Infective Endocarditis

Native Valve Endocarditis (NVE)

Underlying causes

• Rheumatic valvular disease (≈30%), primarily mitral valve involvement.
• Congenital heart disease (≈15%), including patent ductus arteriosus, ventricular septal defect, tetralogy of Fallot, and other high-flow lesions (native or surgical).
• Mitral valve prolapse with an associated murmur (≈20%).
• Degenerative heart disease, such as calcific aortic stenosis, bicuspid valve disease, Marfan syndrome, or syphilitic disease.

Pathogens

• Streptococcus species cause around 70% of NVE, especially S. viridans, S. bovis (S. gallolyticus), and enterococci.
• Staphylococcus species account for ≈25% of cases and tend to present with a more aggressive, acute course.
• Less frequent causes include HACEK organisms, Gram-negative bacilli, and fungi.

Prosthetic Valve Endocarditis (PVE)

Classification

• Early PVE (within 60 days post-surgery) is associated with nosocomial organisms, particularly Staphylococcus aureus and Staphylococcus epidermidis (often methicillin-resistant).
• Late PVE resembles NVE in presentation, most often caused by streptococci or enterococci.

Complications

• Aortic valve prostheses are especially prone to abscesses, fistulae, dehiscence, and associated haemodynamic collapse or embolisation.

Pathogens

• Coagulase-negative staphylococci (≈30%) are the leading cause overall.
• S. aureus causes ≈17% of early and 12% of late cases.
• Less common pathogens include corynebacteria, nonenterococcal streptococci, fungi (Candida, Aspergillus), Legionella, and HACEK organisms.

Intravenous Drug Use–Associated Endocarditis (IVDA IE)

Epidemiology

• Two-thirds of affected patients have no prior structural heart disease.
• Murmurs may be absent, especially with tricuspid valve involvement due to low-pressure gradients.
• Pulmonary features are common, including pleuritic chest pain and radiographic infiltrates from septic emboli.

Pathogens

• Staphylococcus aureus (including MRSA) is the predominant organism, responsible for nearly half of cases.
• Other organisms include groups A, C, and G streptococci, enterococci, Pseudomonas aeruginosa, and HACEK organisms.
• Polymicrobial infections may occur, particularly with Pseudomonas and enterococci.

Healthcare-Associated Infective Endocarditis (HCIE)

Risk factors

• Central or peripheral intravenous catheters, haemodialysis access, cardiac rhythm devices, chemotherapy lines, or hyperalimentation catheters.
• Typically affects older patients with multiple comorbidities.

Pathogens

• Gram-positive cocci predominate, particularly S. aureus, coagulase-negative staphylococci, enterococci, and nonenterococcal streptococci.
• Mortality is high due to delayed diagnosis and severe underlying illness.

Fungal Endocarditis

Epidemiology

• Seen in intravenous drug users and critically ill ICU patients receiving broad-spectrum antibiotics.
• Accounts for ≈1% of cases but has a high fatality rate.

Pathogens

• Candida albicans is most common in both native and prosthetic valve cases.
• Candida parapsilosis and C. tropicalis are associated with IV drug use.
• Aspergillus species cause aggressive PVE and NVE.
• Candida auris is a growing concern in healthcare facilities due to multidrug resistance and persistence on surfaces.

Culture-Negative Endocarditis

Causes

• Often due to prior antibiotic therapy before blood cultures are obtained.
• Other causes include fastidious organisms such as Coxiella burnetii, Bartonella species, Brucella, and HACEK organisms.
• Bartonella quintana is notable in homeless populations with poor hygiene, often presenting as culture-negative IE.

Predilection Sites

• Infective endocarditis (IE) most often involves the mitral valve, followed by the aortic valve, combined mitral–aortic lesions, the tricuspid valve, and rarely the pulmonic valve.
• Mechanical and bioprosthetic valves show similar susceptibility to infection.

Initial Events: Endothelial Injury and Nonbacterial Thrombotic Endocarditis (NBTE)

• Healthy endocardium resists colonisation, but endothelial injury—from turbulent jets, prosthetic material, or intravenous drug use—initiates thrombus formation.
• Platelet and fibrin deposition creates sterile NBTE lesions, a nidus for microbial adherence.
• The Venturi effect explains why vegetations form on the low-pressure side of regurgitant jets or stenoses.

Bacteraemia and Microbial Colonisation

• Bacteraemia may be spontaneous (gingival disease, bowel activity), or provoked by procedures (e.g., dental extraction, colonoscopy, catheterisation).
• Key pathogens include Staphylococcus aureus, Streptococcus viridans, groups A, C, G streptococci, and enterococci, which possess virulence traits:
  • Fibronectin-binding proteins (FimA).
  • Clumping factors and mucoid production in S. aureus.
  • Dextran production in viridans streptococci.
  • Resistance to platelet microbicidal proteins.
• Encapsulation within platelet-fibrin layers shields organisms from immunity and antibiotics.

Vegetation Maturation

• Vegetations enlarge with bacterial proliferation and fibrin-platelet layering.
• Deep-seated microbes become dormant, reducing susceptibility to antibiotics.
• Growth of vegetations predisposes to embolic complications and immune activation.

Immune-Mediated Injury

• Subacute IE often involves immune complex deposition, driving complications such as:
  • Glomerulonephritis.
  • Osler nodes, Roth spots, and vasculitic lesions.
  • Musculoskeletal inflammation.
• High levels of complement-fixing antibodies and cryoglobulins are common.

Acute versus Subacute Disease

Acute IE

• Frequently due to Staphylococcus aureus.
• Produces rapidly developing, necrotic vegetations filled with neutrophils and bacteria.
• Causes aggressive destruction of valves, chordae tendineae, and papillary muscles.
• Complications are dominated by intracardiac extension and septic emboli.

