What is the recommended diagnostic workup and empiric antimicrobial regimen for adult infective endocarditis, including native‑valve and prosthetic‑valve infections, and the indications for surgical consultation?

Management of Infective Endocarditis

Diagnostic Workup

Obtain three sets of blood cultures from separate venipuncture sites at 30-minute intervals before initiating any antimicrobial therapy, with each set including both aerobic and anaerobic bottles. 1, 2, 3 This approach maximizes pathogen identification while avoiding the critical pitfall of culture-negative endocarditis from premature antibiotic administration. 2

Echocardiographic Evaluation

• Transthoracic echocardiography (TTE) is essential for initial evaluation to assess valve morphology, vegetation presence, hemodynamic consequences, and left ventricular function. 1
• Transesophageal echocardiography (TOE) should be performed to detect valve perforations, secondary mitral lesions, aneurysms, and perivalvular abscesses that TTE may miss. 1
• Repeat echocardiography immediately if clinical deterioration occurs or new complications develop during treatment. 2, 4

Additional Diagnostic Considerations

• Maintain high clinical suspicion even without classic fever in immunocompromised patients, as atypical presentations are common. 2
• Consult infectious disease specialists for culture-negative endocarditis to guide extended diagnostic workup for fastidious organisms like Brucella, Coxiella burnetii, and Bartonella. 1, 3

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Empiric Antimicrobial Therapy

Native Valve Endocarditis (Community-Acquired)

For subacute presentations, initiate ampicillin 12 g/day IV in 4-6 divided doses PLUS cloxacillin or oxacillin 12 g/day IV in 4-6 divided doses PLUS gentamicin 3 mg/kg/day IV in a single daily dose. 2, 4 This regimen covers staphylococci, streptococci, and enterococci—the most common pathogens. 1, 3

For acute presentations with suspected Staphylococcus aureus, use nafcillin or oxacillin 12 g/day IV in 4-6 divided doses PLUS gentamicin 3 mg/kg/day IV. 1, 3 In regions with high methicillin-resistant S. aureus (MRSA) prevalence, substitute vancomycin 30 mg/kg/day IV in 2 divided doses for nafcillin/oxacillin. 1, 3

Prosthetic Valve Endocarditis or Healthcare-Associated Infection

Initiate vancomycin 30-60 mg/kg/day IV in 2-3 divided doses PLUS gentamicin 3 mg/kg/day IV in a single dose PLUS rifampin 900-1200 mg IV or orally in 2-3 divided doses. 2, 4 Start rifampin 3-5 days after vancomycin and gentamicin to avoid antagonism. 4 This covers methicillin-resistant staphylococci, enterococci, and non-HACEK gram-negative pathogens. 1, 3

For early prosthetic valve endocarditis (within 2 months of surgery), add cefepime 2 g IV every 8 hours to cover aerobic gram-negative bacilli. 1

Culture-Negative Endocarditis

For patients who received antibiotics before blood culture collection with subacute presentation, use ampicillin-sulbactam 3 g IV every 6 hours combined with gentamicin 1 mg/kg IV every 8 hours. 1 This covers S. aureus, viridans streptococci, enterococci, and HACEK organisms. 1

Immunocompromised Patients

Add antifungal coverage (e.g., amphotericin B or an echinocandin) to standard empiric regimens in immunocompromised hosts due to increased fungal endocarditis risk. 2

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Pathogen-Directed Therapy

Adjust antimicrobial therapy within 48 hours once the pathogen is identified based on susceptibility testing. 1, 3

Streptococcal Endocarditis

• For penicillin-susceptible strains (MIC ≤0.1 mg/L), use penicillin G 12-20 million units/24h IV in 4-6 divided doses for 4 weeks PLUS gentamicin 3 mg/kg/24h IV in 2-3 divided doses for 2 weeks. 1
• For relatively resistant strains (MIC 0.1-0.5 mg/L) or prosthetic valve infection, use penicillin G 20-24 million units/24h IV or ceftriaxone 2 g/24h IV for 4 weeks PLUS gentamicin for 2 weeks. 1
• For penicillin-allergic patients, substitute vancomycin 30 mg/kg/24h IV in 2 divided doses for 4 weeks. 1, 3

Enterococcal Endocarditis

• Use ampicillin 12 g/24h IV in 4-6 divided doses PLUS gentamicin 3 mg/kg/24h IV for 4-6 weeks. 3
• For ampicillin-resistant strains, use vancomycin 30 mg/kg/24h IV PLUS gentamicin. 3

Staphylococcal Endocarditis

• For methicillin-susceptible native valve infection, use nafcillin or oxacillin 12 g/24h IV in 4-6 divided doses PLUS gentamicin 3 mg/kg/24h IV for the first 3-5 days. 3
• For methicillin-resistant infection, use vancomycin 30 mg/kg/24h IV in 2 divided doses for 4-6 weeks. 3
• For prosthetic valve staphylococcal infection, add rifampin 900-1200 mg/24h in 2-3 divided doses to the above regimens for at least 6 weeks. 4, 3

