1. Infective (septic) endocarditis
   • Infection of the endocardial surface, usually heart valves.
   • Covers causes and risk factors, clinical signs, blood cultures, echocardiography, Duke criteria, complications, antimicrobial treatment, and indications for surgery.
2. Aortic valve defects
   • Mainly aortic stenosis and aortic regurgitation.
   • Includes causes, murmur findings, symptoms, ECG/echo findings, complications, and medical versus surgical management.
3. Types of hypersensitivity reactions
   • Gell and Coombs Types I-IV:
     • Type I: immediate, IgE-mediated allergy/anaphylaxis
     • Type II: antibody-mediated cytotoxic reaction
     • Type III: immune-complex disease
     • Type IV: delayed, T-cell-mediated reaction
   • Important examples and mechanisms are usually asked in exams.
4. Why PR prolongation occurs
   • PR interval represents conduction from atria through the AV node to ventricles.
   • PR prolongation usually means delayed AV nodal conduction, classically first-degree AV block.
   • Causes include increased vagal tone, drugs such as beta-blockers/verapamil/diltiazem/digoxin, ischemia, myocarditis, electrolyte disturbance, and AV-node disease. In infective endocarditis, a newly prolonged PR interval can suggest a periannular or aortic-root abscess affecting the conduction system.

1. Infective endocarditis
   • Definition and pathogenesis
   • Causative organisms and risk factors
   • Clinical features and peripheral stigmata
   • Blood cultures and echocardiography
   • Modified Duke diagnostic criteria
   • Complications, including heart failure, emboli, abscess, and conduction defects
   • Principles of antibiotic therapy and surgery
2. Aortic valve defects
   • Aortic stenosis: causes, symptoms, pulse and murmur, ECG/echo, complications, treatment
   • Aortic regurgitation: causes, acute versus chronic disease, clinical signs, murmur, investigations, treatment
   • Key differences between stenosis and regurgitation
3. Hypersensitivity reactions
   • Type I: IgE-mediated immediate reaction
   • Type II: antibody-mediated reaction
   • Type III: immune-complex reaction
   • Type IV: delayed T-cell-mediated reaction
   • Mechanisms, onset, examples, pathology, and comparison table
4. PR-interval prolongation
   • Normal cardiac conduction and PR interval
   • First-degree AV block and causes
   • Drug-, metabolic-, and heart disease-related causes
   • Importance in infective endocarditis: possible aortic-root/perivalvular abscess
   • ECG interpretation and clinical relevance

Infective Endocarditis (IE)

1. Definition

2. Types and classification

A. According to clinical course

B. According to site/device

• Native-valve endocarditis (NVE): infection of a natural valve.
• Prosthetic-valve endocarditis (PVE): infection involving an artificial valve. It may involve the sewing ring and cause paravalvular abscess or dehiscence.
• Cardiac-device-related IE: pacemaker lead, implantable cardioverter-defibrillator lead, or other intracardiac-device infection.
• Right-sided IE: usually tricuspid valve, often associated with injection drug use, central venous catheters, or device leads.
• Left-sided IE: mitral or aortic valve. It is more common and often produces systemic emboli.
• Culture-negative IE: clinical IE in which routine blood cultures fail to grow an organism, commonly because antibiotics were given before cultures or due to fastidious organisms.

3. Etiology: causative organisms

1. Staphylococci
2. Streptococci
3. Enterococci

Important organism-clinical associations

4. Predisposing factors and risk factors

Cardiac risk factors

• Previous infective endocarditis
• Prosthetic heart valve
• Previous valve repair with prosthetic material
• Congenital heart disease
• Rheumatic valvular heart disease
• Mitral valve prolapse with significant regurgitation
• Bicuspid aortic valve
• Degenerative/calcific valve disease
• Hypertrophic cardiomyopathy with obstruction
• Intracardiac electronic devices

Non-cardiac risk factors

• Injection drug use
• Long-term intravenous catheter or haemodialysis catheter
• Recent invasive healthcare procedure
• Haemodialysis
• Diabetes mellitus
• Immunosuppression or malignancy
• Poor dental hygiene or dental infection
• Skin and soft-tissue infection
• Previous IE

5. Pathogenesis

1. Endocardial injury
   • Turbulent blood flow across an abnormal valve or congenital lesion damages endothelium.
   • Foreign material, such as a prosthetic valve or lead, can also promote injury and bacterial adherence.
2. Formation of sterile platelet-fibrin thrombus
   • Platelets and fibrin deposit at the damaged surface.
   • This is termed non-bacterial thrombotic endocarditis before infection develops.
3. Transient or persistent bacteraemia
   • Bacteria enter the bloodstream from oral, skin, gastrointestinal, genitourinary, catheter, or injection-related sources.
4. Adherence of microorganisms
   • Organisms bind to the platelet-fibrin deposit through adhesins and biofilm-related mechanisms.
5. Vegetation formation
   • Vegetations enlarge, contain organisms protected from host defences, and have poor antibiotic penetration.
6. Local destruction and systemic spread
   • Valvular perforation, regurgitation, annular abscess, conduction defects, septic emboli, immune-complex disease, and metastatic infection may follow.

