Infective Endocarditis

David T. Durack, M.B., D.Phil.
Duke University School of Medicine

Adolf W. Karchmer, M.D.
Harvard Medical School

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Localized microbial infection of cardiac valves or mural endocardium caused by bacteria, fungi, rickettsiae, or chlamydiae

• Insidious onset
• Fever
• Sweats
• Weakness
• Myalgias
• Arthralgias
• Malaise
• Anorexia
• Fatigue
• Splenomegaly, clubbing, and Osler nodes in long-standing SBE

• Abrupt onset
• Rigors
• Fevers as high as 102.9° to 105.1° F (39.4° to 40.6° C), often remittent
• Cardiac
  • Murmur
  • New aortic diastolic murmur suggests dilatation of the aortic annulus or eversion, rupture, or fenestration of an aortic leaflet
  • Sudden onset of loud mitral pansystolic murmur suggests rupture of chorda tendineae or fenestration of a mitral valve leaflet
  • Congestive heart failure
  • Cardiac rhythm disturbances
  • Occasionally, pericarditis

• Cutaneous
  • Petechiae of the conjunctivae, oropharynx, skin, and legs
  • Linear subungual “splinter” hemorrhages of the lower or middle nail bed
  • Osler nodes
  • Janeway lesions

• Musculoskeletal
  • Myalgias
  • Arthralgias
  • Arthritis
  • Low back pain
  • Rheumatoid factor in up to 50% of patients with endocarditis for > 6 wk
  • Clubbing of fingers in < 15% of patients

• Ocular
  • Petechial hemorrhages, flame-shaped hemorrhages, Roth spots, and cotton-wool exudates in the retina

• Embolic
  • Significant arterial emboli occur in 30%–50% of patients, causing the following:
    • Stroke
    • Monocular blindness
    • Acute abdominal pain, ileus, and melena
    • Pain and gangrene in the extremities
  • CNS emboli are common
  • Coronary emboli, often asymptomatic, can cause myocardial infarction
  • Pulmonary emboli common in right-sided endocarditis, causing pulmonary infarcts or focal pneumonitis

• Splenic
  • Splenomegaly in 15%–30% of patients
  • Splenic infarcts in up to 40% of patients
  • Splenic abscesses in ~ 5% of patients

• Renal
  • Microscopic hematuria in ~ 50% of patients
  • Embolic renal infarction
  • Diffuse membranoproliferative glomerulonephritis

• Mycotic aneurysms
  • Occur in any artery in 2%–8% of patients, causing the following:
    • Pain or headache
    • Pulsatile mass
    • Fever
    • Sudden expanding hematoma
    • Signs of major blood loss

• Neurologic
  • Neurologic complications occur in 25%–40% of cases
  • Strokes caused by cerebral embolisms in ~ 15% of cases, causing the following:
    • Altered level of consciousness
    • Seizures
    • Fluctuating focal neurologic signs
  • Cerebral aneurysms occur in 1%–5% of cases, causing the following:
    • Headache
    • Focal signs
    • Acute intracerebral or subarachnoid hemorrhage caused by rupture
    • Mild meningeal irritation resulting from slow leakage
  • Brain abscesses may occur in acute endocarditis caused by Staphylococcus aureus
  • Seizures

• High fevers, chills, rigors, malaise, cough, and pleuritic chest pain
• Septic pulmonary emboli causing sputum production, hemoptysis, and signs suggesting pneumonia
• Cardiac murmurs
• Tricuspid insufficiency
• Metastatic infections
• Neurologic manifestations
• Peripheral emboli

• Occurs in 1%–2% of cases at 1 yr and in 4%–5% of cases at 4 yr after implantation
• Infection of perivalvular tissues
• Valvular dysfunction
• Myocardial abscesses
• Fever
• Petechiae, Roth spots, Osler nodes, Janeway lesions
• Emboli

• Tuberculosis, salmonellosis, gastrointestinal and genitourinary infections, and other disorders causing fever of undetermined origin
• Juvenile rheumatoid arthritis, polymyalgia rheumatica
• Acute rheumatic fever
• Marantic endocarditis
• Polyarteritis nodosa
• Systemic lupus erythematosus with antiphospholipid antibody syndrome
• Cardiac myxoma
• Neoplasms

