Infective endocarditis
Infective endocarditis (IE) is a potentially life-threatening infection involving inflammation of the endocardium, the inner lining of the heart's chambers and valves, most commonly caused by bacteria such as Staphylococcus aureus or streptococci that enter the bloodstream and adhere to damaged or prosthetic cardiac structures.[1] It is a rare condition with an annual incidence of 3–10 cases per 100,000 people in the general population, though rates are increasing in certain groups due to aging populations and rising intravenous drug use, and higher among high-risk groups; it carries an in-hospital mortality rate of up to 30%.[2][3] The disease can lead to severe complications including heart failure, embolic events, and sepsis if not promptly diagnosed and treated.[4] The primary causes of IE involve transient bacteremia from sources like poor oral hygiene, invasive dental procedures, intravenous drug use, or indwelling catheters, allowing microorganisms to colonize abnormal heart valves or endocardial tissue.[1] Risk factors include advanced age (most cases occur in adults over 60), pre-existing heart conditions such as prosthetic valves, congenital heart defects, or previous IE, as well as intravenous drug use, chronic kidney disease, and implanted cardiac devices.[2] Fungal or atypical pathogens are less common but associated with higher mortality, particularly in immunocompromised patients.[1] Symptoms of IE often develop insidiously and include fever, chills, fatigue, night sweats, and new or changing heart murmurs, with nonspecific signs like joint pain, shortness of breath, or weight loss; peripheral manifestations such as Osler's nodes, Janeway lesions, or splinter hemorrhages may also appear.[1] Diagnosis relies on the 2023 ESC Guidelines criteria (an update to the modified Duke criteria), which combine clinical, microbiological, and imaging evidence—such as positive blood cultures (demonstrating the causative organism) and echocardiographic findings of vegetations or abscesses—supported by transthoracic or transesophageal echocardiography as first-line imaging.[5] Additional tests like electrocardiography, chest X-rays, or computed tomography may assess complications such as emboli or valve dysfunction.[6] Treatment typically involves prolonged intravenous antibiotics tailored to the identified pathogen, often lasting 4–6 weeks or longer for prosthetic valve involvement, with initial hospitalization followed by possible outpatient management under close monitoring.[5] Surgical intervention, including valve repair or replacement, is indicated in about 25–50% of cases for refractory infection, heart failure, large vegetations (>10 mm), or prevention of emboli, and should be performed by a multidisciplinary endocarditis team at specialized centers.[6] Prevention focuses on antibiotic prophylaxis before high-risk dental procedures in vulnerable patients (e.g., those with prosthetic valves or prior IE) and maintaining excellent oral hygiene to reduce bacteremia risk.[4] Long-term follow-up is essential to monitor for relapse and manage underlying conditions.[5]Classification
By clinical course
Infective endocarditis is classically classified by clinical course into acute and subacute forms, a distinction that guides initial diagnostic and therapeutic approaches based on the tempo of disease progression. Acute infective endocarditis is characterized by a rapid onset over days to weeks, presenting with high fever exceeding 38.0°C, chills, malaise, and severe systemic symptoms such as acute heart failure, often in patients who appear critically ill. This form is typically associated with highly virulent pathogens, such as Staphylococcus aureus, which account for approximately 30-40% of native valve cases and can infect previously normal valves.[7][8][9] In contrast, subacute infective endocarditis develops insidiously over weeks to months, with low-grade fever, fatigue, weakness, and nonspecific systemic manifestations like weight loss and anemia, allowing untreated patients to survive for up to a year. It is commonly linked to less aggressive organisms, including viridans group streptococci, which cause about 20% of community-acquired cases and predominantly affect damaged or abnormal valves.[7][8][9][10] The acute form carries a more aggressive prognosis, with higher risks of rapid valvular destruction, septic shock, and mortality rates of 30-40% if untreated, necessitating prompt intervention to prevent metastatic infections. Subacute cases, while insidious, pose risks of embolization and gradual heart failure, often presenting diagnostic challenges due to their subtle progression. This classification originated from pre-antibiotic era observations in the late 19th century, notably described by Sir William Osler in 1885, who provided the first comprehensive English-language account of the disease's clinical patterns.[7][8][9][10][8]By microbiology
