE. ^, In left-sided IE, Staph. aureus involves the mitral valve more than the aortic valve and results in higher occurrence of embolism compared with other organisms. Staph. aureus endocarditis is characterized by aggressive disease with increased risk of embolism, stroke, persistent bacteremia, and death. Staph. aureus is also the most common cause of PVE, most requiring surgery. Coagulase-negative staphylococci have a rising incidence of approximately 10% currently and play a major role in PVE occurring in the first year after a valve replacement procedure. ^, Coagulase-negative staphylococci cause both NVE and PVE and are often methicillin-resistant, as in the case of Staph. lugdunensis , associated with highly destructive valve and perivalvar lesions. Oral streptococci comprise 20% of cases ( Strep. viridans remains the most common organism causing NVE), other streptococci approximately 10%, and enterococci 10%. Enterococcal IE typically occurs in elderly males with multiple comorbidities, results less commonly in embolic events, and disproportionately affects the aortic valve. HACEK organisms (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis , Eikenella corrodens , and Kingella species), zoonoses, and fungi collectively account for <5% of cases.

Approximately 10% to 20% of patients have negative blood cultures. However, according to Fournier and colleagues, a rigorous diagnostic effort should allow a causative organism to be identified in two-thirds of these patients. In their cohort of 759 patients with blood culture-negative IE, 62% of patients had an etiologic agent identified, most commonly Q fever 48% and Bartonella species 18%, Tropheryma whipplei 2.5%, fungi 1.6%, and other common bacteria 9%. Nineteen (2.5%) were found to have noninfectious endocarditis caused by autoimmune disease or Liebman-Sachs endocarditis.

In PVE occurring within 2 months of operation, Staph. epidermidis is the major offending organism. Later-onset PVE has the same general spectrum of causative organisms as NVE but still dominated by staphylococci, found in almost half of the patients. ^, Enterococcal PVE, usually caused by Enterococcus faecalis or Enterococcus faecium, is usually associated with manipulating the gastrointestinal or genitourinary tract or with malignancy. Heater–cooler-related Mycobacterium chimaera infections, appearing later, were mentioned earlier.

In children overall, Staph. aureus remains the most common pathogen responsible for IE. However, in pediatric patients with congenital heart disease, the most common pathogen responsible for endocarditis is Strep. viridans group of streptococci. ^,

Complications caused by IE are local (vegetations and tissue destruction or disintegration) or distal (embolization or immune response/complex related). Heart failure, invasive disease/paravalvular extension, and embolic events represent the three most frequent and severe complications of IE and constitute the main indications for early surgery (see later “ Indications for Operation ”).

Vegetations, when large, occasionally cause valve stenosis, stenosis occurring more often with prosthetic than native valves. Disintegration of cusp and leaflet tissue underneath vegetations results in valve regurgitation. Disintegration and destruction of cardiac structures, the skeleton of the heart and the conduction system, means extravascular or even extra cardiac extension of the infection and is referred to as invasive disease. The disease progresses and develops in stages, and there are differences depending on the infected valve, location, organism, and between NVE and PVE. Invasive disease with perianular/perivalvular extension occurs in 10% to 40% of all NVE and over 50% of PVE cases. Invasion is more common with aortic valve IE, seen in two-thirds of surgical cases, than with mitral valve IE, where invasion is only seen in one-third of the surgical cases (see Fig. 14.5 ). ^{, ,} Continued destruction leads to abscess formation, pseudoaneurysms, and aorto-cavitary fistula formation, which can develop from any aortic sinus. New conduction abnormalities are an ominous sign and strongly suggest invasive disease toward the right atrium and the Koch triangle and likely to progress to aorto-right atrium fistula and intracardiac shunting. NVE on BAVs carries a higher risk of invasion and abscess formation. Perforations to the pericardium are rare but fatal unless contained by inflammation and scarring, and mortality is reported to exceed 40% despite surgical intervention. Right-sided IE is seldom, if ever, invasive.

Embolic events are very common in patients with IE ( Fig. 14.9 ), with a reported overall prevalence of 43% in NVE, 67% in IV drug–associated IE, and 25% in PVE. Material split off from vegetations (main source) or released from abscesses embolizes and causes strokes, satellite infections, and other septic embolic phenomena. The highest risk of embolic complications occurs with Staph. aureus, Candida , and HACEK species.

