Infective endocarditis

Infective endocarditis (IE) is an infection of the endocardium that typically affects one or more heart valves. The condition is usually due to bacteremia, which is most commonly caused by dental procedures, surgery, distant primary infections, and nonsterile injections. IE may be acute (developing over hours or days) or subacute (developing over weeks to months). Acute bacterial endocarditis is usually caused by Staphylococcus aureus and may cause rapid destruction of endocardial tissue. Subacute bacterial endocarditis is most commonly caused by viridans streptococci and usually affects individuals with preexisting damage to the heart valves, congenital heart defects, and/or prosthetic valves. Clinical features include constitutional symptoms (e.g., fatigue, fever, chills, malaise), signs of pathological cardiac changes (e.g., new or changed heart murmur, heart failure signs), and, in some cases, manifestations of subsequent organ damage (e.g., glomerulonephritis, septic embolic stroke). Management is complex and early involvement of infectious diseases is recommended. The 2023 Duke-ISCVID criteria are used to assess the likelihood of IE, and the diagnosis is confirmed based on culture, histopathology, and/or imaging findings. Initial treatment consists of empiric IV antibiotics, which are adjusted based on blood culture results and continued for several weeks. Distinguishing between native and prosthetic valve IE allows for more tailored treatment. Surgery may be necessary in complex cases (e.g., valve perforation). IE prophylaxis is recommended in specific circumstances (e.g., in patients with congenital heart disease undergoing certain dental procedures). IE is typically fatal if left untreated.

Typical pathogens in IE ^[1]

The identification of one of the following typical pathogens on blood culture may indicate IE.

All patients

• Staphylococcus
  • S. aureus
  • S. lugdunensis
• Enterococcus faecalis
• All Streptococcus spp. (except S. pneumoniae and S. pyogenes)
• Granulicatella spp.
• Abiotrophia spp.
• Gemella spp.
• HACEK group
  • Haemophilus spp.
  • Aggregatibacter actinomycetemcomitans
  • Cardiobacterium hominis
  • Eikenella corrodens
  • Kingella kingae

Patients with intracardiac prostheses

• Coagulase-negative staphylococci
• Corynebacterium
  • C. striatum
  • C. jeikeium
• Serratia marcescens
• Pseudomonas aeruginosa
• Cutibacterium acnes
• Nontuberculous mycobacteria (particularly Mycobacterium chimaerae)
• Candida spp.

Causes of blood culture-negative IE ^[2]

Blood culture-negative IE is most commonly caused by antibiotic use before blood sample collection but can be due to pathogens that are difficult to culture. Selected pathogens are listed below.

• Brucella spp.
• Bartonella spp.
• Coxiella burnetii
• Fungi (e.g., Aspergillus spp.)
• Legionella spp.
• Mycoplasma spp.
• Tropheryma whipplei

Specifics of selected pathogens

Risk factors for infective endocarditis ^[3][6][12]

• Demographics
  • Male sex
  • Age > 60 years
• Cardiac conditions
  • Acquired valvular disease (e.g., rheumatic heart disease, aortic stenosis, degenerative valvular disease)
  • Prosthetic heart valves
  • Congenital heart defects (e.g., VSD, bicuspid aortic valve)
  • Previous IE
  • Cardiac implantable electronic device (CIED) ^[6]
• Noncardiac risk factors
  • Poor dental status
  • Dental procedures
  • Nonsterile venous injections (e.g., in IV drug use)
  • Intravascular devices
  • Surgery
  • Chronic hemodialysis
  • Immunocompromise (e.g., HIV infection, diabetes)
  • Other bacterial infections (e.g., UTIs, spondylodiscitis, periodontal infection)

