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Infective Endocarditis: A Comprehensive Overview

Definition and Epidemiology

Infective endocarditis (IE) is a life-threatening infection of the endocardial surface of the heart, most commonly affecting cardiac valves, with mortality rates ranging from 20-31% despite modern antibiotics and diagnostic advances. 1, 2

• IE represents the fourth most common life-threatening infection syndrome after sepsis, pneumonia, and intra-abdominal abscess 1
• In 2010, IE was associated with 1.58 million disability-adjusted life years globally 1
• Hospital mortality remains approximately 31%, with critically ill patients experiencing mortality rates of 29-84% 3, 2

Microbiology and Causative Organisms

Most Common Pathogens

Staphylococcus aureus is now the most common cause of IE in many series, replacing viridans group streptococci as the predominant pathogen. 4, 2

Native Valve Endocarditis:

• Viridans group streptococci: Most common after the first year of life in patients with underlying congenital heart disease 4
• Staphylococcus aureus: Most common cause of acute bacterial endocarditis; second most common overall but increasingly predominant 4
• Enterococci: Less common in children than adults 4
• Coagulase-negative staphylococci: Well-documented on native valves, typically in patients with underlying valvular abnormalities like mitral valve prolapse 4

Prosthetic Valve Endocarditis:

• Early (<1 year): Coagulase-negative staphylococci and S. aureus predominate 4
• Late (>1 year): Similar to native valve distribution 4

Special Populations:

Injection Drug Users (IDUs):

• S. aureus causes 60.8% of cases 4
• Streptococci: 16.2% 4
• Pseudomonas aeruginosa: 13.5% 4
• Tricuspid valve involvement occurs in 73% of IDU cases, with right-sided disease dominating the clinical picture 4
• Left-sided involvement increasingly recognized and caused equally by viridans streptococci and S. aureus 4

Neonates and Infants:

• S. aureus, coagulase-negative staphylococci, and Candida species most common 4
• Group B Streptococcus, enteric Gram-negative rods, and S. pneumoniae less frequent 4

Unusual and Fastidious Organisms

Gram-Negative Bacilli:

• Escherichia coli, Proteus mirabilis, Klebsiella, and Serratia marcescens rarely cause endocarditis 4
• Pseudomonas aeruginosa: Over 200 cases reported, 95% in IDUs abusing tripelennamine and pentazocine ("T's and blues") 4
• Mortality highest in patients >30 years (73% vs 33% in younger patients) and with left-sided involvement 4

HACEK Group:

• Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species 4
• Less frequently implicated but important fastidious organisms 4

Fungal Endocarditis:

• Candida and Aspergillus species account for the majority of fungal endocardial infections 4
• Candida more common than Aspergillus; blood cultures usually positive with Candida, rarely with Aspergillus 4
• Mortality rates unacceptably high: survival rate for mold-related endocarditis only 20% 4
• Associated with prosthetic cardiac valves, central venous catheters, and cardiovascular devices 4

Culture-Negative Endocarditis:

• Occurs in 5-36% of cases 4
• Most common causes: Prior antibiotic administration (reduces recovery by 35-40%), fastidious organisms (Bartonella, Coxiella burnetii, Brucella), and inadequate microbiological techniques 4
• Bartonella species may be the most common fastidious organism, reported in 3% of cases in multiple countries 4
• Bartonella quintana most common species, followed by B. henselae 4

Clinical Presentation

Cardinal Features

Fever (90%) and cardiac murmurs (81%) are the most common presenting symptoms, though only 35% of IDUs demonstrate heart murmurs on admission. 4, 2

Classic Manifestations:

• Fever: Present in 90% of cases 2
• Cardiac murmurs: Present in 81% of cases 2
• Heart failure: Occurs in 47.6% as a major complication 2

Embolic Phenomena:

• Strokes and cerebral abscess: 23.8% 2
• Vascular emboli: 14.3% 2
• Septic pulmonary emboli: Common in right-sided disease, with roentgenographic evidence in 87% of tricuspid valve infections 4

Immunologic Phenomena:

• Glomerulonephritis 4
• Osler nodes 4
• Roth spots 4
• Rheumatoid factor positivity 4

