Infective endocarditis
Definition & Epidemiology
- Microbial infection of endocardial/endothelial surface, heart valves (native/prosthetic), mural endocardium, septal defects, or intracardiac foreign material.
- Infection involving great vessels/arteries termed infective endarteritis.
- Incidence: 0.34–0.64 cases/100,000 children/year.
- Mortality: High, ranges 10–25%.
- Congenital Heart Disease (CHD) represents overwhelming predisposing factor in developed nations. Rheumatic Heart Disease (RHD) remains globally relevant underlying risk.
- Right-sided IE (60–70%) more frequent in pediatrics.
Etiopathogenesis & Pathophysiology
Endothelial Injury & NBTE Formation
- Pathogenesis relies on complex interaction between pathogenic bacteria and valvular endothelium.
- Turbulent blood flow (high-pressure gradients across VSD, aortic stenosis) traumatizes vascular endothelium.
- Endothelial damage triggers thrombogenesis. Fibrin and platelet deposition forms sterile Nonbacterial Thrombotic Endocarditis (NBTE).
- Implanted mechanical devices (valves, catheters, pacemaker wires) develop biofilm serving as adhesive substrate.
Bacteremia & Adhesion
- Transient bacteremia originates from mucosal surfaces (oropharynx, gastrointestinal, urinary tracts).
- Incidence of bacteremia from daily activities (tooth brushing, chewing) exceeds that from dental procedures.
- Bacteria colonize NBTE/biofilm. Bacterial surface proteins (e.g., FimA antigen in viridans streptococci) act as adhesion factors.
- Staphylococcus aureus possesses high intrinsic pathogenicity. Invades endothelial cells directly, activates coagulation cascade via tissue factor pathway, and increases vegetation formation.
Etiology (Causative Organisms)
| Pathogen Category | Specific Organisms & Clinical Context |
|---|---|
| Gram-Positive Cocci | Most common cause overall (80–90%). |
| Viridans Group Streptococci (VGS) | S. mitis, S. mutans, S. sanguinis. Most common cause of native valve IE or late post-surgical IE. Subacute presentation. |
| Staphylococcus aureus | Emerging predominant cause. Associated with acute/fulminant presentation, high mortality, device infections, central lines, and structurally normal hearts. |
| Coagulase-Negative Staphylococci | S. epidermidis. Common in indwelling central venous catheters, neonates, early prosthetic valve IE (<60 days). |
| Gram-Negative Bacteria | Rare (<10%). HACEK group (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella). Fastidious, insidious onset. |
| Fungal | Candida, Aspergillus. Rare, severe. Associated with neonates, immunosuppression, prolonged antibiotics, central lines. High embolic risk due to large/friable vegetations. |
| Culture-Negative Endocarditis (CNE) | Occurs in 5–10% of clinical IE. Primary cause: prior antibiotic use. Right-sided IE (lungs filter bacteria). Fastidious/atypical organisms (Coxiella burnetii, Bartonella, Brucella, Legionella, Mycoplasma, Tropheryma whipplei). |
Clinical Manifestations
Presentation highly heterogeneous. Symptoms relate to four pathophysiological mechanisms: bacteremia, valvulitis, embolization, and immunologic response.
General Infectious Symptoms
- Fever: Most common symptom (80–90%). May persist for weeks.
- Non-specific: Chills, rigors, night sweats, anorexia, weight loss, severe fatigue, myalgia, arthralgia.
- Neonates: Apnea, cyanosis, feeding intolerance, presentation mimicking sepsis.
Cardiac & Hemodynamic Signs
- New pathologic murmur or change in pre-existing murmur (50–100%).
- Valvular destruction (perforation, chordal rupture) causes acute severe regurgitation (aortic/mitral).
- Congestive heart failure secondary to valve insufficiency.
- Conduction abnormalities/Heart block: Indicates extension of infection into myocardium (myocardial/septal abscess).
Embolic Phenomena
Occur in ~30% of patients. High risk with vegetations >10mm, fungal etiologies, and left-sided lesions.
- Central Nervous System: Ischemic/hemorrhagic stroke, mycotic aneurysm rupture, brain abscess. Presents with seizures, hemiparesis, altered sensorium.
- Pulmonary Emboli: Common in right-sided IE. Presents with chest pain, hypoxemia, hemoptysis.