Infective endocarditis (IE) is predominantly caused by bacteria, which account for 80% to 90% of cases.[7] Among these, Staphylococcus aureus is the most common pathogen overall, responsible for approximately 30% of cases in developed countries, particularly in acute forms, nosocomial infections, and those associated with intravenous drug use.[7] Coagulase-negative staphylococci, such as Staphylococcus epidermidis, are frequent in prosthetic valve endocarditis due to their affinity for indwelling devices and biomaterials.[7] The viridans group streptococci, including species like Streptococcus sanguinis and Streptococcus mutans, typically cause subacute IE on native valves, often originating from oral flora.[7] Enterococci, especially Enterococcus faecalis, are notable in elderly patients or those with gastrointestinal or genitourinary sources, comprising about 15% to 18% of cases depending on the acquisition setting.[7] Fungal causes of IE are rare, representing 1% to 5% of all cases but carrying a high mortality rate of up to 50% to 80%.[11] Candida species, particularly Candida albicans, are the most common fungal pathogens, accounting for over 50% of fungal IE and often linked to intravenous catheters, prosthetic valves, or immunosuppression.[11] Aspergillus species rank second, comprising about 25% of fungal cases, and are associated with similar risk factors but tend to involve more aggressive tissue invasion.[12] Other rare microbial causes include the HACEK group of fastidious gram-negative bacteria (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella species), which collectively cause 3% to 10% of community-acquired cases and require prolonged incubation for culture growth.[7] Intracellular pathogens like Coxiella burnetii (causing Q fever endocarditis) and Bartonella species (e.g., B. henselae or B. quintana, often in homeless individuals or those with cat exposure) are also uncommon but significant in culture-negative scenarios.[7] IE is classified as culture-positive in 70% to 95% of cases, where standard blood cultures identify the pathogen, but culture-negative IE occurs in 5% to 30% of instances, varying by region and influenced by prior antibiotic exposure, fastidious organisms, or nonbacterial etiologies.[13] In industrialized regions, culture-negative rates are around 10%, commonly due to organisms like Coxiella burnetii, Bartonella spp., or the HACEK group.[13] The 2023 Duke-International Society for Cardiovascular Infectious Diseases criteria update incorporates serological evidence, such as Bartonella IgG titer ≥1:800, as a major diagnostic criterion to improve identification in these challenging cases.[13] Recent epidemiological trends show an increasing incidence of S. aureus-associated IE, driven largely by the rise in intravenous drug use, which has led to higher rates of right-sided endocarditis and healthcare burdens in affected populations.[14]By anatomical location
Infective endocarditis is classified anatomically based on the primary site of infection within the cardiac structures, which influences clinical presentation, complications, and management strategies. The majority of cases involve the heart valves, but infection can also affect prosthetic materials, intracardiac devices, or non-valvular endocardial surfaces. This classification helps in understanding the hemodynamic and embolic risks associated with each location. Native valve endocarditis accounts for 70-80% of all cases and predominantly affects the left-sided valves, with the mitral valve involved in approximately 40-50% of instances and the aortic valve in 30-40%. It is often associated with underlying conditions such as congenital heart defects, rheumatic heart disease, or degenerative valve changes that create turbulent blood flow and endothelial damage, facilitating bacterial adhesion. Right-sided native valve involvement is less common in this category, typically limited to the tricuspid valve in specific populations. Prosthetic valve endocarditis comprises 20–30% of cases and is subdivided into early-onset (within 6 months post-surgery, often nosocomial and linked to perioperative contamination) and late-onset (beyond 6 months, resembling community-acquired native valve disease). Early prosthetic valve endocarditis carries a higher mortality rate, up to 40-50%, and frequently necessitates surgical intervention due to the risk of paravalvular abscesses and valve dehiscence. Mechanical and bioprosthetic valves are equally susceptible, though the former may involve more aggressive pathogens in the early phase.[15] Left-sided endocarditis, involving the mitral or aortic valves, represents about 80–95% of cases and is characterized by a higher risk of systemic embolization to organs such as the brain, kidneys, or spleen due to the direct pathway into the arterial circulation. In contrast, right-sided endocarditis, affecting the tricuspid or pulmonic valves in 5–10% of patients overall, is more prevalent among intravenous drug users and predisposes to pulmonary septic emboli, leading to infarcts or abscesses in the lungs. Symptoms may vary by side, with left-sided disease often presenting with more severe systemic manifestations. Surgical considerations, such as the need for valve replacement, are more urgent in left-sided cases due to heart failure risks.[16] Intracardiac device-related endocarditis has become increasingly common with the rising implantation of cardiac devices like pacemakers and implantable cardioverter-defibrillators (ICDs), affecting 1-2% of device recipients over their lifetime. Infection typically involves the leads or generator pocket, leading to bacteremia and vegetation formation on device components, which often requires complete device removal for cure. The incidence has grown by 5-10% annually in parallel with device utilization rates. Non-valvular endocarditis is rarer, involving structures such as the mural endocardium (e.g., in ventricular aneurysms), chordae tendineae, or intracardiac septal defects, and accounts for less than 5% of cases. These infections often arise in the context of prior cardiac surgery or shunts, where endothelial disruption allows seeding, and may present with atypical vegetations that mimic tumors on imaging.By acquisition setting
