Infective Endocarditis

Etiology

Most cases of infective endocarditis are caused by gram-positive organisms, particularly streptococci, staphylococci, and enterococci. Collectively, these groups account for 80% to 90% of all cases, with Staphylococcus aureus alone responsible for about 30% of cases in developed countries.[4] The global proportion of infective endocarditis attributable to Enterococcus species is increasing, a trend that observational studies have linked to rising antimicrobial use.[5][6][7] In addition to various streptococcal species, other oropharyngeal colonizers, such as the HACEK organisms (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella), are less frequent but recognized causes of disease. Numerous other bacterial pathogens have been identified, though they account for only about 6% of cases.

Fungal endocarditis is rare, representing approximately 1% of cases, but it carries a high mortality rate. This condition most often occurs in immunocompromised individuals and is typically associated with systemic infections caused by Candida and Aspergillus species. Risk factors and the setting of bacterial acquisition, whether healthcare-associated or community-acquired, provide important clues to the underlying infectious etiology. Although the definition of nosocomial infections remains variable, healthcare-associated cases generally occur in the context of early prosthetic valve endocarditis, typically within 60 days of surgery, or after recent vascular catheterization, hemodialysis, hospitalization, or extracardiac surgical procedures.

In these settings, S aureus is the predominant pathogen, accounting for approximately 50% of nosocomial cases. Less virulent coagulase-negative staphylococci, such as Staphylococcus epidermidis, are classically associated with indwelling vascular devices or recently implanted prosthetic valves. Enterococcal infections occur at similar frequencies in both nosocomial and community-acquired settings, comprising about 15% and 18% of cases, respectively.[8] These infections are often associated with genitourinary or gastrointestinal sources, particularly in older adults or those with recent instrumentation.

Community-acquired infective endocarditis typically arises in the setting of immunosuppression, intravenous drug use, poor dentition, degenerative valvular disease, and rheumatic heart disease. Intravenous drug use, which accounts for nearly 10% of cases, is associated with repeated inoculation of skin flora, most commonly S aureus and S epidermidis. Notably, S aureus demonstrates a predilection for infecting structurally normal native valves, particularly the tricuspid valve. 

Among people who inject drugs, non-HACEK microorganisms, including Serratia species, Pseudomonas aeruginosa, and Klebsiella species, are more frequently encountered.[9] Although fairly uncommon in healthcare-associated infections, viridans group streptococci account for approximately 20% of community-acquired cases.[10] Infection with Streptococcus gallolyticus (formerly Streptococcus bovis) should raise suspicion for underlying colorectal carcinoma.[11] 

Epidemiology

Infective endocarditis is an uncommon condition with an estimated annual incidence of 3 to 10 cases per 100,000 individuals.[12][13] Historically, this disease process has demonstrated a male predominance, with a male-to-female ratio of approximately 2:1, and higher rates of streptococcal and enterococcal infections observed in men.[14] However, in populations with high rates of intravenous drug use, women who inject drugs have been shown to experience higher rates of discharge against medical advice and increased mortality compared with men.[15][16] 

The average age of patients with infective endocarditis is now 65 or older, with the highest incidence observed in those aged 80 or older.[13] This shift towards an older population likely reflects the increasing prevalence of predisposing factors, including prosthetic valves, indwelling cardiac devices, acquired valvular disease, hemodialysis, and diabetes mellitus.[17] Although rheumatic heart disease remains a major risk factor globally, it is now relatively uncommon in high-income countries, except in specific high-incidence populations such as Aboriginal communities in northern Australia and Maori and Pacific peoples in New Zealand.[18][19] Recreational intravenous drug use is an emerging and significant risk factor, currently accounting for approximatley 10% of all infective endocarditis cases.[10]

Pathophysiology

The intact, healthy endocardium is typically resistant to microbial seeding. The development of infective endocarditis requires an initial endocardial injury followed by a period of bacteremia. Endocardial disruption may occur secondary to turbulent flow across diseased valves or from direct mechanical trauma from catheter or electrode insertion. In individuals who use intravenous drugs, repeated valvular injury from co-injected particulate matter contributes to the necessary injury.[12] 

