Infective endocarditis

What is infective endocarditis?¹

Infective endocarditis (IE) is an infection of the endocardium of the heart. Infective endocarditis is a rare, life-threatening disease that has long-lasting effects even among patients who survive and are cured. It disproportionately affects those with underlying structural heart disease and is increasingly associated with patients who have intravascular prosthetic material. Once established, infective endocarditis can involve almost any organ system in the body.

Infective endocarditis produces both intracardiac effects - eg, valvular insufficiency and a wide variety of systemic effects, both from emboli (sterile and infected) and a variety of immunological mechanisms.

It is a disease that is easily overlooked or misdiagnosed and clinicians should be vigilant and well versed in the manifestations of infective endocarditis to avoid missing the diagnosis.

Staphylococcus aureus spp., which has become the predominant causative organism in the developed world, leads to an aggressive form of the disease, often in the vulnerable or elderly.²

• IE occurs worldwide. In recent decades there has been a doubling of the average patient age (the average age is now over 65) and an increased prevalence in patients with indwelling cardiac devices.

• The microbiology of the disease has also changed and staphylococci, most often associated with healthcare contact and invasive procedures, have overtaken streptococci as the most common cause.

• Infective endocarditis has an annual incidence of 3-10 per 100,000 of the general population.

• Healthcare-related infections now account for 25-30% of newly reported cases of endocarditis.

• Figures for incidence are similar between countries. It is twice as common in men compared to women and increasing in elderly patients (25-50% of cases occur in the over-60s) often associated with other disease - eg, diabetes, cancer, alcoholism.

Risk factors for infective endocarditis

Cardiac conditions considered to increase a patient's risk of developing infective endocarditis:^{5 61}

• Valvular heart disease with stenosis or regurgitation.

• Valve replacement.

• Structural congenital heart disease, including surgically corrected or palliated structural conditions, but excluding:

  • Isolated atrial septal defect.

  • Fully repaired ventricular septal defect.

  • Fully repaired patent ductus arteriosus.

  • Closure devices that are judged to be endothelialised.

• Previous IE.

• Hypertrophic cardiomyopathy.

• Current of previous indwelling catheter.

• Recreational drug use.

• Invasive vascular procedures.

• Recent insertion of a pacemaker.

• Rheumatic fever is much less common as a risk factor than in previous years.

All cases have a non-bacterial thrombotic endocarditis (a sterile fibrin-platelet vegetation) as the prerequisite for adhesion and invasion; the healthy endocardium does not usually allow bacteria to seed on it. The site of this thrombus is influenced by the Venturi effect, with deposition of thrombus on the low pressure side. There are differences in the different clinical situations.

Acute infective endocarditis

The thrombus may be produced either by the invading organism or by valvular trauma (pacing wires, catheters, etc) or a change in blood flow eg, turbulent flow around a small ventricular septal defect.

Subacute infective endocarditis

Sufficient inoculum of bacteria required to allow invasion of the thrombus, bacteria clumping with production of agglutinating antibodies.

Non-bacterial thrombotic endocarditis

This can result from, for example, chronic kidney disease, neoplasia, systemic lupus erythematosus (SLE) or malnutrition.

The valves most commonly affected by IE are (in decreasing order of frequency):

• Mitral valve.

• Aortic valve.

• Combined mitral and aortic valve.

• Tricuspid valve.

• Pulmonary valve - rare.

See also the separate Cardiovascular history and examination article.

• The clinical presentation is very variable. A high index of suspicion and low threshold for investigation to exclude infective endocarditis are therefore essential in higher risk groups.

• It may present as an acute, rapidly progressive infection but also as a subacute or chronic disease, with nonspecific symptoms - eg, fatigue, low-grade fever, flu-like illness, polymyalgia-like symptoms, loss of appetite, back pain, pleuritic pain, abdominal symptoms (may be pain, vomiting and appendicitis-like symptoms) and weight loss.

• The majority of patients present with fever, often associated with systemic symptoms of chills, poor appetite and weight loss.

• Heart murmurs are found in under 50% of patients and so lack of a murmur should not rule out the diagnosis.

• Classic textbook signs may still be seen in the developing world but are increasingly uncommon in developed countries because patients present at an early stage of the disease.

• Immunological phenomena, such as splinter haemorrhages, Roth's spots and glomerulonephritis, are now less common but emboli to brain (cerebrovascular accident), lung or spleen occur in 30% of patients and are often the presenting feature.