6. Pathology and morphology

Vegetation

• Fibrin
• Platelets
• Microorganisms
• Inflammatory cells
• Necrotic material

Consequences of vegetation

• Valve leaflet destruction or perforation
• Rupture of chordae tendineae
• Acute severe valvular regurgitation
• Ring abscess or aortic-root abscess
• Dehiscence of a prosthetic valve
• Embolization of vegetation fragments
• Mycotic aneurysm formation

7. Clinical features

Constitutional symptoms

• Fever, often persistent
• Chills and sweats
• Malaise and fatigue
• Loss of appetite
• Weight loss
• Myalgia and arthralgia
• Back pain, abdominal pain, or focal bone pain, which may indicate embolic or metastatic infection

Cardiac manifestations

• New murmur or changing pre-existing murmur
• Acute heart failure due to severe mitral or aortic regurgitation
• Conduction disturbance, including PR prolongation or AV block
• Chest pain due to coronary embolism
• Pericarditis, rarely

Peripheral stigmata

• Osler = painful
• Janeway = painless

8. Right-sided versus left-sided IE

9. Complications

A. Cardiac complications

1. Heart failure
   • Most important and frequent serious complication.
   • Usually due to severe acute regurgitation from leaflet perforation, rupture, or destruction.
   • Aortic valve IE is particularly likely to cause rapidly progressive heart failure.
2. Perivalvular extension
   • Annular abscess
   • Aortic-root abscess
   • Pseudoaneurysm
   • Fistula
   • Prosthetic valve dehiscence
3. Conduction abnormalities
   • New PR prolongation, AV block, or bundle branch block can signify extension of infection into the conduction tissue.
   • In aortic-valve IE, new PR prolongation should raise concern for an aortic-root abscess.
4. Acute valvular regurgitation
   • Mitral or aortic leaflet perforation or rupture causes sudden severe regurgitation and pulmonary oedema.

B. Embolic complications

• Ischaemic stroke or brain abscess
• Splenic infarction or splenic abscess
• Renal infarction
• Limb ischaemia
• Mesenteric ischaemia
• Coronary artery embolism causing myocardial infarction
• Mycotic aneurysm

• Septic pulmonary emboli
• Pulmonary infarcts/abscesses
• Pleuritic chest pain
• Haemoptysis

C. Renal complications

• Immune-complex glomerulonephritis
• Renal infarction from emboli
• Drug-related renal injury
• Acute kidney injury in severe sepsis

D. Metastatic infection

• Vertebral osteomyelitis/discitis
• Septic arthritis
• Splenic abscess
• Renal abscess
• Brain abscess
• Meningitis

10. Diagnosis

1. Clinical suspicion
2. Blood cultures
3. Echocardiography and other imaging
4. Duke-ISCVID diagnostic criteria
5. Histopathology/culture of valve or embolic material, when available

11. Blood cultures

Essential rule

Standard approach

• Take at least three sets of blood cultures.
• Obtain them from separate peripheral venepuncture sites.
• Do not wait for a fever spike because IE usually produces continuous bacteraemia.
• Each adult set generally includes aerobic and anaerobic bottles.

Causes of culture-negative IE

• Antibiotics administered before cultures
• Fastidious bacteria, including HACEK organisms
• Coxiella burnetii
• Bartonella species
• Brucella
• Fungi
• Non-infective mimics, such as marantic endocarditis or Libman-Sacks endocarditis

12. Echocardiography and imaging

Transthoracic echocardiography, TTE

• Usually first-line.
• Non-invasive.
• Can identify large vegetations, valvular regurgitation, ventricular function, and some complications.
• Less sensitive for small vegetations, prosthetic valves, abscesses, obesity, and device-related IE.

Transoesophageal echocardiography, TEE/TOE

• More sensitive than TTE for:
  • Small vegetations
  • Prosthetic-valve IE
  • Device-lead IE
  • Perivalvular abscess
  • Aortic-root complications
  • Valve dehiscence

Additional imaging

• Cardiac CT: assesses abscess, pseudoaneurysm, fistula, and prosthetic-valve complication.
• FDG-PET/CT: especially useful in prosthetic-valve or cardiac-device infection and for detecting metastatic foci.
• Brain CT/MRI: detects embolic stroke, hemorrhage, abscess, or mycotic aneurysm.
• CT chest/abdomen: can identify lung, splenic, renal, or other embolic complications.

