L09 I&I Infective endocarditis

Overview

This lecture covers infective endocarditis (IE): how bacteraemia can seed the endocardium, the bacteria-platelet-endothelium interaction that builds a vegetation, the acute/subacute/device-associated clinical patterns and their causative organisms, risk factors, clinical signs and complications, diagnosis by modified Duke criteria (including blood culture as the key diagnostic tool), treatment principles for a biofilm infection, and the causal chain linking untreated group A streptococcal infection through rheumatic fever (RF) and rheumatic heart disease (RHD) to IE, with its socioeconomic burden in Aotearoa New Zealand.

Bacteraemia, sepsis and blood culture

• Bacteraemia (bacteria in blood) commonly follows mucosal trauma or secondary infection. In health it is usually transient and cleared by a regulated, localised response, but in a susceptible host it can cause disease: osteomyelitis, meningitis, Yours/Medwiki/Block/CVS/Reference/Disease/Infective endocarditis (IE).
• Septicaemia/sepsis is a pathological, unregulated, generalised intravascular inflammatory response to bacteraemia. Pro-inflammatory effects include vasodilation, DIC, thrombosis, embolism, ischaemia, haemorrhagic necrosis, hypoperfusion, organ failure and death. Sepsis is described as poorly defined clinically.
• Blood is normally sterile, so any organism recovered is potentially significant, but skin-microbiome organisms such as S. epidermidis are usually contaminants; the same organism is an important cause of healthcare-associated bloodstream infection (HA-BSI), especially catheter-associated BSI (CVC, PICC, IV lines); clinical presentation is used to distinguish contamination from true infection.
• Pyrexia of unknown origin (PUO) is the most common reason blood cultures are taken. Samples should be taken before empiric therapy where possible.
• To maximise the chance of isolating an organism: take 3-4 sets over 24 hours, from multiple different sites and at different times of day; if the patient is critically ill, take 3 sets within 1 hour. Culture can take days, so initial therapy must be empiric.
  • A set = 2 bottles (1 aerobic, 1 anaerobic).
  • Special consideration for paediatric patients, fungi and TB.

IE: definition and clinical patterns

• IE is infection of the endocardium, characterised by vegetations (thrombus plus microbes) on native or prosthetic valves, or on devices.
• Acute (short incubation) IE: rapid course over days to weeks; affects previously normal valves; caused by virulent pathogens producing necrotising, ulcerative, destructive lesions; often difficult to treat with antimicrobials alone and may need surgery; significant mortality even with appropriate treatment. Presents as fever with a new or changing cardiac murmur.
• Subacute (long incubation) IE: prolonged course over weeks to months; affects previously damaged valves; caused by lower-virulence organisms in a susceptible host; onset insidious with less specific symptoms (low-grade fever which may be absent, anaemia, weight loss); generally responds to antimicrobials; also associated with a change in murmur.
• Whether IE is acute or subacute reflects the virulence of the infecting organism: S. aureus (more virulent) causes acute IE, often on previously healthy valves; viridans streptococci (less virulent) cause subacute IE and require pre-existing vegetations on previously damaged valves.

Aetiology

• S. aureus: most common cause of acute IE globally; affects native or prosthetic valves.
• S. epidermidis: associated with prosthetic valves/devices (device-associated IE).
• Viridans streptococci: low virulence, part of the oral microbiome; most common cause of subacute IE, and the most common cause of IE in NZ overall.
• Enterococci: cause of healthcare-associated IE following GI/GU procedures; also affect prosthetic valves.
• Together these organisms account for >80% of IE, and are gram-positive cocci.
• Less common causes:
  • HACEK group: gram-negative oropharyngeal organisms, difficult to culture, a suspected cause of culture-negative IE. HACEK = Haemophilus spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, Kingella spp.
  • Other gram-negative bacteria (e.g. E. coli, Pseudomonas), associated with IDU or immunocompromise.
  • Fungi (e.g. Candida), associated with ICU/immunocompromised patients, IDU, and prosthetic valves.

