Culture Negative Endocarditis

Endocarditis in which routine blood cultures stay negative, accounting for about 2 to 7% of cases in high income settings and up to about 30% in some regions. The commonest cause is antibiotic therapy given before cultures were taken (up to about half of cases).

• Other causes:
  • Fastidious organisms: HACEK group, Abiotrophia and Granulicatella (nutritionally variant streptococci), Brucella species.
  • Intracellular organisms: Coxiella burnetii (Q fever), Bartonella species, Chlamydia, Tropheryma whipplei, Mycoplasma and Legionella.
  • Fungi (Candida, Aspergillus), which grow poorly in blood.
  • Non-infective endocarditis: marantic (cancer), Libman-Sacks (lupus), and antiphospholipid syndrome.
• Exposure history matters. Livestock, unpasteurised milk and raw dairy products (brucellosis, Q fever) are important in pastoral and rural East Africa; Bartonella follows cat contact, body lice and homelessness; Whipple disease occurs in farmers and in those with chronic diarrhoea and arthralgia.
• Mortality is about 10 to 25%, higher when diagnosis is delayed. Many patients need valve surgery, especially with Bartonella, Coxiella and Brucella.

• Subacute fever, night sweats, weight loss, anaemia, splenomegaly, clubbing, arthralgia and a valve lesion; heart failure is common at presentation.
  • Coxiella: hepatitis, thrombocytopenia, hypergammaglobulinaemia, clubbing in about half, livestock exposure; endocarditis develops mainly on previously damaged or prosthetic valves.
  • Bartonella: aortic valve disease, glomerulonephritis, cat or louse exposure, culture negative with high immunoglobulin levels.
  • Brucella: undulant fever, sweats, spondylitis, hepatosplenomegaly, raw milk or livestock contact; aortic valve most often.
  • Non-infective endocarditis: no fever or modest fever, multiple emboli, a known cancer, lupus or antiphospholipid antibodies.
• Differential diagnosis: bacterial endocarditis after antibiotics, tuberculosis, lymphoma, vasculitis, atrial myxoma, systemic lupus, antiphospholipid syndrome, sarcoidosis, and other causes of pyrexia of unknown origin.
• Complications: heart failure, embolism, glomerulonephritis, abscess, heart block, vertebral osteomyelitis, relapse, and treatment toxicity.

• Repeat blood cultures (three sets, before any further antibiotic if possible) with extended incubation of 14 days; ask the laboratory to use enriched media and to consider supplemented media for nutritionally variant streptococci.
• Serology: Coxiella burnetii phase I IgG titre of 1:800 or more (diagnostic); Bartonella IgG titre of 1:800 or more; Brucella tube agglutination titre of 1:160 or more with Rose Bengal test; Legionella, Chlamydia and Mycoplasma serology; fungal antigens (galactomannan, beta-D-glucan).
• Molecular tests: broad range 16S and 18S ribosomal PCR on blood and on any excised valve; specific PCR for Coxiella, Bartonella and Tropheryma; histology with special stains and immunohistochemistry.
• Immune tests when infection is not proven: antinuclear antibody, anti-dsDNA, complement, lupus anticoagulant, anticardiolipin and beta-2 glycoprotein I antibodies, and tumour screening.
• Echocardiography (transoesophageal if transthoracic is negative), 18F-FDG PET-CT, CT of the abdomen, and brain imaging. Full blood count, CRP, ESR, liver function, creatinine, urinalysis.
• Valve culture and PCR in every patient who has surgery.

