Introduction
Infective endocarditis, a condition characterized by the colonization of heart valves and the endocardium by microorganisms, primarily bacteria, poses a significant clinical challenge. Its insidious nature and potential for severe complications, including rapid morbidity and mortality, necessitate prompt and accurate diagnosis followed by effective treatment. This article provides an in-depth review of infective endocarditis, emphasizing the crucial aspects of its diagnosis, evaluation, and management. A thorough understanding of Infective Endocarditis Diagnosis is paramount for healthcare professionals to ensure timely intervention and improve patient outcomes. Effective management of this complex condition relies on a multidisciplinary approach, highlighting the indispensable role of an interprofessional team in optimizing patient care.
Etiology of Infective Endocarditis
The diverse microbial landscape of infective endocarditis is predominantly shaped by gram-positive bacteria, namely streptococci, staphylococci, and enterococci. These three bacterial groups collectively account for a substantial 80% to 90% of all infective endocarditis cases. Staphylococcus aureus emerges as a particularly significant pathogen, responsible for approximately 30% of cases in developed countries.[1] Beyond these common culprits, other oropharyngeal inhabitants like HACEK organisms (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella) are less frequent but recognized etiological agents. A broader spectrum of bacteria has been implicated, contributing to around 6% of cases. Fungal endocarditis, although rare at about 1% of cases, carries a high fatality risk, often arising from systemic Candida and Aspergillus infections, particularly in immunocompromised individuals.
Understanding the risk factors and context of infection acquisition—healthcare-associated versus community-acquired—is vital in inferring the underlying etiology. Healthcare-associated infections often manifest as early prosthetic valve endocarditis (within 60 days post-surgery) or following procedures like vascular catheterization, hemodialysis, hospitalization, or other surgeries. In these scenarios, S. aureus is the dominant pathogen, implicated in roughly 50% of nosocomial infections. Coagulase-negative staphylococci, such as S. epidermidis, are typically linked to indwelling vascular devices or recently implanted prosthetic valves. Enterococcal infections show a similar prevalence in both healthcare and community settings, representing around 15% and 18% of cases, respectively.[2]
Community-acquired infective endocarditis often develops in individuals with predisposing conditions such as immunosuppression, intravenous drug use (IVDU), poor dental health, degenerative valve disease, and rheumatic heart disease. IVDU, implicated in nearly 10% of cases, suggests repeated exposure to skin flora like S. aureus and S. epidermidis. S. aureus shows a particular affinity for healthy, native tricuspid valves in this context. Viridans group streptococci, while less common in healthcare-related infections, are responsible for approximately 20% of community-acquired cases.[3] Notably, Streptococcus gallolyticus (bovis) infections should prompt investigation for underlying colon carcinoma.[4]
Epidemiology of Infective Endocarditis
Infective endocarditis remains a relatively rare condition, with an estimated annual incidence ranging from 3 to 10 cases per 100,000 individuals.[5] Historically, males have been more affected, with a male-to-female ratio of approximately 2:1. The average age of patients diagnosed with infective endocarditis has risen to over 65 years. This shift towards older age groups likely reflects the increased prevalence of predisposing factors such as prosthetic valves, implanted cardiac devices, acquired valvular disease, hemodialysis, and diabetes mellitus in this demographic.[6] While rheumatic heart disease was once a major risk factor, it now accounts for less than 5% of cases in the contemporary antibiotic era. Recreational IVDU is an increasing risk factor, now contributing to about 10% of all infective endocarditis cases.[3]
Pathophysiology of Infective Endocarditis
The intact endocardium possesses inherent resistance to bacterial colonization. The development of infective endocarditis typically requires a two-step process: initial endocardial injury followed by bacteremia. Endocardial damage can arise from turbulent blood flow across diseased valves or direct mechanical trauma during catheter or electrode insertion. In IVDU, repeated valvular impact from injected particulate matter causes the necessary endothelial disruption.[5] The predilection for vegetations to form on the ventricular aspect of the aortic valve and the atrial side of the mitral valve underscores the role of hemodynamics in pathogenesis. Vegetations often localize downstream from regurgitant flow, suggesting that intima hypoperfusion predisposes these areas to injury. Moreover, high-turbulence lesions, such as small ventricular septal defects with jet lesions or stenotic valves, are more prone to endocarditis, presumably due to greater localized damage from high-pressure flow compared to defects with larger surface areas or low flow.[7] The damaged endocardium becomes a site for platelet aggregation and coagulation cascade activation, leading to the formation of a sterile, non-bacterial thrombotic vegetation.[8]