Infective endocarditis (IE) is categorized by acquisition setting to facilitate identification of infection sources, guide epidemiological investigations, and inform prevention strategies. This classification distinguishes cases based on the patient's exposure to healthcare environments or high-risk behaviors prior to symptom onset, typically defined as community-acquired, healthcare-associated (including nosocomial and non-nosocomial subtypes), and injection drug use (IDU)-associated.[17][18] Community-acquired IE represents the majority of cases, comprising 50% to 70% of all IE episodes in various cohorts, and arises from transient bacteremia unrelated to recent healthcare contact. These infections often stem from endogenous sources such as oral or skin flora entering the bloodstream during routine activities, including dental manipulations, minor surgical procedures, or gastrointestinal interventions. Viridans group streptococci are the dominant pathogens in this setting, accounting for up to 40% of community-acquired cases, with other streptococci and Streptococcus gallolyticus also common; outcomes are generally favorable with appropriate antimicrobial therapy, though complications like embolization can occur.[17][19][18] Healthcare-associated IE accounts for 20% to 30% of cases and is subdivided into nosocomial (hospital-onset >48 hours after admission) and non-nosocomial (recent outpatient healthcare exposure, such as within 90 days of hospitalization, dialysis, or invasive procedures) subtypes. Nosocomial cases, which form about 10% to 15% of all IE, frequently originate from indwelling intravenous catheters, surgical wounds, or invasive diagnostics, with Staphylococcus aureus implicated in 40% to 50% of instances and associated with higher in-hospital mortality rates of 25% to 40% compared to community-acquired IE. Non-nosocomial healthcare-associated IE, often linked to chronic conditions requiring frequent medical interventions like hemodialysis or chemotherapy, shows similar pathogen profiles but may involve enterococci more prominently (up to 25%); these cases carry elevated risks of complications due to delayed diagnosis and multidrug-resistant organisms.[17][18][19] IDU-associated IE constitutes 10% to 20% of cases overall but has risen significantly amid the opioid epidemic, reaching up to one-third of IE admissions in affected regions, and predominantly affects the tricuspid valve in young adults. This subtype results from direct introduction of skin flora or environmental contaminants into the bloodstream via non-sterile injection practices, with S. aureus causing 60% to 70% of episodes and gram-negative bacilli like Pseudomonas aeruginosa involved in 10% to 20%; right-sided involvement predominates (70% to 90%), though left-sided disease occurs in 20% to 30% of cases, conferring higher mortality (up to 20% in-hospital). The increasing prevalence underscores the need for harm reduction, as recurrent infections are common due to ongoing use.[17][20][21] Within these categories, IE is further differentiated as non-device-related (most cases, involving native or prosthetic valves without implanted hardware) versus device-related (10% to 20% of healthcare-associated IE), where the latter involves cardiac implantable electronic devices, vascular grafts, or indwelling catheters like those for dialysis, often leading to persistent bacteremia and requiring device removal for cure.[17][22] Outbreaks of IE are rare but have been documented in IDU populations due to contaminated heroin batches or shared needles introducing specific pathogens, such as clostridial species or unusual gram-negatives, highlighting the role of public health surveillance in injection networks.[23][24]Causes and risk factors
Microbial causes
Infective endocarditis (IE) is predominantly caused by bacteria, with gram-positive organisms accounting for 80-90% of identified cases worldwide.[7] Transient bacteremia serves as the primary mechanism for bacterial entry into the bloodstream, leading to seeding of the endocardium, particularly at sites of endothelial damage. Common portals include the oral cavity, where poor hygiene or dental procedures introduce viridans group streptococci (responsible for approximately 20% of community-acquired cases); the skin, via intravenous drug use or injections that facilitate entry of Staphylococcus aureus (causing about 30% of cases in developed countries); and the gastrointestinal or genitourinary tracts, where procedures or infections allow enterococci (in ~10% of cases) or Streptococcus gallolyticus (linked to colonic lesions in ~15% of streptococcal cases) to disseminate.[7][25] These bacteria adhere to damaged valves, forming vegetations that perpetuate infection.[7] Fungal causes are rare, comprising only 1-10% of IE cases, but carry high mortality due to aggressive tissue invasion and diagnostic challenges.[26] Candida species, especially C. albicans and C. parapsilosis, predominate, often entering via central venous catheters or broad-spectrum antibiotic use that disrupts normal flora, particularly in intensive care unit patients.[26] Aspergillus species follow, typically through airborne inhalation or direct extension in immunocompromised hosts.[26] Recent trends indicate an increasing incidence of fungal IE among immunocompromised individuals, such as organ transplant recipients or those on prolonged immunosuppression, driven by rising candidemia rates in aging populations.[27] This uptick, noted in reviews from 2023-2025, underscores the need for vigilant monitoring in high-risk settings.[27] Culture-negative IE accounts for 5-10% of cases, often resulting from prior antibiotic exposure that sterilizes blood cultures or from fastidious, intracellular pathogens.[25] Notable examples include Coxiella burnetii (Q fever agent), acquired via inhalation from livestock exposure, and Bartonella species (e.g., B. quintana or B. henselae), transmitted by vectors like lice or cats, respectively.[7][25] Polymerase chain reaction (PCR) testing on valvular tissue has improved detection rates to ~66% in these scenarios, as highlighted in 2023 diagnostic updates.[25] Emerging challenges stem from antibiotic-resistant pathogens, including methicillin-resistant S. aureus (MRSA), which predominates in healthcare-associated IE (up to 50% of nosocomial cases) due to hospital exposures and device-related bacteremia, and vancomycin-resistant enterococci (VRE), increasingly reported in patients with prior broad-spectrum antibiotic use or gastrointestinal procedures.[7][28] These resistant strains complicate empiric therapy and contribute to higher morbidity, with MRSA linked to more aggressive disease progression.[28]Predisposing factors
