Aortic Valve Endocarditis

Aortic valve endocarditis is infection of a native or prosthetic aortic valve. It is a leading left sided form of infective endocarditis and is dangerous because it destroys leaflets, spreads into the aortic root and conduction system, and embolises.

Infective endocarditis occurs in about 3 to 10 people in every 100,000 each year, and the aortic valve is involved in about a third to a half of left sided cases. In hospital mortality is about 15 to 30%, and higher with prosthetic valves, perivalvular abscess or Staphylococcus aureus.

Risk factors: bicuspid or degenerative aortic valve, prosthetic valve (including transcatheter), previous endocarditis, rheumatic heart disease, congenital heart disease, injection drug use, indwelling lines, haemodialysis and poor dentition.

Organisms: Staphylococcus aureus (the commonest), viridans streptococci, Streptococcus gallolyticus, enterococci, coagulase negative staphylococci (early prosthetic), HACEK organisms, and culture negative causes (Coxiella burnetii, Bartonella, Brucella). Brucella and Q fever are regionally important.

Pathophysiology.

Turbulent flow damages the endothelium, forming a sterile platelet and fibrin thrombus. Bacteraemia seeds it, and a vegetation forms. Virulent organisms such as Staphylococcus aureus destroy leaflets quickly.

Infection extends through the aortic annulus into the mitral aortic intervalvular fibrosa and septum, forming abscess, pseudoaneurysm or fistula and conduction block (PR prolongation and atrioventricular block). Perivalvular extension occurs in about a third of native and more than half of prosthetic aortic cases.

Leaflet perforation causes acute aortic regurgitation, which the left ventricle tolerates poorly, producing pulmonary oedema and early mitral valve closure. Vegetations of 10 mm or more carry a high embolic risk, with stroke in 15 to 30% of patients.

Immune complex phenomena (glomerulonephritis, Osler nodes, Roth spots) arise with longer illness.

Fever (not always present in older adults), malaise, weight loss, night sweats, breathlessness and back pain. A new or changing regurgitant murmur, heart failure, and embolic events (stroke, splenic or renal infarcts, limb ischaemia, mycotic aneurysm). Peripheral signs: splinter haemorrhages, Janeway lesions, Osler nodes, Roth spots, petechiae and splenomegaly. New PR prolongation or atrioventricular block suggests root abscess. Prosthetic valve endocarditis is early (under 12 months) or late.

• Blood cultures: at least 3 sets from separate venepunctures, taken at least 1 hour apart before antibiotics, with 8 to 10 mL in each aerobic and anaerobic bottle. Repeat until negative once treatment starts.
• Culture negative disease: serology for Coxiella burnetii (phase I IgG titre of 1:800 or more), Bartonella, Brucella and Legionella; PCR and 16S sequencing of valve tissue; discuss with microbiology.
• Echocardiography: transthoracic first, then transoesophageal in all suspected cases (about 90% sensitive for native vegetations, and more sensitive for abscess); repeat in 5 to 7 days if negative and suspicion remains. Look for vegetation, leaflet perforation, abscess, pseudoaneurysm, fistula and prosthetic dehiscence.
• Cardiac CT angiography for abscess and pseudoaneurysm; fluorodeoxyglucose PET-CT for prosthetic valves; brain MRI or CT and body imaging for embolism.
• Daily ECG for PR interval; inflammatory markers, creatinine, urine dipstick, full blood count, liver tests.
• Modified Duke criteria: definite is 2 major, or 1 major and 3 minor, or 5 minor criteria. Major: typical organism in 2 separate blood cultures or persistent bacteraemia, and endocardial involvement (vegetation, abscess, new dehiscence or new regurgitation). Minor: predisposition, fever of 38.0 degrees Celsius or more, vascular phenomena, immunological phenomena, and microbiological evidence not meeting major criteria.

Differential diagnosis.