Risk factors

• Age >60 years; male sex (males > females).
• Heart/valvular disease: RHD, mitral valve prolapse, congenital defects, degenerative calcific stenosis, previous IE.
• Prosthetic heart valve, pacemaker or implantable defibrillator: S. aureus, S. epidermidis and Enterococci form biofilms on these devices.
• Dialysis, intravascular devices, IDU: all routes to bacteraemia.
• Immunocompromise: diabetes, HIV, cancer, elderly.

Pathogenesis

Bacteria-platelet-endothelium interaction (general mechanism)

1. Adhesion: bacteria bind to receptors on platelets via integrins, glycoproteins, TLRs, or bridge via vWF.
2. Activation: binding upregulates further receptor expression on the platelet and promotes fibrinogen/fibrin binding to platelet integrins.
3. Aggregation: coagulation produces a fibrin clot; the resulting infected vegetation functions as a biofilm.

• Platelets are separately attracted to and activated by areas of endocardial damage (via collagen binding); bacterial presence increases vegetative growth through fibrin and platelet deposition.
• Macro- or microemboli may be released from the vegetation, and deposition of immune complexes can occur, particularly in the kidneys, causing glomerulonephritis.

Subacute IE pathway

Pre-existing valve damage → deposition of platelets/fibrin forms a sterile vegetation → bacteraemia allows bacterial adhesion to platelets → the infected vegetation (platelets, fibrin, bacteria as a biofilm) is protected from neutrophils, complement and antimicrobials → platelet activation → aggregation, with progressively more platelet and fibrin deposition.

Acute IE pathway

Virulent bacteria (S. aureus) do not require pre-existing valve damage. Specialised virulence factors act directly: adhesins bind directly to the valve, and toxins/enzymes cause cell death and inflammation, producing necrotising, ulcerative, destructive lesions and a rapid clinical course.

Device-associated IE

S. epidermidis, S. aureus or Enterococcus (from skin/mucous membrane microbiome) cause biofilm infection of prosthetic valves or pacemaker/defibrillator pacing wires: platelets and fibrin deposit on the sewing ring or pacing wire (conditioning film/thrombus), a vegetation forms, and bacteria adhere to establish IE.

Downstream consequences of the vegetation

• Vegetations occur most commonly on heart valves: typically left-sided (aortic > mitral), rarely right-sided (tricuspid > pulmonary).
• Bacteria released into the bloodstream cause bacteraemia, which can lead to metastatic infection and sepsis.
• Septic emboli can cause septic infarcts: vessel occlusion causing ischaemia plus seeding of infection at the occlusion site.
• Immune complexes can deposit in the basement membrane, causing glomerulonephritis.
• Locally, a vegetation can cause a ring abscess.

Clinical signs and complications

• Fever (as PUO) is the most common sign; in subacute IE, the elderly and debilitated it may be intermittent, low-grade, or absent.
• New or changing heart murmur, often not detected at initial examination.
• Non-specific features (not always present, variable): chills, malaise, anorexia, weight loss, myalgia, arthralgia, dyspnoea, cough, abdominal pain, nausea, vomiting, elevated ESR/CRP/RF.
• Traditional signs (now often absent): Janeway lesions, Osler’s nodes, Roth spots, splinter haemorrhages.
• Complications, which may be the presenting symptom:
  • Cardiac: CHF, valvular insufficiency, MI, ring abscesses.
  • Neurological: embolic stroke, intracerebral haemorrhage, abscesses.
  • Septic emboli to kidneys, spleen, liver, lungs, skin, gut.
  • Metastatic infection: osteomyelitis, septic arthritis, sepsis.
  • Glomerulonephritis leading to renal failure.
  • Pulmonary: embolism, abscesses, pneumothorax, effusion, empyema.