Hemodynamic factors play a key role in pathogenesis, as reflected by the tendency for vegetations to form on the ventricular surface of the aortic valve and the atrial surface of the mitral valve. The vegetations typically develop downstream of regurgitant flow, supporting the hypothesis that relative hypoperfusion of the intima predisposes these regions to injury. Infective endocarditis is also more common in high-turbulence lesions, such as small ventricular septal defects with a jet or stenotic valves, where high-pressure flow produces greater endothelial damage than low-flow or large-surface defects.[20] 

The damaged endocardium then serves as a nidus for platelet aggregation and activation of the coagulation cascade, resulting in sterile, nonbacterial thrombotic vegetations.[21] The vegetations can subsequently become infected during episodes of bacteremia. Bacteremia may arise from a distant, established source of infection or occur transiently through intermittent hematogenous seeding of oral flora following dental or gingival manipulation. Although the minimum bacterial inoculum required for infection is not well defined, experimental models have demonstrated the development of infective endocarditis with slow infusions of 1 mL containing 106 colony-forming units of bacteria.[22] 

Even in the presence of endocardial injury and bacteremia, disease progression requires a sufficiently virulent organism capable of adhering to and promoting platelet-fibrin deposition. For example, S aureus expresses adhesins, including clumping factors A and B, and serine-aspartate repeat proteins, which independently facilitate platelet aggregation. Expansion of these initially sterile platelet-fibrin deposits may shield microorganisms from host immune defenses, allowing progressive growth of infected vegetations.[23]

Histopathology

Mature vegetations are composed of an amalgamation of inflammatory cells, fibrin, platelets, and erythrocyte debris. The initial platelet-fibrin thrombus serves as a nidus for bacterial adherence and ongoing platelet aggregation. Confocal laser scanning microscopic analysis of infected valve tissue demonstrates bacterial biofilms embedded within platelet-rich collections.

In a self-perpetuating cycle, platelets facilitate bacterial colonization, while bacterial surface proteins promote further aggregation and growth.[24] In the acute phase, the vegetation is avascular; however, with the onset of healing, neovascularization, fibroblast proliferation, and fibrosis may develop within the affected valve. Both the gross and histologic appearances of valvular tissue vary with the infecting organism.

Virulent pathogens such as S aureus typically elicit an inflammatory response with neutrophilic predominance and large bacterial colonies. On macroscopic examination, this often manifests as friable tissue with significant valvular destruction. In contrast, infections caused by less virulent organisms, such as viridans group streptococci, are more commonly associated with a predominantly mononuclear cell infiltration.[25]

Histologic staining of valve tissues often reveals focal bacterial colonies. Although cultures are frequently negative after the initiation of antibiotic therapy, Gram staining of valve tissues remains positive in more than 60% of cases during active treatment.[26] In streptococcal and staphylococcal endocarditis, hematoxylin and eosin staining typically demonstrates basophilic cocci. Although primarily used for fungal identification, the Grocott-Gomori methenamine silver stain can delineate streptococcal contours and provide greater sensitivity for detecting bacteria in valve tissue than Gram staining.[27]

Periodic acid-Schiff staining offers greater sensitivity and best highlights the foamy macrophages characteristic of Tropheryma whipplei endocarditis.[25] In prosthetic valve endocarditis, inflammatory cells are often confined to the vegetation on the surface of the valve cusp. In contrast to the inflammatory response seen in degenerative valve calcification, prosthetic valve endocarditis primarily involves neutrophilic infiltrates rather than macrophages and lymphocytes.[28]

History and Physical

Infective endocarditis presents with a myriad of signs and symptoms, and clinicians should consider this diagnosis in any patient with relevant risk factors who develops fever or sepsis of unknown origin.[12] Patients often report an insidious onset of fevers, chills, malaise, and fatigue, typically prompting medical evaluation within the first month. Fever, defined as a temperature greater than 38 °C (100.4 °F), is present in more than 95% of cases across large prospective cohorts.[10] However, this finding may be absent or blunted in individuals with immunosuppression, advanced age, antipyretic use, or prior antibiotic exposure.[29]

Other nonspecific symptoms of systemic infection, including anorexia, headache, and generalized weakness, are common. Cardiopulmonary symptoms such as chest pain, dyspnea, decreased exercise tolerance, orthopnea, and paroxysmal nocturnal dyspnea occur less frequently. Still, they should raise concern for valvular dysfunction, particularly involving the aortic or mitral valves. In cases of acute valvular incompetence, patients may present with sudden-onset heart failure and hemodynamic instability.