• Pathogenesis ^[3]
  1. Damaged valvular endothelium → exposure of the subendothelial layer → adherence of platelets and fibrin → sterile vegetation (microthrombus)
  2. Localized infection or contamination → bacteremia → bacterial colonization of vegetation → formation of fibrin clots encasing the vegetation → valve destruction with loss of function (valve regurgitation) ^[13]
• Valve involvement ^[12]
  • Frequency of valve involvement: mitral valve > aortic valve > tricuspid valve > pulmonary valve
  • The tricuspid valve is the most commonly affected valve in individuals who inject drugs (associated with Pseudomonas, S. aureus, and Candida).
• Clinical consequences ^[3][13]
  • Bacterial vegetation → bacterial thromboemboli → vessel occlusion → infarctions
  • Emboli can lead to metastatic infections of other organs.
  • Formation of immune complexes and antibodies against tissue antigens → glomerulonephritis, Osler nodes

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

Constitutional symptoms ^[3][14]

• Fever and chills (seen in ∼ 90% of patients) ^[3]
• Tachycardia
• General malaise, weakness, weight loss, night sweats
• Dyspnea, cough, pleuritic chest pain
• Arthralgias, myalgias

Patients with subacute IE often present with nonspecific flu-like symptoms, while patients with acute IE often present with signs of acute sepsis.

A high index of suspicion is required in patients with risk factors for IE, as classic extracardiac manifestations (e.g., splinter hemorrhages, Janeway lesions) are absent in the majority of patients. ^[8][15]

Cardiac manifestations ^[3][14]

• Development of a new heart murmur or change in a preexisting murmur (seen in ∼ 75% of patients) ^[3];
  • Tricuspid valve regurgitation
    • Holosystolic murmur that is loudest at the left sternal border
    • Seen in individuals who inject drugs, immunocompromised individuals, patients with congenital heart disease, and patients with instrumentation in the right heart (e.g., central venous catheters) ^[4]
  • Aortic valve regurgitation: early diastolic murmur that is loudest at ; the left 3^rd and 4^thintercostal spaces and along the left sternal border ^[6]
  • Mitral valve regurgitation: holosystolic murmur that is loudest at the heart's apex and radiates to the left axilla
• Heart failure (e.g., dyspnea, lower limb edema) due to valve insufficiency
• Arrhythmias: Suspect a perivalvular abscess in patients with IE who develop a new conduction abnormality (e.g., heart block). ^[16]

Extracardiac manifestations of IE ^[3][14]

Extracardiac manifestations are typically caused by septic microemboli and/or immune complex precipitation and are more commonly seen in left-sided IE, with the exception of pulmonary embolic manifestations, which are more common in right-sided IE. ^[3][17]

• Peripheral embolic and immunologic phenomena: seen in only 5–10% of patients. ^[3][17]
  • Petechiae, especially splinter hemorrhages (hemorrhages underneath fingernails)
  • Janeway lesions
    • Small, nontender, 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
• Emboli to intraabdominal organs
  • Acute renal injury
    • Including hematuria and anuria
    • Due to renal artery occlusion or glomerulonephritis
  • Splenomegaly and possible LUQ pain
    • Due to splenic artery occlusion or splenic abscess
    • May lead to splenic rupture ^[18]
• Neurological manifestations: (e.g., seizures, paresis): due to septic embolic stroke, hemorrhage, meningitis, encephalitis, and/or abscess ^[19][20]
• Pulmonary manifestations: caused by septic emboli resulting from tricuspid valve involvement
  • Signs of pulmonary embolism (e.g., dyspnea)
  • Signs of pulmonary infection, e.g., multifocal pneumonia, lung abscess, and/or empyema. ^[21]
• Others: Arthritis

Up to one-third of patients with left-sided IE present with symptoms of stroke. ^[20]

IE should always be considered as a cause of fever of unknown origin (FUO), especially in the presence of a new heart murmur.

“FROM JANE:” Features of IE include Fever, Roth spots, Osler nodes, Murmur, Janeway lesions, Anemia, Nail bed hemorrhage, and Emboli.

• IE can be classified by:
  • Type of affected valve (native vs. prosthetic)
  • Acuity of the infection
  • Location of the infection (left- vs. right-sided)
• Although this is not a definitive classification system, it can help in the approach to management and selection of empiric antibiotic regimens.