Vascular Phenomena:

• Major arterial emboli 4
• Mycotic aneurysms 4
• Intracranial hemorrhage 4
• Conjunctival hemorrhages 4
• Janeway lesions 4

Special Clinical Scenarios

Right-Sided (Tricuspid) Endocarditis:

• 30% have pleuritic chest pain 4
• Pulmonary findings dominate: chest X-ray abnormalities in 75-85% 4
• Signs of tricuspid insufficiency present in only one-third of cases 4
• Most patients 20-40 years old, male predominance 4-6:1 4

Pseudomonas Endocarditis:

• Major embolic phenomena common 4
• Neurological complications in 53% 4
• Ring and annular abscesses 4
• Rapidly progressive congestive heart failure 4
• Ecthyma gangrenosum occasionally noted 4

Diagnosis

Modified Duke Criteria

The modified Duke criteria serve as the primary diagnostic schema, requiring clinical, microbiological, radiological, and echocardiographic evaluation. 4

Definite IE Requires:

Pathological Criteria:

• Microorganisms demonstrated by culture or histology in vegetation, embolized vegetation, or intracardiac abscess 4
• OR pathological lesions with active endocarditis on histology 4

Clinical Criteria:

• 2 major criteria 4
• OR 1 major + 3 minor criteria 4
• OR 5 minor criteria 4

Major Criteria:

Blood Culture Positive:

• Typical microorganisms from 2 separate blood cultures: viridans streptococci, Streptococcus gallolyticus (bovis), HACEK group, Staphylococcus aureus, or community-acquired enterococci without primary focus 4
• Persistently positive blood cultures: ≥2 positive cultures drawn >12 hours apart, or all 3, or majority of ≥4 cultures (first and last ≥1 hour apart) 4
• Single positive blood culture for Coxiella burnetii or anti-phase 1 IgG antibody titer ≥1:800 4

Evidence of Endocardial Involvement:

• Echocardiogram positive: Oscillating intracardiac mass on valve or supporting structures, abscess, new partial dehiscence of prosthetic valve, or new valvular regurgitation 4
• TEE recommended for prosthetic valves, possible IE by clinical criteria, or complicated IE (paravalvular abscess) 4
• TTE as first test in other patients 4

Minor Criteria:

• Predisposing heart condition or injection drug use 4
• Fever >38°C 4
• Vascular phenomena 4
• Immunological phenomena 4
• Microbiological evidence not meeting major criteria 4

Diagnostic Imaging

Echocardiography is crucial in diagnosis, with vegetations found in 95.2% of cases. 2

• Transthoracic echocardiography (TTE): First-line test for most patients 4
• Transesophageal echocardiography (TEE): Recommended for prosthetic valves, possible IE, or complicated IE 4
• Chamber enlargement found in 73.8% 2
• Mitral regurgitation in 83.3% 2

Blood Cultures

Continuous bacteremia with high frequency of positive blood cultures is typical: 95% of 789 blood cultures yielded causative organisms in one study. 4

• Prior antibiotic administration reduces recovery by 35-40% 4
• Blood cultures negative in up to 20% of cases 4
• At least 50 colony-forming units per milliliter typically detected 4

Antimicrobial Therapy

General Principles

Prolonged bactericidal antibiotic therapy for 2-6 weeks (native valve) or at least 6 weeks (prosthetic valve) is required due to bacterial tolerance, biofilm formation, and limited host defenses. 5

Duration by Pathogen:

• Streptococcal endocarditis: 2-4 weeks depending on regimen 5
• Staphylococcal endocarditis: 4-6 weeks 5
• Enterococcal endocarditis: 4-6 weeks 5
• Prosthetic valve endocarditis: At least 6 weeks 5

Specific Regimens

Gram-Negative Bacilli:

• E. coli or Proteus mirabilis: Ampicillin 2g IV every 4 hours OR penicillin 20 million units IV daily OR broad-spectrum cephalosporin PLUS gentamicin 1.7 mg/kg every 8 hours 4
• Klebsiella: Third-generation cephalosporin PLUS aminoglycoside (gentamicin or amikacin) 4
• Cardiac surgery combined with prolonged antibiotic therapy is a cornerstone of treatment (Class IIa, Level B) for most Gram-negative bacilli endocarditis, particularly left-sided involvement 4

