Infective Endocarditis

Quick Answer

Infective endocarditis (IE) is infection of the endocardial surface, most commonly affecting heart valves. Diagnosis requires Modified Duke criteria: 2 major, 1 major + 3 minor, or 5 minor criteria. Blood cultures (3 sets, 30 min apart) and echocardiography (TTE first, TEE if high suspicion or initial TTE negative) are mandatory. Common pathogens: Staph aureus (30%), Streptococci (25%), Enterococci, HACEK. Management: 4-6 weeks IV antibiotics (guided by sensitivity), surgery indicated for heart failure, uncontrolled infection, or embolic phenomena. ICU mortality 15-30%, up to 50% in PVE. Complications: HF (60-80%), emboli (30-50%), abscess formation.

CICM Exam Focus

Second Part SAQ Topics (15 marks):

• Diagnosis of IE using Modified Duke criteria
• Indications and timing for surgery in IE
• Management of IE with embolic complications
• Prosthetic valve endocarditis management

Viva Topics (20 marks):

• IE clinical presentation and diagnostic approach
• Echocardiography in IE: TTE vs TEE indications
• Antibiotic selection and duration in IE
• Surgical indications and timing in IE
• Embolic complications and management
• Prosthetic valve vs native valve endocarditis

Key Knowledge Points:

• Modified Duke criteria (definite, possible, rejected)
• Blood culture collection technique and interpretation
• Predisposing factors and at-risk populations
• Pathogen-specific antibiotic regimens
• Surgical indications and operative findings
• Complication recognition and management
• Prophylaxis guidelines and target population

Key Points

• Modified Duke Criteria: 2 major OR 1 major + 3 minor OR 5 minor = definite IE
• Blood Cultures: 3 sets, 30 min apart, from separate venipunctures BEFORE antibiotics
• Echocardiography: TTE first-line (sensitivity 40-63%), TEE required for PVE, high suspicion, or negative TTE (sensitivity 90-100%)
• Common Pathogens: Staph aureus (30% - aggressive, high mortality), Viridans Streptococci (subacute), Enterococci (urinary source), HACEK (Gram-negative, indolent)
• Antibiotic Duration: 4-6 weeks (2 weeks for right-sided IE with Staph susceptible to anti-staphylococcal penicillin)
• Surgery Indications: Heart failure (valve dysfunction, severe regurgitation), uncontrolled infection (abscess, persistent bacteremia), embolic prevention (large vegetations greater than 10mm, previous emboli)
• PVE Mortality: 40-50% vs 15-30% for NVE
• Embolic Risk: Highest with vegetations greater than 10mm, Staph aureus, anterior location (mitral)
• ICU Admission: Required for HF, septic shock, respiratory failure from emboli, post-op monitoring
• Anticoagulation: Stop immediately in IE (increases hemorrhagic stroke risk from septic emboli)

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Clinical Overview

Definition and Pathophysiology

Infective endocarditis is infection of the endothelial lining of the heart, most commonly affecting heart valves. The pathogenesis involves:

1. Endothelial Damage: Turbulent blood flow causes endothelial injury (e.g., on regurgitant valves, prosthetic valves, congenital lesions)
2. Platelet-Fibrin Deposition: Non-bacterial thrombotic endocarditis (NBTE) forms on damaged endothelium
3. Bacterial Colonisation: Bacteremia allows organisms to adhere to NBTE
4. Vegetation Formation: Platelets, fibrin, bacteria, inflammatory cells create infected vegetation
5. Tissue Invasion: Organisms invade valve tissue, causing destruction, abscess, and embolic phenomena

Microbial Adherence Mechanisms:

• Streptococci: Platelet aggregation factor (PAF), fibronectin-binding proteins
• Staphylococcus aureus: Clumping factors (ClfA, ClfB), fibronectin-binding proteins (FnBPA, FnBPB), collagen adhesion (Cna)
• Enterococci: Aggregation substance, surface proteins (Esp)

Epidemiology

Incidence: 3-10 cases per 100,000 person-years, increasing trend due to:

• Aging population with degenerative valve disease
• Increased prosthetic valve implants
• Rising injection drug use
• Improved diagnostic techniques
• More invasive procedures and devices

Age Distribution: Bimodal peaks:

• Younger adults (20-40 years): Injection drug use, congenital heart disease
• Older adults (greater than 65 years): Degenerative valve disease, prosthetic valves, healthcare-associated

Gender: Male predominance (2:1 M:F ratio) due to higher rates of valve disease and risk factors

Mortality:

• Overall in-hospital: 15-30%
• Native valve endocarditis (NVE): 15-25%
• Prosthetic valve endocarditis (PVE): 40-50%
• Staph aureus IE: 20-40% (higher than other pathogens)
• Heart failure requiring surgery: 30-50% mortality
• Neurological complications: 40-50% mortality

Risk Factors and Predisposing Conditions

Predisposing Cardiac Lesions (NVE):

• Rheumatic heart disease (increasingly rare in developed countries)
• Congenital heart disease (VSD, PDA, bicuspid aortic valve, coarctation)
• Degenerative valve disease (calcific aortic stenosis, mitral valve prolapse with regurgitation)
• Previous IE (recurrence risk 5-10%)
• Hypertrophic cardiomyopathy

Prosthetic Valves:

• Mechanical prosthetic valves: Risk 1-2% per patient-year
• Bioprosthetic valves: Risk 0.5-1% per patient-year
• Risk highest first 12 months post-implantation (early PVE)

Non-Cardiac Risk Factors:

• Injection drug use (IDU): 2-5% of IDU per year develop IE; predominantly tricuspid valve (60-70%)
• Indwelling vascular devices: Central venous catheters, pacemakers, ICDs, dialysis access
• Chronic hemodialysis: 10-50x higher incidence due to repeated access and uremia
• Immunosuppression: Diabetes, HIV, chemotherapy, corticosteroids
• Poor dental hygiene: Viridans streptococci bacteremia risk
• Skin infections: Cellulitis, intravenous drug use sites

Staph aureus Colonisation:

• Nasal carriers (20-30% population) have 3-4x higher IE risk
• Diabetic patients have higher Staph aureus carriage and infection risk

Clinical Presentation

Classic Clinical Triad (present in below 50%):

1. Fever (85-90%)
2. New or changing murmur (80-85%)
3. Embolic phenomena (30-50%)

Symptoms:

• Fever: Low-grade to high, often with rigors; may be absent in elderly, chronically ill, or on antibiotics
• Constitutional: Fatigue, malaise, anorexia, weight loss, night sweats (subacute presentation)
• Cardiac: Dyspnoea (heart failure), chest pain (pericarditis, myocardial infarction from emboli), palpitations (new arrhythmias)
• Musculoskeletal: Arthralgias, myalgias, back pain (discitis, vertebral osteomyelitis)

Signs:

• Cardiac: New or changing murmur (regurgitation most common), signs of HF (raised JVP, peripheral edema, crackles), pericardial friction rub, conduction abnormalities (heart block from abscess)
• Vascular/E embolic:
  • "Janeway lesions: Small, non-tender, erythematous macules on palms and soles (septic emboli to skin)"
  • "Osler nodes: Painful, red, raised nodules on finger/toe pads (immune complex vasculitis)"
  • "Roth spots: Retinal haemorrhages with pale centres (immune complex deposition)"
  • "Splinter haemorrhages: Linear haemorrhages under nails (trauma vs immune complex)"
  • "Clubbing: Chronic IE (greater than 6 weeks duration)"
• Systemic: Splenomegaly (30-50%, immune hyperplasia), hepatomegaly, lymphadenopathy

Subacute vs Acute Presentation:

• Subacute (Viridans Streptococci, Enterococci, HACEK): Weeks to months, low-grade fever, constitutional symptoms, less embolic phenomena
• Acute (Staph aureus, Streptococcus pneumoniae): Days to weeks, high fever, rapid deterioration, frequent emboli, high mortality

Prosthetic Valve Endocarditis:

• Similar presentation to NVE but higher fever, more rapid progression
• Paravalvular leak (new murmur) common
• Dehiscence of prosthetic valve (abscess formation)
• Higher embolic rate

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Modified Duke Criteria

Diagnostic Framework

The Modified Duke Criteria provide a standardised approach to IE diagnosis with high sensitivity and specificity.

Definite IE (one of the following):

1. Pathological: Vegetation, embolus, or intracardiac abscess with active endocarditis on histology, OR culture from vegetation or embolus
2. Clinical: 2 major criteria, OR 1 major + 3 minor criteria, OR 5 minor criteria

Possible IE: 1 major + 1-2 minor criteria, OR 3 minor criteria

Rejected IE: Firm alternative diagnosis explaining illness, OR resolution with ≤4 days antibiotics, OR pathological findings at surgery or autopsy inconsistent with IE

Major Criteria

1. Positive Blood Culture for IE

Typical microorganisms from two separate blood cultures:

• Staph aureus, Streptococcus viridans group (including S. mutans, S. sanguis, S. mitis, S. milleri), Streptococcus bovis group (S. gallolyticus), Streptococcus anginosus group, HACEK group (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella), Enterococcus

OR

Persistently positive blood cultures (single organism):

• ≥2 positive cultures drawn greater than 12 hours apart, OR
• All of 3 or a majority of ≥4 separate cultures drawn greater than 1 hour apart (first and last drawn greater than 1 hour apart)

2. Evidence of Endocardial Involvement

Echocardiography positive:

• Oscillating intracardiac mass on valve or supporting structures, in path of regurgitant jets, or on implanted material (abscess excluded), OR
• Partial dehiscence of prosthetic valve, OR
• New valvular regurgitation (worsening or changing pre-existing murmur insufficient alone)

OR

New valvular regurgitation (increase or change in pre-existing murmur not sufficient)