Subsequent bacteremia enables colonization of this vegetation. Bacteremia can originate from a distant infection or transiently occur due to intermittent hematogenous spread of oral flora from dental or gingival manipulation. The precise minimum bacterial load required is unknown, but experimental models have induced endocarditis with slow infusions of 106 colony-forming units of bacteria.[9] Even with endocardial injury and bacteremia, pathogenesis requires a virulent organism capable of adhering to and promoting platelet-fibrin deposition. For example, S. aureus proteins like clumping factors A, B, and serine-aspartate repeat protein independently mediate platelet aggregation. The expanding platelet-fibrin vegetation theoretically shields pathogens from the host immune response, facilitating vegetation growth.[10]
Histopathology of Infective Endocarditis
Mature vegetations are complex structures composed of inflammatory cells, fibrin, platelets, and erythrocyte debris. The initial platelet-fibrin clot acts as a scaffold for bacterial adherence and further platelet aggregation. Confocal microscopy of infected valve tissue reveals bacterial biofilms embedded within platelet collections. Platelets promote bacterial colonization, which in turn drives further bacterial aggregation through surface protein interactions in a self-perpetuating cycle.[11] In acute cases, vegetations are avascular; however, as healing begins, neovascularization, fibroblasts, and fibrosis may develop in the affected valve.
The macroscopic and microscopic appearance of valvular tissue varies depending on the infecting organism. Virulent pathogens like S. aureus typically induce a neutrophil-rich inflammatory response with large bacterial colonies. Gross examination may reveal friable tissue with significant destruction. Less virulent organisms, such as viridans group streptococci, elicit a more mononuclear cell-dominated inflammatory infiltrate.[12]
Histological staining often demonstrates focal bacterial colonies. While cultures may be negative after antibiotic initiation, Gram staining of valve tissue remains positive in over 60% of cases undergoing active treatment.[13] Hematoxylin and eosin staining in streptococcal and staphylococcal endocarditis reveals basophilic cocci. Grocott-Gomori methenamine silver stain, typically used for fungal identification, enhances streptococcal contours and improves bacterial detection in valve tissue compared to Gram staining. Periodic acid-Schiff staining also offers greater sensitivity than Gram staining and highlights the foamy macrophages characteristic of Tropheryma whipplei endocarditis.[12]
In prosthetic valve endocarditis, inflammatory cells are often confined to the vegetation on the valve cusp surface. Unlike degenerative valve calcification, which involves macrophages and lymphocytes, prosthetic valve endocarditis is characterized primarily by neutrophilic infiltrates.[14]
History and Physical Examination in Infective Endocarditis Diagnosis
Infective endocarditis presents with a wide spectrum of clinical signs and symptoms. Clinicians should consider this diagnosis in any patient with risk factors presenting with unexplained fever or sepsis.[5] Patients frequently report an insidious onset of fever, chills, malaise, and fatigue, prompting medical evaluation within the first month of symptom onset. Fever, generally defined as a temperature exceeding 38.0°C (100.4°F), is observed in over 95% of patients in large prospective studies.[3] However, factors like immunosuppression, advanced age, antipyretic use, or prior antibiotic therapy can mask or reduce the frequency of fever. Other non-specific systemic infection symptoms, such as anorexia, headache, and generalized weakness, may also be present. Cardiopulmonary symptoms like chest pain, dyspnea, reduced exercise tolerance, orthopnea, and paroxysmal nocturnal dyspnea are less common but should raise suspicion for aortic or mitral valve insufficiency. Acute valvular incompetence can manifest as sudden-onset heart failure symptoms.
Patient history often reveals predisposing conditions and risk factors aiding in infective endocarditis diagnosis. Current or recent indwelling catheterization, IVDU, recent pacemaker implantation, or prosthetic valve history suggest potential endocardial injury.[5] Clinicians should also inquire about known degenerative valve disease, such as calcific aortic stenosis or mitral valve prolapse, which underlie approximately 30% of cases.[3][15] Rheumatic heart disease, once a major risk factor, now precedes fewer than 5% of infective endocarditis cases in developed nations. Diabetes mellitus is a common comorbidity in North America.