HACEK Organisms

Use ceftriaxone 2 g/24h IV as a single dose for 4 weeks (native valve) or 6 weeks (prosthetic valve). 1, 3 Ampicillin-sulbactam 12 g/24h IV in 4 divided doses is an alternative. 1

Fungal Endocarditis

Initiate combined antifungal therapy with an echinocandin or amphotericin B formulation AND proceed urgently to surgical valve replacement, as medical therapy alone has mortality exceeding 50%. 3

Atypical Pathogens in Immunocompromised Patients

• For Coxiella burnetii (Q fever), use doxycycline 200 mg/24h PLUS hydroxychloroquine 200-600 mg/24h orally for >18 months with serum level monitoring. 2
• For Bartonella species, use doxycycline 100 mg every 12 hours orally for 4 weeks PLUS gentamicin 3 mg/kg/day IV for 2 weeks. 2
• For Brucella species, use doxycycline 200 mg/24h PLUS cotrimoxazole 960 mg every 12 hours PLUS rifampin 300-600 mg/24h orally for ≥3-6 months. 2

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Duration of Therapy

Administer parenteral antibiotics for a minimum of 4-6 weeks from the first day of effective treatment for native valve endocarditis. 4, 3 Prosthetic valve endocarditis requires at least 6 weeks of parenteral therapy. 1, 4, 3

Monitoring During Treatment

• Monitor gentamicin trough levels to maintain <0.1 mg/L to prevent nephrotoxicity and ototoxicity. 1, 4
• Monitor vancomycin trough levels to maintain 15-20 mg/L for optimal efficacy. 3
• Repeat blood cultures if fever persists beyond 48-72 hours or clinical deterioration occurs. 2, 3

Outpatient Parenteral Antibiotic Therapy (OPAT)

Consider OPAT only after the critical first 2 weeks if the patient has oral streptococci or Streptococcus bovis native valve infection, is medically stable, and has no complications. 1, 3 Do not use OPAT if heart failure, concerning echocardiographic features, neurological signs, or renal impairment are present. 1, 3 Require daily nurse evaluation and physician assessment 1-2 times weekly. 1

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Surgical Consultation and Indications

Early consultation with a cardiac surgeon is mandatory to determine optimal therapeutic approach, as approximately 50% of patients require surgical intervention. 1, 3, 5

Emergency Surgery (Within 24 Hours)

Operate emergently for aortic or mitral native or prosthetic valve endocarditis with severe acute regurgitation, obstruction, or fistula causing refractory pulmonary edema or cardiogenic shock. 1, 4 This is a Class I, Level B recommendation. 1

Urgent Surgery (Within Days)

Operate urgently for:

• Aortic or mitral valve endocarditis with severe regurgitation or obstruction causing heart failure symptoms or echocardiographic signs of poor hemodynamic tolerance (Class I, Level B). 1
• Locally uncontrolled infection with abscess, false aneurysm, fistula, or enlarging vegetation (Class I, Level B). 1, 4
• Infection caused by fungi or multiresistant organisms (Class I, Level C). 1
• Persistent vegetations >10 mm after one or more embolic episodes despite appropriate antibiotic therapy (Class I, Level B). 1, 4
• Persisting positive blood cultures despite appropriate antibiotic therapy and adequate control of septic metastatic foci (Class IIa, Level B). 1
• Prosthetic valve endocarditis caused by staphylococci or non-HACEK gram-negative bacteria (Class IIa, Level C). 1

Additional Surgical Considerations

Consider urgent surgery for native valve endocarditis with vegetations >10 mm associated with severe valve stenosis or regurgitation in low operative risk patients (Class IIa, Level B). 1 Very large vegetations (>30 mm) warrant urgent surgery even without other indications (Class IIa, Level B). 1

Age alone is not a contraindication to surgery. 1 Surgery is justified in patients with high-risk features making cure with antibiotics unlikely, unless co-morbidities make recovery remote. 1

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Multidisciplinary Team Management

All patients with infective endocarditis must be managed by an "Endocarditis Team" including an infectious disease specialist, cardiologist, cardiac surgeon, and microbiologist. 2, 4, 3 This multidisciplinary approach is particularly critical for:

• Culture-negative endocarditis 1, 3
• Prosthetic valve infections 1
• Immunocompromised patients 2
• Infections with rare pathogens or multi-drug resistant organisms 3
• Determining optimal timing for surgical intervention 1

Early referral to a reference center with immediate surgical capabilities is recommended for complex cases. 4

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Critical Pitfalls to Avoid

• Never delay blood culture collection to start antibiotics, but also never delay antibiotics beyond blood culture collection in unstable patients, as immunocompromised and acutely ill patients can deteriorate rapidly. 2
• Do not use gentamicin monotherapy for enterococcal endocarditis, as synergy with a cell wall-active agent is required. 3
• Do not attempt medical management alone for fungal endocarditis—surgery is mandatory. 3
• Do not discharge patients on OPAT during the first 2 weeks unless they have uncomplicated oral streptococcal native valve infection. 1, 3
• Do not delay surgical consultation when indications are present, as heart failure is the most important predictor of in-hospital mortality. 1