Subacute IE

• Typically caused by viridans streptococci.
• Vegetations contain fewer organisms, more mononuclear cells and lymphocytes.
• Some repair with fibroblast proliferation occurs, though insufficient to halt progressive valve damage.
• Complications mainly result from embolisation and immunological sequelae.

Device-Related Endocarditis

• Pacemaker and defibrillator infections follow fibrin-platelet thrombus formation on leads and generators.
• Bacterial colonisation occurs with bacteraemia, often persisting despite partial tissue embedding.

Catheter-Associated Mechanisms

• Central venous catheters account for a large proportion of nosocomial bacteraemias.
• Sources include insertion-site contamination, catheter colonisation, secondary bacteraemia, or contaminated infusates.
• Fibrin/fibronectin deposition encourages bacterial adherence, especially S. aureus.
• Some strains invade endothelial cells (endotheliosis), explaining persistent bacteraemia despite catheter removal.

Global Incidence and Trends

• Infective endocarditis (IE) is a relatively rare condition, with an estimated annual incidence ranging from 3 to 10 cases per 100,000 people worldwide.
• In the United States, incidence is reported at 12.7 cases per 100,000 persons per year, with comparable figures in other high-income countries.
• Data from England’s Hospital Episode Statistics demonstrated a marked rise in admissions for IE, from 3,969 cases in 2009–10 to 10,097 in 2019–20.
• Across Europe, incidence increased by approximately 4.1% per year between 2000 and 2020.
• In the US, incidence rose from 11 per 100,000 in 2000 to 15 per 100,000 by 2011, reflecting similar upward trends globally.

Demographics

• Historically, IE displayed a male predominance with a male-to-female ratio of nearly 2–3:1.
• The average age of patients has steadily increased; currently, over half of cases occur in individuals older than 50 years, with mean age rising from 58.6 to 60.8 years in recent decades.
• The ageing trend correlates with a higher prevalence of predisposing conditions in older populations, including prosthetic valves, intracardiac devices, haemodialysis dependence, and diabetes mellitus.
• No consistent racial predilection has been demonstrated.

Shifting Risk Factors

• Rheumatic heart disease, once a major driver, now accounts for fewer than 5% of cases in developed countries, but remains a leading cause of IE in developing regions.
• Intravenous drug use (IVDU) is an expanding risk factor, responsible for around 10% of IE cases overall, with some studies reporting a rise in incidence of drug use-related IE from 48 per 10,000 in 2002 to 79 per 10,000 by 2016.
• Healthcare-associated IE is increasingly recognised, linked to central venous catheters, prosthetic devices, and hospital-acquired infections.
• The proportion of patients with intracardiac devices has risen from 13.3% to nearly 19% of cases.
• HIV-associated IE has become less common, coinciding with improvements in antiretroviral therapy.

Special Populations

• Pregnancy: IE is very rare but associated with high maternal risk, particularly among women with prosthetic valves or pre-existing cardiac disease. Maternal mortality is reported at 18–22%, usually due to embolic events or heart failure.
• Elderly patients: A retrospective analysis showed a 26% increase in IE-related hospitalisations among patients ≥65 years, from 3.19 to 3.95 cases per 10,000 discharges.

Outcomes

• In-hospital mortality remains high at 15–30%, despite improvements in diagnostics, antimicrobial therapy, and surgical interventions.
• Prognosis is particularly poor in elderly patients, those with healthcare-associated infections, and in cases complicated by prosthetic valve involvement or embolic events.

Presenting Features and Symptom Pattern

Fever and chills

• Most common presenting complaint, often with rigors.
• May be absent in older or immunocompromised patients.

Constitutional symptoms

• Anorexia, weight loss, malaise, night sweats, headache, myalgias, arthralgias, fatigue.

Respiratory and cardiac symptoms

• Dyspnoea, cough, chest pain, orthopnoea, or paroxysmal nocturnal dyspnoea suggesting acute heart failure.

Time course

• Distinguish acute abrupt onset from indolent subacute course.
• Average delay to diagnosis in subacute cases is ~6 weeks.

Acute versus Subacute Presentations

Acute IE

• Rapid onset of high fevers, rigors, and early congestive heart failure.
• Often preceded by procedures, central lines, or injection drug use.

Subacute IE

• Weeks of low-grade fever, anorexia, fatigue, back pain, and weight loss.
• Embolic or immune complications may develop if treatment is delayed.

Muted IE / Healthcare-associated IE

• Prior or intermittent antibiotics blunt typical fever and blood culture results.
• Presents with elements of sepsis: hypotension, metabolic acidosis, leukocytosis, multiorgan dysfunction.

Embolic and Metastatic Manifestations

Neurological

• Embolic stroke, headache, focal neurological deficits.
• May be the first presentation, especially in younger patients.

Spinal and musculoskeletal

• Lumbosacral back pain (vertebral osteomyelitis, discitis).
• Septic arthritis or diffuse immune-mediated synovitis.

Renal and abdominal

• Flank pain or left upper quadrant pain from renal or splenic infarct.
• Painless haematuria or dark urine.

Pulmonary (IVDU-associated)

• Pleuritic chest pain, cough, dyspnoea due to septic pulmonary emboli.

Cardiac

• Palpitations or abrupt dyspnoea due to valve failure or conduction abnormalities.

Risk Exposures and Predisposing Conditions

Cardiac history

• Previous infective endocarditis.
• Rheumatic or degenerative valvular disease.
• Congenital heart disease (native or repaired).
• Hypertrophic cardiomyopathy.

Intravascular or prosthetic material

• Recent valve surgery (mechanical/bioprosthetic).
• Pacemakers or ICDs (especially recent lead revision).
• Central venous catheters, dialysis access.

Healthcare contact

• Recent hospitalisation, ICU stay, chemotherapy, parenteral nutrition.

Recreational drug use

• Intravenous drug use: substance type, frequency, injection practices.
• Fever resolving on admission (“cotton wool fever”) from adulterants.

