Infective endocarditis

Infective endocarditis (IE) is an infectious inflammation of the endocardium that affects the heart valves. The condition is a result of bacteremia, which is most commonly caused by dental procedures, surgery, distant primary infections, and nonsterile injections. IE clinically presents with either an acute or subacute course. Acute disease is usually caused by Staphylococcus aureus and causes rapid endocardium destruction. Subacute progression is most commonly caused by viridans streptococci species and generally affects individuals with pre-existing damage to the heart valves, structural heart defects, or the presence of prosthetic valves. Unlike acute disease, in which patients develop symptoms over a period of hours to days, subacute disease is associated with a progression of symptoms over weeks to months. Clinical features include constitutional symptoms (fatigue, fever/chills, malaise) in combination with signs of pathological cardiac changes (e.g., new or changed heart murmur, heart failure signs) and possibly manifestations of subsequent damage to other organs (e.g., glomerulonephritis, septic embolic stroke). Diagnosis is made based on the Duke criteria, whose main features include positive blood cultures and evidence of endocardial involvement in echocardiography. Initial treatment of IE consists of empiric IV antibiotic therapy, which is then adapted to blood culture results and continued for four to six weeks. Prophylaxis is only administered in specific circumstances, e.g., in patients with preexisting heart conditions undergoing dental or surgical procedures. If left untreated, infective endocarditis can be fatal within a few weeks.

Pathogens

Main pathogens	Characteristics
Staphylococcus aureus (45–65%)	Most common cause of acute IE for all groups (including IV drug users and patients with prosthetic valves or pacemakers/ICDs) Affects previously healthy valves Usually fatal within 6 weeks (if left untreated)
Viridans streptococci (30%): S. sanguinis, S. mutans, S. mitis	Most common cause of subacute IE, especially in predamaged native valves (mainly the mitral valve) Common cause of IE following dental procedures Produce dextrans that facilitate binding fibrin-platelet aggregates on damaged heart valves
Staphylococcus epidermidis	IE transmitted via infected peripheral venous catheters Common cause of subacute IE in patients with prosthetic heart valves or pacemakers/ICDs [1][2]
Enterococci, especially Enterococcus faecalis (< 10%)	Multiple drug resistance Common cause of IE following nosocomial urinary tract infections (UTIs) Following gastrointestinal or genitourinary procedures
Streptococcus gallolyticus (S. bovis)	S. gallolyticus is associated with colorectal cancer If S. gallolyticus is detected, colonoscopy is indicated
Gram-negative HACEK group (Haemophilus species, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae)	Physiological oral pharyngeal flora (∼ 3% of cases of IE) In patients with poor dental hygiene and/or periodontal infection
Candida species Aspergillus fumigatus	Causes IE in immunosuppressed patients Causes IE in IV drug abusers Cause of IE after cardiosurgical interventions
Coxiella burnetii Bartonella species	Gram-negative pathogens responsible for culture-negative endocarditis

HEAving your KING-size bed from IKEa into your CAR AGGREGATes joy: native valve endocarditis is caused by haemophilus, kingella, eikenella, cardiobacterium, and aggregatibacter.

Risk factors

• Demographics
  • Male sex
  • Age > 60 years
• Preexisting conditions
  • Previous IE
  • Predamaged or prosthetic heart valves
  • Congenital heart defects
  • Need for chronic hemodialysis
  • Impaired immune function (e.g., HIV infection)
• Bacteremia
  • Infected peripheral venous catheters, surgery, dental procedures
  • Non-sterile venous injections (e.g., IV drug abuse)
  • Bacterial infections of various organs (e.g., UTIs, spondylodiscitis)

References:^{[3][4][5][6][1][7][8][9][10][11][12][13][14][2]}

• Pathogenesis: localized infection or contamination → bacteremia → bacterial colonization of damaged valve areas → formation of fibrin clots encasing the vegetation → valve destruction with loss of function
  • Preexisting valvular endothelial damage or prosthetic valves predispose to bacterial colonization, especially of those that cause subacute IE
  • Frequency of valve involvement: mitral valve > aortic valve > tricuspid valve > pulmonary valve
  • The tricuspid valve is the most commonly affected valve in IV drug users (associated with Pseudomonas, S. aureus, and Candida).
• Clinical consequences
  • Bacterial thromboemboli from bacterial vegetation → vessel occlusion with infarctions
  • Formation of immune complexes and antibodies against tissue antigens → glomerulonephritis; , Osler nodes

Don't tri drugs for the sake of your tricuspid valves.