Diagnosis

• Diagnosis is based on the modified Duke criteria, combining clinical assessment (risk factors, physical exam), microbiology and echocardiogram.
• Positive diagnosis requires: 2 major criteria, OR 1 major + 3 minor criteria, OR 5 minor criteria.
• Major criteria include:
  • 2 separate positive blood cultures with organisms typical of IE (viridans streptococci, Streptococcus bovis, HACEK group, S. aureus, community-acquired enterococci); ~90% of cases are blood culture positive if 3 sets are taken.
  • Echocardiographic evidence of endocardial involvement (typical valvular lesions: vegetation, abscess, new partial dehiscence of a prosthetic valve) or new valvular regurgitation.
• Minor criteria include: a predisposing heart condition or IV drug use; temperature >38.0°C; vascular phenomena (major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial haemorrhage, conjunctival haemorrhage, Janeway lesions); immunological phenomena (glomerulonephritis, Osler’s nodes, Roth spots, rheumatoid factor); microbiological evidence (positive blood culture not meeting the major criterion, or serologic evidence of active infection with an organism consistent with IE).
• Culture-negative results (~10% of cases) do not exclude IE: can reflect atypical/fastidious organisms (e.g. HACEK) or prior antimicrobial therapy; PCR and serology are used in this situation.

The minor-criteria table text on the Duke criteria slide was partly difficult to resolve at rendered resolution and is transcribed as best legible; treat the exact minor-criteria wording above as approximate.

Treatment

• Acute IE: treatment is initially empiric, based on the likely cause (commonly S. aureus), guided by clinical history, risk factors and physical exam.
• Subacute IE: can wait for blood culture results before starting targeted therapy.
• IE is a biofilm infection, so it is difficult to treat: therapy is prolonged (2-6 weeks), high dose, bactericidal, and given IV.
• Staphylococci:
  • Native valve: flucloxacillin.
  • Prosthetic valve: flucloxacillin (+/- rifampicin and gentamicin).
  • Methicillin-resistant S. aureus/S. epidermidis: vancomycin.
• Streptococci: penicillin +/- gentamicin.
• Surgery (to repair or replace the damaged valve) may be needed for acute IE, prosthetic valve IE, or fungal IE.

Rheumatic fever, rheumatic heart disease and IE

• Rheumatic fever (RF) is an autoimmune inflammatory process that is a sequela of untreated Streptococcus pyogenes (group A strep, GAS) pharyngitis, or skin infections in high-risk populations.
• 95% of RF occurs in low/middle-income countries; in high-income countries it clusters in socioeconomic risk groups, in NZ particularly Māori and Pacific Peoples.
• Affects children aged 5-14 years typically (NZ risk group extended to 3-35 years); around 20% of first-time cases occur in adults.
• Pathogenesis: molecular mimicry (a type II hypersensitivity reaction), in which antibodies raised against the M protein of S. pyogenes cross-react with self-proteins, producing inflammation in joints and heart.
• New Zealand epidemiology (2023): 183 cases (3.5 per 10^5), versus <0.1 per 10^5 in high-income countries generally; concentrated in North Island regions (Counties-Manukau, Hutt Valley, Lakes, Bay of Plenty); Māori (45%) and Pacific Peoples (52%) most affected, linked to socioeconomic factors: damp/mouldy and overcrowded housing, bed sharing, frequent GAS/respiratory tract infections, and limited access to healthcare. Most affected age group is 10-14 years (more than 5-9 years); males and females equally affected. Recurrent cases disproportionately affect Māori and Pacific Peoples. Notification rates rose from roughly 75-100/year in 2004 to a peak of around 190-200 around 2013, fell during the COVID period (~2020-2021, reduced due to mask use, isolation, distancing and reduced access to physicians), then rose again toward 2022 (back to roughly 170-180). [slide notes actual rates are probably higher than reported, since figures reflect diagnosed and reported cases only]
• Rheumatic heart disease (RHD) is the most serious complication of RF, affecting the mitral and/or aortic valve: causes >500 hospitalisations/year and ~150 deaths/year in NZ.
  • Fibrosis and calcification of the valve affect blood flow: valve incompetence, stenosis or regurgitation, damage to valves, and thrombosis leading to vegetation formation.
  • Shortening and thickening of the heart cords (chordae), and can progress to congestive heart failure.
  • Recurrent RF inflammation worsens scarring and fibrosis, which increases the risk of subsequently developing IE.
• Causal chain (subacute IE via RF/RHD): S. pyogenes pharyngitis or skin infection → cross-reactive anti-M protein antibodies cause inflammation → rheumatic fever → with repeated attacks → rheumatic heart disease, i.e. autoimmune-mediated valve damage with deposition of platelets/fibrin forming a vegetation → over years, and separately seeded by transient bacteraemia with viridans streptococci → colonisation of the valve vegetation → subacute infective endocarditis → complications/presenting symptoms, with the organism recoverable from blood culture.