Classification by valve type and duration of infection

Classification by location

Approach ^[17][23]

• Suspect IE in patients with clinical features (e.g., fever of unclear etiology and a new heart murmur) and predisposing conditions.
• Use the 2023 Duke-ISCVID criteria to determine the diagnostic likelihood of IE: definite, possible, or rejected. ^[8]
  • Intended as a diagnostic guide and not a substitute for clinical judgment
  • Incorporates clinical, microbiological, pathological, and imaging criteria
• Order echocardiography and multiple sets of blood cultures for all patients.
• Obtain ECG and additional imaging to investigate complications, new focal symptoms, and/or signs of metastatic infection.
• Consider serology to evaluate for blood culture-negative endocarditis.
• Consult infectious diseases if there is diagnostic uncertainty.

Draw three sets of blood cultures from different venipuncture sites as soon as IE is suspected, preferably before initiating antibiotic treatment.

Duke criteria

The modified Duke criteria were revised in 2023 to improve diagnostic sensitivity for IE and have now been replaced by the 2023 Duke-ISCVID criteria.

Laboratory studies ^[17]

Routine studies ^[2]

Laboratory findings are nonspecific but may be used to assess disease severity.

• CBC: : leukocytosis (may show left shift), leukopenia, anemia, and/or thrombocytopenia
• Inflammatory markers: : ↑ CRP, ↑ ESR ^[23]
• CMP: Elevated creatinine and liver chemistries indicate end organ damage.
• Serum lactate: may be elevated
• Cardiac biomarkers: Troponin and BNP may be elevated. ^[24]
• Urinalysis: Hematuria and/or nephritic sediment may be present. ^[15][25]

Blood cultures ^[26]

• Blood sample collection
  • Before treatment: three sets of bacterial cultures from different venipuncture sites
  • During treatment: two sets from separate venipuncture sites every 24–48 hours until bacteremia resolves
• Interpretation
  • Positive cultures are interpreted using the 2023 Duke-ISCVID criteria.
  • Negative cultures cannot rule out IE as any of the following may produce a negative result: ^[8][26][27]
    • Antibiotic therapy before blood culture sampling
    • Fastidious bacteria (most commonly C. burnetii or Bartonella spp.) ^[15]
    • Fungal infection
    • Noninfective endocarditis

Negative blood cultures cannot rule out IE since some patients with IE have sterile cultures.

Echocardiography ^[1][2][17]

Transthoracic echocardiography (TTE) is the initial test of choice for all patients with suspected IE. TTE should ideally be performed within 12 hours of presentation and if new complications are suspected. Transesophageal echocardiography (TEE) is more invasive and should be considered in selected cases. ^[2]

• Indications for TEE include:
  • Presence of high-risk features
  • TTE findings inconclusive or suggestive of IE ^[2]
  • Patients due to undergo surgery
  • Concern for intracardiac complications (e.g., abscess)
  • Selected patients based on detected pathogens (e.g., S. aureus, E. faecalis, Streptococcus spp.)
• Findings of IE on echocardiogram: 2023 Duke-ISCVID imaging major criteria have expanded on the modified Duke major criteria. ; ^[8][28][29]
  • Valvular vegetations: hyperechoic mobile masses located on the valve, mural endocardium, or prosthetic material ^[30]
  • Abscess (e.g., perivalvular abscess )
  • New valvular regurgitation (especially in patients with valve prolapse, perforation, and/or destruction)
  • New partial prosthetic valve dehiscence
  • Valvular or leaflet aneurysm or perforation
  • Pseudoaneurysm
  • Intracardiac fistula

TEE is more sensitive (∼ 90%) than TTE (∼ 75%) and is more reliable for ruling out IE in patients with moderate to high pretest probability.