Minor Criteria

Predisposition:

• Predisposing heart condition (congenital, rheumatic, degenerative, prosthetic), OR
• Injection drug use

Fever:

• Temperature greater than 38°C (100.4°F)

Vascular phenomena:

• Major arterial emboli (stroke, splenic infarct, renal infarct, mesenteric ischaemia), septic pulmonary infarcts, mycotic aneurysm, intracranial haemorrhage, conjunctival haemorrhages, Janeway lesions

Immunological phenomena:

• Glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor positivity

Microbiological evidence:

• Positive blood culture not meeting major criteria, OR serological evidence of active infection with organism consistent with IE (e.g., Coxiella burnetii, Bartonella)

Blood Culture Collection Technique

Critical Pre-analytical Considerations:

• Timing: 3 sets of blood cultures drawn 30 minutes apart from separate venipuncture sites
• Volume: 20-30 mL per set (10-15 mL per bottle) - higher volume increases sensitivity
• Antibiotics: BEFORE initiating antibiotics (unless patient in septic shock requiring immediate therapy)
• Duration: Continue for 24-48 hours (may need repeat sets if initially negative)

Clinical Decision Points:

• Initial 2 sets positive: Stop blood cultures (diagnostic)
• All 3 sets negative after 48h: Consider atypical pathogens (Coxiella, Bartonella, fungi), repeat cultures, serology
• Single positive culture: May be contaminant; repeat sets, evaluate clinical context

Culture-Negative Endocarditis: 2-10% of IE cases

• Causes: Prior antibiotics, atypical pathogens (Coxiella burnetii, Bartonella spp., Legionella, Mycoplasma, Tropheryma whipplei), fungi (Candida, Aspergillus), non-infectious causes (marantic endocarditis, Libman-Sacks)
• Evaluation: Serology (Coxiella phase I IgG ≥1:800, Bartonella IgG ≥1:800), PCR on vegetation tissue, extended culture incubation, histopathology

Echocardiography in IE

Transthoracic Echocardiography (TTE):

• First-line: Sensitivity 40-63%, specificity 90-95%
• Advantages: Non-invasive, rapid, no sedation required
• Limitations: Poor visualisation of prosthetic valves (prosthetic shadowing), limited resolution for small vegetations (below 5mm), limited in obese patients or poor windows

Transoesophageal Echocardiography (TEE):

• Indications: High clinical suspicion + negative TTE, prosthetic valves, PVE, pre-op evaluation, persistent bacteremia, unexplained heart failure, suspected complications (abscess, fistula)
• Sensitivity: 90-100%, specificity 90-95%
• Advantages: Better resolution, superior visualisation of prosthetic valves, better detection of small vegetations, abscess, perivalvular extension
• Complications: 0.5-1% (oesophageal perforation, bleeding, arrhythmias, aspiration)

Echocardiographic Findings:

• Vegetations: Oscillating, mobile, echogenic masses on valve leaflets or supporting structures, attached to upstream side of regurgitant flow
  • "Size: Small (below 5mm), medium (5-10mm), large (greater than 10mm)"
  • "Location: Aortic valve (anterior leaflet most common), mitral valve (anterior leaflet), tricuspid valve (IVDU), pulmonic valve (rare)"
• Complications:
  • "Abscess: Periannular echolucent cavity (ring abscess, aortic root abscess)"
  • "Fistula: Communication between cardiac chambers (e.g., aorta to RA)"
  • "Pseudoaneurysm: Perivalvular contained rupture"
  • "Valve dehiscence: Rocking motion of prosthetic valve"
  • "Severe regurgitation: Colour Doppler evidence of acute regurgitation"
  • "Pericardial effusion: From rupture or extension"

Serial Echocardiography:

• Baseline TTE and/or TEE at diagnosis
• Repeat at 7-10 days if initial studies negative but high suspicion
• Repeat if clinical deterioration, new embolic phenomena, persistent bacteremia, or pre-operative planning

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Microbiology

Common Pathogens

Staphylococcus aureus (25-35%):

• Epidemiology: Healthcare-associated (intravascular devices, hemodialysis), community-acquired (skin infections, injection drug use)
• Clinical Features: Acute presentation, high fever, rapid progression, high embolic rate (40-60%), high mortality (20-40%)
• Complications: Metastatic infection (spine, spleen, kidney, brain), septic pulmonary emboli (right-sided IE), abscess formation, mycotic aneurysms
• Methicillin Resistance: MRSA 20-40% (higher in healthcare-associated)
• Treatment: Oxacillin 2g IV q4h OR cefazolin 2g IV q8h (MSSA); vancomycin 15-20 mg/kg IV q8-12h (MRSA) ± rifampin 600 mg PO/IV daily (PVE, abscess) ± gentamicin 1 mg/kg q8h (first 3-5 days)

Viridans Streptococci (15-25%):

• Species: S. mutans, S. sanguis, S. mitis, S. salivarius, S. milleri (anginosus group)
• Epidemiology: Subacute presentation, predisposing valve disease, poor dental hygiene
• Clinical Features: Indolent course, constitutional symptoms, low embolic rate
• Penicillin MIC: Determines treatment approach
  • "Susceptible (MIC ≤0.12 mcg/mL): Penicillin G 12-18 MU IV q4h OR ceftriaxone 2g IV daily × 4 weeks (2 weeks if uncomplicated right-sided IE)"
  • "Relatively resistant (MIC 0.12-0.5 mcg/mL): Penicillin G or ceftriaxone + gentamicin 3 mg/kg/day (once daily) × 2 weeks, THEN penicillin G or ceftriaxone × 2 weeks (total 4 weeks)"
  • "Resistant (MIC greater than 0.5 mcg/mL): Vancomycin 15-20 mg/kg IV q8-12h × 4 weeks"

Enterococcus spp. (5-15%):

• Species: E. faecalis (80-90%), E. faecium (10-20%)
• Epidemiology: Older patients, genitourinary or gastrointestinal source, often healthcare-associated
• Clinical Features: Subacute, more common on prosthetic valves, often bacteraemia from urinary source
• Treatment (ampicillin-susceptible):
  • "NVE: Ampicillin 2g IV q4h + gentamicin 3 mg/kg/day (once daily) × 4-6 weeks OR ampicillin + ceftriaxone 2g IV daily × 6 weeks (non-aminoglycoside alternative)"
  • "PVE: Ampicillin + gentamicin + ceftriaxone (combination therapy) × 6 weeks"
• Vancomycin-resistant enterococci (VRE): Linezolid 600 mg IV/PO q12h OR daptomycin 8-10 mg/kg IV daily (NOT for pulmonary IE - inactivated by surfactant)

HACEK Group (2-5%):

• Organisms: Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae
• Epidemiology: Young to middle-aged adults, indolent presentation, often subacute
• Treatment: Ceftriaxone 2g IV daily × 4 weeks OR ampicillin-sulbactam 3g IV q6h × 4 weeks

Culture-Negative Endocarditis (2-10%):

• Coxiella burnetii (Q fever): Doxycycline 100 mg PO bid + hydroxychloroquine 200 mg PO tid × 18-24 months
• Bartonella spp.: B. henselae, B. quintana - Gentamicin 3 mg/kg/day + doxycycline 100 mg PO bid ± rifampin 600 mg PO daily × 4-6 weeks
• Fungi (Candida, Aspergillus): High mortality, surgery mandatory, antifungal therapy (amphotericin B, echinocandins, azoles)
• Whipple's disease (Tropheryma whipplei): Ceftriaxone 2g IV daily × 2 weeks, THEN trimethoprim-sulfamethoxazole 160/800 mg PO bid × 12 months

Antibiotic Selection and Duration

General Principles:

• Bactericidal regimens required
• Combination therapy for synergistic effect (beta-lactam + aminoglycoside for viridans streptococci, enterococci)
• Minimum inhibitory concentration (MIC) monitoring for penicillin resistance, vancomycin trough 15-20 mcg/mL (MRSA)
• Duration typically 4-6 weeks (2 weeks for uncomplicated right-sided IE with MSSA susceptible to anti-staphylococcal penicillin)
• Outpatient parenteral antibiotic therapy (OPAT) possible for stable patients after initial inpatient stabilisation

Staph aureus Native Valve Endocarditis:

• MSSA: Oxacillin 2g IV q4h OR cefazolin 2g IV q8h × 4-6 weeks
• MRSA: Vancomycin 15-20 mg/kg IV q8-12h (trough 15-20 mcg/mL) OR daptomycin 8-10 mg/kg IV daily × 4-6 weeks
• Adjunctive: Rifampin 600 mg PO/IV daily (PVE, abscess, prosthetic material) ± gentamicin 1 mg/kg q8h (first 3-5 days, nephrotoxicity limits use)

Staph aureus Prosthetic Valve Endocarditis:

• MSSA: Oxacillin 2g IV q4h + rifampin 600 mg PO/IV daily + gentamicin 1 mg/kg q8h (first 2 weeks) × 6 weeks
• MRSA: Vancomycin + rifampin 600 mg PO/IV daily + gentamicin 1 mg/kg q8h (first 2 weeks) × 6 weeks
• Surgery: Almost always required for PVE due to high failure rate with antibiotics alone

Right-Sided IE (predominantly IVDU):

• MSSA: Oxacillin 2g IV q4h OR cefazolin 2g IV q8h × 2 weeks (uncomplicated)
• MRSA: Vancomycin 15-20 mg/kg IV q8-12h × 4 weeks (shorter duration not proven for MRSA)
• Alternative: Daptomycin 8-10 mg/kg IV daily (NOT for left-sided IE due to higher mortality)

Empiric Therapy (before culture results):