A thorough physical exam may reveal stigmata supporting the diagnosis and indicating peripheral embolization complications. Fever is a frequent finding, and tachypnea and tachycardia may occur with valvular insufficiency or systemic infection. Hypotension can develop due to septic or cardiogenic shock in acute valve perforation. Although classically associated with infective endocarditis, a new or worsening murmur is present in less than 50% of cases; however, its presence aids in localizing valve involvement. Severe mitral or aortic regurgitation may manifest with bilateral pulmonary rales on auscultation. Dermatologic findings, classic for infective endocarditis, include immunologic and hemorrhagic cutaneous sequelae. However, Osler nodes (painful subcutaneous nodules on palms), splinter hemorrhages (subungual), and Janeway lesions (painless hemorrhagic plaques on palms/soles) are each observed in fewer than 10% of cases.[3] Abdominal examination may reveal splenomegaly or peritonitis, suggesting bowel perforation from mesenteric arterial occlusion. Intracerebral embolization can present with focal motor or sensory deficits corresponding to affected vascular territories.
Evaluation and Diagnostic Criteria for Infective Endocarditis
Many patients with endocarditis present with nonspecific symptoms such as fatigue, fever, or chest pain, overlapping with various serious conditions. Therefore, a broad diagnostic approach is essential. Patients with chest pain or dyspnea require prompt evaluation for life-threatening cardiopulmonary conditions such as acute coronary syndrome, pulmonary embolism, and pneumonia. Septic patients necessitate rapid, guideline-directed evaluation following established protocols.
For patients presenting with chest pain or dyspnea, an initial 12-lead electrocardiogram (ECG) is a rapid, cost-effective tool to assess for ischemia, dysrhythmias, or structural heart disease. Typically, the ECG in infective endocarditis is normal. ST-segment elevation may occur but should primarily raise suspicion for myocardial infarction and be managed accordingly, even in known infective endocarditis cases.[16][17] A two-view chest X-ray can reveal pulmonary abscesses, infiltrates, or pleural effusions. Severe left-sided valvular insufficiency may show cardiopulmonary edema, cardiomegaly, or cephalization of pulmonary vasculature. Further investigation of potential pulmonary parenchymal disease, empyema, or arterial embolization might require advanced chest imaging like contrast-enhanced computed tomography (CT) or CT angiography. Cardiac biomarkers are crucial in patients with suspected myocardial ischemia or myocarditis to detect underlying infarction.
In the acute setting, a comprehensive laboratory workup is generally indicated due to the nonspecific presentation. A complete blood count often reveals leukocytosis, suggestive of infection. Subacute or chronic presentations may show normocytic anemia consistent with anemia of chronic disease. Inflammatory markers like erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated in approximately 60% of cases, though they are nonspecific.[3] A chemistry panel should assess for electrolyte imbalances requiring immediate correction.
After excluding more immediately life-threatening conditions, infective endocarditis diagnosis hinges on microbiological and echocardiographic evidence of infection. The Modified Duke Criteria are the cornerstone of diagnosis. These criteria are categorized into major and minor criteria, requiring fulfillment of specific combinations for diagnosis: two major criteria, one major and three minor criteria, or five minor criteria.
The first major criterion is confirmation of bacteremia. The Modified Duke Criteria require two separate blood cultures positive for typical pathogens (viridans group streptococci, S. gallolyticus, HACEK organisms, S. aureus, or community-acquired enterococci) without a primary focus. For suspected atypical pathogens, persistent bacteremia is required, defined as either two positive cultures drawn >12 hours apart or positive results from most of ≥3 separate cultures (with initial and final samples collected one hour apart).[18] The American Heart Association (AHA) update also recognizes a single positive blood culture for Coxiella burnetii or an anti-phase 1 IgG antibody titer ≥1:800 as meeting this criterion.[19]
The second major criterion is echocardiographic evidence of endocardial involvement. Echocardiography must demonstrate a mobile intracardiac mass attached to a valve, supporting structure, or implanted material. Transthoracic echocardiography (TTE) is often the initial imaging modality; however, the AHA recommends transesophageal echocardiography (TEE) for increased sensitivity and specificity if infective endocarditis suspicion remains high despite a negative TTE (Class I, Level of Evidence B).[19] Conditions like chronic obstructive pulmonary disease, prior thoracic surgery, obesity, and prosthetic valves can impede TTE visualization and warrant prompt TEE.
The five minor criteria include:
- Predisposing conditions: Underlying valvular abnormalities, structural heart disease, or intravenous drug use.
- Fever: Temperature >38°C (100.4°F).
- Vascular phenomena: Mycotic aneurysms, intracranial hemorrhage, Janeway lesions, major arterial emboli, or septic pulmonary infarcts.