Additional investigations ^[17][26]

• Serology
  • To assess for culture-negative endocarditis, e.g.:
    • C. burnetii anti-phase I IgG titer (> 1:800)
    • B. henselae or B. quintana IgG titer (≥ 1:800)
  • Limitations: cross-reactivity between different pathogens, confounding from prior infections
• Molecular testing (e.g., PCR, RNA sequencing): to assess for culture-negative endocarditis (e.g., due to C. burnetii, Bartonella spp., T. whipplei)
• Tissue sampling (after surgery)
  • Histopathology of resected valves (gold standard) ^[26][31]
  • Gram stain and culture: to plan the duration of postoperative antimicrobial therapy ^[26]
  • Molecular testing (e.g., T. whipplei PCR) ^[31]
• ECG: indicated in all patients to assess for complications (e.g., AV block or bundle branch blocks in paravalvular extension) ^[8][23]
• Dental assessment: in all patients receiving treatment for IE regardless of the initial source of bacteremia
• Colonoscopy: in patients with bacteremia due to S. gallolyticus to rule out colon cancer and mucosal lesions

Obtain an ECG in all patients with suspected IE to assess for new conduction abnormalities that indicate a perivalvular or myocardial abscess (e.g., AV block, bundle branch block). If present, consider urgent cardiac imaging (e.g., TEE, cardiac MRI). ^[8][23]

Imaging

Additional imaging may be performed if echocardiography is inconclusive and in selected patients to assess for complications.

• Cardiac CTA ^[2]
  • Consider in possible IE for diagnostic confirmation and/or assessment of valvular lesions.
  • Consider in native or prosthetic valve IE to assess for paravalvular or periprosthetic complications if TTE and TEE are inconclusive.
• ¹⁸F-FDG PET/CT: Consider to evaluate for IE in patients with a prosthetic valve. ^[32][33][34]
• CXR: The presence of multiple pulmonary infiltrates may suggest right-sided IE. ^[15]
• Abdominal ultrasound: if splenic abscess or infarction is suspected
• MRI head: Consider to assess for intracranial septic emboli.

• Acute disease (leading to valve insufficiency, septic embolic infarcts, tendinous cord rupture) ^[35]
  • Erosion → fibrin deposits on valves
  • Ulceration
  • Perforation
• Chronic disease (leading to valve insufficiency and valve stenosis) ^[35]
  • Erosion → reorganization of fibrin layer
  • Granulation tissue → valve scarring/fibrosis
  • Calcification → thickened and/or shortened tendinous cords

Noninfective endocarditis (nonbacterial thrombotic endocarditis) ^[36][37]

• Description
  • Rare, noninfective form of endocarditis due to sterile platelet thrombus formation on the heart valves (usually mitral and aortic valves)
  • Libman-Sacks endocarditis: a type of noninfective endocarditis with verrucous vegetations in individuals with systemic lupus erythematosus or antiphospholipid syndrome ^[36]
• Etiology
  • Malignancy (e.g., pancreatic adenocarcinoma)
  • Hypercoagulable states
  • Underlying trauma (e.g., from indwelling vascular catheters)
  • Previous rheumatic fever
  • Autoimmune conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome) ^[38]
  • Chronic infections (e.g., TB, pneumonia, osteomyelitis)
• Clinical features
  • Valves and cardiac function are rarely impaired.
  • Compared to IE, vegetations are easily dislodged and embolization is common, leading to hemorrhages under the nails, skin, and retina
  • Most affected individuals are asymptomatic until embolization occurs.
• Diagnostics
  • Negative blood cultures
  • Echocardiography: valve vegetations
  • Biopsy (definitive diagnosis)
    • Sterile vegetations on either surface of the valve composed of immune complexes, mononuclear cells, and thrombi interwoven with fibrin strands
    • Not always feasible, therefore diagnosis is mostly made based on clinical findings, negative blood cultures, echocardiography findings, and no response to antibiotic treatment
• Treatment
  • Anticoagulation with heparin
  • Treatment of the underlying condition

Other

• Intravascular catheter infection
• Infection of prosthetic implants (e.g., prosthetic valves, joints, cardiac electronic devices)
• Prosthetic valve thrombosis
• Hematogenous osteomyelitis
• Septic thrombophlebitis

The differential diagnoses listed here are not exhaustive.

