Endocarditis

01Definition and overview

Infective endocarditis is an infection of the endocardial surface of the heart: the valves most often, but also the mural endocardium, the great intrathoracic vessels and foreign material such as prosthetic valves, pacemaker and defibrillator leads and surgical conduits. Its hallmark is the vegetation, a mass of platelets and fibrin full of organisms.

It is described by where it lies and how it was acquired, because these predict the organism and the treatment:

• native valve endocarditis, on the patient's own valve;
• prosthetic valve endocarditis, early (within a year of the operation, usually from hospital organisms) or late;
• endocarditis on a cardiac implantable electronic device, a pacemaker or defibrillator lead;
• right-sided endocarditis, mostly in people who inject drugs;
• community-acquired or healthcare-associated.

The older division into acute endocarditis (a fulminant illness over days, typically Staphylococcus aureus) and subacute endocarditis (weeks of low fever and malaise, typically oral streptococci) still describes the tempo well.

Non-infective endocarditis grows sterile vegetations: marantic endocarditis (non-bacterial thrombotic endocarditis) in advanced cancer and other hypercoagulable states, and Libman–Sacks endocarditis in lupus and the antiphospholipid syndrome. Both embolise.

02Etiology and pathophysiology

How a vegetation forms

1. 1

   A damaged surface

   Turbulent flow and jets (a regurgitant valve, a ventricular septal defect, a patent ductus), degenerate valves, catheters and prosthetic material damage the endothelium. Platelets and fibrin settle on it as a small sterile thrombus.
2. 2

   Organisms in the blood

   Bacteria enter the blood briefly many times a day from chewing and tooth brushing, and in larger numbers from dental and other procedures, intravenous lines, skin infections, injected drugs and infections of the gut and urinary tract.
3. 3

   Adhesion

   Streptococci and staphylococci carry surface proteins that bind fibrin, fibronectin and platelets, so they stick to the thrombus. Staphylococcus aureus can also invade intact endothelium, which is why it infects normal valves.
4. 4

   A protected colony

   The organisms multiply inside layers of fibrin and platelets, in a biofilm, out of reach of phagocytes and slowed in their metabolism. This is why cure needs high doses of bactericidal antibiotics for weeks.

What the infection does

• Local destruction: the cusps perforate, the chordae rupture and the valve leaks, causing heart failure. Infection can spread beyond the valve as a perivalvular abscess, a pseudoaneurysm or a fistula, and an abscess of the aortic root can reach the conduction tissue and cause heart block. This is commoner with aortic and prosthetic valves and with Staphylococcus aureus.
• Embolism: fragments of the vegetation lodge in the brain, spleen, kidneys, limbs, bowel or coronary arteries, and in the lungs from the right side. Emboli are commonest with large, mobile vegetations and in the first two weeks of treatment, and they can seed abscesses or infected (mycotic) aneurysms.
• Immune complexes: the long-lasting bacteraemia drives antibodies and complement into the tissues, causing glomerulonephritis and some of the skin and eye signs.
• Persistent bacteraemia: metastatic infection, such as discitis, septic arthritis and splenic or renal abscesses, particularly with Staphylococcus aureus.

Who is at risk

The patients most at risk are those with a prosthetic valve or valve repair material, previous endocarditis and congenital heart disease. Rheumatic and degenerative valve disease, a bicuspid aortic valve, hypertrophic cardiomyopathy and cardiac devices raise the risk too. Outside the heart, injecting drugs, haemodialysis, long-term intravenous lines, diabetes, immunosuppression and poor dental health are the main risks. In high-income countries a growing share of cases follows contact with healthcare.

Organisms

Culture-negative endocarditis makes up about 1 in 6 cases in a recent European registry, and the share varies widely between centres. Antibiotics given before the cultures are the usual cause; the rest are organisms that do not grow in routine bottles.

03Clinical features

The presentation depends on the organism and the patient. Staphylococcus aureus causes a septic illness over days, with rapid valve destruction, heart failure and emboli. Oral streptococci cause weeks or months of low fever, night sweats, tiredness, weight loss, joint aches and anaemia, which may be taken for something else.

