Endokarditis Infektif

01Pathophysiology

Infective endocarditis begins with damage to the endothelial surface of a heart valve. In healthy individuals, the endocardium is resistant to bacterial colonization. However, when the endothelium is disrupted by turbulent blood flow (from structural valve disease, congenital defects, or prosthetic valves), a sterile platelet-fibrin thrombus forms on the damaged surface. This is called nonbacterial thrombotic endocarditis (NBTE), and it serves as the nidus for subsequent bacterial seeding.

When transient bacteremia occurs (from dental procedures, IV drug injection, GI/GU procedures, or skin infections), circulating organisms can adhere to the NBTE. Bacteria with surface adhesins, particularly S. aureus with its fibronectin-binding proteins, are especially efficient at colonizing these sites. Once adherent, organisms become embedded within the growing vegetation, which is a mass of platelets, fibrin, inflammatory cells, and bacteria. This vegetation shields bacteria from both host immune defenses and circulating antibiotics, which is precisely why prolonged IV therapy with bactericidal (not bacteriostatic) agents is required.

The clinical manifestations of infective endocarditis are best understood through three pathophysiologic mechanisms:

Direct valvular destruction causes the new or worsening regurgitant murmur. Bacterial enzymes erode leaflet tissue, leading to perforation, chordal rupture, or perivalvular abscess formation. This is the primary mechanism of heart failure in endocarditis, and it is the most common cause of death.

Septic embolization of vegetation fragments explains the peripheral and organ-level manifestations. Right-sided vegetations (tricuspid valve, classically in IV drug users) embolize to the lungs, producing septic pulmonary emboli presenting as multiple bilateral nodular infiltrates, sometimes with cavitation. Left-sided vegetations embolize systemically to the brain (stroke, mycotic aneurysm), spleen (splenic abscess/infarct), kidneys (renal infarction), and skin/extremities (Janeway lesions). Janeway lesions are painless because they result from septic microemboli causing local tissue infarction without significant immune activation.

Immune complex deposition explains several other findings. Prolonged bacteremia triggers a sustained immune response with circulating immune complexes. These deposit in the glomeruli, causing a type III hypersensitivity glomerulonephritis (presenting as hematuria with RBC casts and proteinuria). They also deposit in the skin (Osler nodes, which are painful due to immune-mediated vasculitis) and in the retina (Roth spots). The distinction is testable: Janeway lesions are septic emboli (painless), while Osler nodes are immune-complex mediated (painful). A useful mnemonic is that Osler nodes are "Ouch" (painful).

02Classification and Clinical Manifestation

Classification by Clinical Tempo

Classification by Valve Type

Classification by Valve Location

Peripheral Manifestations Table

03Diagnostic Workup

The cornerstone of diagnosing infective endocarditis is the Modified Duke Criteria, which integrates clinical, microbiologic, and echocardiographic findings. A definite diagnosis requires 2 major criteria, or 1 major + 3 minor, or 5 minor criteria.

Major Criteria:

1. Positive blood cultures with a typical organism from 2 separate cultures, or persistently positive cultures drawn more than 12 hours apart, or all of 3 or a majority of 4+ separate cultures positive (with first and last drawn at least 1 hour apart).

2. Endocardial involvement demonstrated by echocardiography showing vegetation, abscess, new partial dehiscence of a prosthetic valve, or new valvular regurgitation.

Minor Criteria: predisposing heart condition or IV drug use, fever $\ge 38.0\mathrm{°}C\backslash geq\; 38.0°C$, vascular phenomena (Janeway lesions, arterial emboli, septic pulmonary infarcts, mycotic aneurysm, conjunctival hemorrhage, intracranial hemorrhage), immunologic phenomena (Osler nodes, Roth spots, glomerulonephritis, positive rheumatoid factor), and microbiologic evidence not meeting major criteria.

Blood cultures must be drawn before starting antibiotics. The standard is 3 sets from 3 different venipuncture sites over a period of at least 1 hour. Endocarditis causes a continuous (not intermittent) bacteremia, so timing of draws relative to fevers is not critical. The organism identity directs treatment and raises diagnostic associations.

TTE is ordered first because it is non-invasive and adequately sensitive (~60 to 75%) for detecting large vegetations on native valves. However, if TTE is negative and clinical suspicion remains high, or if the patient has a prosthetic valve, or if complications (abscess, perforation) are suspected, then TEE must be performed. TEE has sensitivity greater than 90% and is far superior for posterior structures (mitral valve), prosthetic valves, and perivalvular abscess detection. In practice, patients with prosthetic valves, prior endocarditis, or high clinical suspicion should go directly to TEE.

About 5 to 10% of endocarditis cases are culture-negative, most often due to prior antibiotic use, or infection with fastidious organisms such as HACEK group, Coxiella burnetii (Q fever), Bartonella, Brucella, or fungi (Candida, Aspergillus). When cultures are negative, serologic testing (for Coxiella and Bartonella), fungal cultures, and PCR of excised valve tissue should be pursued.

04Management and Treatment

Acute Stabilization: The first priority when infective endocarditis is suspected is to draw 3 sets of blood cultures from different sites and then initiate empiric IV antibiotic therapy. Do not delay treatment to wait for culture results if the patient is clinically unstable. Empiric coverage should include vancomycin (for MRSA and Enterococcus coverage) plus an antistaphylococcal beta-lactam or gentamicin depending on the clinical scenario. Once cultures return with organism identification and susceptibility data, the regimen is narrowed.