Initial management ^{[8][17][32][39]}

• Unstable patients: Use the ABCDE approach and initiate management of sepsis as needed.
• Consults ^[40]
  • Consult infectious diseases (ID) early to plan treatment and consider empiric therapy.
  • Identify patients with indications for surgery consult in IE.
• Antibiotic therapy
  • Start empiric antibiotic therapy for IE once blood cultures have been sampled. ^[8][39]
  • Switch to targeted antibiotic therapy for IE once blood culture results are available. ^[8][39]
• Supportive care: Treat urgent complications (e.g., AHF, heart block) and the underlying cause (e.g., removal of infected central lines).

If IE is suspected, first obtain blood cultures, then consult ID to plan empiric antibiotic therapy. When culture results are available, adapt the therapy accordingly.

Supportive care

• Antithrombotic agents ^[17][32]
  • Consider holding existing anticoagulation if CNS emboli are present.
  • Continue long-term antiplatelet therapy if there is no bleeding
  • Initiation of antithrombotic therapy is not routinely recommended.
• Cardiovascular complications: See “Acute heart failure management” and “Management of heart block.” ^[41]
• Others
  • Remove infected central lines and CIEDs ^[42][43]
  • Treat opioid use disorder if present, e.g., in IV drug use. ^[44][45]
  • Inpatient dental evaluation

Antibiotics

Empiric antibiotic therapy for IE ^[17][46]

The goal of empiric antibiotic therapy is to provide broad-spectrum coverage for potential bacterial causes of IE (including multidrug-resistant organisms) until blood culture results are available.

• Choice of empiric agents: Consult infectious diseases and consider patient and disease factors as well as local and individual flora and resistance patterns (see “Risk factors for IE” and “Classification”).
• Example regimen ^[46]
  • Vancomycin (off-label) OR daptomycin (off-label) ^[17][46]
  • PLUS a beta-lactam (e.g., ceftriaxone OR cefepime (off-label) ) ^[17]
  • PLUS gentamicin and rifampin in selected cases (e.g., prosthetic valve IE) in consultation with infectious diseases

Targeted antibiotic therapy ^[17]

Targeted antibiotic therapy based on culture and sensitivity results is recommended for all patients with IE.

• Common targeted antibiotic regimens
  • Staphylococci
    • Methicillin-susceptible staphylococci (e.g., MSSA): antistaphylococcal beta-lactam (e.g., nafcillin, oxacillin)
    • Methicillin-resistant staphylococci (e.g., MRSA): vancomycin
    • Prosthetic valve IE (≤ 1 year after placement): Add gentamicin PLUS rifampin.
  • Viridans group streptococci: beta-lactam (e.g., penicillin G, ampicillin)
  • Enterococci: combination therapy (e.g., ampicillin PLUS gentamicin)
  • HACEK: ceftriaxone (first line)
• Oral step-down therapy: After initial IV antibiotics, the course may be completed with oral antibiotics in selected patients in consultation with infectious diseases. ^[2][46]
• Duration of therapy: depends on various factors (e.g., drug regimen, affected valve) and may be continued for more than 2–6 weeks after the first sterile blood culture
• Blood culture-negative endocarditis: targeted therapy based on additional studies (e.g., serology)

Surgery ^[2][17][40]

The decision to perform surgery is typically made by a multidisciplinary team comprising cardiology, cardiothoracic surgery, and infectious diseases.

• Indications for surgery consult in IE include:
  • Prosthetic valve IE
  • Valve dysfunction causing heart failure
  • Uncontrolled infection (e.g., enlarging vegetation, persistent bacteremia)
  • Perivalvular extension or complications (e.g., abscess, pseudoaneurysm, fistula, heart block)
  • IE due to difficult to treat organisms (e.g., fungi, MDRO)
  • High embolic risk (e.g., mobile vegetation ≥ 10 mm, recurrent embolism) ^[2]
• Surgical options: valve replacement or valve repair (see “Treatment” in “Valvular heart diseases”)
• Complications
  • Acute surgical complications (e.g., rebleeding from surgical sites, coagulopathy, acute kidney injury, pneumonia)
  • Cardiac complications (e.g., CHF, myocarditis, pericarditis, new AV block)
  • Systemic emboli (e.g., stroke)