• Libman-Sacks and marantic endocarditis, antiphospholipid syndrome.
• Atrial myxoma, papillary fibroelastoma and Lambl excrescences.
• Rheumatic fever, vasculitis, lymphoma, tuberculosis and other causes of fever with murmur.
• Sepsis from other sources with incidental valve disease.

Organisation. Treat in a unit with an endocarditis team (cardiology, infectious diseases, cardiac surgery, microbiology, neurology when embolic). Take cultures before antibiotics. In stable subacute disease, wait 24 to 48 hours for cultures. Start empirical therapy at once when unwell.

Empirical therapy (after cultures).

• Native valve, community onset: ampicillin 2 g intravenously every 4 hours, flucloxacillin 2 g intravenously every 4 hours, and gentamicin 3 mg/kg intravenously once daily. With penicillin allergy or MRSA risk: vancomycin 25 mg/kg load, then 30 to 60 mg/kg daily in 2 to 3 doses (trough 15 to 20 mg/L), with gentamicin.
• Early prosthetic valve (under 12 months) or health care related: vancomycin 25 mg/kg intravenous loading dose, then 30 to 60 mg/kg daily in 2 to 3 doses (trough 15 to 20 mg/L), gentamicin 3 mg/kg once daily, and rifampicin 900 to 1200 mg daily in 2 to 3 doses (started 3 to 5 days later, once bacteraemia is controlled). Late prosthetic valve (12 months or more): ampicillin 2 g and flucloxacillin 2 g intravenously every 4 hours with gentamicin 3 mg/kg intravenously once daily.

Directed therapy (duration counted from the first negative blood culture).

• Penicillin susceptible streptococci (MIC 0.125 mg/L or under): benzylpenicillin 12 to 18 million units daily in 4 to 6 doses (or amoxicillin 100 to 200 mg/kg daily in 4 to 6 doses, or ceftriaxone 2 g daily) for 4 weeks (6 weeks for prosthetic valves). Uncomplicated native valve disease may be treated for 2 weeks with gentamicin 3 mg/kg daily. Allergy: vancomycin 25 mg/kg intravenous loading dose, then 30 to 60 mg/kg daily in 2 to 3 doses (trough 15 to 20 mg/L), for the same duration.
• Relatively resistant streptococci (MIC over 0.125 to 2 mg/L): the same beta lactam for 4 weeks (6 weeks prosthetic) plus gentamicin 3 mg/kg daily for 2 weeks.
• Methicillin susceptible Staphylococcus aureus, native valve: flucloxacillin 2 g intravenously every 4 hours (12 g daily), or cefazolin 2 g every 8 hours, for 4 to 6 weeks (6 weeks for left sided disease). Prosthetic valve: flucloxacillin plus rifampicin (900 to 1200 mg daily in 2 to 3 doses) for 6 weeks or more, with gentamicin 3 mg/kg daily for the first 2 weeks.
• MRSA: vancomycin 25 mg/kg intravenous loading dose, then 30 to 60 mg/kg daily in 2 to 3 doses (trough 15 to 20 mg/L), or daptomycin 10 mg/kg intravenously once daily (every 48 hours when creatinine clearance is under 30 mL/min), for 6 weeks; add rifampicin and gentamicin for prosthetic valves.
• Enterococcus faecalis: ampicillin 2 g intravenously every 4 hours plus ceftriaxone 2 g every 12 hours for 6 weeks (avoids aminoglycoside nephrotoxicity); alternative ampicillin for 6 weeks with gentamicin 3 mg/kg daily in 2 to 3 doses for the first 2 weeks only, after high level resistance testing.
• HACEK organisms: ceftriaxone 2 g daily for 4 weeks (6 weeks prosthetic).
• Coxiella burnetii: doxycycline 200 mg daily with hydroxychloroquine 200 mg three times daily (target plasma level about 1 mg/L) for at least 18 months for native and 24 months for prosthetic valves.
• Bartonella: ceftriaxone 2 g daily or ampicillin 12 g daily for 6 weeks, with gentamicin 3 mg/kg daily for 3 weeks.
• Brucella: doxycycline 200 mg daily, rifampicin 300 to 600 mg daily and co-trimoxazole 960 mg twice daily for at least 3 to 6 months, with surgery for valve destruction.
• Fungal: surgery plus liposomal amphotericin B 3 to 5 mg/kg daily with or without flucytosine 25 mg/kg four times daily, then long term azole suppression.
• Partial oral switch after at least 10 days of intravenous therapy, when stable with no abscess, is an option in specialist hands.
• Monitoring of drugs: gentamicin levels and creatinine two to three times weekly; vancomycin trough; creatine kinase weekly on daptomycin; full blood count weekly on prolonged beta lactams; liver tests on rifampicin (and check interactions with warfarin, direct oral anticoagulants and antiretrovirals). Adjust beta lactam, vancomycin, gentamicin and daptomycin doses to creatinine clearance with pharmacy support.