Number of embolic events by site of embolization in a series of 365 patients with 131 (34%) embolic events (some patients had more than one site of embolization).

(From Habib G. Management of infective endocarditis. Heart . 2006;92:124-130.)

Accordingly, infection with Staph. aureus increases the risk of neurologic complications. ^, Embolic stroke , 90% of which are in the distribution of the middle cerebral artery, is the most common neurologic event occurring in 20% to 40% of cases, causing disability and decreased survival. ^, Vegetations are seen on echocardiography in about 40% of patients with neurologic complications. Suggested and identified risk factors for embolism are vegetation size >10 mm, density, mobility, mitral valve involvement (anterior leaflet), and Staph aureus infection. ^, Cerebral embolism generally occurs before the start of antibiotic therapy, with risk of stroke falling rapidly after initiating effective antibiotics. A European multicenter study estimated the prevalence of acute ischemic stroke at 12% (CL 10%–14%) on hospital admission but only 3.7% (2.7%–4.9%) after start of appropriate antibiotic therapy. Data from the International Collaboration on Endocarditis indicated a stroke incidence of 4.8 per 1000 patient-days during the first week of antibiotic therapy, which decreased to 1.7 per 1000 patient-days in the second week and fell further thereafter ( Fig. 14.10 ).

Risk of embolic events according to vegetation size in patients followed 1 to 942 days (mean, 151 days) after initiating antibiotic treatment for left-sided infective endocarditis (217 episodes in 211 patients; multicenter study, April 1996 to June 2000). CI, Confidence interval; RR, relative risk.

(From Vilacosta I, Graupner C, San Roman JA, et al. Risk of embolization after institution of antibiotic therapy for infective endocarditis. J Am Coll Cardiol . 2002;39:1489.)

Intracerebral hemorrhage is the most devastating neurologic complication and occurs in about 5% of IE cases, with mortality exceeding 50%. ^, The pathophysiology may involve septic arteritis during uncontrolled infection with erosion of the vessel wall, hemorrhagic conversion of a cerebral infarction with hemorrhage, or formation and rupture of a mycotic aneurysm. Because cerebral hemorrhage is associated with risk of mortality and a relative contraindication to and a reason to delay surgery, this complication is underrepresented in surgical series.

Metastatic infections are common and typically caused by Staph. aureus . Other classic peripheral manifestations of IE, such as petechiae, Osler nodes, and splinter hemorrhages, are less frequently seen now because of earlier intervention in the disease process. Ting and colleagues report a 19% occurrence of splenic emboli in their series of patients with IV drug-related endocarditis. Occurrence of splenic abscess seems lower in contemporary practice, maybe around 5% of patients with left-sided NVE. Coronary emboli may result in myocardial infarction and ventricular dysfunction. Vertebral osteomyelitis is another complication, seen increasingly in recent years, with reported rates of 3% to 33%.

Pericarditis is a relatively uncommon complication of IE. It may be hemorrhagic and exudative and infective with growth of an organism or represent an inflammatory, immune-related response. Pericarditis typically occurs in association with advanced disease with invasion and anular abscesses or perforation/fistula. Arnett and Roberts found pericarditis in 18 (19%) of 95 patients with IE, 14 (78%) of whom had an anulus ring abscess. Pancarditis, including endocarditis, myocarditis, myocardial abscesses, and pericarditis, caused by bacterial or fungal infections, is associated with high mortality.

Circulating immune complexes (CICs) occur in a high percentage of patients with IE. One manifestation is glomerulonephritis, with glomerular dysfunction manifesting itself as slow but steady deteriorating renal function. Histopathologic analysis of kidney tissue may show diffuse proliferative glomerulonephritis, with evidence of deposition of immunoglobulin (Ig)G and IgM. CICs may be found in the glomerular basement membrane, retina, and peripheral lesions (Roth spots and Janeway lesions). ^, Hooper and colleagues identified CICs in patients with PVE. Kauffmann and colleagues found a positive correlation between CIC levels and duration of illness, and several investigators have noted a decline in CIC levels with successful treatment. ^, Various manifestations of complement activation have also been confirmed in IE. Messias-Reason and colleagues in 2002 correlated complement activation with severity and prognosis of the disease.

In clinical practice, however, low cardiac output, septic emboli, and antibiotic toxicity are more common causes and explanations for renal failure associated with IE than immune response-related renal impairment.

