HACEK Endocarditis

HACEK endocarditis is infection of the heart valves, native or prosthetic, by slow growing, fastidious Gram negative organisms of the oral and upper respiratory flora: Haemophilus species (mainly H. parainfluenzae), Aggregatibacter actinomycetemcomitans and A. aphrophilus, Cardiobacterium hominis, Eikenella corrodens and Kingella kingae.

These organisms cause about 1 to 3% of infective endocarditis. Presentation is usually subacute, with large vegetations and a high rate of embolism, but the outcome after prompt treatment is better than with Staphylococcus aureus, with mortality of about 5 to 15%.

Risk factors are periodontal disease and recent dental procedures, pre-existing valve disease (rheumatic, degenerative, congenital), prosthetic valves, injection drug use (Eikenella) and, in children, Kingella kingae infection. Many cases occur in people with no known valve disease.

Historically these organisms caused culture negative disease because of slow growth. Modern continuous monitoring blood culture systems usually detect them within 5 days.

Pathophysiology.

Organisms colonise the gingival and oral mucosa and enter the blood during chewing, tooth brushing or dental procedures, particularly with gingivitis. They adhere to damaged valve endothelium or to platelet fibrin thrombus.

Slow growth and bulky vegetations explain the indolent course, large friable vegetations and frequent emboli. Leaflet destruction and perivalvular extension occur, but less often than with Staphylococcus aureus.

Beta lactamase production is common in Haemophilus and Aggregatibacter species, so ampicillin alone is unreliable. Eikenella is intrinsically resistant to clindamycin, metronidazole and aminoglycosides.

Weeks of low grade fever, fatigue, weight loss, night sweats, anorexia and arthralgia. A new regurgitant murmur, heart failure, splenomegaly and clubbing may be present. Embolic events (stroke, splenic, renal and limb infarcts), splinter haemorrhages, Janeway lesions, Osler nodes and Roth spots occur. Fever can be absent in older adults.

Kingella kingae endocarditis affects young children, often with a preceding oropharyngeal infection or osteoarticular infection. Aggregatibacter actinomycetemcomitans is associated with severe periodontitis and with actinomycosis.

• Blood cultures: at least 3 sets from separate venepunctures before antibiotics. Tell the laboratory that HACEK organisms are suspected. Extended incubation is rarely needed with modern systems, but is justified in culture negative disease with strong suspicion. Request identification (mass spectrometry) and beta lactamase testing with full susceptibility testing.
• Culture negative with strong suspicion: 16S ribosomal RNA PCR on blood or valve tissue, and serology for Coxiella, Bartonella and Brucella.
• Echocardiography: transthoracic then transoesophageal in all cases. Vegetations are often large (over 10 mm), and perforation, abscess and prosthetic dehiscence must be sought. Repeat in 5 to 7 days if negative and suspicion persists.
• Brain, chest and abdominal imaging for emboli. Fluorodeoxyglucose PET-CT for prosthetic valves with doubtful echocardiography.
• Dental assessment with panoramic radiograph, to find the source.
• Modified Duke criteria: HACEK organisms in two separate blood cultures meet the major criterion for a typical organism.

Differential diagnosis.

• Other culture negative endocarditis: Coxiella burnetii, Bartonella, Brucella, Abiotrophia and Granulicatella, Tropheryma whipplei.
• Non-infective endocarditis, atrial myxoma, rheumatic fever and vasculitis.
• Lymphoma, tuberculosis and other causes of fever with a murmur.

Empirical therapy while cultures are pending.

• Native valve: ampicillin 2 g intravenously every 4 hours, flucloxacillin 2 g every 4 hours and gentamicin 3 mg/kg once daily; with severe penicillin allergy or MRSA risk, vancomycin 25 mg/kg loading dose then 30 to 60 mg/kg daily in 2 to 3 doses (trough 15 to 20 mg/L) with gentamicin. Change to the directed regimen once a HACEK organism is identified.
• Prosthetic valve: vancomycin, gentamicin 3 mg/kg once daily and rifampicin 900 to 1200 mg daily in 2 to 3 doses (started 3 to 5 days later), until identification.

Directed therapy.

• Ceftriaxone 2 g intravenously (or intramuscularly) once daily, for 4 weeks for native valves and 6 weeks for prosthetic valves, counted from the first negative blood culture. No renal adjustment is needed unless severe renal and hepatic failure coexist (maximum 2 g daily then). Monitor full blood count weekly, liver tests and for biliary sludge, diarrhoea and Clostridioides difficile.
• Alternative for susceptible isolates (confirmed non-beta-lactamase producers): ampicillin 12 g daily intravenously in 4 to 6 doses with gentamicin 3 mg/kg once daily, for 4 weeks native or 6 weeks prosthetic; gentamicin trough under 1 mg/L, creatinine two to three times weekly; avoid when creatinine clearance is under 30 mL/min. Eikenella is not reliably killed by aminoglycosides.
• Beta lactam allergy or resistance: ciprofloxacin 400 mg intravenously every 8 to 12 hours, or 500 to 750 mg orally every 12 hours, for 4 weeks native or 6 weeks prosthetic; check QTc, avoid with other QT-prolonging drugs, reduce dose in creatinine clearance under 30 mL/min, and monitor for tendinopathy and dysglycaemia. Specialist advice is needed for desensitisation or other agents.
• Oral step down after at least 10 days of intravenous therapy is possible in stable patients without abscess or embolic complications, under specialist direction.

Surgery. Indications are: heart failure from severe regurgitation or obstruction, abscess or fistula, persistent bacteraemia after 7 to 10 days of appropriate therapy, and embolism prevention (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 over 30 mm).

HACEK vegetations are often large, so early echocardiographic reassessment is important. After an ischaemic stroke without haemorrhage and without coma, proceed without delay; after intracranial haemorrhage, delay surgery for 4 weeks or more when feasible.

Source control and prevention. Treat periodontal disease and extract unsalvageable teeth, ideally before valve surgery. Dental prophylaxis for prosthetic valves, previous endocarditis or unrepaired cyanotic congenital disease: amoxicillin 2 g orally 30 to 60 minutes before the procedure; with penicillin allergy, azithromycin 500 mg or doxycycline 100 mg.

Complications. Embolic stroke: avoid alteplase, and consider thrombectomy. Do not start anticoagulation for embolism prevention in native valve disease; continue it for mechanical valves unless there is intracranial haemorrhage. Mycotic aneurysm needs vascular imaging and treatment before valve surgery.

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

Referral and escalation. Refer every patient to the endocarditis team. Urgent surgical review for heart failure, abscess, a vegetation of 10 mm or more or persistent bacteraemia. Immediate intensive care for shock, acute pulmonary oedema or a new neurological deficit.

Special groups.

• Pregnancy: ceftriaxone is acceptable; avoid fluoroquinolones, tetracyclines and aminoglycosides where possible.
• Children: ceftriaxone 100 mg/kg intravenously once daily (maximum 4 g daily) for 4 to 6 weeks; avoid fluoroquinolones when an alternative exists; Kingella kingae needs a search for osteoarticular infection.
• Kidney impairment: ceftriaxone needs no adjustment; avoid aminoglycosides.
• Region specific: poor dental care and rheumatic valve disease raise risk; where blood culture is not available, empirical treatment with ceftriaxone should not be delayed in suspected endocarditis after taking whatever samples can be obtained.