Self-test

1. Distinguish bacteraemia from septicaemia/sepsis.
2. Describe the recommended blood culture sampling strategy for a stable patient with PUO, and how this changes if the patient is critically ill.
3. Distinguish acute from subacute IE in terms of course, valve status, organism virulence and response to antimicrobials.
4. A patient with previously healthy heart valves develops fever and a new murmur over a few days, progressing rapidly. Which organism is most likely responsible, and why does this pattern occur without pre-existing valve damage?
5. List the main organisms causing IE, with one clinical association for each (e.g. valve type or setting).
6. What is the HACEK group, and why is it clinically significant in IE diagnosis?
7. List the major risk factor categories for IE.
8. Describe the three steps of the bacteria-platelet interaction that builds a vegetation.
9. Describe the pathogenesis of subacute IE from pre-existing valve damage to established infected vegetation.
10. Explain how an infected vegetation can lead to glomerulonephritis and to a septic infarct.
11. What are the modified Duke criteria combinations required for a positive diagnosis of IE, and name two major and two minor criteria.
12. Why does a negative blood culture not exclude a diagnosis of IE, and what alternative tests can be used?
13. Outline first-line treatment for native valve staphylococcal IE versus streptococcal IE, and explain why therapy must be prolonged, high dose and IV.
14. Describe the pathogenesis of rheumatic fever, including the immunological mechanism linking S. pyogenes infection to tissue damage.
15. Trace the full causal pathway from S. pyogenes pharyngitis to subacute infective endocarditis via rheumatic fever and rheumatic heart disease.
16. Why are Māori and Pacific Peoples disproportionately affected by rheumatic fever in New Zealand?