The common findings:

• fever, in about 80 to 90 per cent, though it can be absent in older, frail or pretreated patients;
• a murmur, in about two thirds or more, but new in only about half;
• heart failure, from the leaking valve;
• emboli, in about 1 in 5 patients, and more when imaging looks for them: stroke, a cold limb, flank pain from a renal or splenic infarct, and septic pulmonary emboli in right-sided disease;
• splenomegaly, anaemia and, in long-standing disease, clubbing;
• microscopic haematuria.

The classic peripheral signs are now less common, because the disease is caught earlier:

• splinter haemorrhages under the nails (nonspecific on their own);
• Janeway lesions, painless red macules on the palms and soles, from septic microemboli;
• Osler nodes, painful red nodules on the pulps of the fingers and toes, thought to be immunological;
• Roth spots, retinal haemorrhages with a pale centre, and conjunctival haemorrhages;
• petechiae of the skin and mouth.

Right-sided endocarditis, usually on the tricuspid valve in people who inject drugs, presents with fever, cough, pleuritic pain and haemoptysis from septic emboli, seen as multiple, often cavitating, nodules in the lungs. The murmur of tricuspid regurgitation is often soft or absent.

04Diagnosis and management

Tests

• Blood cultures, the most important test: three sets from separate venepunctures, with about 10 mL in each bottle, before any antibiotic. There is no need to wait for a fever spike, because the bacteraemia is continuous. In a septic patient they are taken quickly and treatment starts at once.
• Echocardiography: transthoracic first, then transoesophageal echocardiography in nearly all patients, because it is far more sensitive for small vegetations, prosthetic valves and abscesses. If the first study is negative and the suspicion remains, it is repeated after 5 to 7 days. A negative echocardiogram does not exclude endocarditis.
• Cardiac CT shows abscesses and pseudoaneurysms; FDG PET/CT shows infection around prosthetic valves and devices. Imaging of the brain and abdomen finds emboli, which can change the diagnosis and the timing of surgery.
• Blood tests: anaemia, a raised white cell count, CRP and ESR (the CRP is followed to judge the response), and renal function. The urine shows blood and protein.
• ECG: a lengthening PR interval or new heart block suggests a root abscess.
• Serology and PCR for the culture-negative organisms, and culture, PCR and histology of any valve removed at surgery.

The Duke criteria

The Duke criteria, last revised in 2023, combine the findings. The main points:

Endocarditis is definite with two major criteria, one major and three minor, or five minor, or when organisms or active inflammation are found in the vegetation or tissue. It is possible with one major and one minor, or three minor. The criteria are a guide: a clinician's suspicion still counts where they fall short, particularly with prosthetic valves.

Management

Endocarditis is managed by an endocarditis team: cardiologists, cardiac surgeons, infection specialists and microbiologists, and imaging specialists, with neurologists when the brain is involved.

Antibiotics are given intravenously, in high doses, and are bactericidal. The duration is counted from the first day of effective treatment, or from the first negative culture if the cultures were positive: usually four weeks for a native valve and six weeks for a prosthetic valve. When the organism is unknown and the patient is ill, empirical treatment covers staphylococci, streptococci and enterococci, with a broader regimen including vancomycin for early prosthetic valve and healthcare-associated endocarditis. Once the organism is known:

Gentamicin is no longer added for native-valve staphylococcal endocarditis, because it harms the kidneys without improving the cure. The blood levels of gentamicin and vancomycin are monitored. A penicillin allergy is checked carefully, because an unproven label can deny the patient the best drug.

Most patients settle within a few days. Fever that persists after a week of appropriate treatment suggests a perivalvular abscess, emboli or metastatic infection, an infected line, a drug fever or resistance, and needs a new search, including transoesophageal echocardiography.

Stable patients whose cultures have cleared and who have no abscess can finish treatment outside hospital, as outpatient intravenous therapy or by switching to two oral antibiotics after at least 10 days of intravenous treatment. A large trial showed that the switch was as safe as staying on intravenous drugs for streptococcal, enterococcal and staphylococcal endocarditis of the left heart.