Procedures

• Dental extractions or gingival manipulation.
• Genitourinary (e.g., TURP), gastrointestinal (e.g., colonoscopy), or other invasive procedures.

Intercurrent infections

• Recent pneumonia, pyelonephritis, skin or soft tissue infections, catheter-related bacteraemia.

Antimicrobial exposure

• Prior antibiotics, self-treatment, or misdiagnosed infections leading to culture-negative IE.

Device-Related Clues

Early device infection (weeks–months post-implant)

• Generator pocket erythema, pain, drainage, or erosion.
• Fever may be the only symptom.

Late device infection (months–years post-implant)

• Recurrent unexplained fevers.
• Respiratory symptoms from right-sided seeding.
• Pericarditis or mediastinitis with epicardial systems.

Device complexity

• Dual-chamber and ICD systems carry higher infection risk than single-chamber pacemakers.

Prosthetic Valve–Specific History

Timing

• Early PVE: within 60 days of implantation.
• Late PVE: beyond 60 days, similar to native valve disease.

Early complications

• Heart failure, chest pain, conduction disturbances from abscess or dehiscence.
• High embolic stroke risk within the first 3 days.

Peri-operative history

• Wound infection, prolonged bypass, ICU stay, peri-operative bacteraemia.

Healthcare-Associated Patterns

Sepsis syndrome

• Hypotension, fever, metabolic acidosis, leukocytosis, multiorgan failure.

Prosthetic valve association

• ~45% of HCIE occurs in patients with prosthetic valves.

Dialysis catheter involvement

• High MRSA burden.
• ~80% of cases involve the mitral valve.

Line chronology

• Early infection risk rises after 4 days, with higher risk in jugular versus subclavian placement.
• Long-term lines: hub infection is the main source.

General Features

Vital signs

• Fever is present in ~90% of cases, but may be low-grade or absent in elderly and chronically ill patients.
• Tachycardia and tachypnoea occur with systemic infection or acute valvular insufficiency.
• Hypotension may indicate septic shock or cardiogenic shock due to acute valve perforation.

Systemic appearance

• Pallor is common due to anaemia of chronic infection.
• Patients may show cachexia in long-standing disease.

Cardiac Examination

Murmurs

• New or changing murmurs are heard in fewer than 50% overall but up to 99% in subacute IE.
• Murmurs may be absent in right-sided IE or in rapidly progressive acute cases.
• Worsening regurgitant murmurs increase the likelihood of congestive heart failure.

Additional findings

• Gallops, arrhythmias, pericardial rubs, or pleural friction rubs may be present.
• Pulmonary rales can indicate severe mitral or aortic regurgitation.
• Distended neck veins suggest acute left-sided valve failure.

Dermatological and Ocular Signs

Petechiae

• Common but non-specific, appearing on conjunctivae, oral mucosa, extremities, or trunk.

Splinter haemorrhages

• Dark red linear lesions in nail beds; may reflect trauma but when short and central are suggestive of IE.

Osler nodes

• Tender, purple nodules on the fingers, toes, and thenar/hypothenar eminences; immune complex mediated.

Janeway lesions

• Painless, erythematous or haemorrhagic macules on palms and soles; associated with acute IE, especially S. aureus.

Roth spots

• Retinal haemorrhages with pale centres, found in ~5% of patients.

Abdominal Examination

Splenomegaly

• Common in long-standing subacute disease; may persist after treatment.

Peritonitis

• Localised tenderness suggests mesenteric embolism with bowel infarction.

Neurological Examination

Focal deficits

• Embolic stroke is seen in up to 40%, most often from left-sided vegetations.
• Other neurological signs: hemiparesis, aphasia, seizures, or delirium.

CNS complications

• Intracerebral haemorrhage or multiple microabscesses.
• Purulent meningitis in acute IE versus aseptic meningitis in subacute disease.

Musculoskeletal and Peripheral Manifestations

Arthritis and back pain

• Asymmetrical arthritis affecting few joints, resembling rheumatoid or reactive arthritis.
• Lumbosacral back pain from discitis or vertebral osteomyelitis.

Immune-mediated lesions

• Synovitis, nephritis, and myocarditis due to circulating immune complexes.

Subacute Infective Endocarditis

Characteristic features

• More indolent course with murmurs almost universal.
• Peripheral lesions (petechiae, Osler nodes, Roth spots) now occur in ~20% of cases compared to 85% in the preantibiotic era.
• Clubbing of fingers and toes occurs in <10%, mainly in untreated chronic disease.

Acute Infective Endocarditis

Characteristic features

• Murmurs absent in up to one third; when present, aortic regurgitation is most common.
• Fever is invariably present and usually high grade.
• Janeway lesions are more frequent than in subacute disease.
• Acute septic monoarthritis and purulent meningitis can develop, particularly with S. aureus.

Healthcare-Associated and Device-Related Findings

Prosthetic valve endocarditis

• Heart failure occurs earlier and more severely than in native valve disease.
• High embolic stroke risk in the first days of infection.
• May mimic myocarditis or pericarditis.

Pacemaker/CIED infections

• Early: pocket erythema, swelling, pain, erosion, fever.
• Late: recurrent fevers, pneumonia, or septic emboli suggesting right-sided involvement.
• Infection of leads can mimic pericarditis or mediastinitis.

Dialysis-related endocarditis

• Often involves MRSA, with mitral valve affected in ~80% of cases.

Initial Laboratory Evaluation

Baseline tests

• Full blood count, electrolytes, urea/creatinine, glucose, liver function, coagulation profile to establish baselines and detect complications (anaemia common in subacute disease; leukocytosis typical of acute presentations).
• Inflammatory markers: ESR and CRP are usually raised; CRP is useful for monitoring and levels >40 mg/L correlate with embolic risk.
• Complement (C3/C4/CH50) may be reduced in subacute disease; rheumatoid factor can be positive and usually normalises with treatment.
• Urinalysis: microscopic haematuria, proteinuria, pyuria and red/white cell casts suggest embolic or immune-mediated renal involvement.
• Consider appropriate testing for concurrent viral illnesses (e.g., COVID-19) where clinically relevant.

