In a patient with suspected infective endocarditis (including possible native or prosthetic valve involvement and hemodynamic instability or other high‑risk features), what are the recommended steps for obtaining blood cultures, initiating empiric intravenous antibiotics, performing echocardiography, determining indications for early surgery, and selecting the appropriate duration of antimicrobial therapy?

Management of Suspected Infective Endocarditis

Blood Culture Protocol

Obtain at least 3 blood culture sets from separate venipuncture sites before initiating any antibiotics, with the first and last drawn at least 1 hour apart. 1, 2

• Each set should contain one aerobic and one anaerobic bottle with approximately 10 mL of blood per bottle in adults 2
• Draw from separate peripheral sites to distinguish true bacteremia from contamination 3
• Never administer antibiotics before obtaining blood cultures in patients with known valve disease or prosthetic valves (Class III recommendation) 1
• Prior antibiotic exposure is the leading cause of culture-negative endocarditis and reduces bacterial recovery by 35-40% 1, 2
• If the patient has received antibiotics, wait 3 days after stopping them before repeating cultures when feasible 2

Empiric Antibiotic Therapy

For community-acquired native valve endocarditis, initiate ampicillin 12 g/day IV (divided into 4-6 doses) + (flu)cloxacillin or oxacillin 12 g/day IV (divided into 4-6 doses) + gentamicin 3 mg/kg/day IV as a single daily dose. 2

Native Valve Endocarditis

• Penicillin-allergic patients: Vancomycin 30-60 mg/kg/day IV (divided into 2-3 doses) + gentamicin 3 mg/kg/day IV (single dose) 2
• This regimen covers staphylococci, streptococci, and enterococci—the organisms responsible for 75% of endocarditis cases 4

Prosthetic Valve Endocarditis

• Early prosthetic valve or healthcare-associated infection (<12 months): Vancomycin 30 mg/kg/day IV (divided into 2 doses) + gentamicin 3 mg/kg/day IV + rifampin 900-1200 mg/day IV or orally (divided into 2-3 doses), with rifampin started 3-5 days after vancomycin and gentamicin 2
• Late prosthetic valve infection (≥12 months): Use the same regimen as native valve endocarditis 2
• Healthcare-associated endocarditis with MRSA prevalence >5%: Initiate cloxacillin + vancomycin until S. aureus is identified and susceptibilities are known 2

Culture-Negative Endocarditis

• Obtain infectious disease specialist consultation for every culture-negative case 2
• If no clinical response within 48-72 hours, broaden coverage with doxycycline 200 mg/day or a fluoroquinolone to target Coxiella burnetii, Bartonella spp., and other fastidious organisms 2
• Perform serologic testing for Coxiella burnetii (IgG phase 1 >1:800), Bartonella, Brucella, and Legionella 2
• One treatment option for culture-negative native valve endocarditis with prior antibiotic exposure: ampicillin-sulbactam 3 g IV every 6 hours combined with gentamicin 1 mg/kg IV or IM every 8 hours 1

Echocardiography Strategy

Perform immediate transthoracic echocardiography (TTE) in all patients with suspected infective endocarditis. 2

• TTE detects vegetations in approximately 60-75% of patients 1
• Proceed directly to transesophageal echocardiography (TEE) if:
  • Clinical suspicion remains high despite negative TTE 2
  • Prosthetic valve present 2
  • Prior endocarditis 2
  • New atrioventricular block 2
  • Poor TTE windows 2
• TEE is markedly more sensitive than TTE for detecting vegetations <10 mm, abscesses, and prosthetic valve involvement, with sensitivity >95% 1, 2
• If the initial study is negative but suspicion persists, repeat TTE/TEE 7-10 days later (earlier if Staphylococcus aureus is suspected) 2
• TTE and TEE provide complementary information: TEE excels at detecting vegetations and abscesses, while TTE better assesses pericardial effusion, ventricular function, and pulmonary pressures 2

Indications for Early Surgery

Urgent surgery is indicated for heart failure due to severe valve regurgitation or obstruction. 2

• Locally uncontrolled infection with abscess formation requires surgical intervention 2
• Fungal endocarditis mandates combined antifungal therapy plus surgical valve replacement; mortality exceeds 50% despite aggressive treatment 2
• Persistent positive blood cultures >24 hours despite appropriate antimicrobial therapy 2
• Large vegetations >10 mm with high embolic risk 2
• Prosthetic valve involvement with complications 2
• After cerebral embolism: Surgery should be performed within 72 hours if indicated and after CT excludes intracerebral hemorrhage; otherwise defer 3-4 weeks 2
• Early surgical management, even in high-risk patients, has a mortality benefit because eradication of infection with antibiotics alone is difficult and valve destruction often results in hemodynamic compromise 5