A thorough history often reveals predisposing conditions and risk factors that aid in diagnosis. Relevant factors include current or prior indwelling vascular catheters, intravenous drug use, rheumatic heart disease, recent pacemaker implantation, prosthetic valves, and congenital cardiac defects, including unrepaired cyanotic defects, repaired defects with prosthetic material, or residual cardiac shunts.[12][30] These conditions increase the likelihood of underlying endocardial injury.

Healthcare professionals should assess for degenerative valvular disease, such as calcific aortic stenosis or mitral valve prolapse, which account for approximately 30% of cases.[10][31] In North America, diabetes mellitus is a common comorbidity, affecting up to one-third of individuals with infective endocarditis.[32] A thorough physical examination may reveal findings that support the diagnosis and suggest complications from peripheral embolization. Fever is common, though tachypnea and tachycardia may also be present in the setting of systemic infection or valvular dysfunction. Hypotension can occur with septic or cardiogenic shock, particularly in cases of acute valve perforation.

A new or worsening murmur is identified in fewer than 50% of cases, but it can help localize valvular involvement.[33] Severe mitral or aortic regurgitation may be associated with bilateral pulmonary rales. Classic cutaneous findings include Osler nodes (painful erythematous subcutaneous nodules typically found on the palm, fingers, and toes), splinter hemorrhages, and Janeway lesions (painless hemorrhagic plaques on the palms and soles). However, each occurs in fewer than 10% of patients.[10] Additional findings may include splenomegaly or signs of peritonitis from mesenteric ischemia. Neurologic deficits, including focal motor, sensory, or visual changes, may indicate intracerebral embolization. 

Evaluation

Most patients with infective endocarditis present with nonspecific symptoms such as fatigue, fever, or chest pain, necessitating a broad diagnostic evaluation. Patients with chest pain or dyspnea warrant early assessment for other life-threatening cardiopulmonary processes, including acute coronary syndrome, pulmonary embolism, and pneumonia. Those with signs of severe sepsis require rapid, guideline-directed evaluation using established protocols.

• In patients presenting with chest pain or dyspnea, a 12-lead electrocardiogram (ECG) is a rapid, inexpensive tool for assessing ischemia, dysrhythmias, or structural abnormalities. ECG findings in infective endocarditis are often normal; however, ST-segment elevation should be treated as a myocardial infarction and managed according to ST-elevation myocardial infarction (STEMI) protocols, even in patients with known endocarditis.[34][35]

A chest x-ray may reveal pulmonary infiltrates, abscesses, or pleural effusions. In cases of severe left-sided valvular insufficiency, findings such as pulmonary edema, cardiomegaly, or cephalization of pulmonary vasculature may be present. Advanced imaging, including contrast-enhanced computed tomography (CT) or CT angiography, may be required to evaluate for pulmonary parenchymal disease, empyema, or septic embolism.

Similarly, contrast-enhanced abdominal imaging is indicated when mesenteric and intra-abdominal complications, including abscesses or mycotic aneurysms, are suspected. Cardiac biomarkers are essential in patients with suspected myocardial ischemia or myocarditis. Patients who develop acute focal neurological complications should undergo urgent neuroimaging and early neurologic consultation, especially when anticoagulation decisions must account for the risk of intracerebral bleeding.