13. Duke-ISCVID criteria

Major criteria

1. Microbiological evidence

• Two separate blood cultures, or
• Persistently positive blood cultures

• S. aureus
• Viridans group streptococci
• Streptococcus gallolyticus
• HACEK organisms
• Enterococcus faecalis
• Community-acquired enterococci without an alternative primary focus

2. Evidence of endocardial involvement

• Vegetation on echocardiography
• Abscess, pseudoaneurysm, perforation, or fistula
• New partial prosthetic-valve dehiscence
• New significant valvular regurgitation
• Abnormal uptake around prosthetic material on appropriate nuclear imaging

Minor criteria

• Predisposing condition or injection drug use
• Fever at least 38°C
• Vascular phenomena: arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, Janeway lesions
• Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor
• Microbiological evidence not satisfying a major criterion

Interpretation, traditional form

• Definite IE: 2 major, or 1 major plus 3 minor, or 5 minor criteria.
• Possible IE: 1 major plus 1 minor, or 3 minor criteria.
• Rejected IE: alternative diagnosis, symptoms resolve quickly with short antibiotic therapy, or criteria are not met.

14. Laboratory findings

• Raised CRP and ESR
• Normocytic normochromic anaemia
• Leukocytosis, especially in acute IE
• Elevated rheumatoid factor
• Positive circulating immune complexes
• Microscopic haematuria/proteinuria
• Elevated creatinine if renal involvement
• Thrombocytopenia or coagulopathy in severe sepsis

15. Treatment principles

A. Obtain cultures first

B. Start empirical intravenous antibiotic therapy if indicated

• Native versus prosthetic valve
• Community- versus healthcare-associated infection
• Acute versus subacute illness
• Risk of MRSA
• Renal function
• Local microbiological resistance patterns
• Whether the patient is septic or haemodynamically unstable

C. Give pathogen-directed therapy

• Organism
• Native or prosthetic valve
• Susceptibility pattern
• Presence of abscess or metastatic infection
• Whether surgery occurs

• MSSA: use an anti-staphylococcal beta-lactam when appropriate.
• MRSA: treatment commonly includes vancomycin or another active anti-MRSA agent according to local guidance.
• Viridans streptococci: penicillin/ceftriaxone-based treatment depending on susceptibility.
• Enterococcal IE: requires bactericidal combination therapy and careful renal monitoring.
• Fungal IE: often needs antifungal therapy plus surgery.

D. Monitor response

• Clinical status: fever, heart failure, emboli, neurological symptoms
• Serial blood cultures until sterile
• Renal function and drug levels when required
• CRP/other inflammatory markers
• Repeat echocardiography when clinical deterioration or complication is suspected

16. Indications for surgery

1. Heart failure due to valve dysfunction

• Acute severe aortic or mitral regurgitation
• Pulmonary oedema
• Cardiogenic shock
• Prosthetic-valve dehiscence with severe regurgitation

2. Uncontrolled infection

• Perivalvular or aortic-root abscess
• Persistent bacteraemia or sepsis despite appropriate therapy
• Fungal IE
• Highly resistant organisms
• Enlarging vegetation
• Pseudoaneurysm, fistula, or infected prosthetic material

3. Prevention of embolism

• Large, mobile vegetations, particularly after one or more embolic events
• Recurrent embolization despite therapy
• Vegetation size and valve location are considered along with operative risk

17. Prevention and antibiotic prophylaxis

General prevention

• Good oral hygiene and regular dental care
• Prompt treatment of skin, dental, and other infections
• Strict aseptic technique for vascular lines and invasive procedures
• Avoid injection drug use
• Patient education for those with prosthetic valves or previous IE

Who may need antibiotic prophylaxis before certain dental procedures?

• Previous IE
• Prosthetic valve or prosthetic material used for valve repair
• Certain high-risk congenital heart diseases
• Some cardiac-transplant recipients with valvular disease

18. High-yield clinical pearls

• Persistent fever + new murmur + positive blood cultures = think IE.
• S. aureus can infect a normal valve and commonly causes acute destructive IE.
• Viridans streptococci usually cause subacute IE on a damaged valve.
• Three blood-culture sets before antibiotics is a key examination and clinical point.
• TEE is more sensitive than TTE, particularly for prosthetic valves, device-related IE, and abscesses.
• Painful Osler nodes are immunologic. Painless Janeway lesions are embolic.
• Right-sided IE produces septic pulmonary emboli. Left-sided IE produces systemic emboli.
• A new PR prolongation or AV block, particularly with aortic-valve IE, suggests possible aortic-root/perivalvular abscess.
• Heart failure is a major cause of mortality and a common reason for urgent surgery.
• S. gallolyticus bacteraemia or IE should prompt evaluation for a colorectal lesion.
• Negative cultures do not exclude IE, particularly after antibiotics or with fastidious organisms.