Updates in Culture-Negative Endocarditis

Abstract

Blood culture-negative infective endocarditis (BCNE) is a challenging condition associated with significant morbidity and mortality. This review discusses the epidemiology, microbiology, diagnosis, and treatment of BCNE considering advancements in molecular diagnostics and increased access to cardiac surgery. BCNE can be categorized into bacterial endocarditis with sterilized blood cultures due to previous antibiotic treatment, endocarditis caused by fastidious microorganisms, and true BCNE caused by intracellular organisms that cannot be cultured using traditional techniques. Non-infectious causes such as nonbacterial thrombotic endocarditis should also be considered. Diagnostic approaches involve thorough patient history; blood and serum testing, including appropriate handling of blood cultures; serological testing; and molecular techniques such as targeted and shotgun metagenomic sequencing. Where available, evaluation of explanted cardiac tissue through histopathology and molecular techniques is crucial. The therapy for BCNE depends on the likely causative agent and the presence of prosthetic material, with surgical intervention often required.

Keywords: bacteremia; culture-negative; endocarditis.

Figure 1

Diagnostic algorithm for the identification of the microbiological etiology of infective endocarditis. Adapted from Liesman et al. [33]. The algorithm is intended for use in patients with definite or possible infective endocarditis based on the modified Duke criteria. Strong recommendations appear in boldface. ¹ Details related to the appropriate collection and incubation of blood cultures are included in the text. ² The sensitivity of T. whipplei PCR from blood in endocarditis is unknown; a negative result should not be used to rule out T. whipplei endocarditis. ³ Brucella serology should be performed routinely in endemic regions or where the patient has specific risk factors (see Table 1). ⁴ Consider autoantibodies and work-up for malignancy as detailed in the text. ⁵ Histopathologic evaluation is used to evaluate for infectious and noninfectious etiologies and for correlation with microbiology test results. Subsequent directed testing may include specialized stains e.g., PAS-D staining for T. whipplei, or specific PCR assays e.g., Bartonella sp., Coxiella burnetii, Cutibacterium acnes. ⁶ If sufficient valvular tissue is available after sampling for histopathological and molecular (microorganism-specific and broad-range) testing, consider culture and microbiology Gram stain. Due to the low sensitivity and specificity of culture, molecular testing should be prioritized over culture.