Answers

Reveal answers

1. Bacteraemia is bacteria present in the blood, usually transient and cleared by a regulated, localised response, though it can cause disease (e.g. osteomyelitis, meningitis, IE) in a susceptible host. Septicaemia/sepsis is a pathological, unregulated, generalised intravascular inflammatory response to bacteraemia, producing effects such as vasodilation, DIC, thrombosis, embolism, ischaemia, haemorrhagic necrosis, hypoperfusion and organ failure; it is described as poorly defined clinically.
2. Take 3-4 sets of blood cultures over 24 hours, from multiple different sites and at different times of day, ideally before starting empiric therapy. Each set is 2 bottles (1 aerobic, 1 anaerobic). If the patient is critically ill, take 3 sets within 1 hour instead. Because culture can take days, initial treatment must be empiric.
3. Acute IE: rapid course (days-weeks), affects previously normal valves, caused by virulent organisms producing necrotising/ulcerative/destructive lesions, often difficult to treat with antimicrobials alone (may need surgery), significant mortality. Subacute IE: prolonged course (weeks-months), affects previously damaged valves, caused by lower-virulence organisms, generally responds to antimicrobials.
4. S. aureus. It is highly virulent and carries specialised virulence factors: adhesins that bind directly to the valve, and toxins/enzymes that cause cell death and inflammation, so it does not need pre-existing platelet/fibrin deposition to establish infection, producing rapid, destructive disease.
5. S. aureus: most common cause of acute IE, native or prosthetic valves. S. epidermidis: prosthetic valves/devices (device-associated IE). Viridans streptococci: low virulence, most common cause of subacute IE (and of IE overall in NZ). Enterococci: healthcare-associated IE after GI/GU procedures, and prosthetic valves. HACEK group, other gram-negatives, and fungi (e.g. Candida) are less common causes, associated with IDU, immunocompromise, or prosthetic valves.
6. HACEK is a group of gram-negative oropharyngeal organisms (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella corrodens, Kingella). They are difficult to culture, making them a suspected cause of culture-negative IE.
7. Age >60 years; male sex; underlying heart/valvular disease (RHD, mitral valve prolapse, congenital defects, degenerative calcific stenosis, previous IE); prosthetic valve/pacemaker/implantable defibrillator; dialysis/intravascular devices/IDU (routes to bacteraemia); immunocompromise (diabetes, HIV, cancer, elderly).
8. Adhesion: bacteria bind platelet receptors (integrins, glycoproteins, TLRs) or bridge via vWF. Activation: this upregulates further platelet receptor expression and promotes fibrinogen/fibrin binding to platelet integrins. Aggregation: coagulation forms a fibrin clot, and the resulting infected vegetation functions as a biofilm.
9. Pre-existing valve damage leads to deposition of platelets and fibrin, forming a sterile vegetation. Bacteraemia then allows bacterial adhesion to the platelets within this vegetation. The resulting infected vegetation (platelets, fibrin, bacteria) forms a biofilm that is protected from neutrophils, complement and antimicrobials. Platelet activation follows, then aggregation, with progressively more platelet and fibrin deposition building the vegetation further.
10. Immune complexes shed from the infected vegetation can deposit in the renal basement membrane, triggering glomerulonephritis. Separately, septic emboli released from the vegetation can lodge in a vessel, causing occlusion (ischaemia) at that site plus seeding of infection there, i.e. a septic infarct.
11. Positive diagnosis requires 2 major criteria, or 1 major plus 3 minor criteria, or 5 minor criteria. Major criteria (any two): 2 separate positive blood cultures with an organism typical of IE, and echocardiographic evidence of endocardial involvement (vegetation, abscess, new prosthetic valve dehiscence) or new valvular regurgitation. Minor criteria (any two): predisposing heart condition or IV drug use, and temperature >38.0°C (vascular phenomena and immunological phenomena are also minor criteria).
12. Around 10% of true IE cases have negative blood cultures, which can occur with atypical/fastidious organisms (e.g. HACEK) or after prior antimicrobial therapy. PCR and serology can be used as alternative diagnostic tools in this situation.
13. Native valve staphylococcal IE: flucloxacillin (vancomycin if methicillin-resistant). Streptococcal IE: penicillin +/- gentamicin. Because IE is a biofilm infection, organisms are protected within the vegetation, so treatment must be prolonged (2-6 weeks), high dose, bactericidal and given IV to achieve adequate penetration and killing.
14. Rheumatic fever follows untreated S. pyogenes (GAS) pharyngitis or skin infection. It arises through molecular mimicry, a type II hypersensitivity reaction: antibodies raised against the bacterial M protein cross-react with self-proteins, causing inflammation in the joints and heart.
15. S. pyogenes pharyngitis/skin infection triggers cross-reactive anti-M protein antibodies causing inflammation, leading to rheumatic fever; repeated attacks cause rheumatic heart disease (autoimmune-mediated valve damage with platelet/fibrin deposition forming a vegetation). Over years, this damaged valve is seeded by transient bacteraemia with viridans streptococci, leading to colonisation of the valve vegetation, which develops into subacute infective endocarditis, presenting with complications and with the organism recoverable from blood culture.
16. Socioeconomic factors concentrated in these groups in NZ: damp, mouldy and overcrowded housing, bed sharing, frequent GAS/respiratory tract infections, and limited access to healthcare, which together increase both initial and recurrent RF episodes.