Blood Cultures

How many and when

• Never take only one set. Obtain three sets from separate venepuncture sites before antibiotics wherever possible.
• In acute sepsis, do not delay empiric therapy unduly, but draw at least two sets first if feasible.
• For subacute presentations, obtain 3–5 sets over 24 hours (higher yield if no prior antibiotics). 
• In acute presentations, three sets over 30 minutes may help document continuous bacteraemia.

Technique and volume

• Use peripheral venepuncture with meticulous asepsis; aim for ~10 mL per aerobic and anaerobic bottle (volume is more important than number of sets).
• If a central venous catheter (CVC) is present and line infection is suspected, draw cultures from the CVC and peripherally; consider CVC removal if bacteraemic.

Interpretation and repeat sampling

• 5–10% may be falsely negative (recent antibiotics/fastidious organisms/low volume).
• Repeat cultures 48–72 hours after starting therapy to document clearance.
• If cultures remain negative 48 hours after stopping antibiotics, repeat after ~7 days
• Persistent negativity should prompt reassessment of the diagnosis or targeted testing for fastidious pathogens.

Staphylococcus aureus Bacteraemia (SAB): IE Rule-In Strategy

Why it matters

• At least a quarter of SAB represents IE or metastatic infection. 
• Continuous bacteraemia in the presence of intravascular lines does not always prove valve infection (endotheliosis can sustain SAB without vegetations).

Practical steps

• Treat any SAB as possible IE until excluded.
• Look for S. aureus bacteriuria with haematuria as a clue to renal emboli or glomerulonephritis.
• Escalate to early echocardiography (see below), and obtain repeat blood cultures to ensure clearance.

Echocardiography

Choice of modality

• TTE is the screening test for suspected native valve IE; good for baseline assessment, valve dysfunction quantification, anterior myocardial abscess, and haemodynamics.
• TOE/TEE is preferred for prosthetic valves, intracardiac devices, right-sided lesions, suspected abscess/fistula, or when TTE is non-diagnostic but suspicion remains high. 
• 3D TOE can add value in prosthetic/device cases.
• If initial echo is negative but clinical suspicion remains high, repeat TTE/TOE within 5–7 days (earlier for SAB).

Diagnostic performance and pitfalls

• Sensitivity (approximate): TTE 60–80% (native valves; higher with harmonic imaging); TTE ~20% (prosthetic valves); TOE 90–100% (native) and >90% (prosthetic).
• About 15% of positive studies may be false positives (thickened cusps, nodules, calcification). 
• Up to ~60% of vegetations identified in low-pretest-probability contexts may be sterile.

Prognostic/complication assessment

• Embolic risk increases with large (>10 mm), mobile, pedunculated, non-calcified, enlarging or prolapsing vegetations and with multiple vegetations.
• TOE with colour Doppler improves detection of abscess, fistula, and perivalvular extension.

Culture-Negative Infective Endocarditis

Common reasons

• Prior antibiotics are the leading cause.
• Fastidious organisms or insufficient blood volume can contribute.

Targeted investigations

• Serology (guided by epidemiology): Coxiella burnetii (Q fever), Bartonella spp., Brucella, Chlamydia, Legionella.
• Targeted PCR on blood or excised tissue: Bartonella spp., Tropheryma whipplei; broad-range fungal PCR in prosthetic valve cases.
• Consider staged algorithms: first-line serology for Q fever/Bartonella → second-line organism-specific and broad PCR if serology negative and suspicion persists.

Catheter-Related Bloodstream Infection (CRBSI) Evaluation

Differential time to positivity and quantitative methods

• Differential time to positivity: growth from the catheter hub ≥2 hours earlier than peripheral blood supports CRBSI.
• Quantitative cultures: a ≥3-fold higher colony count from the suspected lumen vs peripheral sample supports CRBSI.
• Roll-plate culture of removed catheters is standard but requires device removal.
• A sterile insertion-site swab has a high negative predictive value for line infection.

Advanced Microbiological Methods

MALDI-TOF mass spectrometry

• Enables rapid species identification from culture plates; does not provide phenotypic susceptibilities or reliably influence resistance emergence.

Molecular diagnostics

• PCR / multiplex PCR / PNA-FISH / nanoparticle assays: identify organism DNA/RNA directly, shorten turnaround, detect multiple targets, and may identify resistance determinants.
• Limitations: contamination risk, incomplete panels in polymicrobial disease, and lack of full phenotypic susceptibility data. 
• Evidence for outcome benefit remains limited.

Imaging Beyond Echocardiography

Computed tomography (CT)

• Cardiac CT: detects abscesses, pseudoaneurysms, fistulae, and complex anatomy; may miss small perforations (≤2 mm) or vegetations <10 mm. 
• Useful for pre-operative coronary assessment.
• Whole-body/brain CT: surveys for distant septic emboli or alternative diagnoses
• CT angiography is sensitive and specific for mycotic aneurysms.

Magnetic resonance imaging (MRI)

• Preferred modality for cerebral complications (infarcts in up to ~80% on systematic imaging; many clinically silent).
• Assesses spinal involvement (spondylodiscitis/vertebral osteomyelitis).

Nuclear medicine and PET

• 18F-FDG PET/CT and WBC SPECT support diagnosis in prosthetic valve IE and device infection when echo is equivocal
• Helps localise distant lesions/portals of entry
• Can assist in response assessment in surgical candidates.

Plain radiography and V/Q scanning

• Chest radiograph: septic pulmonary emboli suggest tricuspid/right-sided IE, particularly in people who inject drugs.
• V/Q scans may support the diagnosis of pulmonary embolic phenomena in right-sided disease.