- Immunologic phenomena: Osler’s nodes, Roth spots, glomerulonephritis, or positive rheumatoid factor.
- Microbiological evidence: Positive blood cultures not meeting major criteria or serological evidence of infection consistent with infective endocarditis.[19]
Treatment and Management of Infective Endocarditis
Effective treatment aims to eradicate endocardial vegetations and minimize secondary complications. Patients presenting with acute decompensated heart failure, septic shock, or stroke require immediate stabilization, prioritizing airway, breathing, and circulation. Subsequent management focuses on prolonged bactericidal antibiotic therapy and potential cardiothoracic surgical intervention.
Antibiotic selection and duration depend on the affected valve and the infecting organism’s resistance profile. For native valve endocarditis due to penicillin-susceptible viridans group streptococci or S. gallolyticus, the shortest recommended regimen is a two-week course of ceftriaxone 2 g IV every 24 hours plus gentamicin 3 mg/kg IV every 24 hours.[19] [Class IIa, level of evidence B] Alternative regimens for this patient group include ceftriaxone 2 g IV every 24 hours for four weeks or aqueous penicillin G 12 to 18 million units every 24 hours via continuous IV infusion or in 4 to 6 divided doses. Prosthetic valve endocarditis with these pathogens typically requires a minimum 6-week course of penicillin G 24 million units every 24 hours or ceftriaxone 2 g with or without gentamicin 3 mg/kg every 24 hours.
Patients at risk for staphylococcal infection require prolonged antibiotic therapy. Native valve methicillin-sensitive S. aureus (MSSA) infections can be treated with 6-week courses of nafcillin 2 g every four hours or cefazolin 2 g every 8 hours. Methicillin-resistant S. aureus (MRSA) infections are typically treated with vancomycin 15 mg/kg every 12 hours or daptomycin 8 mg/kg daily for 6 weeks. Gentamicin dual therapy is no longer recommended for MSSA or MRSA infections due to lack of benefit and renal toxicity.[19][20] Prosthetic valve staphylococcal infections require similar therapy but with rifampin and gentamicin augmentation. Prosthetic valve MSSA infections should receive gentamicin 3 mg/kg IV in 2 to 3 divided doses plus rifampin 900 mg IV in 2 to 3 divided doses every 24 hours for 2 and 6 weeks, respectively, in addition to nafcillin. MRSA cases should receive the same gentamicin and rifampin regimen alongside vancomycin.[19][21]
Enterococcal infections, both native and prosthetic valve, necessitate combination regimens as beta-lactam monotherapy is not bactericidal against enterococci. Examples include ampicillin or penicillin G plus an aminoglycoside like gentamicin for 4 to 6 weeks. Ampicillin plus ceftriaxone, a dual beta-lactam regimen, can achieve bactericidal activity against Enterococcus faecalis and may be used.[22] Penicillin resistance warrants combined vancomycin-gentamicin therapy; however, emerging resistance to penicillin, gentamicin, and vancomycin may necessitate linezolid or daptomycin treatment.
Antimicrobial treatment guidelines are continuously evolving and require regular review. Early infectious disease consultation is recommended to guide antibiotic therapy. As a crucial aspect of medical management, blood cultures should be repeated every 24 to 48 hours to confirm bloodstream infection clearance and guide ongoing antimicrobial therapy.[19]
Early surgical intervention, including valve repair or replacement, is generally indicated for acute heart failure, extensive infection with localized complications, and recurrent arterial embolization. Acute valvular compromise causing heart failure typically warrants surgery within 24 hours. The AHA/ACC also recommends early surgical treatment before antibiotic completion for associated atrioventricular block, paravalvular abscess, or destructive infiltrative lesions.[23] [Level IB] Preventing and treating recurrent embolic events are major reasons for surgery. The AHA/ACC recommends early surgery for recurrent embolic events or large, mobile native valve vegetations (>10 mm). A large study found that antibiotic therapy alone reduced stroke incidence from 4.82 to 1.71 per 1000 patient days within one week.[24] Kang et al. found early surgery within 48 hours significantly reduced in-hospital mortality (3% vs. 23% in conventional therapy) and 6-week embolic event risk (0% vs. 21%).[25] Currently, surgical intervention is part of management in nearly half of all infective endocarditis cases due to these mortality benefits.[3]
Differential Diagnosis of Infective Endocarditis