Before the antibiotic era, bacterial endocarditis was probably close to universally fatal. Acute endocarditis caused by Staph. aureus killed most patients within 2 months. Subacute and chronic endocarditis (also named endocarditis lenta) were primarily caused by Strep. viridans and had a more protracted course, with patients living up to a year and occasional patients recovering and surviving.

Antimicrobials and surgery have dramatically improved outcomes, and current mortality associated with IE has been reported at 15% to 20% during initial hospitalization and 20% to 30% during the first year. ^, Gram-negative bacillus and fungal IE have carried a higher mortality exceeding 50%. Development of heart failure, intracardiac abscess, embolism, a large mobile vegetation, hemodynamic instability, altered mental status, immune compromise, and advanced age have also been identified as risk factors for mortality. ^,

Multidisciplinary team management, the latest major strategy development currently advocated by all professional societies, has significantly improved outcomes. Introducing a formalized multidisciplinary team approach, defined by quick evaluation within 12 hours, surgery when indicated within 48 hours, and weekly reviews, Chirillo and colleagues reduced hospital mortality from 28% to 13% and 3-year mortality from 34% to 16%, despite older and sicker patients. Similarly, a French multidisciplinary team, using standardized antibiotic protocols and indications for surgery, reduced 1-year mortality from 18.5% to 8.2 %.

IE requires prompt diagnosis for early antimicrobial treatment and decision-making related to risk of additional new complications and need for surgery. The diagnosis of IE is difficult and frequently delayed, allowing more time for embolic events, continued structural damage to the heart, and immunologic manifestations. Patients present complex clinical scenarios with cardiac and systemic manifestations and require a multispecialty team approach, initially including specialists from infectious disease, cardiology, and cardiac surgery. Input from other specialties such as neurology, nephrology, psychiatry, and others is often required. When patients with IE need cardiac surgery, the level of surgical expertise is important because operations for IE remain associated with the highest mortality of any surgery for noninfective valve disease. The value of multidisciplinary team management in improving outcomes is well documented and generally supported. ^{, ,}

All patients diagnosed with IE receive antimicrobial therapy; however, before initiating antimicrobial therapy, blood cultures should be obtained, and two sets of blood cultures are the minimum for a secure microbiologic diagnosis of IE. The leading cause of “culture-negative IE” is treatment with antibiotics without blood cultures being obtained. Many IE cases can be managed solely with antimicrobials.

The goal of antimicrobial treatment is to eradicate the infection, including sterilizing vegetations. Challenges include focal infection with high bacterial density and low microorganism metabolic activity and slow growth within biofilm. Antimicrobials may face increased binding to serum proteins, a barrier to penetration into the vegetation, and unique antimicrobial pharmacokinetic and pharmacodynamic features. The main strategy to overcome all these issues is parenteral, high-dose, bactericidal, multidrug therapy, which is given over an extended period.

Once blood cultures have been drawn, treatment is started with an antimicrobial regimen covering all likely and possible organisms, only to narrow the regimen down when organism(s) and sensitivities are known. Success of antimicrobial therapy is related to how early the treatment is started, but the severity of cardiac and extracardiac complications also decides the outcome. Antimicrobials may kill the organisms but neither repair disintegrated valves nor restore cardiac integrity. A biofilm, metaphorically described as “cities for microbes,” keeps microorganisms embedded within a slimy extracellular polysaccharide matrix, which prevents immune cells and antimicrobials from reaching the organisms. The bacteria in the biofilm communicate using quorum sensing based on chemical signals to modulate cellular functions. The phases of biofilm development include adhesion, matrix formation, accumulation of multilayered clusters of microbial cells, maturation, and dispersion of planktonic bacteria/cells. The common organisms causing IE can form biofilm.

Because antibiotic penetration of vegetations and biofilm is difficult, successful treatment requires a combination of antimicrobials given intravenously in high doses, normally for 6 weeks. Once antibiotics are started, blood cultures should be drawn every 1 to 2 days until they become negative. The total duration of antibiotic therapy is counted from the time of the first negative culture. The idea that the entire antimicrobial course must be given intra-venous is being questioned. The recent POET (Partial Oral Treatment of Endocarditis) trial randomized patients with “stable” left-sided IE caused by streptococcus, Enterococcus faecalis , and Staph. aureus , or coagulase-negative staphylococci, who had been on IV antibiotics for at least 10 days to continue the usual course of IV antibiotics or discharge to ambulatory treatment with oral antibiotics. Early switch to oral antibiotic therapy was noninferior to traditional long-term IV therapy. Although the switch to oral treatment has not been validated for operated patients, this may still be considered for patients who inject drugs and refuse to complete the normally recommended IV course.

