Blood Culture–Negative Endocarditis: AHA Scientific Statement (2025)

Authors, Journal, Affiliations, Type, DOI

• Authors: Daniel C. DeSimone MD (Chair), Zerelda Esquer Garrigos MD (Vice Chair), Grace E. Marx MD MPH, Pierre Tattevin MD, Barbara Hasse MD, David W. McCormick MD, Margaret M. Hannan MD, Liesl J. Zuhlke MD, Connie S. Radke MSN NP, Larry M. Baddour MD FAHA
• Journal: Journal of the American Heart Association, 2025;14:e040218
• Affiliations: Mayo Clinic, University of Mississippi, CDC, Pontchaillou University Hospital (France), University Hospital Zurich, Mater Misericordiae University Hospital (Dublin), University of Cape Town; endorsed by the International Society for Cardiovascular Infectious Diseases (ISCVID)
• Type: AHA Scientific Statement (multidisciplinary writing group)
• DOI: 10.1161/JAHA.124.040218

Overview

Blood culture–negative endocarditis (BCNE) affects up to 30% of infective endocarditis (IE) cases and is associated with worse outcomes than culture-positive IE, primarily because pathogen-directed therapy is difficult to achieve. The predominant cause is prior antibiotic exposure before blood culture collection; the minority of cases involve fastidious or nonculturable organisms. Novel diagnostic tools — metagenomic next-generation sequencing, 18F-FDG PET/CT, and the updated 2023 Duke-ISCVID criteria — are changing the landscape of BCNE diagnosis and are the impetus for this statement. Four real-world clinical scenarios structure the practical guidance, and a comprehensive pathogen-specific table and diagnostic algorithm are provided to support frontline clinicians.

Keywords

Blood culture–negative infective endocarditis; diagnosis; management; prevention; AHA Scientific Statements

Key Takeaways

Definition and Epidemiology

• BCNE is defined as IE without positive blood cultures; affects up to 30% of all IE cases
• Two principal causes: (1) antibiotic administration before blood cultures (most common), (2) fastidious or nonculturable organisms in patients without prior antibiotics
• BCNE associated with worse outcomes vs. blood culture–positive IE due to inability to provide pathogen-specific therapy
• Recent data from Germany and Denmark show declining BCNE prevalence, possibly attributable to advances in laboratory molecular techniques

2023 Duke-ISCVID Criteria Updates Relevant to BCNE

• Major criterion expanded: nucleic acid detection of Coxiella burnetii, Tropheryma whipplei, and Bartonella spp; serologic evidence of Bartonella henselae or B. quintana; amplicon or metagenomic sequencing and in situ hybridization of tissue specimens; "Surgical Evidence" now a new major criterion
• Minor criterion added: positive nucleic acid–based test for an organism consistent with IE from a sterile body site other than cardiac tissue
• Separate venipunctures for blood culture sets no longer required by 2023 criteria (though strongly preferred to minimise contamination)

Diagnostic Approach

• Obtain minimum 2 (ideally 3) blood culture sets (8–10 mL/bottle, 40 mL total minimum) under strict aseptic technique before starting antibiotics — prior antibiotic exposure is the #1 cause of BCNE
• If all cultures negative at 72 hours, expand to: prolonged incubation, serology for C. burnetii and Bartonella spp (+ Brucella if endemic area), and metagenomic sequencing on plasma or whole blood
• Shotgun metagenomic sequencing: collect specimen early (store if needed); submit if conventional workup negative at 72 hours; less affected by prior antibiotics but DNA quantity reduced by effective antibiotics; turnaround delay must be considered
• Metagenomics interpretation: only C. burnetii, Bartonella spp, and T. whipplei fulfil a major Duke-ISCVID criterion; other organisms (e.g., Brucella, N. gonorrhoeae) from whole blood in compatible clinical picture are likely reliable
• Excised cardiac tissue (if surgery performed): send for bacterial/fungal/mycobacterial cultures + pathology + PCR for fastidious organisms; broad-range 16S PCR/sequencing where available