• May present with congestive cardiac failure

• Atypical presentation (eg, no fever) is more common in the elderly, after antibiotic pre-treatment, in the immunocompromised patient and in IE involving less virulent or atypical organisms.

• The diagnosis of IE should also be considered in patients who present with a stroke or transient ischaemic attack and a fever.

Examination

• Fever: elderly, chronically ill patients with subacute IE may not have fever but the majority do.

• Heart murmurs:

  • Only 15% have the classic 'changing murmur'.

  • The most common murmur is aortic regurgitation.

• Petechiae:

  • Conjunctivae.

  • Hands and feet (dorsum).

  • Chest and abdominal wall.

  • Oral mucosae and soft palate.

• Splinter or subungual haemorrhages: linear and red.

• Osler's nodes: small tender red-to-purple nodules on the pulp of the terminal phalanges of the fingers and toes

• Clubbing: only 10% of cases and usually in long-standing subacute IE.

• Roth's spots: retinal haemorrhages with pale centres.

• Janeway's lesions: irregular painless erythematous macules on the thenar and hypothenar eminence (usually with acute IE and S. aureus).

• Arthritis:

  • With subacute IE, usually asymmetric and up to three joints affected (fluid sterile).

  • Acute IE can give acute septic monoarticular arthritis.

• Splenomegaly: most often observed in long-standing subacute disease and often persisting after treatment.

• Meningism/meningitis: purulent disease occurs in acute IE and aseptic variety in subacute IE.

Criteria for consideration and investigation of possible infective endocarditis⁵

• A febrile illness and a murmur of new valvular regurgitation.

• A febrile illness, a pre-existing at-risk cardiac lesion (see 'Risk factors', above) and no clinically obvious site of infection.

• A febrile illness associated with any of:

  • Predisposition and recent intervention with associated bacteraemia.

  • Evidence of congestive heart failure.

  • New conduction disturbance.

  • Vascular or immunological phenomena: embolic event, Roth's spots, splinter haemorrhages, Janeway's lesions, Osler's nodes.

  • A new stroke.

  • Peripheral abscesses (renal, splenic, cerebral, vertebral) of unknown cause.

• A protracted history of sweats, weight loss, anorexia or malaise and an at-risk cardiac lesion (see 'Risk factors', above).

• Any new unexplained embolic event (eg, cerebral or limb ischaemia).

• Unexplained, persistently positive blood cultures.

• Intravascular catheter-related bloodstream infection with persistently positive blood cultures 72 hours after catheter removal.

Patients present to a variety of specialists who may consider a range of alternative diagnoses, including chronic infection, rheumatological and autoimmune disease or malignancy. Some of the more unusual diseases which may also have similar complex and varied manifestations include:

• SLE.

• Cardiac tumours - eg, atrial myxoma.

• Lyme disease.

• Antiphospholipid syndrome.

• Polymyalgia rheumatica.

• Reactive arthritis.

Presentations that may cause difficulty with diagnosis include:

• Acute meningitis - signs and symptoms but with sterile CSF.

• Hemiplegia from emboli in the middle cerebral artery (50% of patients may be first manifestation; has high mortality).

• Renal infarcts causing painless haematuria.

• Splenic infarction causing pain.

• Sight loss from retinal artery occlusion.

• Myocardial infarction from emboli in the coronary artery.

• Pulmonary emboli.

• Interstitial nephritis or proliferative glomerulonephritis from deposition of circulating immune complexes.

• Acute kidney injury or chronic kidney disease which may result.

• Musculoskeletal symptoms (nearly half of patients) - often from immunologically mediated synovitis.

• Immune-mediated vasculitis (causing Osler's nodes and Roth's spots).

• Palpitations from immune-mediated myocarditis.

• Back pain (15% of patients) may have origin in immune complex deposition in disc spaces.

This is always done in hospital - any patient with suspected IE should be referred to secondary care on the same day. Investigations may include echocardiography, dimensional CT, fluorodeoxy-glucose PET, and leukocyte scintigraphy, as well as bloods such as FBC and CRP to track the progression or infection, as well as blood cultures. The Duke criteria are used to make the diagnosis.

Have a high index of suspicion. Admit any patient with suspected IE to hospital for full investigation. A cardiologist and infection specialist should be closely involved in the diagnosis, treatment and follow-up of patients with IE.