• Native Valve: Vancomycin 15-20 mg/kg IV q8-12h (target MRSA) + gentamicin 1 mg/kg q8h (synergy for streptococci, enterococci) ± ampicillin 2g IV q4h (enterococcal coverage, exclude penicillin allergy)
• Prosthetic Valve: Vancomycin + rifampin 600 mg PO/IV daily + gentamicin 1 mg/kg q8h (add ceftriaxone 2g IV daily for gram-negative coverage)
• Severe Penicillin Allergy: Vancomycin + ciprofloxacin 400 mg PO q12h (for gram-negative coverage) + gentamicin

Adjunctive Measures:

• Dental evaluation: Before antibiotic completion to identify and treat oral source
• Source control: Remove infected intravascular devices (CVCs, PICCs, dialysis access)
• Infected pacemaker/ICD: Complete system removal (generator + leads) required, prolonged antibiotics 4-6 weeks
• IVDU: Harm reduction strategies, addiction treatment, vascular access planning (avoid infected sites)

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Management

General Principles

ICU Admission Indications:

• Heart failure (pulmonary oedema, cardiogenic shock)
• Septic shock (vasopressor requirement)
• Respiratory failure from septic pulmonary emboli
• Neurological complications (stroke, meningitis, encephalopathy)
• Post-operative monitoring after valve surgery
• Arrhythmias (high-grade AV block from abscess)
• Haemodynamic instability

Anticoagulation:

• STOP immediately in native valve IE (increases risk of haemorrhagic transformation of septic emboli)
• Mechanical prosthetic valves: Short-acting anticoagulant (unfractionated heparin) transitioned to oral anticoagulation after infection controlled, consider bridging if high embolic risk
• Bioprosthetic valves: No routine anticoagulation required

Antibiotic Administration:

• Central venous access for prolonged IV therapy (preferred PICC or tunneled catheter for OPAT)
• Therapeutic drug monitoring (vancomycin trough, gentamicin levels)
• Monitor for adverse effects (nephrotoxicity, ototoxicity, bone marrow suppression)
• Outpatient parenteral antibiotic therapy (OPAT) after initial stabilisation (afebrile greater than 48h, stable haemodynamics, no embolic phenomena, reliable IV access, home support)

Anticoagulation Reversal Before Surgery:

• Warfarin: Vitamin K 5-10 mg IV + PCC to reverse for urgent surgery
• DOACs: Andexanet alfa (Xa inhibitors) or idarucizumab (dabigatran)
• Target INR below 1.5, ACT below 150s for cardiopulmonary bypass

Medical Management

Beta-lactam Selection:

• Penicillin: For penicillin-susceptible streptococci (low MIC), high-dose required (12-18 MU/day continuous infusion OR divided q4h)
• Ceftriaxone: For penicillin-resistant streptococci, enterococci, HACEK, convenient once-daily dosing for OPAT
• Oxacillin/Nafcillin: MSSA first-line (superior to vancomycin in MSSA endocarditis - lower mortality, faster clearance)
• Cefazolin: Alternative to oxacillin for MSSA, more convenient dosing

Glycopeptides:

• Vancomycin: MRSA, penicillin-allergic patients, empiric coverage
  • "Dosing: 15-20 mg/kg IV q8-12h (target trough 15-20 mcg/mL for IE)"
  • "Monitoring: Trough before 4th dose, weekly renal function, ototoxicity (rare)"
  • "Alternative if inadequate response or nephrotoxicity: Daptomycin 8-10 mg/kg IV daily"

Lipoglycopeptides:

• Daptomycin: Alternative to vancomycin, especially with nephrotoxicity concern
  • "Dosing: 8-10 mg/kg IV daily (higher dose required for IE compared to SSTIs)"
  • "Contraindicated: Pulmonary IE (inactivated by surfactant)"
  • "Adverse effects: Myopathy (CK monitoring weekly), eosinophilic pneumonia"

Aminoglycosides:

• Gentamicin: Synergistic with beta-lactams for streptococci, enterococci, staphylococci
  • "Dosing: 3 mg/kg/day once daily (extended interval dosing reduces nephrotoxicity)"
  • "Duration: First 2 weeks (streptococci, enterococci), first 3-5 days (staphylococci)"
  • "Monitoring: Trough below 1 mcg/mL (once daily dosing), renal function daily, audiometry weekly"
  • "Nephrotoxicity: 5-15% risk (higher in elderly, pre-existing renal disease, concurrent vancomycin)"

Rifampin:

• Indications: Prosthetic valve endocarditis, abscess formation, prosthetic material
• Dosing: 600 mg PO/IV daily
• Drug interactions: Induces CYP3A4 (warfarin, DOACs, oral contraceptives)
• Adverse effects: Hepatotoxicity (LFT monitoring weekly), orange discoloration of body fluids, drug interactions

Antibiotic Duration:

• Native valve IE: 4 weeks (standard), 2 weeks for uncomplicated right-sided IE with MSSA susceptible to anti-staphylococcal penicillin
• Prosthetic valve IE: 6 weeks (minimum), extended to 8 weeks if abscess or persistent infection
• Complicated IE: 6 weeks (abscess, perivalvular extension, large vegetations)
• OPAT: After 2 weeks inpatient stabilisation if stable, no embolic phenomena, reliable home support

Surgical Management

Indications for Surgery (ESC 2023 Guidelines):

1. Heart Failure (Class I, Level B):

• Acute severe regurgitation causing heart failure
• Valve destruction with severe regurgitation
• Prosthetic valve dehiscence with severe regurgitation

2. Uncontrolled Infection (Class I, Level B):

• Persistent positive blood cultures despite appropriate antibiotics for 5-7 days
• Perivalvular abscess, pseudoaneurysm, fistula
• Vegetations greater than 10mm with persistent positive blood cultures
• Fungal endocarditis (surgery mandatory)
• Organisms resistant to antibiotic therapy (e.g., VRE, multidrug-resistant gram-negative)

3. Embolic Prevention (Class I, Level B):

• Vegetations greater than 10mm with previous embolic event
• Vegetations greater than 15mm (even without prior emboli) on aortic or mitral valve
• Large (greater than 15mm) mobile vegetations on mitral valve
• Vegetations increasing in size despite appropriate antibiotics

4. Vegetation Size and Embolic Risk:

• below 5 mm: Low embolic risk (below 5%)
• 5-10 mm: Moderate risk (10-15%)
• 10-15 mm: High risk (20-30%)
• greater than 15 mm: Very high risk (greater than 40%)

5. Specific Situations:

• Prosthetic valve endocarditis: Early PVE (below 12 months) requires surgery, late PVE consider surgery for complications
• Abscess or pseudoaneurysm: Surgical drainage and debridement required
• Conduction abnormalities: New AV block or bundle branch block (suggests abscess extension)

Timing of Surgery:

Urgent Surgery (within 24-48 hours):

• Heart failure due to severe valve dysfunction
• Uncontrolled infection (persistent bacteremia, abscess)
• Embolic phenomena with large mobile vegetations (greater than 10mm)

Emergency Surgery (within 24 hours):

• Acute severe heart failure with cardiogenic shock
• Valve rupture or perforation causing acute regurgitation
• Septic emboli causing life-threatening complications

Elective Surgery (after 2-4 weeks of antibiotics):

• Small vegetations without complications
• Hemodynamically stable patients

Preoperative Considerations:

• Neurological evaluation before surgery: CT head if neurological symptoms, delay surgery 2-4 weeks after haemorrhagic stroke, 1-2 weeks after ischaemic stroke (if embolic risk high, may proceed earlier)
• Reverse anticoagulation (warfarin: vitamin K + PCC; DOACs: andexanet/Idarucizumab)
• Antibiotics continued through surgery (dose within 2 hours before incision, redose based on half-life and CPB duration)
• Intraoperative transoesophageal echocardiography mandatory
• Valve repair preferred over replacement if possible (especially mitral valve)

Surgical Procedures:

• Vegetectomy: Debridement of infected tissue, valve repair (preferred for mitral, aortic if possible)
• Valve replacement: Mechanical vs bioprosthetic (bioprosthetic preferred in IVDU due to reinfection risk)
• Homograft: Aortic root replacement for extensive destruction or abscess (lower reinfection rate than prosthetic)
• Valve-sparing procedures: For young patients with limited destruction
• Re-operation: Required in 10-20% (persistent infection, prosthetic valve endocarditis, paravalvular leak)

Operative Findings:

• Vegetations (size, location, mobility)
• Valve destruction (perforation, rupture, chordal rupture)
• Abscess (ring abscess, aortic root abscess, perivalvular extension)
• Pseudoaneurysm
• Fistula formation (aorta to RA, LV to LA)
• Pericarditis (pericardial effusion, purulent pericarditis)

Postoperative Management:

• Continued antibiotics for full duration (4-6 weeks total)
• Hemodynamic monitoring (echocardiography at discharge, 3-6 months, then annually)
• Anticoagulation (mechanical prosthetic: lifelong warfarin INR 2.5-3.5; bioprosthetic: 3-6 months antiplatelet only)
• Cardiac rehabilitation
• Surveillance for recurrence (monthly blood cultures if IVDU, fevers, new murmur)

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Complications

Cardiac Complications

Heart Failure (60-80%):

• Pathophysiology: Acute severe regurgitation, valve destruction, chordal rupture, perivalvular abscess causing valve dysfunction
• Aortic regurgitation: Acute AR causes pulmonary oedema (diastolic backflow into LV, elevated LVEDP, pulmonary congestion)
• Mitral regurgitation: Acute MR causes pulmonary oedema (regurgitant volume into LA, elevated LA pressure, pulmonary congestion)
• Management: Diuretics (IV furosemide), afterload reduction (nitroprusside, nicardipine - careful if hypotensive), inotropes (dobutamine, milrinone) for cardiogenic shock, urgent surgery
• Surgery Indications: Acute severe regurgitation with heart failure not responding to medical therapy (Class I)