Infective endocarditis susceptibility is markedly increased by underlying cardiac conditions that disrupt normal blood flow or provide surfaces for microbial adhesion. Valvular abnormalities, such as mitral valve prolapse and bicuspid aortic valve, are common predisposing factors, as they generate turbulent flow and endothelial damage. Congenital heart disease, particularly unrepaired cyanotic forms or repaired defects with residual valvular insufficiency, further elevates risk by creating similar hemodynamic disturbances. Prior episodes of infective endocarditis represent the highest risk, with recurrence rates up to 10% in affected individuals due to persistent structural vulnerabilities.[7] The presence of prosthetic materials significantly heightens susceptibility by introducing foreign surfaces conducive to biofilm formation and non-laminar flow patterns. Prosthetic heart valves, whether mechanical or bioprosthetic, are associated with a significantly increased incidence (0.3–1.2% per patient-year) compared to native valves, particularly in the early postoperative period.[29] Similarly, cardiac devices such as pacemakers, implantable cardioverter-defibrillators, and ventricular assist devices promote adhesion through exposed synthetic components.[7] Behavioral risks play a critical role in host predisposition, primarily through direct endothelial injury or recurrent bacteremia. Intravenous drug use, often involving opioids, causes repeated vascular trauma and introduces pathogens directly into the bloodstream, accounting for approximately 10-30% of cases and leading to a notable rise in infections among young adults amid the ongoing opioid epidemic. Poor dental hygiene contributes via transient bacteremia from oral flora, with inadequate flossing or untreated gum disease increasing exposure to viridans streptococci.[7][30] Comorbidities that impair immune function or vascular integrity also predispose individuals to infective endocarditis. Diabetes mellitus is linked to higher infection rates and worse outcomes through microvascular damage and hyperglycemia-induced immune dysregulation. Chronic kidney disease, especially in patients on hemodialysis, elevates risk via frequent vascular access and uremia-related immunosuppression. Immunosuppressive states, including HIV infection and chemotherapy, further compromise host defenses, facilitating opportunistic pathogens.[7][31] Demographic factors influence overall vulnerability, with advanced age over 60 years associated with degenerative valve changes and multimorbidity, contributing to the majority of cases in developed countries. Male sex predominates with a 2:1 ratio, possibly due to higher rates of IV drug use and healthcare exposures. Conversely, recent trends indicate a surge in cases among younger adults, driven by opioid-related IV drug use, with hospitalizations for injection drug use-associated endocarditis increasing 12-fold from 2007 to recent years.[7][32]Pathophysiology
Initial adhesion and vegetation formation
The initial step in the pathogenesis of infective endocarditis involves endothelial damage to the cardiac endocardium, typically caused by turbulent blood flow across damaged or abnormal valves, which exposes subendothelial collagen and tissue factor.[7] This injury can also result from mechanical trauma, such as indwelling catheters or intravenous drug use, creating a receptive surface for thrombus formation.[7] Following endothelial disruption, platelet activation and fibrin deposition occur, leading to the formation of non-bacterial thrombotic endocarditis (NBTE), characterized by sterile vegetations composed of platelets and fibrin on the valve surfaces.[7] These sterile thrombi serve as a nidus for microbial colonization during episodes of bacteremia.[7] Microorganisms, particularly virulent pathogens like Staphylococcus aureus, adhere to the exposed extracellular matrix proteins such as fibronectin and fibrinogen within the NBTE lesions via specific adhesins, including fibronectin-binding proteins A and B (FnBPA and FnBPB).[33] This adhesion is facilitated by bacterial surface proteins that bind to the fibrin-platelet scaffold, promoting initial colonization and subsequent proliferation.[34] Once adhered, bacteria embed within a protective extracellular polymeric substance matrix, forming biofilms that shield them from host immune defenses and antimicrobial agents, thereby enabling persistent infection and vegetation enlargement.[35] This process adapts Virchow's triad—endothelial injury, hemodynamic stasis from turbulent flow, and hypercoagulability via platelet-fibrin deposition—to explain the localized thrombotic predisposition on endocardial surfaces.[7]Immune response and complications