ECG and Conduction Assessment

What to look for

• PR prolongation, new AV block or bundle-branch block may signal septal or perivalvular extension (notably with aortic valve IE) and portend a poorer prognosis.

2023 Duke–ISCVID Diagnostic Criteria Update

Major updates

• Incorporates new microbiological techniques (e.g., molecular assays), advanced imaging, and intra-operative findings as major criteria in defined contexts.
• Recognises pathogens that predominantly infect implanted material as typical in the appropriate setting.
• Removes rigid standards for blood culture timing/spacing and clarifies predisposing conditions.

Caveats and concerns

• Risk of over-reliance on imaging despite modality limitations; potential dilution of the classical emphasis on persistent bacteraemia.
• Necessity to interpret criteria within clinical context to avoid misclassification in “sterile vegetation” scenarios or device-related artefacts.

Summary

First-line (all suspected IE)

• Three sets of peripheral blood cultures (plus from CVC if line infection suspected).
• TTE promptly; TOE early if prosthesis/device, poor windows, high suspicion, or SAB.
• Baseline labs, CRP, urinalysis, ECG.

If cultures negative but suspicion persists

• Repeat echo within 5–7 days.
• Targeted serology/PCR guided by exposures/epidemiology.
• Consider PET/CT or cardiac CT in prosthetic/device cases with equivocal echo.

Chest Pain and Acute Cardiothoracic Mimics

Acute coronary syndrome

• Chest pain with dynamic ECG changes and troponin rise; embolic MI from IE is possible but rare.
• Coronary angiography supportive; echocardiography lacks vegetations.

Aortic dissection

• Sudden tearing chest/back pain, pulse deficits, mediastinal widening.
• CT aortography confirms; diastolic AR murmur may mimic IE but blood cultures are negative.

Myopericarditis

• Pleuritic chest pain, pericardial rub, diffuse ST-elevation/PR-depression.
• Troponin leak disproportionate to systemic features; echo shows pericardial effusion without vegetations.

Pulmonary embolism

• Acute dyspnoea/pleuritic pain, hypoxia; risk factors for venous thromboembolism.
• V/Q scan or CTPA diagnostic; right-sided IE causes septic pulmonary emboli but usually with fever and positive cultures.

Pneumonia or empyema

• Fever, cough, focal chest signs; lobar consolidation or pleural collection on imaging.
• Blood cultures often negative or show a respiratory pathogen rather than typical IE organisms.

Prosthetic Valve and Device-Related Mimics

Perivalvular thrombosis (prosthetic valve)

• Dyspnoea or emboli after anticoagulation interruption; no bacteraemia.
• Fluoroscopy/TEE show leaflet restriction or thrombus; resolves with anticoagulation or lysis.

Suture dehiscence or prosthetic dysfunction

• Acute heart failure with new regurgitation, rocking valve on TEE.
• Blood cultures negative unless secondary infection occurs.

Device pocket infection without endocarditis

• Local erythema, drainage, pocket pain; may have fever.
• Positive pocket/lead cultures after extraction; TEE shows no valve vegetation.

Embolic/Thrombotic Sources of Recurrent Events

Ventricular mural thrombus after myocardial infarction

• Recurrent systemic emboli weeks after large anterior MI.
• Echo/CMR show apical thrombus; blood cultures negative.

Atrial myxoma

• Constitutional symptoms from cytokine release, positional syncope, embolic events.
• Echo reveals mobile atrial mass; histology diagnostic after resection.

Non-Bacterial Endocarditis Entities

Non-bacterial thrombotic endocarditis (NBTE; marantic)

• Sterile fibrin-platelet vegetations in malignancy (classically pancreatic, lung, colorectal) or hypercoagulable states.
• Negative blood cultures, absence of valve destruction; CT chest/abdomen/pelvis may reveal occult tumour; manage hypercoagulability and underlying disease.

Libman–Sacks endocarditis (systemic lupus erythematosus/antiphospholipid syndrome)

• Often asymptomatic; may present with emboli or murmurs.
• Positive ANA/dsDNA and/or antiphospholipid antibodies; echodense verrucae (classically on ventricular surface of mitral valve); immunohistology lacks neutrophilic/infective pattern.

Systemic/Autoimmune and Other Infectious Mimics

Rheumatic fever (acute carditis)

• Fever, migratory polyarthritis, chorea, erythema marginatum, subcutaneous nodules; evidence of preceding streptococcal infection.
• Jones criteria guide diagnosis; echo shows pancarditis but no discrete vegetations.

Lyme disease

• Fever, arthralgia, erythema migrans; AV conduction block can mimic IE-related conduction disease.
• Serology (two-tier testing) supports diagnosis.

Reactive arthritis / polymyalgia rheumatica

• Arthralgia/arthritides or proximal girdle pain and raised inflammatory markers without bacteraemia or vegetations.
• Autoimmune screens supportive; symptoms improve with anti-inflammatory therapy.

COVID-19–related presentations

• Post-infection fevers, myopericarditis, thromboembolic phenomena; vaccine-related myocarditis in rare cases.
• SARS-CoV-2 testing, cardiac MRI, and inflammatory markers help differentiate from IE.

Practical Clues that Favour IE vs a Mimic

Features pointing toward IE

• Persistent bacteraemia (especially Staphylococcus aureus), positive blood cultures for typical organisms.
• Echocardiographic vegetations, abscess, new dehiscence, or prosthetic involvement.
• Peripheral stigmata (Janeway lesions, Osler nodes, Roth spots), septic emboli, immune-mediated renal findings.

Features pointing away from IE

• Negative serial blood cultures without prior antibiotics; absence of valve destruction.
• Clear alternative explanation on imaging (e.g., atrial mass, ventricular thrombus, acute dissection).
• Autoimmune serologies strongly positive with typical non-infective echo features (e.g., Libman–Sacks).