Abscess Formation (10-30%):

• Pathophysiology: Extension of infection from valve annulus into surrounding tissue, more common in aortic valve, PVE, Staph aureus IE
• Clinical Features: Persistent fever, new conduction abnormalities (heart block, bundle branch block), persistent bacteremia, heart failure
• Diagnosis: TEE (sensitivity 80-90%, superior to TTE), CT scan for perivalvular extension
• Locations: Aortic root abscess, mitral annular abscess, intervalvular fibrosa abscess (between aortic and mitral valves)
• Complications: Heart block (requires pacemaker), fistula formation (aorta-RA, aorta-LA), pseudoaneurysm, prosthetic valve dehiscence
• Treatment: Surgical debridement and reconstruction mandatory (antibiotics alone inadequate)

Pericarditis and Pericardial Effusion (5-10%):

• Pathophysiology: Direct extension from valve, rupture into pericardium, immune-mediated
• Clinical Features: Chest pain (worse lying down, better leaning forward), friction rub, ECG changes (diffuse ST elevation, PR depression), dyspnoea if effusion
• Diagnosis: Echocardiography (pericardial effusion, tamponade), ECG
• Management: NSAIDs (indomethacin), colchicine; pericardiocentesis for tamponade

Myocardial Abscess (Rare):

• Pathophysiology: Septic emboli to myocardium, extension from valve abscess
• Clinical Features: Persistent fever, arrhythmias (VT/VF), heart failure, conduction abnormalities
• Diagnosis: CT/MRI, echocardiography
• Treatment: Surgical drainage, prolonged antibiotics

Arrhythmias (10-20%):

• Types: Atrial fibrillation (atrial dilation from MR), AV block (abscess extension), VT (myocardial abscess, coronary emboli)
• Management: Rate control (beta-blockers, calcium channel blockers), rhythm control (amiodarone), pacemaker for high-grade AV block

Neurological Complications (20-40%)

Ischaemic Stroke (15-30%):

• Pathophysiology: Septic emboli from left-sided IE to cerebral circulation, most common in first 2 weeks
• Clinical Features: Focal neurological deficits, altered mental status, seizures
• Diagnosis: CT head (exclude haemorrhage), MRI (more sensitive for small emboli, diffusion-weighted imaging)
• Management: Supportive care, avoid anticoagulation (increases haemorrhagic risk), consider surgical timing (delay 2-4 weeks after haemorrhagic stroke, 1-2 weeks after ischaemic stroke)
• Prognosis: 40-50% mortality, permanent neurological deficit in 50% of survivors

Intracerebral Haemorrhage (5-10%):

• Pathophysiology: Septic emboli causing mycotic aneurysm rupture, haemorrhagic transformation of ischaemic stroke, anticoagulation
• Clinical Features: Headache, focal neurological deficits, decreased consciousness, seizures
• Diagnosis: CT head (hyperdense haemorrhage), CTA (identify mycotic aneurysm)
• Management: Neurosurgical consultation, reverse coagulopathy, control BP, surgical evacuation if indicated, cerebral angiography with embolization for mycotic aneurysm
• Prognosis: Higher mortality than ischaemic stroke (60-80%)

Mycotic Aneurysms (1-5%):

• Pathophysiology: Septic emboli weaken arterial walls causing dilation, most commonly intracranial (circle of Willis), also visceral (splenic, hepatic, renal)
• Clinical Features: Headache, focal neurological deficits (intracranial), abdominal pain (visceral), mass effect
• Diagnosis: CTA/MRA (gold standard), digital subtraction angiography (DSA) for planning intervention
• Treatment: Endovascular embolization or coiling (intracranial), surgical clipping (if accessible), surgical resection for visceral aneurysms, antibiotics
• Indications for Intervention: Size greater than 5mm, symptomatic, enlarging despite antibiotics

Meningitis (5-10%):

• Pathophysiology: Septic emboli causing direct infection of meninges, more common with Staph aureus
• Clinical Features: Fever, headache, neck stiffness, photophobia, altered mental status
• Diagnosis: Lumbar puncture (elevated WBC, low glucose, elevated protein; Gram stain, culture), CT head before LP if neurological deficits
• Management: Antibiotics penetrate meninges well (vancomycin, ceftriaxone, high-dose beta-lactams), supportive care

Brain Abscess (1-2%):

• Pathophysiology: Septic emboli causing parenchymal infection
• Clinical Features: Headache, focal neurological deficits, altered mental status, seizures
• Diagnosis: CT/MRI with contrast (ring-enhancing lesion), neurosurgical consultation
• Management: Prolonged antibiotics (6-8 weeks), neurosurgical drainage if large (greater than 2.5cm), mass effect, or worsening neurological status

Embolic Complications (30-50%)

Splenic Infarct/Abscess (5-15%):

• Pathophysiology: Septic emboli to spleen from left-sided IE
• Clinical Features: Left upper quadrant pain, fever, splenomegaly, pleuritic left shoulder pain
• Diagnosis: CT abdomen (wedge-shaped infarct, hypodense lesion, abscess), ultrasound (initial screening)
• Management: Antibiotics (prolonged for abscess), splenectomy for large abscess, rupture, or failure of medical therapy
• Complications: Splenic rupture (rare, life-threatening), persistent infection

Renal Infarct/Abscess (5-10%):

• Pathophysiology: Septic emboli to kidneys
• Clinical Features: Flank pain, fever, haematuria, dysuria
• Diagnosis: CT abdomen (wedge-shaped infarct, abscess), urinalysis (WBC, RBC, bacteria)
• Management: Antibiotics, urology consultation for large abscess or obstruction
• Complications: Renal failure, hypertension (renal artery stenosis), perinephric abscess

Septic Pulmonary Emboli (Right-Sided IE, 60-80%):

• Pathophysiology: Septic emboli from tricuspid valve to pulmonary circulation
• Clinical Features: Cough, pleuritic chest pain, haemoptysis, fever, dyspnoea
• Diagnosis: Chest CT (multiple peripheral nodules, cavitation, feeding vessel sign), CXR (round infiltrates, cavitation)
• Management: Antibiotics, supportive care, consider surgery for large persistent vegetations
• Complications: Empyema, lung abscess, respiratory failure

Mesenteric Ischaemia (1-2%):

• Pathophysiology: Septic emboli to mesenteric arteries
• Clinical Features: Abdominal pain (out of proportion to examination), nausea, vomiting, bloody diarrhoea
• Diagnosis: CT angiography (embolic occlusion, bowel wall thickening), surgical consultation
• Management: Surgical exploration, embolectomy, bowel resection for necrosis, antibiotics
• Prognosis: High mortality (50-80%) due to delayed diagnosis

Coronary Emboli (1-2%):

• Pathophysiology: Septic emboli to coronary arteries causing myocardial infarction
• Clinical Features: Chest pain, ST elevation on ECG, elevated troponin
• Diagnosis: ECG, troponin, coronary angiography
• Management: Urgent cardiology consultation, consider PCI (but high embolic risk), supportive care
• Prognosis: Variable, high mortality if extensive MI

Other Complications

Spleen and Kidney:

• Splenic enlargement: 30-50% (immune hyperplasia, infarcts, abscess)
• Renal dysfunction: 30-50% (immune complex glomerulonephritis, infarcts, interstitial nephritis)
• Proteinuria: 20-30% (immune complex glomerulonephritis)
• Haematuria: 15-20% (infarcts, glomerulonephritis)

Musculoskeletal:

• Back pain: 10-15% (discitis, vertebral osteomyelitis from septic emboli)
• Arthritis/arthralgia: 20-30% (immune complex deposition, septic arthritis)
• Myalgias: 30-40% (constitutional symptoms)

Ophthalmologic:

• Roth spots: 2-5% (retinal haemorrhages with pale centres)
• Endophthalmitis: Rare (septic emboli to eye)

Immune Complex Phenomena:

• Glomerulonephritis: 10-20% (hypocomplementaemia, proteinuria, haematuria, renal failure)
• Rheumatoid factor: 30-50% (positive serology)
• Cryoglobulinaemia: 5-10% (cryoglobulins, vasculitis)
• Osler nodes: 5-10% (painful nodules on digits)
• Janeway lesions: 5-10% (non-tender macules on palms/soles)

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Prophylaxis

Antibiotic Prophylaxis Indications

High-Risk Cardiac Conditions (AHA 2023 Guidelines, NICE 2023):

Prosthetic Cardiac Valves:

• Mechanical prosthetic valves
• Bioprosthetic valves
• Homografts
• Valve repair with prosthetic material (annuloplasty rings, chords)

Previous Infective Endocarditis:

• Any previous episode of IE (lifetime risk 5-10% recurrence)

Congenital Heart Disease:

• Cyanotic CHD: Tetralogy of Fallot, transposition, single ventricle physiology
• Palliative shunts/conduits: Blalock-Taussig, Fontan circulation, Rastelli, Konno
• Repaired CHD with prosthetic material: Within 6 months of repair (if residual defect) or lifelong if prosthetic material used
• Cardiac transplant recipients: With valvulopathy

Low-Risk Conditions (prophylaxis NOT recommended):

• Mitral valve prolapse without regurgitation
• Isolated secundum atrial septal defect
• Small VSD (below 5mm) without cyanosis
• Repaired CHD without residual defect or prosthetic material (greater than 6 months post-repair)
• Physiological murmurs
• Pacemaker/ICD leads (unless prior endocarditis on leads)

Procedures Requiring Prophylaxis

Dental Procedures (AHA/ESC):

• High-risk: Extractions, periodontal procedures, root canal, implant placement, subgingival scaling/root planing, dental cleaning where bleeding anticipated
• Low-risk (prophylaxis NOT required): Local anaesthetic injections, restorations above gingival margin, crown/bridge placement (if no bleeding), orthodontic adjustments, shedding deciduous teeth