In the acute setting, a broad laboratory evaluation is warranted given the nonspecific presentation. A complete blood count often reveals leukocytosis, while subacute or chronic cases may demonstrate normocytic anemia consistent with anemia of chronic disease. Inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein, are elevated in approximately 60% of cases but are nonspecific.[10] 

A comprehensive or basic metabolic panel should be obtained to identify electrolyte abnormalities requiring correction during initial management. Urinalysis may show proteinuria, microscopic hematuria, or pyuria, reflecting glomerular injury, renal infarction, or inflammatory changes.[36] After excluding more immediately life-threatening conditions, the diagnosis of infective endocarditis relies on both microbiologic and echocardiographic evidence. Diagnosis is based on the Modified Duke Criteria, originally developed in 1994 and subsequently refined in 2000 and 2023.[37] 

The criteria are divided into major and minor components. A diagnosis requires one of the following:

• 2 major criteria
• 1 major plus 3 minor criteria
• 5 minor criteria

The first major criterion is microbiologic confirmation of bacteremia. This includes 2 separate blood cultures that are positive for typical organisms, such as viridans group streptococci, S gallolyticus (S bovis), HACEK organisms, S aureus, or community-acquired enterococci in the absence of an alternative source. For less typical pathogens, cultures must demonstrate persistent bacteremia, defined as either 2 positive cultures obtained more than 12 hours apart or the majority of at least 4 separate cultures (with first and last drawn at least 1 hour apart).[38] The American Heart Association (AHA) also accepts a single positive blood culture for Coxiella burnetii or an anti-phase 1 IgG antibody titer 1:800 or greater.[39] In regions with a high prevalence of blood culture-negative endocarditis, particularly due to Bartonella species, these microbiological criteria may have reduced sensitivity.[40]

The second major criterion requires evidence of endocardial involvement, typically demonstrated by echocardiography showing a mobile intracardiac mass attached to a valve, supporting structure, or prosthetic material. Transthoracic echocardiography (TTE) is the usual initial study; however, if clinical suspicion remains high despite a negative TTE, the AHS recommends a TTE because of its greater sensitivity and specificity.[39] 

Certain factors, including chronic obstructive pulmonary disease, prior thoracic surgery, obesity, and prosthetic valve involvement, may limit TTE visualization and warrant early use of transesophageal echocardiogram (TEE). Echocardiography may also reveal elevated pulmonary pressures, reflecting increased left atrial pressure and potentially indicating the need for urgent surgical intervention.[41] Cardiac CT is an increasingly important adjunct, particularly for evaluating paravalvular complications, such as abscesses, with some studies demonstrating higher sensitivity than echocardiography.[42] 

One meta-analysis highlighted a superior sensitivity of 88% for CT compared with 74% for TEE in detecting paravavular abscess.[43] Nonetheless, the 2023 European Society of Cardiology guidelines continue to recommend TTE as the first-line imaging modality for suspected cases.[44] In diagnostically uncertain cases, the AHA considers F-fluorodeoxyglucose positron emission tomography/CT a reasonable adjunct to improve diagnostic accuracy.[41]

The 5 minor criteria include the following:

• Predisposing conditions, such as underlying valvular abnormalities, structural heart disease, or IV drug use
• Fever, defined as a temperature greater than 38 °C
• Evidence of vascular phenomena, including mycotic aneurysms, intracranial hemorrhage, Janeway lesions, major arterial emboli, or septic pulmonary infarcts
• Evidence of immunologic phenomena such as Osler nodes, Roth spots, glomerulonephritis, or positive rheumatoid factor
• Positive blood cultures that do not satisfy the major criteria or serologic evidence consistent with infective endocarditis [39]

Treatment / Management

Effective treatment promotes the eradication of endocardial vegetation and reduces the risk of secondary complications. Patients presenting in extremis with acute decompensated heart failure, septic shock, or stroke require immediate stabilization, prioritizing airway, breathing, and circulation. Following initial stabilization, management focuses on prolonged bactericidal antibiotic therapy and, when indicated, cardiothoracic surgical intervention.

Antibiotic selection and duration depend on the valve involved and the susceptibility profile of the causative organism.