Multidisciplinary Care and Early Escalation

Endocarditis team

• Arrange prompt review by a dedicated endocarditis team (cardiology with echocardiography expertise, cardiac surgery, infectious diseases/microbiology, neurology ± neurosurgery). 
• Early joint decision-making improves timeliness of imaging, antimicrobial optimisation, and surgical planning.

“Red flags” for urgent transfer to a surgical centre

• Valve dysfunction/heart failure, prosthetic valve endocarditis, valve dehiscence, IE in congenital heart disease, or neurological complications (ischaemic stroke, haemorrhage, mycotic aneurysm).
• Discuss surgery early; approximately half of patients ultimately require an operation.

Initial Stabilisation and Empiric Therapy

ABC approach

• Oxygen with a conservative target (usually SpO₂ 92–96% unless at risk of hypercapnia).
• Treat shock promptly (balanced crystalloid preferred; avoid large volumes of normal saline to limit hyperchloraemic acidosis).
• Control pulmonary oedema (IV loop diuretic), support blood pressure, and correct arrhythmias/electrolyte disturbances.

Blood cultures and timing of antibiotics

• Do not take a single set. Aim for three sets from separate venepuncture sites before antibiotics. 
• In sepsis/instability, obtain at least two sets rapidly and start empiric therapy without delay.
• Repeat cultures 48–72 hours after starting therapy to document clearance.
  
  

Choosing empiric therapy (illustrative patterns—adapt locally)

• Base choice on native vs prosthetic valve, community vs healthcare acquisition, MRSA prevalence, recent antibiotics, and renal function.
  • Community-acquired NVE (low MRSA risk): a beta-lactam active against streptococci and MSSA (e.g., benzylpenicillin or amoxicillin plus an anti-staphylococcal agent such as flucloxacillin) ± gentamicin in selected, critically ill cases.
  • Healthcare-associated NVE or high MRSA risk: vancomycin (AUC-guided where available) plus a broad Gram-negative agent (e.g., ceftriaxone or piperacillin-tazobactam), tailoring to local epidemiology.
  • PVE or intracardiac device in situ: cover staphylococci (including MRSA) and Gram-negatives; vancomycin-based combination plus a third-generation cephalosporin is common while awaiting cultures.
• Narrow therapy as soon as susceptibilities return (often within ~48 hours).

Targeted Antimicrobial Therapy

Native valve — streptococci

• Penicillin-susceptible viridans streptococci / S. gallolyticus:
  • 4 weeks of a beta-lactam (e.g., benzylpenicillin or ceftriaxone).
  • Selected uncomplicated cases may receive 2 weeks beta-lactam + gentamicin (renal function and ototoxicity permitting).
• Reduced penicillin susceptibility: extend duration and add gentamicin early (usually for the first 2 weeks).
• Immediate type-I penicillin allergy: vancomycin for 4 weeks (dose by AUC/levels).

Native valve — Staphylococcus aureus

• MSSA: anti-staphylococcal beta-lactam (e.g., flucloxacillin or cefazolin) 4–6 weeks.
• MRSA: vancomycin or high-dose daptomycin (8–10 mg/kg) for 4–6 weeks. For persistent bacteraemia, consider daptomycin + ceftaroline or vancomycin + ceftaroline (specialist advice).
• Aminoglycosides are generally avoided because added nephrotoxicity outweighs benefit.
• Rifampicin is not started until bloodstream infection has cleared (to limit resistance); it is mainly used when prosthetic material is involved.

Prosthetic valve — streptococci

• Usually 6 weeks total therapy.
• Beta-lactam-based regimens preferred if susceptible; for immediate type-I allergy use vancomycin (often with a short course of gentamicin if indicated).

Prosthetic valve — staphylococci

• MSSA PVE: anti-staphylococcal beta-lactam plus rifampicin (for biofilm) ± gentamicin (short course, if renal function permits).
• MRSA PVE: vancomycin + rifampicin ± gentamicin with close toxicity monitoring.

Enterococci (native or prosthetic)

• Prolonged courses (typically 6 weeks).
• Ampicillin/amoxicillin + ceftriaxone (synergy without aminoglycoside toxicity) or beta-lactam + gentamicin if high-level aminoglycoside resistance is absent.
• Beta-lactam resistance or intolerance: vancomycin + gentamicin; for E. faecium with multidrug resistance, seek urgent specialist input (options may include linezolid or daptomycin-based regimens).

HACEK organisms

• Ceftriaxone: 4 weeks (native) or 6 weeks (prosthetic). Avoid ampicillin empirically due to beta-lactamase production unless susceptibility proven. 
• Fluoroquinolones are alternatives where appropriate but require caution due to adverse-effect profile and local restrictions.

Fastidious / non-HACEK Gram-negative and atypical pathogens

• Examples: Coxiella burnetii, Bartonella, Brucella, Legionella.
• Use organism-specific regimens (often prolonged, multidrug) and maintain a low threshold for surgery; involve specialists early.

Fungal endocarditis

• Consider in prosthetic valves, immunocompromise, ICU care, or non-response to antibiotics.
• Valve surgery plus antifungal therapy (e.g., an echinocandin or liposomal amphotericin B; step-down azole per susceptibility). Mortality remains high; manage in a tertiary centre.

Therapeutic Drug Monitoring and Safety

Vancomycin and aminoglycosides

• Use AUC-guided vancomycin where available (target AUC24/MIC 400–600).
• For aminoglycosides (when used), monitor serum levels, renal and hepatic function, and ototoxicity throughout—and reconsider need daily.

Penicillin allergy evaluation

• Many reported allergies are low risk on detailed history; consider formal assessment to expand beta-lactam options. Avoid penicillins/cephalosporins in clear type-I reactions.