The host immune response to infective endocarditis (IE) involves a robust inflammatory cascade triggered by persistent microbial antigens on valvular vegetations. Proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) are significantly elevated in serum during active infection, contributing to systemic symptoms like fever and malaise by promoting endothelial activation and acute-phase responses. [36] Complement activation, primarily through the classical pathway mediated by circulating immune complexes, further amplifies this response, leading to opsonization of pathogens but also potential tissue injury when dysregulated. [37] A major complication arises from embolization, where fragments of friable vegetations dislodge into the bloodstream, forming septic emboli that disseminate infection. These emboli commonly target the brain (causing ischemic strokes or abscesses in up to 65% of nonpulmonary cases), spleen (leading to infarction or abscess in 19–32% of cases), and kidneys (resulting in infarcts or acute renal injury in 6–14% of cases), often manifesting as focal organ dysfunction. [38] Local complications stem from the extension of infection beyond the valve, eroding surrounding structures. Valve perforation disrupts leaflet integrity, causing acute regurgitation, while perivalvular abscesses—particularly in the aortic root—can invade the annulus and myocardium, leading to ring abscesses. These abscesses frequently result in conduction abnormalities, such as high-degree atrioventricular heart block in 10–20% of aortic valve IE cases, due to proximity to the atrioventricular node. [17] Immune complex phenomena occur as bacterial antigens persist in circulation, forming complexes that deposit in vascular and glomerular endothelium. This deposition triggers glomerulonephritis, characterized by hypocomplementemia and renal inflammation in a subset of patients. Peripheral manifestations include Osler's nodes (painful, tender nodules on the finger pads from immune vasculitis) and Roth spots (retinal hemorrhages with pale centers), both recognized as minor diagnostic criteria for IE. [39] [17] Chronic sequelae primarily involve cardiac remodeling from ongoing valvular damage, culminating in heart failure due to severe regurgitation and ventricular dilation. In right-sided IE, the 2023 European Society of Cardiology guidelines highlight an elevated embolic risk, particularly to the pulmonary circulation, where septic emboli can cause infarcts and respiratory compromise, necessitating vigilant monitoring for vegetation size greater than 10 mm. [40]Clinical presentation
Signs and symptoms
Infective endocarditis typically presents with a combination of constitutional, cardiac, and peripheral manifestations, reflecting systemic infection and local valvular involvement. The clinical features vary based on the infecting organism's virulence, the affected valve, and the patient's underlying conditions, with symptoms often developing over days in acute cases or weeks to months in subacute forms.[7][41] Constitutional symptoms are nearly universal and often the initial complaints. Fever, typically exceeding 38°C, occurs in over 95% of patients, accompanied by chills, night sweats, malaise, fatigue, anorexia, weight loss, and generalized weakness.[7] These symptoms arise from the ongoing bacteremia and inflammatory response, and they may be low-grade and insidious in subacute presentations or high-grade with rigors in acute cases.[41][17] Cardiac manifestations include signs of valvular dysfunction and hemodynamic compromise. A new or changing heart murmur, indicative of regurgitation, is detected in 47-85% of cases, though it may be absent early on.[7][41][8] Symptoms of heart failure, such as dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, and fatigue, develop in up to 40% of patients, particularly with left-sided involvement leading to acute valvular insufficiency.[17][41] Chest pain or tachycardia may also occur, and conduction abnormalities like heart block can signal perivalvular extension.[7] Peripheral stigmata represent immune-mediated or embolic phenomena and aid in clinical recognition, though they are less common in modern series. Osler's nodes, painful tender nodules on the finger or toe pads, occur in fewer than 10% of cases and reflect vasculitis.[7] Janeway lesions, painless erythematous macules or hemorrhages on the palms or soles, are similarly infrequent (<10%) and result from septic emboli.[7] Splinter hemorrhages, linear subungual streaks under the nails, are seen in <10% and may appear in chronic cases.[7] Roth spots, retinal hemorrhages with pale centers, are rare but pathognomonic when present.[41] Digital clubbing may develop in prolonged subacute infections. Petechiae on the conjunctivae, oral mucosa, or extremities occur in up to 20-30% and are nonspecific.[41] Splenomegaly is noted in about 20-50% of left-sided cases due to immune hyperplasia or infarction.[41] Presentations differ by acuity and location. Acute infective endocarditis, often caused by Staphylococcus aureus, features rapid onset with severe sepsis, high fever, toxicity, and prominent cardiac decompensation, affecting even normal valves.[17][7] In contrast, subacute forms, typically due to viridans streptococci or enterococci, have an insidious course with prominent constitutional and peripheral symptoms over weeks.[41] Right-sided endocarditis, common in injection drug users, manifests with pulmonary symptoms such as cough, pleuritic chest pain, hemoptysis, and dyspnea from septic emboli to the lungs, alongside tricuspid regurgitation murmur.[17][41]Associated complications