Surgery is required in 50–60% of patients with IE. ^[40]

Unstable patients

• Perform ABCDE survey.
• Begin treatment of complications causing hemodynamic instability, e.g.:
  • Sepsis management
  • Management of acute heart failure
  • Management of bradycardia (e.g., due to heart block)

All patients

• Perform a clinical evaluation, e.g., cardiac surgical history, screening for extracardiac manifestations of IE.
• Establish IV access
• Draw 3 sets of blood cultures from different sites,
• Obtain routine laboratory studies (e.g., CBC, BMP).
• Order echocardiogram.
• Use the 2023 Duke-ISCVID criteria to categorize the diagnostic likelihood of IE.
• Obtain ECG and screen for new conduction abnormalities.
• Consult infectious diseases.
• Start empiric antibiotics for IE after blood samples are obtained.
• Screen for metastatic infections and consider confirmatory imaging (e.g., CXR, CT abdomen and pelvis, CT head).
• Identify patients with indications for surgery consult in IE.
• Switch to targeted antibiotic therapy for IE once blood culture results are available.
• Treat underlying conditions (e.g., remove infected central lines and CIEDs, treat opioid use disorder)
• Admit to hospital.
• Screen and monitor for complications (e.g., valvulopathy, AHF, perivalvular abscess, AV block, stroke, PE).

• Cardiac complications
  • New or worsened valvular regurgitation
  • Partial dehiscence of a prosthetic valve ^[17]
  • Congestive heart failure (most common cause of death in patients with infective endocarditis)
  • Perivalvular abscess and fistula
  • Myocarditis
  • Conduction abnormalities: e.g., AV blocks
• Embolic complications
  • Systemic embolism in left-sided endocarditis: e.g., stroke, renal infarct, splenic infarct
  • Pulmonary embolism in right-sided endocarditis
  • Septic emboli and mycotic aneurysms
• Metastatic infections: due to septic emboli or bacteremia
  • Multifocal pneumonia, lung abscess
  • Spondylodiscitis
  • Splenic abscess
  • Meningitis, brain abscess
• Acute kidney injury: Often multifactorial ^[6]

We list the most important complications. The selection is not exhaustive.

Endocarditis prophylaxis ^{[2][47][48][49]}

Prophylaxis is indicated prior to certain procedures with a high risk of bacteremia in patients with high-risk cardiac features. ^[47]

• Cardiac risk factors requiring IE prophylaxis (for procedures that may cause bacteremia)
  • Presence of prosthetic cardiac valve or material
  • History of endocarditis
  • Certain types of congenital heart disease (CHD), e.g., unrepaired cyanotic CHD, repaired CHD (within 6 months of repair), repaired CHD with residual post-operative shunt or regurgitation
  • Valvulopathy in cardiac transplant recipients ^[32][49]
• Procedures requiring IE prophylaxis in patients at risk for IE
  • Some dental procedures including tooth extraction and routine dental cleaning
  • Any invasive procedure involving respiratory tract or infected tissue (e.g., abscess drainage)
  • Placement of a CIED ^[43][50]
  • Surgical placement of prosthetic cardiac or intravascular material (e.g., heart valve, intravascular graft) ^[50]
• Common regimens (usually administered 30–60 minutes prior to the procedure) ^[32]
  • Prior to dental procedures ^[47]
    • No penicillin allergy: amoxicillin OR ampicillin OR cefazolin
    • Penicillin allergy: a macrolide (e.g., azithromycin ) OR doxycycline
  • Prior to CIED placement: cefazolin
  • Pathogen-specific agents may be indicated depending on the site of the procedure. ^[32]

IE prophylaxis is not routinely recommended prior to nondental procedures (including respiratory, skin, musculoskeletal, gastrointestinal, and genitourinary procedures) unless infected tissue is present. ^[32]