Antibiotic Principles: Treatment requires prolonged IV bactericidal therapy because bacteria within vegetations are metabolically less active and protected by the fibrin-platelet matrix. Bacteriostatic agents are insufficient. The standard duration is 4 to 6 weeks, and the clock starts from the first day of negative blood cultures, not from the day therapy was initiated.

For penicillin-susceptible streptococci, penicillin G or ceftriaxone monotherapy for 4 weeks is curative. A shortened 2-week course of penicillin or ceftriaxone combined with gentamicin is an option for uncomplicated native valve disease in patients with normal renal function, though aminoglycoside nephrotoxicity must be monitored.

For MSSA native valve endocarditis, nafcillin or oxacillin for 6 weeks is the treatment of choice. Vancomycin is inferior to nafcillin for MSSA and should only be used if the patient has a true beta-lactam allergy or MRSA is confirmed. This is a commonly tested concept: vancomycin is not the first choice for MSSA endocarditis.

For prosthetic valve endocarditis caused by staphylococci, triple therapy is required: vancomycin (or nafcillin if MSSA) plus rifampin plus gentamicin. Rifampin is added because it penetrates the biofilm on prosthetic material, and gentamicin provides synergistic killing. Gentamicin is given only for the initial 2 weeks to limit nephrotoxicity and ototoxicity.

For Enterococcal endocarditis, synergistic combination therapy is mandatory because enterococci are inherently tolerant to killing by penicillins alone. The classic regimen is ampicillin plus gentamicin. In patients with high-level gentamicin resistance or renal insufficiency, ampicillin plus ceftriaxone (dual beta-lactam therapy) is an acceptable alternative.

Surgical Indications: Surgery (valve replacement or repair) is necessary in the following situations and is commonly tested:

1. Heart failure due to severe valvular regurgitation (most common and most important indication).

2. Perivalvular abscess or fistula (especially aortic root abscess causing conduction abnormalities on ECG, such as a new PR prolongation).

3. Persistent bacteremia or sepsis despite 5 to 7 days of appropriate antibiotics.

4. Recurrent systemic emboli despite adequate therapy.

5. Prosthetic valve endocarditis caused by S. aureus or fungal organisms (nearly always requires surgery).

6. Fungal endocarditis (medical therapy alone is almost never curative).

7. Large vegetations greater than 10 mm, especially if associated with embolic events or on the anterior mitral leaflet.

Post-treatment monitoring: Repeat blood cultures every 24 to 48 hours until negative to document clearance. Persistent positive cultures beyond 5 to 7 days should trigger reassessment of antibiotic adequacy and consideration of surgery. After completing therapy, follow-up echocardiography should be performed to establish a new baseline.

Important associations to remember:

• S. gallolyticus (bovis) endocarditis: always order a colonoscopy to evaluate for colorectal carcinoma.

• Culture-negative endocarditis with large vegetations in a patient who has not received prior antibiotics: think HACEK organisms (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella).

• Endocarditis in a patient with exposure to cats: consider Bartonella henselae.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most common mistake students make on endocarditis questions is anchoring on the wrong valve based on the patient population. When a vignette describes an IV drug user with fever and a new murmur, many students correctly identify endocarditis but then select left-sided valve management. In IV drug users, the tricuspid valve is most commonly affected, and the embolic pattern is pulmonary, not systemic. If the vignette describes an IV drug user with bilateral cavitary lung nodules on chest X-ray, the answer is right-sided endocarditis with septic pulmonary emboli, not pneumonia.

Another frequently tested trap is the choice of antibiotic for MSSA endocarditis. Students reflexively select vancomycin because it covers S. aureus, but vancomycin is inferior to nafcillin/oxacillin for methicillin-susceptible organisms. The vignette will provide the susceptibility data, and the tested concept is that you should de-escalate to nafcillin when MSSA is confirmed.

The association between S. gallolyticus (bovis) and colorectal cancer is tested repeatedly. When a vignette gives you endocarditis caused by this organism, the next best step is to order a colonoscopy, even if the patient has no GI symptoms.

Students also miss questions about surgical indications. The highest-yield scenario is a patient on appropriate antibiotics who develops worsening heart failure from acute aortic or mitral regurgitation. Medical management alone is insufficient; the next step is surgical consultation for valve replacement. Another surgical trigger is the finding of a new conduction delay (prolonged PR interval or new bundle branch block) on ECG in a patient with aortic valve endocarditis, which signals a perivalvular (aortic root) abscess.

Finally, be aware that culture-negative endocarditis is not the same as "no endocarditis." If clinical suspicion is high (Duke criteria met by echo findings and minor criteria), prior antibiotic use is the most common explanation for negative cultures. The management is to hold antibiotics (if clinically safe), repeat cultures, and consider serologic testing for fastidious organisms.

The core competency being tested across all endocarditis questions is your ability to integrate a clinical presentation (fever, murmur, embolic phenomena), identify the valve and organism, initiate the correct diagnostic sequence (cultures before antibiotics, TTE then TEE), and select the right treatment while recognizing indications for surgical intervention.