Antimicrobial therapy

Antibiotic management of endocarditis, especially in culture-negative cases, is complex. The choice of regimens and ongoing input should be provided by an infection specialist.⁴

Oral therapy for endocarditis has been used but is rarely advocated in guidelines because of concerns about efficacy. In general, intravenous therapy is recommended to ensure adequate dosing and administration. Occasionally, especially in intravenous drug users, problems obtaining or maintaining safe intravenous access mean that oral therapy may be the safest treatment option. Agents with oral bioavailability that is close to that achieved with intravenous administration can be given. Ciprofloxacin, linezolid and rifampicin have excellent oral bioavailability.

Home/community/outpatient intravenous therapy is an appropriate method for managing selected patients with IE - eg, those who are stable and responding well to therapy without signs of heart failure, have no indications for surgery (see below) and no uncontrolled extracardiac foci of infection. S. aureus is associated with highest mortality and complications, and caution is therefore advised where this is the cause. Ceftriaxone, teicoplanin, daptomycin and vancomycin are suitable agents for home/community/outpatient therapy for endocarditis.

Surgery

A surgical opinion should be sought at the earliest opportunity for every patient with endocarditis affecting intracardiac prosthetic material.

Antibiotics are the standard treatment for native valve infective endocarditis, with surgery primarily reserved for patients with heart failure or inadequate response to antibiotic treatment.

The timing and indications for surgical intervention to prevent systemic embolism in IE remain controversial. A trial to compare clinical outcomes of early surgery and conventional treatment in patients with left-sided IE, severe valve disease and large vegetations found that early surgery in patients with IE and large vegetations significantly reduced mortality from embolic events by effectively decreasing the risk of systemic embolism.⁸

These are an inherent part of the progression of the disease. Potential complications of IE include:⁶¹

Intracardiac complications:

• Myocardial infarction, pericarditis, cardiac arrhythmias.

• Heart valve insufficiency.

• Congestive heart failure.

• Sinus of Valsalva aneurysm.

• Aortic root or myocardial abscesses.

Embolic complications

• Arterial emboli, infarctions, mycotic aneurysms.

• Pulmonary abscesses, pneumonia or empyema.

• Arthritis, myositis.

• Stroke syndromes.

• Glomerulonephritis, acute kidney injury which may be immune-mediated or secondary to emboli.

• Mesenteric or splenic abscess or infarction.

. Predictors of poor outcome include:

• Patient characteristics: older age, prosthetic valve IE, diabetes, comorbidity (eg, frailty, immunosuppression, renal or pulmonary disease).

• Clinical complications of IE: heart failure, renal failure, greater than moderate area of ischaemic stroke, brain haemorrhage, septic shock.

• Micro-organism: S. aureus, fungi, non-HACEK Gram-negative bacilli.

• Echocardiogram findings: peri-annular complications, severe left-sided valve regurgitation, low left ventricular ejection fraction, pulmonary hypertension, large vegetations, severe prosthetic valve dysfunction, premature mitral valve closure and other signs of elevated diastolic pressures.

Mortality

• Increased mortality rates are associated with increased age, infection involving the aortic valve, development of congestive heart failure, central nervous system complications and underlying disease - eg, diabetes.

• Mortality rates also vary with the infecting organism:

  • Acute endocarditis due to S. aureus is associated with a high mortality rate (30-40%), except when it is associated with intravenous drug use.

  • Endocarditis due to streptococci has a mortality rate of approximately 10%.

• Those with prosthetic valve endocarditis in the first two months after valve surgery have in-hospital mortality of 30%, with an average in-hospital mortality for all causes of 18% and average one-year mortality of 40%.

Guidelines on antibiotic prophylaxis were updated in 2023. Prophylaxis should be considered in those who have any of the following conditions and the relevant guidelines consulted. The professional carrying out the procedure should make the decision about prophylaxis - for example, a dentist should make their own decision and not pass this decision-making responsibility to the GP.

High risk:

• A history of IE.

• A prosthetic valve made of any material.

• Congenital heart disease other than congenital valve abnormalities.

• Ventricular assist devices.

Intermediate risk

• Rheumatic heart disease.

• Non-rheumatic degenerative valve disease.

• Congenital valve abnormalities.

• Cardiovascular implanted electronic devices.

• Hypertrophic cardiomyopathy.

See the separate Prevention of infective endocarditis article.