Imaging-Led Decisions During Treatment

Echocardiography

• TTE for initial assessment of suspected native valve IE; TOE/TEE for prosthetic valves/devices, suspected abscess/fistula, or poor TTE windows.
• Repeat echo in 5–7 days (earlier in Staphylococcus aureus bacteraemia) if the first study is negative but suspicion remains.
• High embolic risk with large (>10 mm), mobile, pedunculated, enlarging, or multiple vegetations.

Advanced imaging

• Cardiac CT for perivalvular extension (abscess, pseudoaneurysm, fistula) and pre-operative coronary assessment.
• 18F-FDG PET/CT and WBC SPECT support diagnosis when prosthetic/device IE is suspected but echo is equivocal and help identify occult foci/mycotic aneurysms.
• Brain and whole-body MRI/CT to detect silent emboli and guide timing of surgery.

Indications and Timing for Surgery

Emergency (hours)

• Cardiogenic shock or persistent pulmonary oedema despite medical therapy due to acute valve failure.

Urgent (days)

• Uncontrolled infection (abscess, enlarging vegetation, fistula, persistent positive cultures despite appropriate antibiotics), highly resistant bacteria/fungi, staphylococcal or non-HACEK Gram-negative PVE.

Early to mitigate embolic risk

• Vegetation ≥10 mm with recurrent emboli or with another surgical indication (e.g., severe valve dysfunction).
• Aim to excise infected tissue completely and repair/replace valves to restore anatomy and haemodynamics. 
• Early surgery (within the first week) can improve outcomes in selected patients.
  
  

Management of Special Situations

Neurological events

• After ischaemic stroke, surgery is often not delayed if haemorrhage is excluded and the indication is compelling; coordinate with neurology.
• After intracranial haemorrhage, delay surgery where possible; individualise based on haemorrhage size, location, and haemodynamic urgency.
• Screen for mycotic aneurysm (CTA/MRA) when neurological symptoms, persistent headache, or S. aureus bacteraemia raise suspicion.

Anticoagulation/antiplatelet therapy

• Do not initiate routinely for IE.
• Review existing anticoagulation (e.g., mechanical valve): balance prosthetic valve thrombosis risk against intracranial haemorrhage/embolism; make team-based decisions.

Cardiovascular implantable electronic device (CIED) infection

• Complete system extraction (generator and all leads) is typically required when device infection or lead-related endocarditis is confirmed/suspected
• Treat with targeted antibiotics and plan re-implantation at a new site after clearance.

Outpatient parenteral antibiotic therapy (OPAT)

• Consider OPAT only after clinical stabilisation, with robust programme support, reliable venous access, daily review capability, transport and telephone access, and clear criteria for readmission.

Prevention and Patient Education

Antibiotic prophylaxis (align with local policy)

• ESC: consider prophylaxis only for highest-risk patients (e.g., prosthetic valves/repairs, previous IE, certain cyanotic CHD, ventricular assist devices) undergoing invasive dental procedures involving gingival/periapical manipulation or oral mucosal perforation.
• NICE (UK): do not routinely prescribe prophylaxis for interventional procedures in at-risk patients; prioritise oral health and education on IE symptoms and procedure-related risks (including non-medical procedures such as body piercing/tattoos).
• When used, prophylaxis targets viridans streptococci and is given 30–60 minutes pre-procedure.

Overall Mortality and Trends

In-hospital and 1-year mortality

• Contemporary cohorts report in-hospital mortality ~15–30% and 1-year mortality up to ~40%, reflecting organism virulence, complication burden, comorbidity, and valve/prosthesis status.
• Adoption of a dedicated endocarditis team is associated with improved survival and fewer complications; centres using team-based pathways report substantial reductions in 1-year mortality.

Left- versus right-sided disease

• Left-sided IE (aortic/mitral) has higher morbidity and mortality than right-sided disease, largely due to heart failure, systemic embolisation, and perivalvular extension.
• Right-sided IE (often in people who inject drugs) generally has better haemodynamic tolerance but carries risks of septic pulmonary emboli and recurrence.

Key Predictors of Poor Outcome

Cardiac factors

• Heart failure (any cause, especially acute severe regurgitation) is the strongest predictor of death.
• Prosthetic valve involvement, peri-annular complications (abscess, fistula, pseudoaneurysm), and conduction block signal invasive disease and worse outcomes.

Embolic burden and vegetation profile

• Vegetation length >10 mm, marked mobility, and growth on therapy correlate with embolism and mortality; recurrent emboli despite antibiotics portend poor prognosis.

Pathogen and microbiology

• Staphylococcus aureus (particularly MRSA) and non-HACEK Gram-negative bacilli are linked to higher mortality.
• Fungal IE (Candida/Aspergillus) has very high case-fatality (>40–50%), even with combined surgery and antifungals.
• Persistent bacteraemia at 48–72 h despite appropriate therapy is an adverse marker.

Patient profile and context

• Older age, stroke or intracranial haemorrhage, diabetes, renal impairment, and early postoperative PVE worsen outcomes.
• Device-related IE (pacemakers/ICDs) can be severe; reported fatality for pacemaker IE approaches one third in some series without prompt extraction.

Organism- and Setting-Specific Outlook

Typical cure rates in native valve IE (selected patterns)

• Viridans streptococci / Streptococcus gallolyticus: cure rates ~95–98% with appropriate beta-lactam therapy.
• Enterococci and S. aureus in people who inject drugs: cure rates ~90% in carefully selected, uncomplicated right-sided disease.
• Community-acquired S. aureus (non-IVDU, left-sided): cure ~60–70% with optimal therapy.
• Aerobic Gram-negative bacilli: cure ~40–60%; outcomes vary with source control and resistance.
• Fungal IE: cure <50% despite aggressive combined management.