• Native valve endocarditis due to penicillin-susceptible viridans group streptococci or S gallolyticus requires one of the following:
  • Ceftriaxone 2 gm intravenous daily + gentamicin 3 mg/kg intravenous daily for 2 weeks [39] 
  • Ceftriaxone 2 gm intravenous daily for 4 weeks
  • Aqueous penicillin G 12 to 18 million units daily via continuous intravenous
• Prosthetic valve involvement, same pathogens typically require a minimum of a 6-week course of 1 of the following:
  • Penicillin G 24 million units daily
  • Ceftriaxone 2 gm +/- gentamicin 3 mg/kg daily

Staphylococcal endocarditis generally requires longer treatment courses as follows:

• Native valve methicillin-sensitive S aureus (MSSA):
  • Nafcillin 2 g intravenous every 4 hours for 6 weeks
  • OR cefazolin 2g intravenous every 8 hours for 6 weeks
• Native valve methicillin-resistant S aureus (MRSA):
  • Vancomycin 15 mg/kg intravenous every 12 hours for 6 weeks
  • OR daptomycin 8 mg/kg intravenous daily for 6 weeks

Gentamicin dual therapy is no longer recommended for MSSA or MRSA native valve infections due to a lack of benefit and concern for nephrotoxicity.[39][44][45] (B3)

Prosthetic valve staphylococcal infections require combination therapy with rifampin and gentamicin. Therapy is as follows:

• Prosthetic valve MSSA
  • Nafcillin (as above) for 6 weeks
  • Gentamycin 3mg/kg intravenous in 2 to 3 divided doses for 2 weeks
  • Rifampin 900 mg/day intravenously in 2 to 3 divided doses for 6 weeks
• Prosthetic valve MRSA
  • Vancomycin (as above) for 6 weeks
  • Gentamycin and rifampin as above [39][46]
(B3)

Enterococcal endocarditis requires combination therapy, as beta-lactam monotherapy is not bactericidal. Native and prosthetic valve enterococcal infections require combination regimens. Examples include ampicillin or penicillin G plus an aminoglycoside such as gentamicin for 4 to 6 weeks. An alternative regimen against Enterococcus faecalis includes ampicillin plus ceftriaxone (a dual beta-lactam regimen with effective bactericidal activity).[44][47] Of note, penicillin resistance warrants combined vancomycin and gentamicin therapy; however, emerging resistance to penicillin, gentamicin, and vancomycin may require treatment with linezolid or daptomycin.(B3)

Antimicrobial treatment guidelines are continually evolving and should be routinely reviewed. Early consultation with infectious disease specialists is recommended to guide appropriate antibiotic selection and duration. Additionally, repeat blood cultures should be obtained every 24 to 48 hours to confirm clearance of bacteremia and to direct antimicrobial management.[39]

Indications for emergent surgical intervention (within 24-48 hours) before completion of initial antibiotic therapy, as outlined by the AHA and American College of Cardiology (ACC), include the following:

• Acute congestive cardiac failure associated with infective endocarditis
• Cardiac complications, including heart block, aortic or anular abscess
• Systemic embolization or large vegetations (>10 mm), or valvular lesions (>15 mm), even without embolic disease
• Cerebrovascular complications
• Persistent bacteremia for more than 5 to 7 days despite appropriate antibiotic therapy
• Infection with difficult-to-treat microorganisms (eg, Pseudomonas spp, Coxiella burnetti, S lugdunensis, Brucella spp, and fungal species)
• Most cases of early prosthetic valve endocarditis [48][49]
(A1)

Prevention and management of recurrent embolic events represent a major impetus for surgical intervention in infective endocarditis. Antimicrobial therapy alone has been shown to reduce stroke incidence significantly within the first week of treatment.[50] However, early surgical intervention (within 48 hours) has demonstrated substantial benefits, including reduced in-hospital mortality and a lower risk of embolic events compared with conventional therapy. As a result, nearly half of all patients with infective endocarditis now undergo some form of surgical management.[10](B2)

Surgery should be performed urgently once clinical indications are met to reduce the risk of initial or recurrent embolic events.[51] Intraoperative TEE is used to guide the complete removal of infected and necrotic tissue, including any foreign material. The choice of valve repair versus replacement depends on the extent of valvular damage, patient age, comorbidities, life expectancy, and the risks associated with long-term anticoagulation. Observational data suggest higher in-hospital mortality with valve replacement compared with repair, with increased rates of shock and need for tracheostomy.[52] Advanced age (>70) and hemodialysis dependence are among the strongest predictors of inpatient mortality.