Infective endocarditis (IE) frequently leads to embolic events, occurring in 13% to 49% of cases clinically, with asymptomatic events detected in up to 86% via imaging such as MRI.[42] These emboli, originating from valvular vegetations, commonly affect the cerebral circulation, causing ischemic strokes in 20% to 40% of left-sided IE patients, and may result in hemorrhagic transformation or meningitis.[42] Splenic involvement manifests as infarcts or abscesses, with subclinical events in up to 61% on contrast ultrasound, while renal emboli contribute to infarction and acute kidney injury.[42] In right-sided IE, pulmonary emboli predominate, affecting 34% to 55% of patients with vegetations ≥1 cm.[42] Cardiac complications arise from local extension of infection or embolization. Acute valvular regurgitation develops due to vegetation-induced valve destruction, often precipitating heart failure as a major sequela.[17] Perivalvular abscesses occur in 10% to 40% of native valve IE and up to 56% to 100% of prosthetic valve cases, potentially leading to fistulas or annular rupture.[17] Conduction abnormalities, such as atrioventricular block, result from abscess extension near the conduction system, with new AV block showing an 88% positive predictive value for abscess presence.[17] Myocardial infarction from coronary emboli is less common but increases heart failure risk.[17] Neurological complications affect 20% to 40% of IE patients, primarily through embolic mechanisms. Ischemic stroke is the most frequent, presenting with focal deficits or encephalopathy, while intracranial hemorrhage occurs in 4% to 27% and may involve microhemorrhages in up to 57%.[43] Seizures arise in association with strokes, hemorrhages, or abscesses, and meningitis complicates 1% to 20% of cases, often with nuchal rigidity or headache.[43] Renal complications include immune-mediated glomerulonephritis and embolic injury, contributing to acute kidney injury (AKI) in 6% to 30% of patients, though some series report up to two-thirds affected.[44][45] Glomerulonephritis, characterized by hypocomplementemia and immune complex deposition, leads to proteinuria and hematuria, while embolic infarcts exacerbate AKI progression.[45] Other systemic issues encompass sepsis and multi-organ failure, with septic shock developing in approximately 12% of cases and carrying high mortality.[46] Recent cohorts highlight increasing mycotic aneurysms, occurring in 2% to 4% of left-sided IE, predominantly cerebral and risking rupture with 35% to 40% mortality.[42]Diagnosis
Diagnostic criteria
The diagnosis of infective endocarditis (IE) relies on standardized criteria that integrate clinical, microbiological, and imaging findings to classify cases as definite, possible, or rejected. The Modified Duke criteria, originally proposed in 2000, provide the foundational framework for this diagnosis.[47] These criteria are divided into major and minor categories: major criteria include evidence of endocardial involvement, such as echocardiographic findings of vegetations, abscesses, new valvular regurgitation, or dehiscence of a prosthetic valve, and microbiological evidence, such as persistently positive blood cultures for typical IE pathogens (e.g., Staphylococcus aureus, viridans group streptococci) or a single positive culture for Coxiella burnetii or phase I IgG antibody titer >1:800 for that organism.[47] Minor criteria encompass predisposing heart conditions or injection drug use, fever greater than 38°C, vascular phenomena (e.g., septic emboli, mycotic aneurysm), immunologic phenomena (e.g., glomerulonephritis, Osler nodes), and microbiological or echocardiographic findings that do not meet major criteria thresholds.[47] In 2023, the Duke-International Society for Cardiovascular Infectious Diseases (Duke-ISCVID) updated these criteria to incorporate advances in diagnostics and address limitations in prosthetic valve endocarditis (PVE) and culture-negative cases.[48] Key modifications include elevating cardiac computed tomography (CT), [18F]fluorodeoxyglucose positron emission tomography/CT ([18F]FDG PET/CT), and intraoperative inspection as major imaging criteria specifically for PVE and cardiac device-related IE, enhancing detection of perivalvular complications.[48] Microbiological updates expand typical pathogens to include Staphylococcus lugdunensis and Enterococcus faecalis, incorporate polymerase chain reaction (PCR) or metagenomic sequencing on blood, valve tissue, or emboli for culture-negative IE (e.g., for Bartonella spp., Tropheryma whipplei), and specify serologic thresholds such as IgG titer ≥1:800 for both Coxiella burnetii and Bartonella species.[48] These changes aim to improve diagnostic accuracy in complex cases without altering the core structure of major and minor criteria. Under both the Modified Duke and 2023 Duke-ISCVID frameworks, IE is classified as definite if two major criteria are met, or one major criterion plus three minor criteria, or five minor criteria; additionally, pathologic evidence from histopathology or microscopy confirming endocardial involvement fulfills definite diagnosis.[47][48] Possible IE is diagnosed with one major and one minor criterion or three minor criteria alone, while rejected IE applies in the presence of a firm alternative diagnosis, resolution of manifestations after fewer than four days of antibiotics, or absence of pathologic evidence at surgery or autopsy despite prolonged antibiotic therapy.[47][48] The Modified Duke criteria demonstrate approximately 70% sensitivity for definite IE, with specificity around 80-90%, though integration of echocardiography boosts overall performance to around 85-90% sensitivity in validated cohorts.[49] The 2023 updates further enhance sensitivity to about 84% in external validations, particularly for PVE, without compromising specificity.[50] Despite these strengths, the criteria have limitations, including reduced sensitivity (around 50-70%) in culture-negative or early IE cases where microbiological evidence is absent, potentially delaying diagnosis in patients with fastidious organisms or prior antibiotic exposure.[48] External validation of the 2023 criteria is ongoing to confirm their performance across diverse populations.[48]Imaging modalities