References:^{[15][16][7][17]}

Course of disease

	Acute bacterial endocarditis	Subacute bacterial endocarditis	Prosthetic valve endocarditis
Course	Acute onset Rapid, fulminant progression (days to weeks) More severe constitutional symptoms (e.g., high fever)	Insidious onset Slow progression (weeks to months) Less severe constitutional symptoms (e.g., low fever possible, often absent)	Early-onset: < 60 days after surgery Late-onset: ≥ 60 days after surgery
Main pathogens	Most common: S. aureus (associated with large vegetations that can destroy the valves) Others: group A hemolytic streptococci, S.pneumoniae, N.gonorrhoeae	Most common: viridans streptococci species (small vegetations) Others: nonenterococcal group D streptococci and enterococci	Early onset: S. epidermidis or S. aureus (most common) [1][2] Late onset: streptococci and S. aureus (most common) [1][2]
Affected valves	Native healthy valves	Native previously injured or congenitally defect valves	Prosthetic valves

Constitutional symptoms

• Fever and chills (∼ 90% of cases), tachycardia
• General malaise, weakness, night sweats, weight loss
• Dyspnea; , cough, pleuritic chest pain
• Arthralgias, myalgias

Cardiac manifestations

• New heart murmur development or change to a preexisting one
  • Mitral valve regurgitation → holosystolic murmur, loudest at the heart's apex, and radiates to the left axilla
  • Tricuspid valve regurgitation → holosystolic murmur; loudest at the left sternal border; ; seen in IV drug users; and concomitant HIV infection; , immunosuppressed patients,; and patients with central venous catheters
  • Aortic valve regurgitation → early diastolic murmur; loudest at the left sternal border
• Signs of progressive heart failure (e.g., dyspnea, edema)
• Signs of acute cardiac decompensation (pulmonary edema)
• Arrhythmias
  • Suspect perivalvular abscess in patients with infective endocarditis who develop a new conduction abnormality (e.g., a third-degree atrioventricular block)

Extracardiac manifestations

• These manifestations are mainly caused by bacterial microemboli and/or the precipitation of immune complexes .
• Petechiae; especially splinter hemorrhages (hemorrhages underneath fingernails)
• Janeway lesions
  • Small, non-tender, erythematous macules on palms and soles
  • Microabscesses with neutrophilic capillary infiltration and areas of hemorrhage caused by septic microemboli from valve vegetations
• Osler nodes
  • Painful nodules on pads of the fingers and toes
  • Caused by immune complex deposition
• Roth spots: round retinal hemorrhages with pale centers
• Signs of acute renal injury, including hematuria and anuria; (due to renal artery occlusion or glomerulonephritis)
• Splenomegaly and possible LUQ pain
• Neurological manifestations; (e.g., seizures, paresis): due to septic embolic stroke, hemorrhages, meningitis, encephalitis, and/or abscess.
• Signs of pulmonary embolism (e.g., dyspnea); : typically caused by septic emboli resulting from tricuspid valve involvement
• Possible arthritis

Infective endocarditis should always be considered as a cause of fever of unknown origin (FUO), especially if a new heart murmur develops!

FROM JANE - Fever, Roth spots, Osler nodes (Ouch = painful), Murmur, Janeway lesions, Anemia, Nail bed hemorrhage, Emboli

References:^{[16][1][7][18][19][20][21][22][23][24][2]}

Laboratory studies

• Best initial test: multiple blood cultures
  • Coxiella burnetii and Bartonella spp. commonly have negative cultures
• Leukocytosis (with left shift); , ↑ ESR, ↑ CRP

Echocardiography

• Detects valve vegetations; , new valvular regurgitation, abscess, dehiscence of prosthetic valve
• Transthoracic echocardiography (TTE) usually performed first (sensitivity: ∼ 75%)
• Transesophageal echocardiography (TEE) to confirm findings; higher sensitivity (> 90%) than TTE

(Modified) Duke criteria

• The Duke criteria help to diagnose infective endocarditis. To confirm the diagnosis, one of the following requirements must be met:
  • Two major criteria
  • One major and three minor criteria
  • Five minor criteria
• Major diagnostic criteria
  • Two separate blood cultures positive for typical pathogens (see “Etiology” above)
  • Evidence of endocardial involvement in echocardiography
    • Valve vegetation or abscess or new dehiscence of artificial valves
    • A new valvular regurgitation (worsening of a pre-existing murmur is not sufficient)
• Minor diagnostic criteria
  1. Predisposition: underlying heart disease or IV drug abuse
  2. Fever ≥ 38°C (100.4F)
  3. Vascular abnormalities
  4. Immunologic disorder
  5. Microbiology