Detailed recommendations about antibiotic therapy for IE are available from the American Heart Association. However, regional- and site-specific differences in antimicrobial susceptibility profiles and changes over time require an infectious disease consultant to recommend regimen and management of the antimicrobial treatment.

In 1967, Yeh and colleagues reported that therapeutic anticoagulation not only failed to control emboli in PVE but increased the risk of bleeding among patients with infected prostheses. Although vegetations consist of platelets, cells, and fibrin, IE is not an indication for anticoagulation therapy but rather a relative contraindication. Neither anticoagulation nor antiplatelet therapy is effective in preventing embolism in patients with IE, and being on anticoagulation increases the risk of brain hemorrhage and hemorrhagic conversion of an ischemic stroke. A randomized trial of aspirin on risk of embolic events in patients with IE, NVE, or PVE failed to show benefit. ^, For patients with PVE, the findings are not equally clear, but most studies suggest that the risk of anticoagulation outweighs the potential benefits. If the patient has a mechanical prosthetic valve or other strong indications for anticoagulation, the treatment team must decide whether anticoagulation is necessary, what to use, and for what level of INR/PTT to aim. For patients with mechanical valve IE who have suffered an embolic stroke, AHA guidelines suggest that anticoagulation should be discontinued for at least 2 weeks to prevent hemorrhagic conversion.

Heparin, outside of its use in the operating room for cardiopulmonary bypass, should be avoided in patients with IE.

The importance of surgery in the treatment of IE is well established ( Fig. 14.11 ). ^, In recent population-based and international multicenter cohorts, about 50% of patients with either NVE or PVE undergo valve surgery during the active phase of IE. Surgery is performed with a hospital mortality of <10% and 6-month survival of >80%. ^,

An algorithm for endocarditis treatment. ^a IE caused by streptococcus, E. faecalis, S. aureus , or coagulase-negative staphylococci deemed stable by the Heart Valve Team. ^b Early surgery defined as during initial hospital course and before completing a full course of appropriate antibiotics. ^c In patients with an indication for surgery and a stroke but no evidence of intracranial hemorrhage or extensive neurologic damage, surgery without delay may be considered. DUA, drug use associated endocarditis; HF , heart failure; ICD, implantable cardioverter-defibrillator; ID , infectious disease; IE , infective endocarditis; IV , intravenous; NVE , native valve endocarditis; OST , opioid substitution treatment; pt , patient; PVE , prosthetic valve endocarditis; Rx , therapy; S. aureus , Staphylococcus aureus ; TEE , transesophageal echocardiography; TTE , transthoracic echocardiography; VHD , valvular heart disease; VKA , vitamin K antagonist.

(From Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation . 2021;143(5):e72-e227.)

When valves are destroyed or the disease is too advanced with large bulky vegetations and the infection has invaded and started destruction of the skeleton of the heart, antimicrobial treatment cannot cure the infection alone. Large mobile vegetations are an important source of embolism. Disintegrated tissue does not regrow. The role of surgery is to macroscopically remove infected and necrotic tissue and foreign material (including removal of any source of embolism), restore cardiac integrity (reconstruct atrioventricular or ventriculoarterial continuity), and restore functional valves. In children, an operation may also include repairing underlying congenital malformations. There are important differences related to patient factors (comorbidities, drug use, etc.), causative organism ( Staph. aureus , fungi, etc.), infected valve (aortic, mitral, right-sided), disease stage, and complications (stroke, renal failure, satellite infections, mycotic aneurysms, etc.) that interact and modulate indications for and timing of surgery, as well as the operation itself.