- Systemic Emboli: Renal infarcts (hematuria), splenic infarcts (splenomegaly, left flank pain), mesenteric ischemia.
- Janeway Lesions: Non-tender, erythematous/hemorrhagic macules on palms and soles.
Immunologic Phenomena
- Osler Nodes: Tender, erythematous nodules on finger/toe pulps.
- Roth Spots: Exudative retinal hemorrhagic lesions.
- Splinter Hemorrhages: Linear hemorrhagic streaks under nail beds.
- Glomerulonephritis: Immune complex deposition causing hematuria, proteinuria, renal failure.
Diagnosis & Investigations
Modified Duke Criteria
Definitive diagnosis requires:
2 Major OR
1 Major + 3 Minor OR
5 Minor criteria.
Possible diagnosis requires:
1 Major + 1 Minor OR
3 Minor criteria.
| Category | Specific Criteria |
|---|---|
| Major Criteria | 1. Positive Blood Culture: Typical microorganisms (VGS, S. aureus, HACEK, Enterococci) from 2 separate cultures; OR persistently positive cultures (>12h apart); OR single positive culture for Coxiella burnetii or Phase I IgG >1:800. 2. Positive Imaging for IE: Echo showing vegetation, abscess, pseudoaneurysm, fistula, new partial dehiscence of prosthetic valve. OR Positive 18F-FDG PET/CT or SPECT/CT (in prosthetic valves >3 months post-op). OR Definite paravalvular lesions on Cardiac CT. 3. New Valvular Regurgitation. |
| Minor Criteria | 1. Predisposition: Underlying heart disease, IV drug use. 2. Fever: >38.0°C. 3. Vascular Phenomena: Major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions. 4. Immunologic Phenomena: Glomerulonephritis, Osler nodes, Roth spots, Rheumatoid factor. 5. Microbiologic Evidence: Positive blood culture not meeting major criteria, or serologic evidence of active infection. |
Laboratory Diagnostics
- Blood Cultures:
- Cornerstone of diagnosis.
- Obtain 3 sets of aerobic cultures from separate venipunctures.
- Timing relative to fever spikes irrelevant due to continuous bacteremia.
- Withhold antibiotics for 48h in stable patients to optimize yield.
- Molecular Diagnostics:
- 16S rDNA (bacteria) or 18S rDNA (fungi) sequencing/PCR on resected valve tissue or blood.
- Highly valuable for Culture-Negative Endocarditis or prior antibiotic administration. Metagenomic next-generation sequencing (mNGS) utilized for atypical/fastidious organisms.
- Supportive Labs:
- Elevated CRP, ESR, procalcitonin. Leukocytosis, normocytic normochromic anemia, thrombocytopenia. Hypocomplementemia, elevated Rheumatoid factor. Microscopic hematuria/proteinuria.
Advanced Imaging
- Echocardiography (TTE/TEE): TTE adequate for most children <60 kg. Transesophageal Echo (TEE) superior and indicated for: poor acoustic windows, prosthetic valve IE, high suspicion with negative TTE, detection of paravalvular abscess, fistula, or leaflet perforation.
- Cardiac CT: Excellent for clarifying valve anatomy, diagnosing perivalvular abscess, pseudoaneurysms, and pre-operative planning.
- MRI: Brain MRI detects silent ischemic lesions, mycotic aneurysms, and microbleeds (T2 sequences). Cardiac MRI evaluates myocardial extension.
- 18F-FDG PET/CT & SPECT/CT: Increases diagnostic accuracy for prosthetic valve IE (if >3 months post-implantation) and localizing peripheral embolic/infectious metastases.
Management
Medical Therapy Principles
- Multidisciplinary approach (Cardiology, Infectious Disease, Cardiothoracic Surgery).
- Prolonged parenteral administration of bactericidal antibiotics (4-6 weeks) required to penetrate avascular vegetations and clear biofilm.
- Empirical therapy (Native valve or Prosthetic >1yr): Ampicillin-sulbactam + Gentamicin OR Ampicillin + Oxacillin + Gentamicin.
- Empirical therapy (Prosthetic <1yr): Vancomycin + Cefepime + Rifampicin + Gentamicin.