Only negative findings on transesophageal echocardiography (TEE) can reliably rule out endocarditis, as transthoracic echocardiography (TTE) is not sensitive enough! References:^{[15][16][7][20][25]}

Pathogenesis

• Acute disease (leading to valve insufficiency, septic embolic infarcts, tendinous cord rupture)
  1. Erosion → fibrin deposits on valves
  2. Ulceration
  3. Perforation → adaptation of valve edges not possible
• Chronic disease (leading to valve insufficiency and valve stenosis)
  1. Erosion → reorganization of fibrin layer
  2. Granulation tissue → valve scarring/fibrosis
  3. Calcification → thickened and/or shortened tendinous cords

References:^[7]

Noninfective endocarditis (nonbacterial thrombotic endocarditis)

• Description: rare, noninfectious form of endocarditis due to sterile platelet thrombus formation on the heart valves (usually mitral and aortic valves)
• Etiology
  • Most commonly associated with underlying trauma (e.g., catheters), malignancy, hypercoagulable states, previous rheumatic fever, chronic infections (e.g., TB, pneumonia, osteomyelitis), or autoimmune conditions (systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, etc.)
  • A nonbacterial thrombotic endocarditis with verrucous vegetations in a patient with systemic lupus erythematosus is also referred to as Libman-Sacks endocarditis.
• Clinical features
  • Valves and cardiac function are rarely impaired.
  • Compared to infectious endocarditis, vegetations are easily dislodged and embolization is common, leading to hemorrhages under the nails, skin, and retina; most patients are asymptomatic until embolization occurs
• Diagnostics
  • Negative blood cultures
  • Echocardiography: findings of valve vegetations
  • Definitive diagnosis can only be made pathologically: findings show sterile vegetations on either surface of the valve that are composed of immune complexes, mononuclear cells, and thrombi interwoven with fibrin strands
• Treatment: anticoagulation with heparin and treatment of the underlying condition

Prosthetic valve thrombosis

• Etiology
  • Occurs if insufficient anticoagulatory therapy after valve replacement
  • Usually affects mechanic valves
  • Rare if anticoagulation is adequate
  • Presence of a cardiac defect raises the risk of recurrent endocarditis
• Clinical course
  • Signs of acute heart failure
    • Left heart failure: dyspnea and cough
    • Right heart failure: edema and jugular venous distention
  • Deterioration of general condition, cardiac arrhythmias, cerebral emboli (stroke)
• Diagnostics: transesophageal echocardiography
• Treatment: anticoagulation and fibrinolysis, surgical valve replacement

References:^[26][27]

The differential diagnoses listed here are not exhaustive.

Empirical therapy

Condition/patient group	Antibiotic therapy
Native valves	Initial intravenous empiric antibiotic treatment with vancomycin → adapt intravenous antibiotics according to resistogram results from blood cultures The duration of treatment depends on the patient's profile, the pathogen's resistances, and the patient's response to treatment. 4-week treatment Drug of choice: penicillin G Alternatives: ampicillin, IV ceftriaxone, IV vancomycin 2-week treatment regimens Drug of choice: gentamicin + penicillin G Alternative: gentamicin + ceftriaxone
Prosthetic valves	Generally the same antibiotic regimen as for native valves, but longer duration (at least 6 weeks) Exceptions for staphylococci Methicillin-susceptible: nafcillin (or oxacillin, cefazolin) + rifampin + gentamicin Methicillin-resistant: vancomycin + rifampin + gentamicin
IV drug users	Intravenous empiric antibiotic treatment with vancomycin After confirmation of a susceptible pathogen IV nafcillin (2 weeks) PO cloxacillin (2 weeks)
Indications for surgery: congestive heart failure, uncontrolled infection, systemic embolization, prosthetic valve, fungal endocarditis

If infective endocarditis is suspected: 1. Obtain blood cultures → 2. Start empiric antibiotic therapy → 3. adapt the therapy according to culture results.

Targeted therapy

HACEK organisms

• Drug of choice
  • First-line: 3^rd or 4th generation IV cephalosporin (e.g., ceftriaxone, cefotaxime)
  • Second-line : ampicillin-sulbactam , IV fluoroquinolone
• Duration of therapy
  • Native valve infectious endocarditis: 4 weeks
  • Prosthetic valve endocarditis: 6 weeks

References:^{[16][7][17][28][29][30][31]}

Endocarditis prophylaxis:

• Indicated for high-risk patients undergoing procedures with risk of bacteremia
• Regimens
  • Usually PO amoxicillin (administer 1 hour before procedure)
  • Patients who are unable to take oral medication: IV ampicillin
  • Patients with penicillin allergy: PO clarithromycin or azithromycin

References:^[15][32][33]