Fastidious Pathogen Table Summary

Empiric Antibiotic Management

• No consensus on optimal empiric regimen; infectious diseases specialist consultation mandatory
• Key distinction:
  • Prior antibiotics → target methicillin-susceptible staphylococci, streptococci, enterococci (vancomycin ± ceftriaxone USA; amoxicillin + cefazolin France/Europe)
  • No prior antibiotics → add coverage for fastidious organisms (Bartonella, C. burnetii, T. whipplei): doxycycline + rifampin (some centres)
• Transition to oral therapy (POET criteria) reasonable once stable with confirmed susceptible pathogen

Advanced Imaging in BCNE

• Cardiac CT: comparable sensitivity to TEE for large vegetations, perivalvular abscess, fistula, valve perforation/aneurysm, prosthetic dehiscence
• 18F-FDG PET/CT: pooled sensitivity 76.8%/specificity 77.9% for native valve IE; 80.5%/73.1% for prosthetic valve IE; one study found only 22% sensitivity for native valve vs 93% for prosthetic valve
• WBC SPECT/CT: high specificity but limited sensitivity, especially native valve
• Both modalities detect extracardiac infection sites; use when TEE inconclusive in ≥possible IE with prosthetic material, perivalvular involvement, or suspected extracardiac foci

Nonbacterial Thrombotic Endocarditis (NBTE)

• Noninfectious cause of BCNE; associated with malignancy, SLE, antiphospholipid antibody syndrome
• Women predominate (mean age 54–60y); stroke most common presentation (54–59%) due to hypercoagulability
• Activated PTT prolongation: useful simple screening marker for NBTE associated with antiphospholipid syndrome and SLE
• TEE superior to TTE for valvular abnormalities; multimodality imaging (CT + 18F-FDG PET/CT) important for cancer-associated marantic endocarditis

Prevention Messages

• Patients with prosthetic valves/at-risk individuals: obtain ≥2 blood culture sets before starting any antibiotics
• IE prophylaxis for at-risk dental/surgical procedures
• Regular dental visits; early management of skin/foot infections
• In low- and middle-income countries: antibiotic access without prescription compounded by limited diagnostic capacity → empiric therapy must be guided primarily by epidemiological factors

Limitations of the Document

• Empiric antibiotic recommendations are based entirely on expert opinion and clinical practice; no RCT evidence
• Much of the metagenomics evidence is observational; no validated microbial DNA quantification cutoffs exist for clinical practice
• Advanced imaging data specific to BCNE is extremely limited; most imaging data derived from culture-positive IE studies
• Significant global disparity in access to molecular diagnostics and advanced imaging; guidance may not be applicable in low-resource settings
• False-positive results are a recognised limitation of metagenomic sequencing; results must always be interpreted in clinical context

Key Concepts Mentioned

• concepts/Infective-Endocarditis — parent framework: Duke-ISCVID criteria, echocardiographic approach, surgical indications
• concepts/Blood-Culture-Negative-Endocarditis — the primary focus of this statement

Key Entities Mentioned

• Coxiella burnetii (Q fever endocarditis) — role: major fastidious BCNE pathogen; serology-diagnosed
• Bartonella spp (B. henselae, B. quintana) — role: emerging major BCNE cause; social determinant risk factors
• Tropheryma whipplei — role: Whipple disease cardiac manifestation; increasingly identified with metagenomics
• Mycobacterium chimaera — role: heater-cooler device outbreak–associated prosthetic valve BCNE
• Fungal IE (Candida, Aspergillus) — role: highest-mortality BCNE category

Wiki Pages Updated

• Created: wiki/sources/BCNE-AHA-2025.md
• Created: wiki/concepts/Infective-Endocarditis.md
• Created: wiki/concepts/Blood-Culture-Negative-Endocarditis.md
• Updated: wiki/wikiindex.md
• Updated: wiki/sourceindex.md