In 1978, Richardson and colleagues reported that operative treatment in 81 patients with NVE resulted in 11 deaths (14%; CL 10%–19%), compared with 24 deaths (44%; CL 37%–52%) in 54 patients treated medically. Operative mortality was affected by urgency of operation. For elective operations (next convenient operative date), mortality was 5%, for urgent operations (next day) 16%, and for emergency operations in patients with severe heart failure and low cardiac output (immediate operation) 33%. Hospital mortality for valve operations (and associated procedures) in patients with IE varies between 4% and 30%. ^{, ,} In a 2018 meta-analysis of patients with aortic valve IE and root abscess, the pooled 30-day postoperative mortality was 20% (95% CI 17–23%). Among patients with PVE, 30-day mortality after operation was significantly higher than among patients with NVE, relative risk 1.72. In a 2014 Cleveland Clinic study of outcomes after surgical treatment of left-sided IE, overall hospital mortality was 8%, for aortic valve IE 7%, for mitral valve IE 6 %, and for combined aortic and mitral valve IE 14%. Hospital mortality was higher (10%) for those with PVE than for those with NVE (6.3%) and higher among patients with invasive IE compared to those with noninvasive disease, 11% versus 4.4%.

Operations in patients with IE often demand complex procedures that affect hospital mortality. ^, Complexity of the procedure is frequently dictated by infecting organism and duration of the illness deciding severity of destruction and invasion. Tissue destruction is characteristic of staphylococcal and some gram-negative organisms.

PVE is an incremental risk factor for operative mortality in the domain of all IE. Again, overall survival for patients with PVE is improved in those treated surgically compared with those treated only medically. Although results may not be strictly comparable, most series report a difference in outcome when operative treatment of NVE is compared with PVE. In the Brigham and Women’s Hospital experience, mortality was 22% in 49 PVE patients vs. 6% in 109 NVE patients. Several factors, more prevalent in the PVE group, are likely responsible for this difference, including reoperation, prevalence of abscess, invasive disease (cellulitis, abscess, cavity, pseudoaneurysm), insidious onset of infection, and fastidious or fungal organisms. However, Sabik and colleagues at the Cleveland Clinic reported a 3.9% (CL 2%–7%) hospital mortality among 103 patients with PVE managed with radical debridement of infected tissue and aortic root replacement with a cryopreserved allograft. In a 2014 study of left-sided IE treated surgically, mortality after matching was similar for NVE and PVE, as well as for aortic, mitral, and double valve IE.

After surgical treatment of right-sided IE, in-hospital mortality was 5.9%, with no significant differences across predisposing conditions. No injection drug user died in-hospital.

Despite pediatric patients presenting unique challenges when IE is encountered, results of surgical management seem better than those observed in adults. ^, In children, IE is more often successfully treated without operative intervention. When surgical intervention is undertaken, postoperative mortality is around 10%.

For patients with complicated, left-sided NVE, valve surgery was associated with reduced 6-month mortality compared to medical treatment only, and surgery for acute heart failure provided the greatest benefit. Late survival after valve replacement for NVE is good but not as good as after the same operations for noninfective indications. Death and other events late after operations for IE often are not related to IE or recurrent infection but rather to other conditions associated with heart disease, such as the valve replacement device and associated complications, myocardial dysfunction, and coronary artery disease. Using mechanical valves exclusively, Bauernschmitt and colleagues reported 81% survival among 138 patients after 8 years. Data for long-term survival after heart valve replacement in patients with IE are typified by those reported by d’Udekem and colleagues from Toronto; survival at 10 years was 61% ± 6%. Aranki and colleagues, in two separate publications from Brigham and Women’s Hospital, reported 81% to 83% 5-year survival and 61% to 63% 10-year survival for both mitral and aortic valve replacement. ^, A recent Swedish registry study, with 100% follow-up, compared outcomes after surgery for IE involving bicuspid versus tricuspid aortic valves, and survival rates at 1, 5, 10, and 14 years were 88%, 81%, 78%, and 76% versus 85%, 69%, 58% and 43%, respectively, in patients with a BAV who underwent transcatheter aortic valve replacement (TAVT). In patients with NVE, a BAV was associated with improved postoperative survival, but survival was not affected by the original valve morphology among patients with PVE.

In a Cleveland Clinic 2014 study of left-sided IE, overall unadjusted survival at 30 days, 6 months, and 1, 3, 5, and 7 years for these patients was 92%, 84%, 81%, 72%, 66%, and 60%, respectively. The hazard function resolved into 2 phases, with an early phase lasting about 6 months and accounting for about half of the 245 deaths and a late declining phase thereafter. Survival was higher for those with isolated aortic valve IE than for the mitral and combined groups (73% at 5 years vs. 60% and 51%, respectively, P <.0001. Survival was similar after surgery for PVE or NVE (67% vs 64% at 5 years; Fig. 14.17 ). Patients with invasive IE had worse survival than those with noninvasive IE for mitral and aortic plus mitral IE but not for isolated aortic IE ( Fig. 14.18 ); this difference persisted in matched patients ( Fig. 14.19 ).