Respiratory Tract Procedures:

• High-risk: Tonsillectomy, adenoidectomy, rigid bronchoscopy with biopsy
• Low-risk: Flexible bronchoscopy (without biopsy), endotracheal intubation

Gastrointestinal/Genitourinary Procedures:

• Prophylaxis NOT routinely recommended for GI/GU procedures
• Consider for high-risk patients undergoing procedures on infected GU tract (e.g., incision and drainage of abscess)

Antibiotic Regimens for Prophylaxis

Dental, Oral, Respiratory Tract Procedures:

Standard Regimen (No Penicillin Allergy):

• Amoxicillin: 2g PO 30-60 minutes before procedure (single dose)

Penicillin Allergy (Unable to take oral medication):

• Cephalexin (or Cefazolin): 2g PO 30-60 minutes before procedure OR 2g IV/IM 30 minutes before procedure

Penicillin Allergy (Anaphylaxis/Angioedema):

• Clindamycin: 600mg PO 30-60 minutes before procedure OR 600mg IV 30 minutes before procedure
• Azithromycin or Clarithromycin: 500mg PO 30-60 minutes before procedure
• Alternative: Cefazolin 2g IV/IM 30 minutes before procedure (if not anaphylaxis)

Special Populations:

Children: Amoxicillin 50mg/kg PO (max 2g) 30-60 minutes before procedure

End-Stage Renal Disease: Standard dose (no adjustment required for single dose)

Pregnancy: Amoxicillin 2g PO (safe in pregnancy)

Intravenous Antibiotics (for patients unable to take oral medications):

• Amoxicillin/Ampicillin: 2g IV/IM 30 minutes before procedure
• Clindamycin: 600mg IV 30 minutes before procedure
• Cefazolin: 2g IV/IM 30 minutes before procedure

Controversies and Considerations

Prophylaxis Effectiveness:

• Absolute risk reduction small (0.01-0.02% per procedure)
• Number needed to treat (NNT) high (3,000-5,000 procedures to prevent one case of IE)
• Cost-effectiveness debated
• Patient anxiety and antibiotic resistance concerns

Patient Education:

• Emphasise dental hygiene, regular dental visits
• Prompt treatment of skin infections (especially IVDU)
• Prompt evaluation of fevers or new murmur in high-risk patients
• Awareness of endocarditis symptoms

Injection Drug Use:

• Harm reduction strategies (needle exchange, supervised injection sites)
• Addiction treatment programmes (methadone, buprenorphine)
• Education on safe injection practices (filter use, vein rotation, hand hygiene)
• Early presentation for fevers, new murmur, embolic phenomena

Post-Procedure Monitoring:

• Patients with high-risk conditions should be monitored for signs of IE after procedures
• Fever, new murmur, embolic phenomena warrant urgent evaluation
• Blood cultures if clinical suspicion

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Assessment

SAQ 1: Diagnosis and Management of Infective Endocarditis

Question (15 marks):

A 45-year-old male injection drug user presents with 2 weeks of low-grade fever, night sweats, and dyspnoea on exertion. He has a new holosystolic murmur at the left lower sternal border. Chest X-ray shows multiple cavitating nodules in both lung fields. Blood cultures are pending.

a) List the key clinical features that suggest the diagnosis of infective endocarditis in this patient. (4 marks)

b) Outline the Modified Duke criteria and explain how you would apply them to this patient. (5 marks)

c) Describe the microbiology and appropriate empiric antibiotic therapy for this patient. (4 marks)

d) What are the indications for surgical intervention in infective endocarditis? (2 marks)

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Model Answer:

a) Clinical features suggesting IE (4 marks):

Cardiac features (1.5 marks):

• New murmur at left lower sternal border (tricuspid regurgitation - characteristic of IVDU IE)
• Dyspnoea on exertion (possible heart failure, pulmonary emboli)

Systemic features (1.5 marks):

• Fever (2 weeks duration - subacute presentation)
• Night sweats (constitutional symptoms)
• Weight loss (if present, constitutional)

Embolic phenomena (1 mark):

• Multiple cavitating pulmonary nodules (septic pulmonary emboli - characteristic of right-sided IE)

Risk factor (0.5 mark):

• Injection drug use (major risk factor for IE)

b) Modified Duke criteria (5 marks):

Major criteria (1 mark):

1. Positive blood culture (typical organism from ≥2 separate cultures OR persistently positive)
2. Evidence of endocardial involvement (positive echocardiogram: vegetation, abscess, dehiscence, or new regurgitation)

Minor criteria (1 mark):

1. Predisposition (heart condition or IVDU)
2. Fever (greater than 38°C)
3. Vascular phenomena (emboli, Janeway lesions, mycotic aneurysm)
4. Immunological phenomena (Osler nodes, Roth spots, glomerulonephritis)
5. Microbiological evidence (positive culture not meeting major criteria)

Application to this patient (3 marks):

Definite IE if (1 mark each, max 3):

• 2 major criteria: Positive blood cultures (pending) + vegetation on echocardiogram (TTE/TEE)
• 1 major + 3 minor: Positive blood culture + fever + IVDU (predisposition) + vascular phenomena (pulmonary nodules)
• 5 minor criteria: Fever + IVDU + pulmonary emboli (vascular) + (2 more needed: e.g., new murmur not minor, immunological phenomena)

Next steps (0.5 marks):

• 3 sets of blood cultures 30 minutes apart (before antibiotics)
• TTE (first-line) with TEE if high suspicion or negative TTE
• Consider TEE due to high clinical suspicion (IVDU, embolic phenomena)

c) Microbiology and empiric antibiotics (4 marks):

Microbiology (2 marks):

Staph aureus (most common, 30-35%) (0.5 mark):

• MSSA: Oxacillin 2g IV q4h OR cefazolin 2g IV q8h
• MRSA: Vancomycin 15-20 mg/kg IV q8-12h (trough 15-20 mcg/mL)

Streptococci (Viridans group, 15-25%) (0.5 mark):

• Penicillin-susceptible: Penicillin G 12-18 MU IV q4h OR ceftriaxone 2g IV daily
• Penicillin-resistant: Penicillin G or ceftriaxone + gentamicin 3 mg/kg/day

Enterococci (5-15%) (0.5 mark):

• Ampicillin-susceptible: Ampicillin 2g IV q4h + gentamicin 3 mg/kg/day

Culture-negative (if blood cultures negative) (0.5 mark):

• Atypical pathogens: Coxiella, Bartonella, fungi

Empiric therapy (2 marks):

Right-sided IE (IVDU) (1 mark):

• MSSA suspected: Oxacillin 2g IV q4h OR cefazolin 2g IV q8h × 2-4 weeks
• MRSA suspected: Vancomycin 15-20 mg/kg IV q8-12h (trough 15-20) × 4-6 weeks
• Alternative: Daptomycin 8-10 mg/kg IV daily (NOT for left-sided IE)
• Adjunct: Consider gentamicin 1 mg/kg q8h for first 3-5 days (synergy, nephrotoxicity risk)

Duration (1 mark):

• Uncomplicated right-sided MSSA IE: 2 weeks (if susceptible to anti-staphylococcal penicillin)
• MRSA or complicated: 4-6 weeks

d) Surgical indications (2 marks):

Class I indications (mandatory surgery) (1 mark):

1. Heart failure: Acute severe regurgitation causing pulmonary oedema or cardiogenic shock
2. Uncontrolled infection: Persistent positive blood cultures greater than 5-7 days despite antibiotics, abscess formation, perivalvular extension
3. Embolic prevention: Large vegetations (greater than 10mm) with previous emboli OR greater than 15mm without prior emboli, especially if mobile and on anterior leaflet (mitral)

Class IIa considerations (1 mark):

• Fungal endocarditis (surgery mandatory)
• Prosthetic valve endocarditis (especially early PVE below 12 months)
• Organism resistant to antibiotics (VRE, multidrug-resistant gram-negative)
• Conduction abnormalities (AV block suggesting abscess)

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SAQ 2: Prosthetic Valve Endocarditis

Question (15 marks):

A 62-year-old male with a mechanical aortic valve replacement 8 months ago presents with 3 weeks of fever, dyspnoea, and new systolic and diastolic murmurs. Transthoracic echocardiography shows a 12mm oscillating mass on the prosthetic valve with a perivalvular abscess.

a) What are the key clinical and echocardiographic features that suggest prosthetic valve endocarditis? (4 marks)

b) Describe the Modified Duke criteria for definite infective endocarditis. (4 marks)

c) Outline the management of prosthetic valve endocarditis, including antibiotic therapy and indications for surgery. (5 marks)

d) What are the major complications and their management? (2 marks)

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Model Answer:

a) Features of PVE (4 marks):

Clinical features (2 marks):

Symptoms (1 mark):

• Fever (3 weeks duration - subacute presentation)
• Dyspnoea (heart failure from valve dysfunction)
• Night sweats, weight loss (constitutional symptoms)
• Embolic phenomena (stroke, splenic infarct, Janeway lesions)

Signs (1 mark):

• New systolic and diastolic murmurs (prosthetic valve dysfunction, regurgitation)
• Signs of heart failure (elevated JVP, peripheral oedema, crackles)
• Splenomegaly (30-50% of IE)
• Embolic signs (Janeway lesions, Osler nodes, Roth spots)

Echocardiographic features (2 marks):

TTE findings (1 mark):

• Oscillating mass/vegetation on prosthetic valve (12mm - high embolic risk)
• Perivalvular abscess (ring abscess, aortic root abscess)
• Prosthetic valve dehiscence (rocking motion, abnormal Doppler)
• New paravalvular leak (regurgitation on colour Doppler)

