Infective Endocarditis (IE)

1. Definition

Classification

2. Causative Agents

Gram-Positive Organisms (majority)

• Tietz Textbook of Laboratory Medicine, p. 3154

Gram-Negative Organisms (~4%)

• Haemophilus spp.
• Aggribatibacter actinomycetemcomitans / aphrophilus (formerly Actinobacillus)
• Cardiobacterium hominis
• Eikenella corrodens
• Kingella kingae

Fungi (rare)

Culture-Negative IE (~10%)

3. Pathogenesis

Step 1 - Endothelial Damage

Step 2 - Non-Bacterial Thrombotic Endocarditis (NBTE)

Step 3 - Bacteremia

• Dental or surgical procedures
• IV drug injection
• Infections elsewhere (skin, gut, urinary tract)
• Trivial injuries or occult sources

Step 4 - Microbial Adherence and Colonization

Step 5 - Vegetation Formation

• Friable and bulky
• Contain large numbers of organisms
• Poorly penetrated by host defenses and antibiotics (avascular)

Step 6 - Local and Systemic Complications

• Local: valve destruction, ring abscess (extension into myocardium), conduction abnormalities, perforation
• Embolic: septic emboli lodge in brain, kidneys, spleen, lungs; cause infarcts, abscesses, mycotic aneurysms
• Immunologic: circulating immune complexes cause glomerulonephritis, Osler nodes, Roth spots

Predisposing Conditions

• Mitral valve prolapse (most common preexistent risk factor today)
• Rheumatic heart disease, bicuspid aortic valve, calcific stenosis
• Prosthetic heart valves (10-20% of all IE cases)
• IV drug use
• Neutropenia, immunodeficiency, diabetes, malignancy, alcohol use
• Robbins & Kumar, p. 367-368

4. Vegetation Morphology

• IE vegetations affect aortic and mitral valves most commonly (tricuspid in IV drug users)
• Can be single or multiple, may erode into underlying myocardium causing ring abscess
• Shedding of emboli is common given their friable nature

5. Clinical Features

• Fever - most consistent sign (may be absent in subacute disease in elderly)
• Murmur - present in ~90% of left-sided lesions; new or changing murmur is significant
• Peripheral stigmata (from emboli or immune reactions):
  • Splinter hemorrhages (nail bed)
  • Janeway lesions - painless erythematous macules of palms/soles (septic emboli)
  • Osler nodes - painful tender subcutaneous nodules on fingers/toes (immune complex)
  • Roth spots - retinal hemorrhages (immune complex)
  • Petechiae
• Splenomegaly (especially subacute)
• Embolic events: stroke, renal/splenic infarcts, septic pulmonary emboli (right-sided IE)
• Glomerulonephritis, hematuria, renal failure

6. Laboratory Diagnosis

A. Blood Cultures (most important)

• 3 sets of blood cultures from separate venipuncture sites, ideally drawn 30-60 minutes apart before starting antibiotics
• 90% of culture-positive cases are identified with the first 3 sets
• Modern automated blood culture systems reliably detect HACEK organisms within 2-3 days (historically took longer)
• Blood cultures should be incubated for ≥5 days
• Repeat cultures 48-72 h after starting therapy to document clearance

B. Duke Criteria (Modified - now Duke-ISCVID Criteria)

Major Criteria

1. Blood culture positive for IE:
   • Typical microorganism from 2 separate blood cultures (S. viridans, S. gallolyticus, HACEK group, S. aureus, community-acquired enterococci with no primary focus)
   • Persistently positive blood cultures (≥2 cultures drawn >12 h apart, or all 3 of 3, or majority of ≥4)
   • Single positive culture for Coxiella burnetii or Phase 1 IgG antibody >1:800
2. Evidence of endocardial involvement on echocardiography (vegetation, abscess, new valvular regurgitation, or prosthetic valve dehiscence)
3. Imaging criteria: abnormal FDG-PET/CT within 3 months of prosthetic valve implantation
4. New valvular regurgitation on auscultation

Minor Criteria

1. Predisposing heart condition or IV drug use
2. Fever ≥38°C
3. Vascular phenomena (emboli, mycotic aneurysm, Janeway lesions, conjunctival hemorrhage)
4. Immunologic phenomena (glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor)
5. Positive blood culture not meeting major criterion

Classification

• Definite IE: 2 major, OR 1 major + 3 minor, OR 5 minor (clinical); OR pathologic criteria from surgical/autopsy specimen
• Possible IE: 1 major + 1 minor, OR 3 minor
• Rejected: Firm alternative diagnosis, or resolution with <4 days of antibiotics
• Harrison's Principles of Internal Medicine 22E, p. (Duke-ISCVID section)

C. Echocardiography

• Transthoracic echocardiography (TTE): Highly specific but misses 20-35% of vegetations, especially those <2 mm. Images are inadequate in ~20% of patients.
• Transesophageal echocardiography (TEE): Preferred when TTE is negative/equivocal with high suspicion, in prosthetic valve IE, staphylococcal bacteremia, or complications (abscess, fistula) suspected. More sensitive (TEE detects ~90% of vegetations).
• All patients with suspected IE should have echocardiography. - Braunwald's Heart Disease; Harrison's

D. Non-Culture Laboratory Tests

• Harrison's Principles of Internal Medicine 22E; Tietz Textbook of Laboratory Medicine

7. Treatment

A. Antibiotic Therapy (general principles)

• Use bactericidal agents (not bacteriostatic)
• Prolonged courses are required because organisms within vegetations are metabolically inactive and protected from host defenses - typically 4-6 weeks of IV antibiotics
• Parenteral therapy is standard; oral step-down is considered in selected uncomplicated cases (supported by the POET trial)
• Start empirically only after ≥3 blood culture sets are drawn; delay in hemodynamically stable patients to allow cultures to guide therapy

B. Pathogen-Specific Regimens (Harrison's 22E)

C. Empirical Therapy (before cultures available)

• Native valve, community-acquired: Cover streptococci + staphylococci - ampicillin + cloxacillin + gentamicin OR vancomycin + gentamicin
• Health care-associated or prosthetic valve: Vancomycin + gentamicin ± rifampicin (prosthetic) to cover MRSA and coagulase-negative staphylococci

D. Surgical Indications

1. Heart failure from valve dysfunction (most common indication - urgent/emergency)
2. Uncontrolled infection: abscess, fistula, enlarging vegetation despite therapy, persistent bacteremia >5-7 days
3. Prevention of embolism: large mobile vegetations (>10 mm), especially with prior embolic event
4. Fungal IE (almost all cases require surgery)
5. Prosthetic valve endocarditis with dehiscence or new regurgitation

E. Antibiotic Prophylaxis (Updated 2021 AHA Guidelines)

• Prosthetic cardiac valve or material
• Previous IE
• Certain congenital heart diseases (unrepaired cyanotic CHD, repaired with prosthetic material within 6 months, repaired with residual defects)
• Cardiac transplant with valve abnormalities
• Ventricular assist devices and implantable hearts (added in 2021)

• Braunwald's Heart Disease, p. 824; Harrison's Principles of Internal Medicine 22E

Summary Table

Sources: Robbins & Kumar Basic Pathology; Braunwald's Heart Disease (11e); Tietz Textbook of Laboratory Medicine (7e); Harrison's Principles of Internal Medicine 22E (2025)