Survival after surgery for native or prosthetic valve left-sided valve infective endocarditis (IE). Each symbol represents a death, and vertical bars 68% confidence limits, equivalent to ±1 standard error. Solid green lines indicate native valve endocarditis; dashed orange lines, prosthetic valve endocarditis; filled circles, aortic valve IE alone; open circles, mitral valve IE alone; and triangles, aortic and mitral valve IE.

(From Hussain ST, Shrestha NK, Gordon SM, Houghtaling PL, Blackstone EH, Pettersson GB. Residual patient, anatomic, and surgical obstacles in treating active left-sided infective endocarditis. J Thorac Cardiovasc Surg . 2014;148(3):981-988.e4.)

Survival after surgery for invasive versus noninvasive left-sided infective endocarditis according to valve position. Solid blue lines indicate noninvasive infective endocarditis and dashed red lines invasive infective endocarditis; filled circles, aortic valve IE alone; open circles, mitral valve IE alone; and triangles, aortic and mitral valve IE. Each symbol represents a death, and vertical bars represent the 68% confidence limits, equivalent to ± 1 standard error.

(From Hussain ST, Shrestha NK, Gordon SM, Houghtaling PL, Blackstone EH, Pettersson GB. Residual patient, anatomic, and surgical obstacles in treating active left-sided infective endocarditis. J Thorac Cardiovasc Surg . 2014;148(3):981-988.e4.)

Survival after surgery for invasive infective endocarditis. Depiction is for aortic unmatched (solid purple line) and balancing score matched (solid green line) patients and mitral unmatched (dashed purple line) and matched (dashed green line) . Each symbol represents a death and vertical bars 68% confidence limits equivalent to ± 1 standard error.

(From Hussain ST, Shrestha NK, Gordon SM, Houghtaling PL, Blackstone EH, Pettersson GB. Residual patient, anatomic, and surgical obstacles in treating active left-sided infective endocarditis. J Thorac Cardiovasc Surg . 2014;148(3):981-988.e4.)

Postoperative morbidities are more common after surgery for IE than after corresponding operations in patients without IE. These include bleeding, heart block, stroke, renal failure, dialysis, and sepsis, resulting in prolonged ventilation and longer ICU and hospital stays. Inflamed tissue, inflammatory pericarditis, complex reconstructions, renal dysfunction, and platelet dysfunction may all play a role in excessive bleeding. Patients with PVE and patients with invasive disease have more renal failure and recurrent sepsis compared to patients with NVE and less invasive disease.

Heart block occurs more often than in patients without endocarditis. In most situations, this is a predictable consequence of the radical debridement necessary to eradicate infections around the aortic root. Prolongation of preoperative PR-and QRS-intervals, Staph. aureus as a causative organism, intracardiac abscess, tricuspid valve involvement, and prior valve surgery were identified as risk factors for new need for a permanent postoperative pacemaker.

All complications described previously in this chapter are still relevant postoperatively and require consideration. A few patients with IE have continuing episodes of sepsis despite a seemingly adequate cardiac operation. Although the source of this sepsis is not the heart, it may still require evaluation with repeat TEE. If not done preoperatively, whole-body screening with CT should be considered. Splenic and other visceral infarcts from emboli and abscesses are not infrequent, but usually but not always, these lesions do not cause continuing sepsis and are amenable to continued antibiotic therapy. Renal parenchymatous disease as a cause of sepsis is rare, as are mycotic aneurysms, cerebral or peripheral.

The most serious nonfatal complication is a new or worsening neurologic deficit after valve replacement. The risk of aggravating an existing stroke or brain bleeding by the operation is discussed with references in the paragraph below on “Timing of surgery in patients with neurologic deficits.” However, even with meticulous surgical technique, friable vegetations may dislodge to cause new CNS deficits. In one study, the risk of new or worsening stroke was 3.9%, and similar for NVE versus PVE and noninvasive versus invasive IE. Stroke risk is higher than anticipated after corresponding valve surgery in patients without IE.