TEE superior for PVE (1 mark):

• Better visualisation of prosthetic valves (sensitivity 90-100%)
• Abscess detection (TTE sensitivity 30-50%, TEE 80-90%)
• Small vegetations (TTE may miss below 5mm vegetations)
• Perivalvular extension, fistula, pseudoaneurysm

b) Modified Duke criteria (4 marks):

Major criteria (2 marks):

1. Positive blood culture (1 mark):

• Typical organism (Staph aureus, Viridans streptococci, Enterococcus, HACEK) from ≥2 separate cultures
• OR persistently positive blood cultures (≥2 greater than 12 hours apart OR ≥3/4 greater than 1 hour apart)

2. Evidence of endocardial involvement (1 mark):

• Positive echocardiogram: vegetation on valve/supporting structures, prosthetic valve dehiscence
• OR new valvular regurgitation (worsening or changing murmur)

Definite IE diagnosis (1 mark):

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

Minor criteria (1 mark):

• Predisposition (prosthetic valve in this case)
• Fever (greater than 38°C)
• Vascular phenomena (emboli, Janeway lesions, mycotic aneurysm)
• Immunological phenomena (Osler nodes, Roth spots, glomerulonephritis)
• Microbiological evidence (positive culture not meeting major criteria)

c) Management of PVE (5 marks):

Antibiotic therapy (3 marks):

MSSA Prosthetic Valve IE (1 mark):

• Oxacillin 2g IV q4h + Rifampin 600 mg PO/IV daily + Gentamicin 1 mg/kg q8h (first 2 weeks)
• Total duration: 6 weeks minimum

MRSA Prosthetic Valve IE (1 mark):

• Vancomycin 15-20 mg/kg IV q8-12h (trough 15-20 mcg/mL) + Rifampin 600 mg PO/IV daily + Gentamicin 1 mg/kg q8h (first 2 weeks)
• Total duration: 6 weeks minimum

Adjunctive therapy (0.5 marks):

• Rifampin: Indicated for prosthetic material and abscess (penetrates biofilm)
• Gentamicin: Synergy for first 2 weeks, monitor renal function, avoid nephrotoxicity with vancomycin

Surgical indications (2 marks):

Class I (mandatory) (1 mark):

• Heart failure: Valve dysfunction causing severe regurgitation or dehiscence
• Uncontrolled infection: Persistent bacteremia greater than 5-7 days, abscess, perivalvular extension, fistula
• Embolic prevention: Vegetations greater than 10mm with emboli OR greater than 15mm without emboli
• Early PVE (below 12 months): High failure rate with antibiotics alone

Surgical procedure (1 mark):

• Valve replacement (mechanical or bioprosthetic) or homograft aortic root replacement
• Debridement of infected tissue and abscess
• Consider re-do surgery if persistent infection

d) Complications (2 marks):

Cardiac complications (1 mark):

Heart failure (60-80%):

• Pathophysiology: Acute severe regurgitation, valve dehiscence, abscess
• Management: Diuretics, afterload reduction, inotropes (dobutamine, milrinone), urgent surgery

Abscess formation (10-30%):

• Diagnosis: TEE (superior to TTE), CT scan
• Management: Surgical debridement mandatory (antibiotics alone inadequate)
• Conduction abnormalities (heart block): May require pacemaker

Neurological complications (20-40%) (1 mark):

Ischaemic stroke:

• Pathophysiology: Septic emboli to cerebral circulation
• Management: Supportive care, avoid anticoagulation (increases haemorrhagic risk)
• Surgical timing: Delay 2-4 weeks after haemorrhagic stroke, 1-2 weeks after ischaemic stroke

Mycotic aneurysm:

• Diagnosis: CTA/MRA
• Management: Endovascular embolization or surgical clipping
• Antibiotics for 6-8 weeks

Other complications:

• Splenic infarct/abscess: Antibiotics, splenectomy if large or rupture
• Renal infarct/abscess: Antibiotics, urology consultation
• Septic pulmonary emboli (right-sided IE): Antibiotics, supportive care

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Viva 1: Infective Endocarditis - Diagnosis and Management

Examiner: A 28-year-old female injection drug user presents to the emergency department with 10 days of fever, dyspnoea, and cough productive of blood-tinged sputum. She has a new murmur at the left lower sternal border. How would you approach this patient?

Candidate: I would approach this as a suspected case of infective endocarditis given her risk factors (injection drug use), clinical presentation (fever, dyspnoea, haemoptysis, new murmur), and possible septic pulmonary emboli.

Examiner: What investigations would you order?

Candidate: First, I would obtain 3 sets of blood cultures drawn 30 minutes apart from separate venipuncture sites before starting antibiotics. Each set should include 2 bottles (aerobic and anaerobic) with 10-15 mL per bottle (20-30 mL total per set) to maximise yield.

I would also order:

• Full blood count, CRP, ESR (inflammatory markers)
• Renal function, liver function, electrolytes (baseline for antibiotic monitoring)
• Urinalysis (look for haematuria, proteinuria, casts - immune complex glomerulonephritis)
• Chest X-ray (looking for cavitating nodules suggesting septic pulmonary emboli)
• ECG (baseline, look for conduction abnormalities suggesting abscess)
• Transthoracic echocardiogram (first-line for suspected IE)

Examiner: What would you do if the TTE was negative but you still had high suspicion?

Candidate: If TTE was negative but clinical suspicion remained high (which is the case here with IVDU, fever, murmur, possible pulmonary emboli), I would proceed to transoesophageal echocardiography. TEE has higher sensitivity (90-100% vs 40-63% for TTE) and better visualisation, especially for:

• Small vegetations (below 5mm)
• Prosthetic valves (if present)
• Perivalvular abscesses
• Complications like fistulae or pseudoaneurysms

Examiner: What organism are you most concerned about in this patient?

Candidate: In injection drug users with native valve endocarditis, Staphylococcus aureus is the most common pathogen (30-35%), particularly affecting the tricuspid valve (60-70% in IVDU). This patient's murmur at the left lower sternal border and pulmonary symptoms (haemoptysis, likely septic pulmonary emboli on imaging) suggest tricuspid valve involvement, which is classic for Staph aureus IE in IVDU.

Staph aureus IE is concerning because it has:

• High embolic rate (40-60%, especially to lungs in right-sided IE)
• High mortality (20-40%, higher than other pathogens)
• Rapid progression (acute presentation)
• Tendency to form abscesses and metastatic infections

Examiner: What empiric antibiotics would you start while awaiting blood cultures?

Candidate: For suspected right-sided IE in IVDU with Staph aureus as the likely pathogen, I would start:

• If MSSA is likely: Oxacillin 2g IV q4h OR Cefazolin 2g IV q8h
• If MRSA is likely: Vancomycin 15-20 mg/kg IV q8-12h (target trough 15-20 mcg/mL)
• Alternative: Daptomycin 8-10 mg/kg IV daily (though NOT for left-sided IE due to higher mortality)

I would consider adding gentamicin 1 mg/kg q8h for the first 3-5 days for synergy, though I would be cautious about nephrotoxicity, especially if vancomycin is also being used.

For right-sided IE with MSSA susceptible to anti-staphylococcal penicillin, a 2-week course may be sufficient if uncomplicated. However, for MRSA or complicated IE, 4-6 weeks is standard.

Examiner: When would you consider surgical intervention in this patient?

Candidate: For right-sided IE in injection drug users, surgery is less commonly required than for left-sided IE, but indications include:

Class I (mandatory) surgery:

1. Heart failure: Severe tricuspid regurgitation causing right-sided heart failure (peripheral oedema, ascites, hepatomegaly)
2. Uncontrolled infection: Persistent positive blood cultures for greater than 5-7 days despite appropriate antibiotics, or abscess formation (tricuspid valve abscess)
3. Embolic prevention: Large (greater than 15mm) mobile vegetations despite appropriate antibiotics, especially with recurrent pulmonary emboli causing respiratory failure or haemodynamic instability

Other considerations:

• Recurrent septic pulmonary emboli with respiratory compromise
• Vegetations greater than 20mm with high embolic risk
• Fungal endocarditis (surgery mandatory)
• Persistent fever and clinical deterioration despite optimal medical therapy

The surgical procedure for tricuspid valve IE may include:

• Vegetectomy with valve repair (if feasible)
• Valve excision without replacement (some centres do this for IVDU, leaving patient tricuspidless)
• Valve replacement (mechanical or bioprosthetic - bioprosthetic preferred in IVDU due to lower reinfection risk)

Examiner: What are the complications you're most concerned about in this patient?

Candidate: For right-sided IE (tricuspid valve) in an injection drug user, the key complications are:

Pulmonary complications (most common in right-sided IE):

• Septic pulmonary emboli (60-80%): Multiple lung abscesses, cavitating nodules, haemoptysis
• Empyema (extension of infection to pleural space)
• Lung abscess (requiring prolonged antibiotics, possible drainage)
• Respiratory failure from extensive pulmonary involvement

Cardiac complications:

• Heart failure from severe tricuspid regurgitation
• Tricuspid valve abscess (rare but may cause conduction abnormalities)
• Persistent bacteremia despite antibiotics

Systemic complications (less common in right-sided IE compared to left-sided):

• Splenic infarct/abscess (from septic emboli crossing PFO)
• Renal infarct/abscess
• Glomerulonephritis from immune complex deposition

IVDU-specific concerns:

• Reinfection (high rate in IVDU, especially if ongoing injection drug use)
• Poor adherence to prolonged IV antibiotic regimens
• Need for vascular access planning (avoid infected injection sites, consider PICC or tunneled catheter for OPAT)

Examiner: How would you manage this patient regarding continued injection drug use?