• Echocardiography
  • Transthoracic echocardiography
    • For detecting vegetations in native valve endocarditis: sensitivity, 60%; specificity, 90%
    • For detecting abscess: sensitivity, 18%–28%; specificity, 99%
• Transesophageal echocardiography
  • For detecting vegetations in native valve endocarditis: sensitivity, 95%; specificity, 100%
  • For detecting abscess: sensitivity, 76%–87%; specificity, 96%
  • Better than transthoracic for evaluating patients with suspected prosthetic valve endocarditis and for detecting paravalvular abscesses
• Blood culture
  • Incubate for 5 days (Bartonella species may need > 5 days for isolation)
  • Blood cultures are negative in 5%–20% of patients with endocarditis
• Serologic tests
  • Can diagnose endocarditis caused by Bartonella, Legionella, and Brucella species; Chlamydia psittaci and Coxiella burnetii in cases of culture-negative endocarditis
• Duke criteria for the diagnosis of infective endocarditis
  • Definite
    • Pathologic criteria
      • Microorganisms: demonstrated by culture or histologically in a vegetation, in a vegetation that has embolized, or in an intracardiac abscess specimen
      • Pathologic lesions: vegetation or intracardiac abscess confirmed by histologic examination showing active endocarditis
      • Clinical criteria (see definition of terms, below)
        • Two major criteria
        • One major and three minor criteria
        • Five minor criteria
  • Possible
    • Findings consistent with infective endocarditis that fall short of “definite” but are not “rejected”
  • Rejected
    • Firm alternative diagnosis for manifestations of infective endocarditis
    • Resolution of endocarditis syndrome with antibiotic therapy for ≤ 4 days
    • No pathologic evidence of infective endocarditis at surgery or autopsy, with antibiotic therapy for ≤ 4 days

• Definitions of terms used in Duke criteria for diagnosis of infective endocarditis
  • Major criteria
    • Positive blood cultures for any one of the following:
      • Typical microorganism consistent with diagnosis from two separate blood cultures
      • Viridans streptococci, Streptococcus bovis, or HACEK organisms (Haemophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella, Kingella)
      • Community-acquired S. aureus or enterococci, in the absence of a primary focus
    • Persistently positive blood cultures, defined as microorganisms consistent with diagnosis from any one of the following:
      • At least two blood samples drawn > 12 hr apart
      • Three of three or a majority of more than three blood cultures drawn, with first and last samples drawn at least 1 hr apart
  • Evidence of endocardial involvement
    • Echocardiogram positive for infective endocarditis (any one of the following)
      • Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material, in the absence of an alternative anatomic explanation
      • Abscess
      • New partial dehiscence of prosthetic valve
      • New valvular regurgitation (changing of preexisting murmur not sufficient)
  • Minor criteria
    • Predisposition: predisposing heart condition or I.V. drug use
    • Fever: temperature ≥ 100.4° F (38° C)
    • Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions
    • Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor
    • Microbiologic evidence: positive blood culture but not meeting a major criterion (see above; excludes single positive cultures for coagulase-negative staphylococci, diphtheroids, and organisms that do not commonly cause endocarditis) or serologic evidence of active infection with organism consistent with infective endocarditis
    • Echocardiogram consistent with infective endocarditis but not meeting a major criterion (see above)

• Effective treatment requires identification of the etiologic agent and determination of its antimicrobial susceptibility
• Antibiotic therapy for subacute or indolent disease can be delayed until results of blood cultures are known; in fulminant infection or valvular dysfunction requiring urgent surgical intervention, begin empirical antibiotic therapy promptly after blood cultures have been obtained
• For prosthetic valve endocarditis, treat for 6–8 wk

Penicillin-Susceptible Viridans and Other Nonenterococcal Streptococci (minimum inhibitory concentration [MIC] < 0.2 ΅g/ml)

• Penicillin G: preferred regimen
  • Dose: 12–18 million units I.V. daily in divided doses q. 4 hr for 4 wk
• Penicillin G + gentamicin or ceftriaxone: preferred regimen
  • Dose: penicillin G, dose as above; gentamicin, 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr for 2 wk (peak serum concentration should be ~ 3 ΅g/ml and trough concentrations < 1 ΅g/ml); ceftriaxone, 2 g I.V. daily as a single dose for 2 wk
• Vancomycin: for patients with history of penicillin hypersensitivity
  • Dose: 30 mg/kg I.V. daily in divided doses q. 12 hr for 4 wk