• Start empirical therapy after cultures and adjust once serology or PCR identifies the organism.
• Empirical therapy:
  • Native valve: ampicillin with sulbactam 3 g IV every 6 hours plus gentamicin 3 mg/kg/day IV, with doxycycline 100 mg IV or orally twice daily added where Bartonella, Brucella or Coxiella is possible; alternatively vancomycin 30 mg/kg/day IV plus gentamicin 3 mg/kg/day plus ciprofloxacin 400 mg IV every 12 hours.
  • Early prosthetic valve: vancomycin 30 mg/kg/day IV plus gentamicin 3 mg/kg/day plus rifampicin 300 to 450 mg every 8 hours, with ciprofloxacin 400 mg IV every 12 hours.
• Directed therapy:
  • Brucella: doxycycline 100 mg twice daily plus rifampicin 600 to 900 mg daily plus co-trimoxazole 960 mg twice daily, for at least 3 to 6 months (until agglutination titre falls to 1:60 or less), with gentamicin 3 to 5 mg/kg once daily for the first 2 to 3 weeks. Surgery is usually needed.
  • Coxiella burnetii: doxycycline 100 mg twice daily plus hydroxychloroquine 200 mg three times daily for at least 18 months (native valve) or 24 months (prosthetic valve). Monitor hydroxychloroquine levels, QT interval and the retina; check serology every 3 months and stop only when phase I IgG is less than 1:200 and IgA less than 1:50. Surgery in about half.
  • Bartonella: doxycycline 100 mg twice daily for 6 weeks plus gentamicin 3 mg/kg/day for 2 weeks (or rifampicin 300 mg twice daily if gentamicin is contraindicated). Surgery is needed in most patients (about 90%) because of heart failure.
  • Abiotrophia and Granulicatella: benzylpenicillin 12 to 18 million units/day or ceftriaxone 2 g daily for 6 weeks plus gentamicin 3 mg/kg/day for at least the first 2 weeks.
  • HACEK organisms: ceftriaxone 2 g IV daily for 4 weeks (6 weeks for a prosthetic valve).
  • Tropheryma whipplei: ceftriaxone 2 g IV daily for 2 to 4 weeks, then co-trimoxazole 960 mg twice daily for at least 1 year (evidence is limited); hydroxychloroquine plus doxycycline is an alternative.
  • Fungal: liposomal amphotericin B 3 to 5 mg/kg/day IV with surgery, then lifelong fluconazole 400 to 800 mg daily.
  • Legionella: levofloxacin 750 mg daily or azithromycin 500 mg daily for at least 6 weeks; Chlamydia and Mycoplasma: doxycycline plus a fluoroquinolone.
• Non-infective endocarditis:
  • Antiphospholipid syndrome: warfarin to INR target 2.5 (range 2.0 to 3.0); with arterial events, target 3.0 (range 2.5 to 3.5); avoid direct oral anticoagulants.
  • Marantic endocarditis: treat the cancer, with enoxaparin 1 mg/kg SC every 12 hours or IV unfractionated heparin (aPTT 1.5 to 2.0 times control); avoid direct oral anticoagulants and warfarin.
  • Lupus: prednisolone 0.5 to 1 mg/kg/day with specialist input.
• Surgery indications (during the same admission, within days):
  • Heart failure from severe regurgitation or obstruction, or fistula.
  • Uncontrolled infection: abscess, pseudoaneurysm, enlarging vegetation, or persistent fever despite effective therapy.
  • Embolism with a vegetation greater than 10 mm, or a vegetation greater than 30 mm.
  • Fungal infection, Bartonella and most Brucella and Coxiella cases.
  • Send the valve for histology, culture and PCR. Operative mortality about 10 to 20%.
• Monitor: weekly full blood count, creatinine and liver function; retinal review and plasma level monitoring on hydroxychloroquine, and photosensitivity checks on doxycycline; serology every 3 months for Coxiella, Brucella and Bartonella; audiometry on prolonged aminoglycoside therapy.
• Special groups:
  • Pregnancy: doxycycline and fluoroquinolones are unsafe; use ampicillin or ceftriaxone for fastidious organisms and seek specialist advice for Brucella and Coxiella (rifampicin with co-trimoxazole may be used, with folic acid support, in the second and third trimesters).
  • Children: doxycycline is used for severe intracellular infection (2.2 mg/kg twice daily, maximum 100 mg) when the benefit justifies it; co-trimoxazole 8 mg/kg/day of trimethoprim in 2 doses.
  • Renal impairment: avoid gentamicin; adjust vancomycin by trough.
  • Prevention: boil or pasteurise milk, avoid contact with birth products from animals, and control lice and vermin.
• Red flags: heart failure, new neurological deficit, shock, rising creatinine, relapse after stopping therapy.
• Follow up: echocardiography at completion, 3, 6 and 12 months; serology every 3 months until normal and then every 6 months for 2 years; lifelong dental care; specialist infection follow up.