Duration of Antimicrobial Therapy

Standard antimicrobial course is 4-6 weeks for most infective endocarditis cases. 2, 6

Pathogen-Specific Durations

• HACEK organisms: Ceftriaxone 2 g/day IV for 4 weeks (native valve) or 6 weeks (prosthetic valve) 1, 2
• Non-HACEK Gram-negative bacteria: β-lactam + aminoglycoside for ≥6 weeks 2
• Coxiella burnetii (Q fever): Doxycycline 200 mg/24 h + hydroxychloroquine 200-600 mg/24 h orally for >18 months 2
• Bartonella spp.: Doxycycline 100 mg q12h orally for 4 weeks + gentamicin 3 mg/kg/day IV for 2 weeks 2
• Brucella spp.: Doxycycline 200 mg/24 h + cotrimoxazole 960 mg q12h + rifampin 300-600 mg/24 h orally for ≥3-6 months 2
• Uncomplicated penicillin-sensitive viridans streptococcal endocarditis: May be treated with combined penicillin and streptomycin for 2 weeks 4, 6
• Enterococcal endocarditis: 4-6 weeks with aqueous penicillin G plus either streptomycin or gentamicin 4

Therapeutic Drug Monitoring

Perform weekly serum level measurements and renal function testing for gentamicin and vancomycin. 2

• Target gentamicin trough <1 mg/L 2
• Target vancomycin trough 10-15 mg/L (or 15-20 mg/L for complicated infections) 2
• Adjust dosing based on renal function and measured drug levels 2
• Serial audiograms should be performed during aminoglycoside therapy to detect ototoxicity 1
• Audiological and vestibular toxicity can develop despite maintenance of appropriate serum concentrations 1

Monitoring During Treatment

• Repeat blood cultures until sterility is achieved; causative organisms are usually identified within 48 hours 2
• If fever persists or clinical status worsens despite appropriate therapy, repeat cultures and evaluate for alternative diagnoses or complications 2
• Obtain a follow-up TTE at the end of therapy to establish a new baseline for subsequent comparison (Class IIb recommendation) 1, 2

Special Populations

Injection Drug Users

• Staphylococcus aureus accounts for 60-70% of cases; >70% involve the tricuspid valve 2
• Empiric therapy must cover S. aureus with a penicillinase-resistant penicillin or vancomycin, guided by local MRSA prevalence 2
• For pentazocine users, add antipseudomonal coverage 2
• For brown-heroin users (dissolved in lemon juice), consider Candida infection and add antifungal therapy 2
• Outpatient therapy for injection drug users may be problematic because of compliance difficulties and misuse of intravenous access 1

Cardiac Device-Related Infective Endocarditis

• Obtain ≥3 blood culture sets before starting antibiotics 2
• Perform both TTE and TEE; TEE is superior for detecting lead-related vegetations 2
• Definitive treatment requires 4-6 weeks of targeted antibiotics plus complete hardware removal (device and all leads) 2
• Percutaneous extraction is recommended even when vegetations exceed 10 mm 2
• Surgical extraction should be considered if percutaneous removal fails or in cases of severe destructive tricuspid involvement 2

Immunocompromised Patients

• Immediate empiric broad-spectrum therapy covering typical bacteria and expanded fungal coverage is mandatory 2
• Management requires a multidisciplinary team (infectious disease, cardiology, cardiac surgery, microbiology) 2
• Fever may be absent; maintain a high index of suspicion even without classic signs 2

Common Pitfalls

• Administering antibiotics before blood cultures: This is the most common preventable cause of culture-negative endocarditis and reduces diagnostic yield by 35-40% 1, 2
• Inadequate blood culture volume: Each bottle requires approximately 10 mL of blood in adults to maximize yield 2
• Relying solely on TTE in high-risk patients: TEE should be performed directly in patients with prosthetic valves, prior endocarditis, or poor TTE windows 2
• Delaying infectious disease consultation in culture-negative cases: Specialist input is essential for selecting appropriate empiric therapy and pursuing advanced diagnostics 2
• Failing to monitor aminoglycoside levels: Weekly monitoring is mandatory to prevent nephrotoxicity and ototoxicity 2