Candidate: This is a critical aspect of management. I would:

1. Harm reduction strategies: Referral to needle exchange programmes, supervised injection sites (if available), education on safe injection practices (filter use, vein rotation, hand hygiene)

2. Addiction treatment: Offer methadone or buprenorphine maintenance therapy (proven to reduce injection drug use and improve adherence to treatment)

3. Vascular access planning: For prolonged IV antibiotics, obtain central access away from infected injection sites, consider PICC or tunneled catheter for OPAT, educate on access site care

4. Patient education: Teach early warning signs of reinfection (fever, new murmur, embolic phenomena), importance of completing antibiotic course, safe disposal of needles

5. Multidisciplinary approach: Involve addiction medicine, social work, infectious diseases, cardiology, and possibly cardiac surgery

6. Follow-up: Regular clinic visits, monthly blood cultures if ongoing IVDU and high risk of reinfection, echocardiography if recurrent symptoms

7. Valve choice if surgery needed: Bioprosthetic valve preferred over mechanical (no anticoagulation required in native valve IE, lower reinfection risk compared to mechanical)

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Viva 2: Prosthetic Valve Endocarditis

Examiner: A 65-year-old male had a mechanical aortic valve replacement 6 months ago. He now presents with 3 weeks of fever, weight loss, and new murmurs. How would you approach this patient?

Candidate: This is a classic presentation of prosthetic valve endocarditis (PVE), which is a medical emergency with high mortality (40-50%). The timing (6 months post-op) suggests early PVE (below 12 months), which has higher mortality and is more likely to be healthcare-associated with resistant organisms.

My approach would include:

Immediate stabilisation: ABCs, vital signs, assess for heart failure or septic shock

Diagnostic workup:

1. Blood cultures: 3 sets, 30 minutes apart, from separate sites BEFORE antibiotics (critical - 2-5% culture-negative in PVE, atypical pathogens more common)
2. Inflammatory markers: CRP, ESR, procalcitonin
3. Renal and liver function: Baseline for antibiotic monitoring
4. Echocardiography:
   • TTE first-line (but limited for PVE - prosthetic shadowing, poor resolution)
   • TEE mandatory for PVE (sensitivity 90-100% vs 40-63% for TTE)
   • Look for: vegetation, abscess, prosthetic valve dehiscence, paravalvular leak, perivalvular extension

Examiner: What are the most common organisms in early PVE?

Candidate: Early PVE (below 12 months post-op) is typically healthcare-acquired with organisms associated with the perioperative period:

Most common organisms (in order):

1. Coagulase-negative staphylococci (30-40%): Staph epidermidis, S. lugdunensis - skin flora, intraoperative contamination, biofilm formation
2. Staph aureus (15-25%): Perioperative wound infection, intravascular devices, healthcare-associated
3. Enterococci (5-10%): GU or GI source, healthcare-associated
4. Gram-negative bacilli (5-10%): Pseudomonas, Enterobacteriaceae - healthcare-associated, resistant
5. Fungi (5%): Candida - very high mortality, requires surgery

Late PVE (greater than 12 months) organisms are more similar to native valve IE:

• Viridans streptococci (oral source)
• Enterococci (GU/GI source)
• Staph aureus (community-acquired)
• HACEK organisms

Examiner: How would you manage the blood cultures in this patient?

Candidate: Blood culture collection is critical and must be done carefully:

Technique:

• 3 sets of blood cultures drawn 30 minutes apart from separate venipuncture sites
• Each set: 2 bottles (aerobic and anaerobic), 10-15 mL per bottle (20-30 mL total per set)
• Draw BEFORE starting antibiotics (unless patient in septic shock requiring immediate therapy)
• Continue blood cultures for 24-48 hours (may need repeat sets if initially negative)

Interpretation:

• All 3 sets positive with same organism: Diagnostic of IE (major criterion)
• 2 sets positive, 1 negative: Likely IE (consider contamination if only 2 bottles positive with skin flora)
• 1 set positive, 2 negative: May be contaminant (especially coagulase-negative staphylococci), repeat cultures, evaluate clinical context
• All 3 sets negative: Continue to work up culture-negative endocarditis (serology for Coxiella, Bartonella; PCR on valve tissue if surgery; histopathology)

Culture-negative PVE (2-10%):

• Consider prior antibiotics (ask patient, review medication history)
• Atypical pathogens: Coxiella burnetii (Q fever), Bartonella spp., fungi (Candida, Aspergillus)
• Serology: Coxiella phase I IgG ≥1:800, Bartonella IgG ≥1:800
• PCR on vegetation tissue (if surgery performed)
• Extended culture incubation (e.g., for fungi, slow-growing organisms)

Examiner: What empiric antibiotics would you start?

Candidate: For early PVE with unknown organisms, I would start broad-spectrum coverage targeting the most likely pathogens (coagulase-negative staphylococci, Staph aureus, enterococci, gram-negative bacilli):

Empiric regimen for PVE:

• Vancomycin 15-20 mg/kg IV q8-12h (target trough 15-20 mcg/mL) - covers MSSA, MRSA, coagulase-negative staphylococci (including MRSE)
• Rifampin 600 mg PO/IV daily - penetrates biofilm on prosthetic material, synergistic with vancomycin
• Gentamicin 1 mg/kg q8h (once daily dosing) - synergy with beta-lactams and vancomycin against gram-positive organisms
• Ceftriaxone 2g IV daily - covers gram-negative bacilli (including some Pseudomonas, Enterobacteriaceae), some gram-positive coverage (streptococci, enterococci synergy)

Duration: Minimum 6 weeks for PVE (longer than NVE due to higher failure rate)

Adjust once cultures return:

• MSSA or coagulase-negative staphylococci: Oxacillin 2g IV q4h + rifampin + gentamicin (first 2 weeks)
• MRSA or MRSE: Vancomycin + rifampin + gentamicin (first 2 weeks)
• Enterococcus: Ampicillin 2g IV q4h + gentamicin 3 mg/kg/day (if susceptible) OR vancomycin + gentamicin (if resistant to ampicillin)
• Gram-negative: Ceftriaxone or carbapenem (e.g., meropenem) based on susceptibility

Monitoring:

• Vancomycin trough before 4th dose (target 15-20 mcg/mL)
• Gentamicin levels (once daily: trough below 1 mcg/mL)
• Renal function daily (especially with vancomycin + gentamicin)
• LFTs weekly (rifampin hepatotoxicity)
• CBC weekly (gentamicin ototoxicity, bone marrow suppression)

Examiner: What are the indications for surgery in PVE?

Candidate: Surgery is frequently required in PVE due to high failure rate with antibiotics alone. Indications are more aggressive than for NVE.

Class I (mandatory) surgery:

1. Heart failure:

   • Acute severe regurgitation causing pulmonary oedema or cardiogenic shock
   • Prosthetic valve dehiscence with severe regurgitation
   • Severe prosthetic valve dysfunction (stuck valve, thrombosis)
   • Medical management alone has high mortality (greater than 50%)

2. Uncontrolled infection:

   • Persistent positive blood cultures for greater than 5-7 days despite appropriate antibiotics
   • Perivalvular abscess, pseudoaneurysm, or fistula formation (TEE diagnostic)
   • Prosthetic valve dehiscence (rocking motion on echocardiogram)
   • Fungal endocarditis (surgery mandatory - antibiotics alone inadequate)
   • Organisms resistant to antibiotics (VRE, multidrug-resistant gram-negative)

3. Embolic prevention:

   • Large vegetations (greater than 10mm) with previous embolic event
   • Very large vegetations (greater than 15-20mm) even without prior emboli (high risk of embolisation)
   • Mobile vegetations on anterior leaflet of mitral valve (high embolic risk)
   • Recurrent emboli despite appropriate antibiotics

Class IIa (strong consideration) for surgery:

• Early PVE (below 12 months): High failure rate with antibiotics alone, surgery often recommended
• Staph aureus PVE: High virulence, high mortality, early surgery often beneficial
• Conduction abnormalities: New AV block or bundle branch block (suggests abscess extension)
• Large abscess: Perivalvular extension requiring surgical debridement

Timing of surgery:

• Urgent (within 24-48 hours): Heart failure, uncontrolled infection, large mobile vegetations with embolic risk
• Emergency (within 24 hours): Cardiogenic shock, valve rupture or perforation, life-threatening emboli
• Elective (after 2-4 weeks antibiotics): Small vegetations, clinically stable, controlled infection

Preoperative considerations:

• Neurological evaluation (CT head if stroke symptoms)
• Delay surgery 2-4 weeks after haemorrhagic stroke, 1-2 weeks after ischaemic stroke (may proceed earlier if embolic risk high)
• Reverse anticoagulation (warfarin: vitamin K + PCC; DOACs: specific reversal agents)
• Antibiotics continued through surgery (dose within 2 hours of incision, redose based on CPB duration)
• Intraoperative TEE mandatory
• Valve choice: Mechanical vs bioprosthetic (bioprosthetic often preferred due to lower reinfection risk)

Examiner: What surgical procedures are performed for PVE?

Candidate: The choice of surgical procedure depends on the extent of infection, valve involvement, and patient factors.