Pseudomonas aeruginosa:

• Right-sided disease: High-dose antipseudomonal penicillins combined with aminoglycosides successful in 50-75% of cases 4
• Left-sided disease: Early surgery recommended due to gloomy outlook and frequent complications 4
• Refractory right-sided disease: Partial tricuspid valvulectomy or "vegetectomy" without valve replacement 4

Staphylococcus aureus (Right-Sided, Uncomplicated in IDUs):

• β-lactam short-course (2 weeks) therapy effective, with or without aminoglycoside 4
• Cloxacillin monotherapy for 2 weeks equivalent to cloxacillin plus gentamicin 4
• Glycopeptide-based regimens (teicoplanin or vancomycin) less effective and often require more prolonged treatment 4
• Uncomplicated defined as: no renal failure, no extrapulmonary metastatic infections, no aortic/mitral involvement, no meningitis, no ORSA 4

Culture-Negative Endocarditis:

Native Valve:

• Ampicillin-sulbactam 12g/24h IV in 4 divided doses PLUS gentamicin 3 mg/kg/24h IV/IM in 3 divided doses for 4-6 weeks (Class IIb, Level C) 4
• Alternative: Vancomycin 30 mg/kg/24h IV in 2 divided doses PLUS gentamicin (only for penicillin-intolerant patients) 4
• Consultation with infectious diseases specialist recommended 4

Prosthetic Valve (Early <1 year):

• Vancomycin 30 mg/kg/24h IV in 2 divided doses for 6 weeks PLUS gentamicin 3 mg/kg/24h for 2 weeks PLUS cefepime 6g/24h IV in 3 divided doses for 6 weeks PLUS rifampin 900 mg/24h for 6 weeks (Class IIb, Level C) 4

Suspected Bartonella:

• Ceftriaxone 2g/24h IV/IM in 1 dose for 6 weeks PLUS gentamicin (Class IIa, Level B) 4
• At least 2 weeks of aminoglycoside therapy required 4

Risks of Prolonged/Indefinite Therapy

There is no evidence supporting indefinite antibiotic use after completing appropriate treatment courses. 5

• Development of antibiotic resistance 5
• Adverse drug effects including nephrotoxicity 5
• Disruption of normal microbiota 5

Surgical Management

Indications for Surgery

Patients with IE and congestive heart failure should be immediately evaluated for possible surgical therapy (Class I, Level B), regardless of mechanism. 4

Specific Scenarios Requiring Surgery:

Gram-Negative Bacilli:

• Cardiac surgery combined with prolonged antibiotics is cornerstone of treatment for most patients, particularly left-sided involvement (Class IIa, Level B) 4

Pseudomonas aeruginosa:

• Early surgery recommended for left-sided disease due to high mortality and frequent complications 4
• Right-sided disease refractory to antibiotics: partial tricuspid valvulectomy 4

Fungal Endocarditis:

• Aggressive combined medical and surgical intervention required despite unacceptably high mortality rates 4

General Indications:

• Congestive heart failure 4
• Aggressive or persistent infections 6
• Embolic phenomena 6
• Valvular compromise or rupture 6
• Perivalvular extension (abscess) 4

Surgical Considerations

Decisions regarding surgical intervention should be individualized with input from both cardiologist and cardiovascular surgeon. 4

• Coumadin should be discontinued and replaced by heparin immediately after IE diagnosis in patients on long-term anticoagulation 4
• Higher operative mortality in patients with CHF, but surgery still beneficial 4
• SOFA scores >15 on day of surgery indicate extremely poor outcomes 3

Complications and Outcomes

Major Complications

Heart failure with severe acute regurgitation or obstruction is the most common fatal complication. 3, 2

• Heart failure: 47.6% 2
• Strokes and cerebral abscess: 23.8% 2
• Vascular emboli: 14.3% 2
• Intracranial hemorrhage from ruptured mycotic aneurysms 3

Mortality

Hospital mortality remains 31% overall, with variation by organism and clinical scenario. 2