Transthoracic echocardiography (TTE) serves as the first-line imaging modality for suspected infective endocarditis due to its non-invasive nature and accessibility. It effectively detects vegetations larger than 2 mm, valvular regurgitation, and other cardiac abnormalities, with a sensitivity of 60-70% for native valve endocarditis and approximately 50% for prosthetic valve endocarditis.[51] TTE is particularly useful in initial screening for right-sided endocarditis in patients with good acoustic windows, though its diagnostic yield is limited by obesity, lung disease, or prosthetic materials that obscure visualization. Transesophageal echocardiography (TEE) provides higher resolution imaging of the heart, especially the atria and prosthetic valves, and is indicated when TTE is negative or non-diagnostic but clinical suspicion remains high. TEE achieves a sensitivity of 90-100% for detecting vegetations and perivalvular complications in native valves, outperforming TTE in prosthetic cases where sensitivity reaches 70-90%. It is recommended as a complementary tool in all cases of prosthetic or device-related endocarditis to assess for abscesses, pseudoaneurysms, and fistula formation. Recent updates in the 2023 Duke-International Society for Cardiovascular Infectious Diseases criteria incorporate 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) as a major diagnostic criterion for prosthetic valve and cardiac device infective endocarditis.[13] This modality excels in identifying metabolic activity in infected tissues, with sensitivity of 70-90% for prosthetic valve involvement, and is particularly valuable for detecting perivalvular extensions, extracardiac emboli, and occult infection sites not visible on echocardiography. It is recommended for cases with inconclusive echocardiographic findings, especially within the first three months post-implantation to avoid false positives from inflammation. Cardiac computed tomography (CT) and magnetic resonance imaging (MRI) play adjunctive roles in evaluating complications and anatomy in complex infective endocarditis cases. Multidetector CT offers high spatial resolution for identifying perivalvular abscesses, mycotic aneurysms, and embolic phenomena, with sensitivity exceeding 80% for these features, and is useful preoperatively to delineate coronary anatomy. MRI is superior for assessing neurological and musculoskeletal emboli, detecting silent brain lesions in up to 60% of cases, though it has limited direct utility in cardiac vegetation imaging. The 2023 European Society of Cardiology guidelines advocate a multi-modality imaging approach, integrating TTE/TEE with advanced techniques like 18F-FDG PET/CT and CT for high-risk patients, such as those with prosthetic valves or devices, to improve diagnostic accuracy and guide management. This strategy enhances the overall sensitivity of imaging from 60-70% with echocardiography alone to over 90% in challenging scenarios.Laboratory investigations
Laboratory investigations play a crucial role in supporting the diagnosis of infective endocarditis (IE) by identifying microbiological evidence, inflammatory responses, and associated systemic effects. Blood cultures remain the cornerstone, with at least three sets obtained from separate venipuncture sites before initiating antibiotic therapy to maximize yield and identify the causative pathogen.[17] In culture-positive IE cases, blood cultures are positive in approximately 90% when drawn prior to antibiotics, with typical pathogens like Staphylococcus aureus or enterococci detected in two or more sets serving as a major diagnostic criterion per the 2023 Duke-ISCVID criteria.[52] For suspected acute IE, cultures should be spaced 30-60 minutes apart if the patient is unstable, though standard practice recommends obtaining them over 1-2 hours to detect intermittent bacteremia.[53] Inflammatory markers are often elevated and provide supportive evidence, though they are nonspecific. Erythrocyte sedimentation rate (ESR) is typically >50 mm/h in approximately 56% of cases, reflecting ongoing inflammation, while C-reactive protein (CRP) levels exceed 10 mg/L in most patients, often much higher (e.g., mean around 50 mg/L).[54] Normocytic anemia occurs in 70-90% of subacute IE cases due to chronic disease and hemolysis, and leukocytosis is present in about 25% overall, more commonly in acute forms.[55] These markers, along with elevated CRP or ESR, can contribute to minor criteria in diagnostic schemes like the modified Duke criteria.[17] Urinalysis frequently reveals renal involvement from immune complex deposition or emboli, with microscopic hematuria in up to 50% of cases and proteinuria in those with glomerulonephritis.[52] This finding supports a minor diagnostic criterion when accompanied by acute kidney injury and other features like cellular casts.[49] In culture-negative IE, which accounts for 10-30% of cases often due to prior antibiotics or fastidious organisms, serologic testing and PCR are essential for pathogens like Coxiella burnetii (Q fever), Bartonella species, and fungi. The 2023 Duke-ISCVID criteria designate serologic evidence as a major criterion, specifying C. burnetii phase I IgG titer >1:800 or Bartonella IgG ≥1:800, while PCR detection of these organisms in blood or valve tissue also qualifies as major.[49] Fungal IE may require broad PCR panels on excised valve material, as serology is less standardized.[56] Additional tests include rheumatoid factor, which is positive in about 50% of subacute IE cases as part of immunologic phenomena and serves as a minor criterion.[49] Troponin levels may be elevated in approximately 27% of patients, indicating myocardial involvement such as abscess or ischemia, and are associated with increased in-hospital mortality (adjusted odds ratio 7.3).[57]Management