Specific Antimicrobial Regimens
| Organism | Native Valve Regimen | Prosthetic Valve Regimen |
|---|---|---|
| Streptococci (Penicillin susceptible) | Penicillin G, Ampicillin, or Ceftriaxone IV (4 weeks). | Penicillin G, Ampicillin, or Ceftriaxone IV (6 weeks) + Gentamicin (first 2 weeks). |
| Enterococci / Penicillin resistant | Penicillin G or Ampicillin + Gentamicin IV (4-6 weeks). | Penicillin G or Ampicillin + Gentamicin IV (6 weeks). |
| Staphylococci (MSSA) | Oxacillin or Nafcillin IV (4-6 weeks) ± Gentamicin (first 3-5 days). | Oxacillin IV (>6 weeks) + Rifampicin IV + Gentamicin IV (first 2 weeks). |
| Staphylococci (MRSA) | Vancomycin IV (6 weeks) ± Gentamicin (first 3-5 days). | Vancomycin IV (>6 weeks) + Rifampicin IV + Gentamicin IV (first 2 weeks). |
| HACEK Group | Ceftriaxone or Ampicillin + Gentamicin IV (4 weeks). | Extended-spectrum cephalosporin + Aminoglycoside (6 weeks). |
| Fungal | Amphotericin B + 5-Fluorocytosine (5-FC) + Early Surgical Excision. | Universal surgical replacement required. |
Note: Monitor Gentamicin trough levels strictly to prevent nephrotoxicity/ototoxicity.
Indications for Surgical Intervention
Early surgical intervention improves survival in complicated IE. Do not delay surgery due to active infection if hemodynamically compromised.
- Heart Failure: Severe acute aortic/mitral insufficiency or obstruction causing intractable heart failure, pulmonary edema, or cardiogenic shock.
- Uncontrolled Infection: Perivalvular extension (abscess, pseudoaneurysm, fistula, new heart block). Persistent bacteremia (>7-10 days) despite appropriate antibiotics.
- High-Risk Organisms: Fungal IE, Prosthetic valve S. aureus IE, multi-resistant pathogens.
- Embolic Prevention: Large vegetations (>10-15 mm) with severe valve dysfunction or recurrent embolization despite appropriate antimicrobial therapy.
- Prosthetic Complications: Relapsing prosthetic valve endocarditis, partial dehiscence, infected shunts/conduits, or pacing leads.
Prevention & Prophylaxis
Shift in Paradigm
- Routine antibiotic prophylaxis abandoned for majority of CHD. Risk of IE from daily activities (chewing, tooth brushing) significantly outweighs risk from isolated dental procedures.
- Primary focus: Maintenance of meticulous oral hygiene and regular dental care.
High-Risk Conditions Requiring Prophylaxis
Antibiotic prophylaxis limited to patients with highest risk of adverse IE outcomes:
- Prosthetic cardiac valves or prosthetic material used for valve repair.
- Previous history of Infective Endocarditis.
- Unrepaired cyanotic CHD (including palliative shunts/conduits).
- Completely repaired CHD utilizing prosthetic material or device (surgical or transcatheter), during the first 6 months post-procedure (allows endothelialization).
- Repaired CHD with residual defects at or adjacent to the site of a prosthetic patch/device.
- Cardiac transplantation recipients who develop cardiac valvulopathy.
Procedures Requiring Prophylaxis
- Dental: Procedures involving manipulation of gingival tissue, periapical region of teeth, or perforation of oral mucosa (Excludes routine cleaning, shedding deciduous teeth, orthodontic bracket adjustment).
- Respiratory: Invasive procedures involving incision/biopsy of respiratory mucosa (e.g., tonsillectomy, adenoidectomy).
- Skin/Musculoskeletal: Procedures on infected tissue (must cover S. aureus and Group A Strep).
- Note: Prophylaxis is NO LONGER recommended for routine gastrointestinal or genitourinary procedures.
Prophylactic Antibiotic Regimens
Administer single dose 30-60 minutes prior to procedure.
- Standard Oral: Amoxicillin 50 mg/kg (Max 2g).
- Unable to take PO: Ampicillin, Cefazolin, or Ceftriaxone 50 mg/kg IV/IM.
- Penicillin Allergic (Oral): Cephalexin 50 mg/kg, Azithromycin/Clarithromycin 15 mg/kg, or Clindamycin 20 mg/kg. (Note: Newer 2021 AHA updates de-emphasize clindamycin due to adverse effects, but historically cited as alternative)
- Penicillin Allergic (IV/IM): Cefazolin/Ceftriaxone 50 mg/kg or Clindamycin 20 mg/kg.