A broad differential diagnosis is crucial when evaluating for infective endocarditis, encompassing infectious, inflammatory, neoplastic, and mechanical etiologies. Presenting symptoms guide the differential. Chest pain necessitates considering acute coronary syndrome, acute heart failure, aortic dissection, myopericarditis, pulmonary embolism, pneumonia, and empyema. In patients with prosthetic valves, perivalvular thrombosis (especially with anticoagulation interruption) or suture dehiscence should be considered. Recurrent arterial emboli post-myocardial infarction may indicate ventricular mural thrombus. A new murmur in a young, otherwise healthy patient should prompt consideration of atrial myxoma. Non-bacterial endocarditis with sterile valvular thrombi can occur in malignancy (marantic endocarditis) or systemic lupus erythematosus (Libman-Sacks endocarditis), although rare.[26]
Prognosis of Infective Endocarditis
Prognosis in infective endocarditis varies widely based on pathogen virulence, secondary complications, comorbidities, and native versus prosthetic valve involvement. In-hospital mortality is approximately 18%, with one-year mortality reaching up to 40%.[27] Prosthetic valve endocarditis within 60 days of surgery has the highest in-hospital mortality (around 30%). A large Japanese study identified staphylococcal infection and heart failure as major predictors of in-hospital mortality.[28] Surgical intervention, performed in nearly 50% of cases, does not appear to increase in-hospital mortality risk.[3]
Complications of Infective Endocarditis
Infective endocarditis can lead to numerous intracardiac complications. Acute valvular incompetence, causing heart failure symptoms, occurs in about one-third of cases, resulting from valve perforation or chordae tendineae/papillary muscle compromise. Mitral or tricuspid regurgitation can cause atrial enlargement and subsequent atrial fibrillation and other supraventricular dysrhythmias. Less common intracardiac complications include abscesses (14%) and atrioventricular blocks (8%).[3]
Peripheral embolization can cause widespread extracardiac complications. Right-sided vegetations can lead to pulmonary arterial emboli manifesting as disseminated pulmonary abscesses, pneumonia, empyema, or pulmonary infarcts. Neurological sequelae are the most severe and frequent extracardiac complications, affecting 15% to 30% of cases.[3] Potential neurologic complications include ischemic stroke, intracranial hemorrhage, meningitis, brain abscess, and infective intracranial aneurysms. Ischemic strokes are the most common neurologic complication, typically from cerebral artery occlusion by embolized mitral/aortic vegetations.[29] Septic embolization into vasa vasorum microcirculation can cause vessel wall degradation and mycotic aneurysms, which are typically symptomatic only upon rupture.[30]
Less frequent complications include acute renal failure from immune-mediated glomerulonephritis or embolic infarction. Splenic infarcts and abscesses, especially with S. aureus infection, can also result from infected emboli. Acute mesenteric ischemia with bowel necrosis and perforation is a serious arterial embolization complication.
Deterrence and Patient Education for Infective Endocarditis
While antibiotic prophylaxis remains debated, the AHA/ACC recommends it for specific high-risk individuals undergoing high-risk procedures. The 2017 AHA/ACC update recommends prophylaxis for patients with prosthetic cardiac valves, prosthetic valve repair material, prior infective endocarditis, unrepaired cyanotic congenital heart disease, repaired congenital heart disease with residual valvular insufficiency, or cardiac transplants with structurally abnormal valves undergoing dental procedures involving mucosal perforation or gingival/periapical tissue manipulation.[23] A prophylactic regimen includes amoxicillin 2 g or clindamycin 600 mg (for beta-lactam allergy) within 60 minutes before the procedure.[20] Current guidelines do not recommend antibiotic prophylaxis for cutaneous, genitourinary, or gastrointestinal procedures.
Enhancing Healthcare Team Outcomes in Infective Endocarditis Management
Infective endocarditis diagnosis and management are complex and lengthy processes. Effective patient care necessitates early involvement of an interprofessional team, including cardiology, cardiothoracic surgery, infectious diseases, and primary care providers.[31] While antibiotics are often sufficient, intracardiac complications or peripheral embolization warrant surgical consultation. Patients with IVDU-related infective endocarditis should receive inpatient counseling and access to outpatient treatment and addiction services.[32] Early diagnosis and guideline-directed management are crucial to minimizing infective endocarditis morbidity and mortality.
Review Questions
(Review questions from the original article would be listed here if present)
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Disclosure: Aaron Yallowitz declares no relevant financial relationships with ineligible companies.
Disclosure: Lawrence Decker declares no relevant financial relationships with ineligible companies.