• Serratia marcescens: 70% mortality 4
• Pseudomonas aeruginosa: 73% in patients >30 years vs 33% in younger patients 4
• Fungal (mold) endocarditis: 80% mortality (20% survival) 4
• Critically ill patients: 29-84% mortality depending on emergency/salvage surgery status 3

Mechanisms of Sudden Death

When IE causes sudden death, the mechanism is often acute valvular disruption, coronary emboli, or tamponade from rupture. 3

Post-Treatment Management

Follow-Up Requirements

Close follow-up is necessary to detect signs of recurrent infection after completing antibiotic therapy. 5

• Echocardiographic evaluation to assess valve function 5
• Maintenance of optimal oral health and hygiene essential to prevent recurrence 5
• Education about importance of daily dental hygiene and regular dental visits 6
• Antibiotic prophylaxis before certain procedures 6

Prevention of Recurrence

Surgical intervention (valve replacement or repair) can reduce risk of persistent or recurrent infection. 5

Special Populations

Injection Drug Users

IDUs have distinct epidemiology with 73% tricuspid valve involvement and S. aureus causing 60.8% of cases. 4

• Two-thirds have no clinical evidence of underlying heart disease 4
• Only 35% demonstrate heart murmurs on admission 4
• 80% are 20-40 years old, male predominance 4-6:1 4
• Almost two-thirds have extravalvular sites of infection 4
• Oxacillin-resistant S. aureus (ORSA) emergence is disturbing: 24% of IDUs with bacteremia developed ORSA 4
• Predictors of ORSA: previous hospitalizations, long-term addiction (particularly men), use of nonprescribed antibiotics 4

Pediatric Patients

After the first year of life, viridans group streptococci are most frequently isolated in children with underlying congenital heart disease. 4

• S. aureus now most common cause in some pediatric series 4
• Nutritionally variant streptococci (Abiotrophia and Granulicatella species) require special media supplemented with L-cysteine or pyridoxal phosphate 4
• Pediatric IDUs at risk for S. aureus endocarditis 4

Prosthetic Valve Endocarditis

Prosthetic valve endocarditis comprises 12% of cases and has distinct implications warranting specific documentation given association with biofilm formation and treatment challenges. 3

• Early (<60 days): S. aureus or coagulase-negative staphylococci most common 4
• Late (>60 days or ≥1 year): VGS, Abiotrophia/Granulicatella, or enterococci most common 4
• Coagulase-negative staphylococci may present ≥1 year after surgery 4

Common Pitfalls and Caveats

Diagnostic Challenges

Prior antibiotic administration is a critical cause of culture-negative endocarditis, reducing bacterial recovery by 35-40%. 4

• Blood cultures may remain negative for weeks after prolonged high-dose bactericidal therapy 4
• Laboratory must use special media for nutritionally variant streptococci 4
• Aspergillus rarely causes positive blood cultures, making it a cause of culture-negative endocarditis 4

Treatment Pitfalls

Glycopeptide-based short-course regimens appear less effective for right-sided S. aureus IE due to limited bactericidal activity, poor vegetation penetration, and increased drug clearance in IDUs. 4

• Tube-dilution MBC determinations often necessary to guide therapy for Gram-negative bacilli (Class IIb, Level C) 4
• Specific aminoglycoside selection critical and cannot be predicted from MIC data alone 4

Organism-Specific Warnings

Staphylococcus lugdunensis causes substantially more virulent IE with high rates of perivalvular extension and metastatic infection, requiring careful monitoring. 4

• Many laboratories cannot differentiate S. lugdunensis from other coagulase-negative staphylococci 4
• Pneumococcal endocarditis with meningitis: high-dose cefotaxime required; if resistant (MIC ≥2 μg/mL), add vancomycin and rifampin 4

Noninfectious Mimics

Antiphospholipid syndrome can produce sterile valvular vegetations that embolize, clinically mimicking culture-negative endocarditis. 4

• Associated with autoimmune disorders (especially SLE) and malignancies 4
• Mitral valve most often affected 4
• Other mimics: atrial myxoma, marantic endocarditis, rheumatic carditis, postvalvular surgery changes 4