Blood Culture-Negative Endocarditis: A Scientific Statement From the American Heart Association: Endorsed by the International Society for Cardiovascular Infectious Diseases

Abstract

Blood culture-negative endocarditis has been associated with worse outcomes when compared with blood culture-positive endocarditis, because pathogen-directed antimicrobial therapy and other management aspects have been difficult to achieve. Novel diagnostic tools, however, have changed the landscape of this syndrome and will likely improve patient outcomes. This American Heart Association scientific statement highlights these advances. The writing group, which represents a multidisciplinary team, provides an update on blood culture-negative endocarditis. Clinical scenarios representative of real-world experiences are included to assist frontline clinicians in the diagnosis and management of this syndrome.

Keywords: AHA Scientific Statements; blood culture–negative infective endocarditis; diagnosis; management; prevention.

Figure 1. Blood culture–negative infective endocarditis.

BC indicates blood culture; and BCNE, blood culture–negative endocarditis. *Antibiotics before BC collection remain the number 1 cause of BCNE. ^†Advanced imaging refers to mainly fluorine‐18‐fluorodeoxyglucose positron‐emission tomography/computed tomography.

Figure 2. Suggested diagnostic algorithm for blood culture–negative infective endocarditis.

18F‐FDG‐PET/CT indicates fluorine‐18‐fluorodeoxyglucose positron‐emission tomography/computed tomography; BCNE, blood culture–negative endocarditis; CT, computed tomography; IE, infective endocarditis; IHC, immunohistochemistry; ITS, internal transcribed spacer; NBTE, nonbacterial thrombotic endocarditis; PCR, polymerase chain reaction; TEE, transesophageal echocardiogram; TTE, transthoracic echocardiogram; and WBC SPECT/CT, white blood cell single‐photon emission tomography/computed tomography. *IE should be considered in patients with symptoms of endocarditis (eg, new glomerulonephritis, cerebrovascular event, Janeway lesions/Osler nodes, prolonged unexplained fevers, new heart failure, new valvular dysfunction, new cardiac murmur), especially in patients with identifiable risks, including patient exposures (eg, recent surgery, history of intravenous drug use, homelessness, body lice infestation, animal exposure), anatomic risks (eg, congenital heart disease, prosthetic heart valves, implantable cardiac devices, valvular disease) or comorbid conditions (eg, immunosuppression, hemodialysis), and indwelling catheters. ^† Contact the microbiology laboratory for instructions on sample collection and specimen submission. ^‡Communication with the laboratory is key in cases of BCNE. ^§Communication with the surgical team before an operative procedure is highly encouraged to ensure appropriate specimen collection and that diagnostic tests are submitted.

Figure 3. Empirical antibiotic treatment options for blood culture–negative endocarditis: literature‐based recommendations.*,

AUC₂₄/MIC indicates area under the serum concentration versus time curve for 0 to 24 hours/minimum inhibitory concentration; BCNE, blood culture–negative endocarditis; HCA‐IE, health care–associated infective endocarditis; NVE, native valve endocarditis; and PVE, prosthetic valve endocarditis. *A clear distinction must be made between BCNE in patients who received antibiotics before blood cultures were sampled, when empirical treatment should primarily target methicillin‐susceptible staphylococci, streptococci, and enterococci, and BCNE in patients not previously treated with antibiotics, where empirical treatment active on fastidious organisms such as Bartonella spp, Coxiella burnetii, and Tropheryma whipplei may be warranted. Current recommendations are only based on expert opinion and clinical practice. ^†USA‐based regimens per the 2015 AHA scientific statement “Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications.” Some members of the writing group use a combination of vancomycin and ceftriaxone only to treat NVE. ^‡European‐based regimens per the 2023 European Society of Cardiology guidelines for the management of endocarditis. In France, amoxicillin plus cefazolin is the preferred empirical treatment for acutely ill patients with community‐acquired native valve or late prosthetic valve IE, because it allows optimal coverage of the 3 major pathogens in this setting: cefazolin for methicillin‐susceptible staphylococci, amoxicillin for penicillin‐susceptible streptococci, and the synergistic effect of both for Enterococcus faecalis. ^§The writing group favors adding rifampin once source control is attained. Some writing group members include rifampin in late PVE. ^‖Gentamicin is often avoided by writing group members due to risk of toxicity and side effects.