Prosthetic valve IE

• Outcomes are 10–15% poorer than equivalent native-valve infections; early PVE (<60 days), especially staphylococcal, carries the highest in-hospital mortality.
• Surgery is required more frequently, and relapse risk is higher without complete source control.

Impact of Surgery and Team-Based Care

Effect of timely surgery

• When indicated (e.g., refractory heart failure, uncontrolled infection, high embolic risk), surgery is associated with lower overall mortality compared with medical therapy alone, despite higher peri-operative risk in this population.
• Early surgery (particularly in heart failure or large vegetations) reduces all-cause mortality and embolic events in multiple analyses.

Multidisciplinary pathways

• Structured endocarditis teams improve diagnostic yield (early TOE/advanced imaging), antimicrobial optimisation, surgical timing, and post-operative management, translating to better survival and fewer complications.

Long-Term Sequelae and Recurrence

Functional outcomes

• Survivors may have residual valvular dysfunction, heart failure readmissions, or neurocognitive deficits after embolic stroke; systematic cardiac and neurological follow-up is warranted.

Relapse and reinfection

• Relapse (same organism within weeks) occurs in a small minority and reflects inadequate source control or difficult pathogens (e.g., enterococci).
• Reinfection risk is higher with ongoing injection drug use, poor dentition/oral health, and residual intracardiac prosthetic material.

Prognostic Tools and Imaging Markers

Laboratory and imaging indicators

• CRP trajectory and clearance of bacteraemia within 48–72 h align with outcome; persistently positive cultures suggest uncontrolled focus.
• TOE, cardiac CT, and FDG-PET/CT refine risk by detecting abscess, dehiscence, and occult metastatic foci; brain MRI frequently identifies silent infarcts that influence surgical timing.
• Troponin elevation may reflect myocardial involvement and correlates with severity but is non-specific.

Intracardiac complications

Acute valvular incompetence and heart failure

• Sudden severe regurgitation (mitral or aortic) causes pulmonary oedema and cardiogenic shock
• This is the single strongest predictor of mortality and often mandates urgent surgery. Chordal rupture, papillary muscle dysfunction, or leaflet perforation are typical mechanisms.

Periannular extension (abscess, fistula, pseudoaneurysm)

• Infection can extend beyond the leaflet to the annulus and aorto‐mitral curtain, forming abscesses or fistulous tracts. 
• These complications frequently present with persistent fever or bacteraemia despite appropriate antibiotics and carry a high risk of conduction disturbance and haemodynamic collapse.

Atrioventricular (AV) conduction abnormalities

• New PR prolongation, bundle branch block, or complete heart block suggests septal/annular involvement (classically in aortic valve IE)
• A red flag for urgent surgical evaluation.

Prosthetic complications

• Dehiscence, rocking of the prosthesis, or paravalvular regurgitation signal invasive disease.
• Early prosthetic valve endocarditis is particularly prone to periannular destruction and fistulation.

Embolic and systemic complications

Neurological events

• Occur early and are among the most common and morbid extracardiac complications.
• Ischaemic stroke predominates (embolisation from left-sided vegetations), typically in the middle cerebral artery territory.
• Intracranial haemorrhage may follow haemorrhagic transformation or rupture of an infective (mycotic) aneurysm.
• Silent cerebral lesions are frequent on MRI and may influence surgical timing and anticoagulation decisions.

Infective (mycotic) aneurysms

• Result from septic emboli to the vasa vasorum with transmural arterial infection; most are intracranial. 
• Presentation ranges from headache and focal deficits to subarachnoid haemorrhage when ruptured. Dedicated cerebral vascular imaging (CTA/MRA/angiography) is required when suspected.

Pulmonary septic emboli (right-sided IE)

• Tricuspid or device-lead vegetations shower the pulmonary circulation, causing nodular/cavitating lesions, pneumonia, empyema, and pleuritic pain.

Splenic and other visceral emboli

• Splenic infarction/abscess presents with left upper quadrant pain, fevers, or persistent bacteraemia; CT/MRI are preferred for diagnosis. 
• Hepatic, renal, mesenteric, and peripheral arterial beds may also be involved, causing infarction, abscess, or acute mesenteric ischaemia.

Coronary embolism

• Rare but important cause of acute coronary syndrome; consider when chest pain occurs without atherosclerotic risk factors in active IE.

Renal complications

Acute kidney injury (AKI)

• Multifactorial: immune complex glomerulonephritis, renal infarction from septic emboli, haemodynamic instability (sepsis/heart failure), peri-operative insults, and drug toxicity (aminoglycosides, vancomycin—especially when combined).
• Mitigation includes dose adjustment to creatinine clearance, therapeutic drug monitoring, contrast minimisation, and early nephrology input; renal replacement therapy may be required for severe AKI.

Musculoskeletal and other foci

Vertebral osteomyelitis/discitis and septic arthritis

• Haematogenous seeding can produce back pain or monoarthritis; MRI spine is indicated when focal spinal tenderness or persistent bacteraemia occurs.

Metastatic abscesses

• Hepatic, splenic, psoas and other soft-tissue abscesses may complicate persistent staphylococcal or enterococcal bacteraemia; source control (drainage) plus prolonged targeted antibiotics is essential.

Determinants of embolic risk (bedside implications)

Vegetation profile

• Larger (>10 mm), highly mobile, pedunculated, anterior mitral leaflet vegetations carry higher embolic risk—particularly in the first 1–2 weeks of therapy. 
• Failure of vegetations to shrink, or interval growth on treatment, also increases risk.

Microbiology and host factors

• Staphylococcus aureus infection, intravenous drug use, and mitral valve involvement are consistently associated with higher embolic rates.

Antithrombotic therapy

• Routine antiplatelet or anticoagulant therapy is not recommended solely to prevent emboli in IE; studies have not shown clear benefit and suggest increased bleeding risk in some settings. 
• Continue existing indications (e.g., mechanical prosthesis) with team-based risk–benefit review, especially after neurological events.

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