Surgery

About half of patients with left-sided endocarditis have surgery. It replaces or repairs the valve and removes the infected tissue, and it is done during the antibiotic course when one of three reasons applies:

• heart failure from severe regurgitation, obstruction or a fistula, the commonest reason: emergency surgery within 24 hours for pulmonary oedema or shock that does not respond to treatment, urgent surgery within days otherwise;
• uncontrolled infection: an abscess, pseudoaneurysm or fistula, an enlarging vegetation, new heart block, blood cultures that stay positive despite appropriate antibiotics, fungi or multiresistant organisms, and prosthetic valve endocarditis caused by Staphylococcus aureus or by gram-negative bacteria other than the HACEK group. Early prosthetic valve endocarditis, within six months of the operation, is usually treated by replacing the valve again;
• prevention of embolism: a vegetation of 10 mm or more on the aortic or mitral valve that has already embolised despite treatment, or one of 10 mm or more when there is another reason to operate. In a patient at low surgical risk, surgery may be considered for a vegetation of 10 mm or more alone. A trial of operating within 48 hours on young, low-risk patients with large vegetations showed fewer emboli, but no difference in deaths.

A stroke from an embolus does not usually delay surgery that is needed, once bleeding into the brain is excluded and the patient is not in coma, but an intracranial haemorrhage usually delays surgery by about four weeks. Infected pacemakers and defibrillators are removed completely, leads and all, and right-sided endocarditis rarely needs surgery.

Other measures:

• Anticoagulants do not prevent emboli in endocarditis and are not started for it. Patients who already take them for another reason continue; those with a mechanical valve usually switch to heparin. A bleed into the brain stops all anticoagulants and antiplatelets, and with a mechanical valve heparin is restarted as soon as the team judges it safe.
• The source is sought and treated: a dental review for every patient, and colonoscopy after Streptococcus gallolyticus.

Prevention

All patients with valve disease or a prosthetic valve are taught oral and skin hygiene: dental check-ups (twice a year for those at highest risk, once a year for the others), prompt treatment of skin and other infections, no self-treatment with antibiotics, and no piercings or tattoos. These measures cover patients at high and at intermediate risk. Hospitals limit the use of intravenous catheters.

Antibiotic prophylaxis, a single dose of amoxicillin 2 g taken 30 to 60 minutes before the procedure, is recommended by European guidance for the highest-risk patients before dental procedures that involve the gums or the roots of the teeth or perforate the oral mucosa:

• previous endocarditis;
• surgical prosthetic valves, material used to repair a valve surgically, and transcatheter aortic and pulmonary valves (it is considered after a transcatheter repair of the mitral or tricuspid valve);
• cyanotic congenital heart disease left unrepaired, and congenital heart disease repaired with prosthetic material, for six months after the repair or for life if a shunt or leak remains;
• ventricular assist devices.

Penicillin-allergic patients take azithromycin, clarithromycin or doxycycline, or a cephalosporin if the allergy was not anaphylaxis, angioedema or urticaria. Clindamycin is no longer used, because of the risk of Clostridioides difficile. UK guidance does not recommend routine prophylaxis for dental or other procedures, and dentists in the UK discuss the highest-risk patients with their cardiologist.

05Epidemiology

Endocarditis affects about 3 to 15 people per 100,000 a year, about 14 on a global estimate, and its incidence is rising, most of all among older people in high-income countries. Men are affected about twice as often as women. The typical patient has changed: once a young adult with rheumatic heart disease, now usually over 60 with degenerative valve disease, a prosthetic valve or a cardiac device, or with frequent healthcare contact. In a large European registry, among cases with a known organism, staphylococci caused about 44 per cent, enterococci about 16 per cent, oral streptococci about 12 per cent and Streptococcus gallolyticus about 7 per cent, and prosthetic valves and devices accounted for 40 per cent. Endocarditis in young people who inject drugs, mostly from Staphylococcus aureus, has risen in many countries. In low-income countries rheumatic heart disease and oral streptococci still dominate.

06Prognosis

Untreated, endocarditis is almost always fatal. With treatment, about 1 in 6 patients dies in hospital, and up to 1 in 3 within a year. The risk is higher with older age, diabetes and kidney disease, with Staphylococcus aureus, fungi and prosthetic valves, and with heart failure, perivalvular complications, large vegetations and stroke. Heart failure is the commonest complication and the strongest predictor of death, and timely surgery is the measure that most reduces it.

Survivors carry a higher risk of another episode, of relapse (the same organism within about six months, usually from undertreated infection) or of reinfection (a new organism, especially in people who continue to inject drugs). They are seen after treatment with an echocardiogram as a new baseline, a dental review, advice on hygiene and on reporting fever without taking antibiotics first, and long-term follow-up of the valve.