Infected cardiac material, including implantable cardiac devices with leads and generators, should be removed. Intraoperative specimens should be sent for microbiologic and molecular analyses to guide antimicrobial therapy, which is typically continued for at least 6 weeks postoperatively, depending on the organism's susceptibility. Patients remain at increased risk for recurrent infective endocarditis and should be counseled accordingly, including the potential role of antimicrobial prophylaxis before future dental procedures.[53](A1)

Differential Diagnosis

A broad array of infectious, inflammatory, neoplastic, and mechanical conditions should be considered when evaluating suspected infective endocarditis. The differential diagnosis depends on presenting symptoms; for example, chest pain warrants evaluation for acute coronary syndrome, acute heart failure, aortic dissection, myopericarditis, pulmonary embolism, pneumonia, and empyema. In patients with prosthetic valves, alternative diagnoses include perivalvular thrombosis—particularly with interrupted anticoagulation—or suture dehiscence.

Recurrent arterial emboli following a recent myocardial infarction should raise suspicion for a ventricular mural thrombus. In otherwise healthy young individuals with a new murmur, atrial myxoma should be considered. Rarely, nonbacterial endocarditis with sterile valvular thrombi may occur in the setting of underlying malignancy (marantic endocarditis) or systemic lupus erythematosus (Libman-Sacks endocarditis).[54]

Prognosis

Prognosis in infective endocarditis varies widely and depends on the virulence of the pathogen, the development of complications, underlying comorbidities, and whether a native or prosthetic valve is involved. In-hospital mortality is approximately 18%, with one-year mortality approaching 40%.[55] Early prosthetic valve endocarditis, particularly within 60 days of surgery, carries the highest in-hospital mortality (around 30%).[56] 

Outside this subgroup, S aureus infection and heart failure are among the strongest predictors of mortality.[57] Additional risk factors include older age, IV drug use, multivalvular involvement, diabetes mellitus, hemodialysis, stroke, congestive cardiac failure, and cardiac abscess.[58][59] Although up to half of patients undergo surgical intervention, surgery itself does not independently increase in-hospital mortality.[10][60] Operative mortality ranges from 7.6% to 20%, with worse outcomes associated with preoperative neurologic complications, intraoperative cardiogenic shock, and older age.[61][62] 

Complications

Infective endocarditis can result in a range of intracardiac complications. Acute valvular incompetence occurs in approximately one-third of cases and may lead to heart failure, often due to valve perforation or damage to the chordae tendineae and papillary muscles. Mitral or tricuspid regurgitation can also cause atrial enlargement, predisposing patients to atrial fibrillation and other supraventricular dysrhythmias. Less commonly, complications include intracardiac abscesses (14%) and atrioventricular blocks (8%).[10]

Peripheral embolization can lead to a wide range of extracardiac complications. Right-sided vegetations may result in pulmonary embolization, manifesting as pulmonary abscesses, pneumonia, empyema, or focal pulmonary infarctions, particularly in people who inject drugs. Neurologic complications are among the most common and severe, occurring in 15% to 30% of cases.[10] 

Potential complications include ischemic stroke, intracranial hemorrhage, meningitis, intracerebral abscess, and infective intracranial aneurysms. Ischemic strokes represent the vast majority of neurologic complications and typically result from embolization of mitral or aortic valve vegetations.[63] Septic emboli to the vasa vasorum can also weaken vessel walls, leading to mycotic aneurysm formation, which typically remains asymptomatic until rupture.[64] 

Less common complications include acute kidney injury stemming from immune-mediated glomerulonephritis or renal infarction due to embolic occlusion. Splenic infarcts and abscess formation, especially in S aureus infection, can also occur from septic emboli.[65] Acute mesenteric ischemia and subsequent bowel necrosis and perforation represent a rare but life-threatening consequence of arterial embolization.