Antimicrobial therapy
Antimicrobial therapy is the cornerstone of treatment for infective endocarditis (IE), aiming to eradicate the infecting pathogen while minimizing toxicity and addressing potential complications. Therapy must be bactericidal, typically administered intravenously for extended periods, and tailored based on pathogen identification, susceptibility testing, and patient factors such as valve type and comorbidities. The 2023 European Society of Cardiology (ESC) guidelines emphasize prompt initiation of empirical antibiotics after blood cultures are obtained, followed by de-escalation to targeted regimens once microbiology results are available, with multidisciplinary input from endocarditis teams to optimize outcomes.[29] Empirical therapy is initiated in suspected IE to cover common pathogens, including staphylococci, streptococci, and enterococci, pending culture results. For community-acquired native valve endocarditis (NVE), the recommended regimen is vancomycin (30 mg/kg/day IV in two doses, adjusted for renal function) plus ceftriaxone (2 g IV every 12 hours), providing broad coverage without routine aminoglycoside addition to reduce nephrotoxicity risk. In prosthetic valve endocarditis (PVE) or nosocomial cases, the regimen includes vancomycin plus ceftriaxone plus rifampin (300 mg IV/PO every 8 hours), with gentamicin (1 mg/kg IV every 8 hours for the first 2 weeks) added if enterococcal infection is suspected, to address staphylococcal biofilms on foreign material. These recommendations are class I, level B, reflecting observational data and expert consensus.[29][5] Once the pathogen is identified, therapy is adjusted to targeted regimens based on minimum inhibitory concentrations (MICs) and local resistance patterns. For penicillin-susceptible viridans group streptococci or Streptococcus gallolyticus causing NVE, options include penicillin G (12-18 million units/day IV continuous or in 4-6 doses) or ceftriaxone (2 g IV once daily) for 4 weeks, which is sufficient for uncomplicated cases without gentamicin synergy. In methicillin-resistant Staphylococcus aureus (MRSA) IE, vancomycin (target trough 15-20 mg/L) or daptomycin (10 mg/kg IV once daily) is used for at least 6 weeks, with daptomycin preferred in cases of vancomycin failure or high MICs due to better tissue penetration. For Enterococcus faecalis, ampicillin (2 g IV every 4 hours) plus ceftriaxone (2 g IV every 12 hours) for 4-6 weeks is standard for NVE, avoiding gentamicin if renal impairment exists, as supported by randomized trial data showing equivalent efficacy to ampicillin-gentamicin combinations.[29] The total duration of therapy is typically 4-6 weeks for NVE and at least 6 weeks for PVE, starting from the first day of effective therapy, with longer courses for complicated cases involving perivalvular abscesses or persistent bacteremia. Recent evidence from the POET trial supports partial oral therapy in stable patients after an initial 10-day intravenous phase, randomizing them to oral regimens (e.g., linezolid or moxifloxacin-based) versus continued IV, demonstrating noninferiority for 90-day mortality and complications (13% vs. 12.6%). This approach, updated in 2023 Danish guidelines via the POETry implementation study, allows outpatient management in low-risk patients with negative follow-up blood cultures, transesophageal echocardiography (TEE) confirmation of vegetation stability, and no signs of heart failure, reducing hospitalization length without increased adverse events.[29] Fungal IE, often caused by Candida or Aspergillus species, requires aggressive therapy due to high mortality (up to 50%), with liposomal amphotericin B (3-5 mg/kg IV daily) as first-line, combined with flucytosine (25 mg/kg PO four times daily) for 6 weeks minimum, followed by lifelong oral suppression with fluconazole (400 mg daily) in survivors. Surgical debridement is nearly always indicated alongside antifungals, as medical therapy alone yields poor cure rates.[29] Therapy monitoring involves serial blood cultures (negative within 3-7 days indicating response), serum antibiotic levels (e.g., vancomycin troughs, gentamicin peaks), inflammatory markers like C-reactive protein (CRP), and repeat echocardiography to assess vegetation size and complications. The 2023 ESC guidelines stress the role of multidisciplinary endocarditis teams in overseeing therapy adjustments, with class I recommendation for their involvement to improve adherence and outcomes.[29] Rising antimicrobial resistance poses challenges, particularly with vancomycin-resistant Enterococcus (VRE), where incidence in IE has increased due to nosocomial spread, necessitating alternatives like daptomycin (8-12 mg/kg IV daily) combined with beta-lactams or linezolid (600 mg IV/PO twice daily) for 6 weeks, though data are limited to case series showing variable success rates (50-70% cure). Multidisciplinary consultation is essential for VRE cases to select regimens based on susceptibility and avoid monotherapy failures.[58][59]| Pathogen/Group | Regimen Example (NVE, uncomplicated) | Duration | Citation |
|---|---|---|---|
| Empirical (community-acquired) | Vancomycin + ceftriaxone | Until cultures available | [29] |
| Viridans streptococci (penicillin-susceptible) | Penicillin G or ceftriaxone | 4 weeks | [29] |
| MRSA | Vancomycin or daptomycin | ≥6 weeks | [29] |
| Enterococcus faecalis | Ampicillin + ceftriaxone | 4-6 weeks | [29] |
| Fungal (Candida) | Liposomal amphotericin B + flucytosine, then fluconazole suppression | ≥6 weeks + lifelong | [29] |
| VRE | Daptomycin + beta-lactam or linezolid | ≥6 weeks | [58] |