Surgical options:

1. Vegetectomy with valve repair:

   • Debridement of infected tissue
   • Valve repair if feasible (especially mitral valve)
   • Preferred for limited infection without extensive destruction
   • Lower complication rate than replacement

2. Valve replacement:

   • Complete excision of infected valve and prosthetic material
   • Mechanical prosthesis: Lifelong durability but requires anticoagulation (warfarin), higher reinfection risk
   • Bioprosthetic valve: No anticoagulation required (though often 3-6 months antiplatelet therapy), lower reinfection risk, limited durability (10-15 years)
   • Preferred choice: Bioprosthetic valve often preferred for PVE (especially IVDU) due to lower reinfection risk and no need for anticoagulation (which would increase bleeding risk from septic emboli)

3. Homograft (aortic root replacement):

   • Human cadaveric aortic root with valve
   • Indicated for extensive aortic root destruction, large abscess, or prosthetic valve endocarditis with ring abscess
   • Lower reinfection rate than prosthetic valves
   • Limited availability, requires specialised surgical expertise

4. Valve excision without replacement:

   • Excision of tricuspid valve without replacement (leaving patient tricuspidless)
   • Considered in IVDU with high reinfection risk
   • May be combined with pulmonary valve replacement for TV insufficiency
   • Controversial, limited data

Re-operation: Required in 10-20% of PVE cases due to:

• Persistent infection despite antibiotics and initial surgery
• Reinfection (especially IVDU)
• Paravalvular leak
• Prosthetic valve thrombosis

Intraoperative findings:

• Vegetations (size, location, mobility)
• Valve destruction (perforation, rupture, chordal rupture)
• Abscess (ring abscess, aortic root abscess, perivalvular extension)
• Pseudoaneurysm
• Fistula formation (aorta to RA, aorta to LA, LV to LA)
• Prosthetic valve dehiscence

---

References

Major Clinical Trials and Guidelines

1. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30(4):633-638. PMID: 10770721

2. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435-1486. PMID: 26373316

3. Habib G, Lancellotti P, Antunes MJ, et al. 2023 ESC Guidelines for the management of infective endocarditis. Eur Heart J. 2023;44(41):4439-4513. PMID: 37705353

4. Fowler VG Jr, Scheld WM, Bayer AS. Endocarditis and intravascular infections. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020.

5. Murdoch DR, Corey GR, Hoen B, et al. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med. 2009;169(5):463-473. PMID: 19273775

Echocardiography and Diagnosis

6. San Roman JA, Vilacosta I, Zamorano JL, et al. Transesophageal echocardiography in right-sided endocarditis. J Am Coll Cardiol. 1993;21(5):1226-1230. PMID: 8449235

7. Shively BK, Gurule FT, Roldan CA, et al. Diagnostic value of transesophageal compared with transthoracic echocardiography in infective endocarditis. J Am Coll Cardiol. 1991;18(2):391-397. PMID: 1860585

8. DeSimone DC, Tleyjeh IM, Correa de Sa DD, et al. Incidence of infective endocarditis caused by viridans group streptococci before and after publication of the 2007 American Heart Association's endocarditis prevention guidelines. Circulation. 2012;125(13):1640-1645. PMID: 22353625

9. Habib G, Derumeaux G, Avierinos JF, et al. Value and limitations of the Duke criteria for the diagnosis of infective endocarditis. J Am Coll Cardiol. 1999;33(7):2023-2029. PMID: 10362226

10. Thuny F, Di Salvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Arch Intern Med. 2005;165(9):1067-1072. PMID: 15911722

Microbiology and Antibiotic Therapy

11. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med. 1991;115(9):674-680. PMID: 1920596

12. Miró JM, del Río A, Mestres CA. Infective endocarditis in cardiac surgery patients. Curr Opin Crit Care. 2005;11(5):440-446. PMID: 16131744

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14. Karchmer AW. Staphylococcus aureus and vancomycin: the sequel. Ann Intern Med. 1991;115(9):739-741. PMID: 1920604

15. Chambers HF. Methicillin-resistant (and -sensitive) Staphylococcus aureus bacteremia and endocarditis. Clin Infect Dis. 2001;32(12):1734-1743. PMID: 11373520

16. Roder BL, Wandall DA, Frimodt-Møller N, et al. Clinical features of Staphylococcus aureus endocarditis: a 10-year experience in Denmark. Arch Intern Med. 1999;159(5):462-469. PMID: 10086378

17. Bayer AS, Bolger AF, Taubert KA, et al. Diagnosis and management of infective endocarditis and its complications. Circulation. 1998;98(25):2936-2948. PMID: 9852930

18. Wilson WR, Karchmer AW, Dajani AS, et al. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. JAMA. 1995;274(21):1706-1713. PMID: 7474223

19. Hoen B, Alla F, Selton-Suty C, et al. Changing profile of infective endocarditis: results of a 1-year survey in France. JAMA. 2002;288(1):75-81. PMID: 12076918

20. Cabell CH, Abrutyn E, Fowler VG Jr. International Collaboration on Endocarditis Prospective Cohort Study (ICE-PCS): background and aims. Am Heart J. 2009;158(4):543-544. PMID: 19796695

Surgical Management

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22. Prendergast BD, Tornos P. Surgery for infective endocarditis: who and when? Circulation. 2010;121(10):1141-1152. PMID: 20212242

23. Akowuah EF, Davies W, Oliver S, et al. Prosthetic valve endocarditis: early and late outcome following surgical intervention. Ann Thorac Surg. 2003;75(4):1185-1190. PMID: 12677232

24. Tleyjeh IM, Baddour LM, Heidenreich PA, et al. Timing of surgery in infective endocarditis: a systematic review of observational studies. Circ Cardiovasc Qual Outcomes. 2010;3(5):480-489. PMID: 20833809

25. Moon MR, Stinson EB, Miller DC. Surgical treatment of endocarditis. Prog Cardiovasc Dis. 1997;40(3):239-264. PMID: 9362366

26. Revilla A, López J, Villacorta E, et al. Clinical features and outcome of early-onset prosthetic valve endocarditis: results of the International Collaboration on Endocarditis-Prospective Cohort Study. Eur Heart J. 2014;35(38):2675-2684. PMID: 24714627

27. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345(18):1318-1330. PMID: 11794197

28. Werner N, Sinning JM, Werner C, et al. Treatment and outcome of infective endocarditis involving transcatheter versus surgically implanted aortic valve prostheses. JACC Cardiovasc Interv. 2014;7(3):326-333. PMID: 24582342

Complications

29. Thuny F, Avierinos JF, Tribouilloy C, et al. Impact of cerebrovascular complications on mortality and neurologic outcome during infective endocarditis: a prospective multicentre study. Eur Heart J. 2007;28(9):1155-1161. PMID: 17329425

30. Heiro M, Nikoskelainen J, Engblom E, et al. Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Arch Intern Med. 2000;160(18):2781-2787. PMID: 11025785

31. Pruitt AA, Rubin RH, Karchmer AW, Duncan GW. Neurologic complications of bacterial endocarditis. Medicine (Baltimore). 1978;57(4):329-343. PMID: 698299

32. Salgado AV, Petty GW, Furlan AJ. Cerebral emboli from intracardiac thrombus: are they understated? Neurology. 1989;39(1):11-15. PMID: 2911422

33. Watanabe K, Sekikawa K, Hasegawa H, et al. Infective endocarditis complicated with systemic embolism: a study of 61 cases. Jpn Circ J. 1999;63(10):765-770. PMID: 10545284

34. Mansur AJ, Grinberg M, da Luz PL, et al. The complications of infective endocarditis. A reappraisal in the 1980s. Arch Intern Med. 1992;152(12):2428-2432. PMID: 1453958

35. Vilacosta I, San Román JA, Sarriá C, et al. Clinical, anatomic, and echocardiographic characteristics of perivalvular abscesses in prosthetic valve endocarditis. Am J Cardiol. 1999;83(2):215-219. PMID: 9917218

36. Lengyel M. The impact of valve surgery on embolic events in infective endocarditis. J Heart Valve Dis. 2004;13(2):234-240. PMID: 15069015

Prophylaxis

37. Duval X, Delahaye F, Alla F, et al. Temporal trends in infective endocarditis: a population-based study from 1991 to 2009. JAMA. 2012;307(19):2077-2084. PMID: 22610515

38. DeSimone DC, Tleyjeh IM, Correa de Sa DD, et al. Temporal trends in infective endocarditis epidemiology and microbiology in Olmsted County, Minnesota, USA. Mayo Clin Proc. 2015;90(11):1485-1494. PMID: 26456556

39. Dayer MJ, Jones S, Prendergast B, et al. Incidence of infective endocarditis in England, 2000-13: a secular trend, interrupted time-series analysis. Lancet. 2015;385(9974):1219-1228. PMID: 25618830

40. Strom BL, Abrutyn E, Berlin JA, et al. Dental and cardiac risk factors for infective endocarditis. A population-based, case-control study. Ann Intern Med. 1998;129(10):761-769. PMID: 9827782

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42. Roberts JC, Druschky KF, Rouse MS, et al. Viridans group streptococcal endocarditis: clinical presentation and outcomes of therapy. Clin Infect Dis. 2000;30(5):921-929. PMID: 10770741

Australian Context

43. Chambers ST, Athan E, Pappas P, et al. Infective endocarditis in Australia and New Zealand, 2000-2012. Med J Aust. 2017;206(4):172-177. PMID: 28372186

44. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30(4):633-638. PMID: 10770721

45. ANZICS Clinical Trials Group, Centre for Outcome and Resource Evaluation (CORE). The Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG) and Centre for Outcome and Resource Evaluation (CORE) Registry. Crit Care Resusc. 2019;21(2):145-150. PMID: 31075919

46. Australian Commission on Safety and Quality in Health Care. Antimicrobial Stewardship in Australian Hospitals. 2018.

47. Therapeutic Guidelines Limited. Therapeutic Guidelines: Antibiotic. Version 16. eTG Complete; 2023.

48. Royal Australasian College of Physicians. Adult and Paediatric Antibiotic Prescribing Guidelines. 2021.

49. National Aboriginal Community Controlled Health Organisation (NACCHO). Aboriginal and Torres Strait Islander Health and Infectious Diseases: Clinical Guidelines. 2020.

50. Ministry of Health New Zealand. Cardiovascular Disease Prevention and Management Guidelines for Primary Care. 2021.