Relatively Penicillin-Resistant Streptococci

• MIC 0.2–0.5 ΅g/ml
  • Penicillin G + gentamicin: preferred regimen
    • Dose: penicillin G, 20–30 million units I.V. daily in divided doses q. 4 hr for 4 wk; gentamicin, 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr for 2 wk (peak serum concentration should be ~ 3 ΅g/ml and trough concentrations < 1 ΅g/ml)
• MIC > 0.5 ΅g/ml
  • Penicillin G + gentamicin: preferred regimen
    • Dose: penicillin G, 20–30 million units I.V. daily in divided doses q. 4 hr for 4 wk; gentamicin, 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr for 4 wk (peak serum concentration should be ~ 3 ΅g/ml and trough concentrations < 1 ΅g/ml)
  • Vancomycin: regimen for patients with history of penicillin hypersensitivity
    • Dose: 30 mg/kg I.V. daily in divided doses q. 12 hr for 4 wk

Enterococci

• Penicillin G + gentamicin: preferred regimen
  • Dose: penicillin G, 20–30 million units I.V. daily in divided doses q. 4 hr for 4–6 wk; gentamicin, 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr for 4–6 wk (peak serum concentration should be ~ 3 ΅g/ml and trough concentrations < 1 ΅g/ml)
• Ampicillin + gentamicin
  • Dose: ampicillin, 12 g I.V. daily in divided doses q. 4 hr for 4–6 wk; gentamicin, dose as above
• Vancomycin + gentamicin: regimen for patients with history of penicillin hypersensitivity
  • Dose: vancomycin, 30 mg/kg I.V. daily in divided doses q. 12 hr for 4–6 wk; gentamicin, dose as above

Staphylococci (Methicillin Susceptible) in the Absence of Prosthetic Material

• Nafcillin or oxacillin + gentamicin (optional): preferred regimen
  • Dose: nafcillin or oxacillin, 12 g I.V. daily in divided doses q. 4 hr for 4–6 wk; gentamicin, 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr for 3–5 days (peak serum concentration should be ~ 3 ΅g/ml and trough concentrations <1 ΅g/ml)
• Cefazolin + gentamicin (optional): alternative regimen for patients with history of penicillin hypersensitivity
  • Dose: cefazolin, 12 g I.V. daily in divided doses q. 4 hr for 4–6 wk; gentamicin, dose as above
• Vancomycin: alternative regimen for patients with history of penicillin hypersensitivity
  • Dose: 30 mg/kg I.V. daily in divided doses q. 12 hr for 4–6 wk

Staphylococci (Methicillin Resistant) in the Absence of Prosthetic Material

• Vancomycin
  • Dose as above

Staphylococci (Methicillin Susceptible) in the Presence of Prosthetic Material

• Nafcillin or oxacillin + rifampin + gentamicin
  • Dose: nafcillin or oxacillin, 12 g I.V. daily in divided doses q. 4 hr for 6–8 wk; rifampin, 300 mg p.o., q. 8 hr for 6–8 wk; gentamicin (administer during the initial 2 wk), 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr for 2 wk

Staphylococci (Methicillin Resistant) in the Presence of Prosthetic Material

• Vancomycin + rifampin + gentamicin
  • Dose: vancomycin, 30 mg/kg I.V. daily in divided doses q. 12 hr for 6–8 wk; rifampin, 300 mg p.o., q. 8 hr for 6–8 wk; gentamicin (administer during the initial 2 wk), 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr for 2 wk

HACEK Organisms

• Ceftriaxone or another third-generation cephalosporin
  • Dose: 2 g I.V. daily as a single dose for 4 wk

• Indications for surgical debridement of vegetations and infected perivalvular tissue, with valve replacement or repair as needed
  • Moderate to severe heart failure
  • Vegetations that obstruct the valve orifice
  • Perivalvular invasion and abscess formation
  • Uncontrolled infection for > 1–3 wk despite maximal antimicrobial therapy
  • Fungal endocarditis
  • Prosthetic valve endocarditis with perivalvular invasion
  • Endocarditis caused by Pseudomonas aeruginosa or other gram-negative bacilli that has not responded after 7–10 days of maximal antimicrobial therapy

• In intravenous drug users with isolated right-sided S. aureus endocarditis, surgery should be postponed and antibiotic therapy continued for a prolonged period

• Anticoagulants can cause or worsen hemorrhage in patients with endocarditis but may be carefully administered when needed
• Prothrombin time should be carefully maintained at INR of 2.0–3.0
• Anticoagulation should be reversed immediately in the event of CNS complications and interrupted for 1–2 wk after acute embolic stroke
• Avoid heparin during active endocarditis if possible

Best References

Durack: JAMA 290:3250, 2003

Lisby, et al: Infect Dis Clin North Am 16:393, 2002

Olaison, et al: Cardiol Clin 21:235, 2003

Towns, et al: Cardiol Clin 21:197, 2003

March 2005

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