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Infective Endocarditis - Harrison's Principles of Internal Medicine (22nd Ed., 2025)

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Definition and Pathology

• Low-pressure side of a ventricular septal defect
• Mural endocardium damaged by aberrant blood jets or foreign bodies
• Intracardiac devices

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Classification

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Epidemiology

• Incidence: ~15 cases per 100,000/year in the United States (increasing over recent decades)
• Traditional predisposition (chronic rheumatic heart disease) has shifted in developed countries to:
  • Injection drug use (PWID)
  • Degenerative valve disease
  • Intracardiac devices
• 25-35% of native-valve endocarditis (NVE) in developed countries is health care-associated
• 16-30% of all cases are prosthetic-valve infections (PVE)
• Risk of PVE is greatest in the first year after valve replacement
• CIED-IE (cardiovascular implantable electronic devices): 0.5-1.14 cases per 1000 recipients
• Acceleration in mortality in ages 25-44 years linked to opioid use disorder (OUD)

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Etiology

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Pathogenesis

1. Endothelial injury - turbulent blood flow, jet lesions, or foreign body → platelet-fibrin thrombus (nonbacterial thrombotic endocarditis, NBTE)
2. Bacteremia - even transient (dental work, IV drug use, skin breaks) → organisms adhere to NBTE
3. Vegetation growth - organisms proliferate within the platelet-fibrin matrix, protected from host defenses and antibiotics
4. Most bacteria (S. aureus) can directly invade intact endothelium; viridans streptococci require pre-existing valve damage

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Clinical Features

Symptoms and Signs

Peripheral Stigmata (classic but now less common)

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Complications

Cardiac

• Congestive heart failure - most common; due to valvular destruction (especially aortic valve perforation or rupture), intracardiac fistulae, or myocarditis
• Perivalvular infection/abscesses - especially in PVE and aortic IE; may cause new conduction abnormalities (new PR prolongation = aortic root abscess until proven otherwise)
• Pericarditis, mycotic coronary artery aneurysms

Embolic

• Arterial emboli: clinically apparent in up to 50% of patients; one-half precede diagnosis
• S. aureus IE, mobile vegetations >10 mm, and mitral anterior leaflet involvement independently increase embolization risk
• Cerebrovascular emboli (stroke/encephalopathy): 15-35% of cases; MRI shows asymptomatic emboli in 30-65%
• Stroke frequency: 8/1000 patient-days pre-diagnosis → drops to 1.7/1000 patient-days in second week of therapy
• Only 3% of strokes occur after 1 week of effective therapy

Neurologic

• Aseptic or purulent meningitis
• Intracranial hemorrhage (hemorrhagic infarcts or ruptured mycotic aneurysms)
• Seizures
• Microabscesses (common in S. aureus IE)

Renal

• Immune complex glomerulonephritis (diffuse, hypocomplementemic) - typically improves with therapy
• Embolic renal infarcts (flank pain, hematuria)

Pulmonary (right-sided IE)

• Septic pulmonary emboli: cough, pleuritic chest pain, nodular infiltrates, empyema

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Special Predisposing Conditions

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Diagnosis

Blood Cultures

• 3 sets from different sites before starting antibiotics
• For fastidious organisms (HACEK), most labs use extended automated culture systems (5-7 days)
• Culture-negative: hold bottles 3 weeks and use serologic tests (Coxiella, Bartonella PCR/IgG)

Duke-ISCVID Diagnostic Criteria

Major Criteria

1. Positive blood cultures (typical organisms in ≥2 separate cultures, persistently positive, or single positive for Coxiella burnetii IgG ≥1:800)
2. Evidence of endocardial involvement on imaging (echo/CT/PET-CT) - vegetation, abscess, new valvular regurgitation, prosthetic valve dehiscence

Minor Criteria

• Predisposing heart condition or PWID
• Fever ≥38°C
• Vascular phenomena (emboli, septic pulmonary infarcts, mycotic aneurysm, Janeway lesions)
• Immunologic phenomena (glomerulonephritis, Osler nodes, Roth spots, RF positive)
• Positive blood culture not meeting major criteria

Non-Culture Tests (added to microbiologic major criteria in Duke-ISCVID)

• PCR/nucleic acid tests for C. burnetii, Bartonella spp., T. whipplei from blood
• Indirect immunofluorescence for Bartonella henselae/quintana IgG ≥1:800
• Next-generation metagenomic sequencing (emerging; non-C. burnetii/Bartonella results count as minor criteria for now)

Cardiac Imaging

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Treatment

Empirical Therapy

• Stable patients with suspected subacute IE: withhold antibiotics if cultures not yet obtained (especially if antibiotics received in prior 2 weeks)
• Sepsis/hemodynamic deterioration or urgent surgery needed: treat immediately after 3 blood cultures

Antimicrobial Regimens (Key Principles)

• MSSA: Nafcillin/oxacillin 2g IV q4h x 6 weeks (or cefazolin as alternative)
• MRSA: Vancomycin 15-20 mg/kg IV q8-12h x 6 weeks; target AUC/MIC 400-600

• Short-course IV (2 weeks) with nafcillin/cefazolin may suffice for MSSA
• Oral step-down with daptomycin or newer agents under investigation

• Penicillin G 12-18 MU/day IV continuously or in 6 divided doses x 4 weeks
• Or ceftriaxone 2g IV/IM once daily x 4 weeks

• Ampicillin + gentamicin (synergy) x 4-6 weeks
• High-level aminoglycoside resistance: ampicillin + ceftriaxone (double beta-lactam) x 6 weeks

• Ceftriaxone 2g IV/IM once daily x 4 weeks

• Antifungal therapy (usually amphotericin B or an echinocandin) + valve surgery; long-term suppression often required

Role of Surgery

• Valve dysfunction causing heart failure
• Perivalvular extension (abscess, fistula)
• Persistent bacteremia after 5-7 days of appropriate antibiotics
• Relapsing PVE after completing antibiotics
• Fungal IE or highly resistant organisms
• Recurrent emboli despite therapy or large vegetations >10 mm (especially if additional embolic risk factors)
• S. aureus PVE (high mortality; surgery often needed)

• Embolic stroke without hemorrhage and without coma: surgery can proceed without delay (benefit likely outweighs risk if cardiac indication is strong)
• Hemorrhagic stroke or intracranial hemorrhage: delay surgery ≥4 weeks if possible

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Prevention

• The American Heart Association (AHA) limits prophylaxis recommendations to patients at highest risk for adverse outcomes from IE:
  • Prosthetic heart valves (including transcatheter)
  • Previous IE
  • Congenital heart disease (unrepaired cyanotic CHD; repaired with prosthetic material within 6 months; residual defects adjacent to prosthetic material)
  • Cardiac transplant recipients with valvulopathy
• Prophylaxis regimen for dental procedures: Amoxicillin 2g PO 30-60 minutes before procedure (clindamycin no longer recommended as an alternative due to C. difficile risk)
• Routine prophylaxis is NOT recommended for GI or GU procedures

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Prognosis

• In-hospital mortality: ~15-20% for NVE; ~20-40% for PVE
• Worse prognosis with: S. aureus, aortic valve involvement, HF, paravalvular extension, neurologic events, older age
• Mortality from PWID-associated right-sided IE is lower (~5%) but recurrence is high without address of underlying drug use disorder

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