Early surgery (during the same admission):

• Emergency (within 24 hours): refractory pulmonary oedema or cardiogenic shock from severe regurgitation or obstruction, or aorto cavitary fistula.
• Urgent (within 3 to 5 days): heart failure symptoms from severe regurgitation, perivalvular abscess or pseudoaneurysm, persistent fever or positive cultures after 7 to 10 days of appropriate antibiotics, new atrioventricular block, fungal or multiresistant organisms, and early prosthetic valve endocarditis.
• To prevent embolism: vegetation of 10 mm or more with a recent embolic event despite treatment, vegetation of 10 mm or more with severe valve disease and low operative risk, or an isolated vegetation of over 30 mm.
• Surgery involves debridement and valve replacement, with root replacement (homograft, stentless or composite) for abscess.
• Timing after stroke: after an ischaemic stroke without haemorrhage and without coma, proceed without delay; after intracranial haemorrhage, delay surgery for 4 weeks or more when feasible.
• When valve cultures are positive after surgery, discuss a new full course with infectious diseases.

Complications.

• Heart block: temporary pacing; permanent pacing once infection is controlled and block persists.
• Embolic stroke: alteplase is avoided in infective endocarditis because of haemorrhage risk; consider mechanical thrombectomy.
• Anticoagulation: do not start for embolism prevention in native valve disease. Continue for mechanical valves unless there is intracranial haemorrhage, then switch to unfractionated heparin by aPTT and discuss timing.
• Mycotic aneurysm: vascular imaging and neurosurgical or endovascular treatment before valve surgery.

Prevention of recurrence. Dental review and oral hygiene. Prophylaxis for dental procedures involving gingival manipulation in patients with prosthetic valves, previous endocarditis or unrepaired cyanotic disease: amoxicillin 2 g orally as a single dose 30 to 60 minutes before the procedure; penicillin allergy: azithromycin 500 mg or doxycycline 100 mg. Patients on benzathine benzylpenicillin should receive a different class for dental prophylaxis. Treat intravenous drug use with addiction services.

Monitoring. Temperature, C-reactive protein and creatinine at least twice weekly; blood cultures at 48 to 72 hours until negative; echocardiography at completion of treatment and at 1, 3, 6 and 12 months; daily ECG for PR interval. Outpatient parenteral therapy only after the first 2 weeks, once complications are controlled.

Referral and escalation. All patients need the endocarditis team. Urgent surgical review for heart failure, abscess, embolism or persistent bacteraemia. Immediate intensive care for shock, acute pulmonary oedema or new neurological deficit.

Special groups.

• Pregnancy: use penicillins and cephalosporins; avoid aminoglycosides, tetracyclines and fluoroquinolones where possible; surgery in a high risk obstetric centre.
• Injection drug use: surgery when indicated, together with addiction treatment and a plan for adherence.
• Older adults and kidney impairment: prefer the dual beta lactam regimen for enterococci, avoid aminoglycosides where possible, and dose by creatinine clearance.
• Region specific: rheumatic heart disease, brucellosis and Q fever cause a large share of culture negative cases; limited access to cardiac surgery should lead to early transfer.