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glomerulonephritis, remain common. The main symptoms and signs observed in the EURO-ENDO registry are shown in the Supplementary data online, Table S1. Atypical presentation is common in elderly or immunocompromised patients.139–141 A high index of suspicion and low threshold for investigation are therefore essential to exclude IE or avoid delays in diagnosis in these and other high-risk groups, such as those with CHD or prosthetic valves.142 It is important to inform those patients about the risk of IE who should be aware of compatible symptoms to ask for advice in referral centres.

5.2 Laboratory findings

Laboratory investigations and biomarkers typically yield non-specific results. A large number of potential biomarkers have been proposed, reflecting the complex pathophysiology of the pro- and anti-inflammatory processes, humoral and cellular reactions, and both circulatory and end-organ abnormalities involved in IE.143 The degree of anaemia, leucocytosis/leucopaenia, the number of immature white cell forms, concentrations of C-reactive protein and procalcitonin, erythrocyte sedimentation rate, and markers of end-organ dysfunction (serum lactate, serum creatinine, bilirubin, thrombocytopaenia, cardiac troponin, and natriuretic brain peptides) can be used to estimate the severity of sepsis, but none is diagnostic of IE. C-reactive protein and procalcitonin are the most widely evaluated biomarkers in RCTs of antibiotic stewardship. Furthermore, several of these biomarkers are included in scores used for risk stratification in critically ill patients. Unfortunately, no biomarker has sufficient accuracy for the diagnosis of sepsis or specificity for IE.144 Therefore, the main role of biomarkers is to facilitate initial risk stratification and monitor the response to antibiotic therapy.

5.3 Microbiological diagnosis

The aetiology of IE is described in the EURO-ENDO registry5 and the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS).145 In 2009, the ICE-PCS showed that the most frequent microorganisms causing IE were S. aureus (31%), followed by oral streptococci (17%), and CoNS (11%).145 Similar results were reported in the EURO-ENDO registry.5,145 Other registries have highlighted the increasing incidence of IE caused by E. faecalis and CoNS, particularly in the elderly.146–149 However, the results of these registries should be carefully interpreted due to inherent biases (type of participating centres, geographical differences, lack of complete granular data, etc.).

5.3.1 Blood culture-positive infective endocarditis

Positive blood cultures remain the cornerstone of IE diagnosis and provide live bacteria for both identification and susceptibility testing. At least three sets of blood cultures should be obtained at 30-minute intervals prior to antibiotic therapy, each containing 10 mL of blood, and should be incubated in both aerobic and anaerobic atmospheres.150,151 Sampling should be obtained from a peripheral vein rather than from a central venous catheter (because of the risk of contamination and misleading interpretation), using a meticulous sterile technique. In the absence of previous antimicrobial therapy, this is virtually always sufficient to identify the usual causative microorganisms. The need for culture before antibiotic administration is self-evident. In IE, bacteraemia is almost constant and has two implications: (i) there is no rationale for delaying blood sampling to coincide with peaks of fever; and (ii) nearly all blood cultures are positive during bacteraemia. As a result, a single positive blood culture should be regarded cautiously for establishing IE diagnosis. The microbiology laboratory should be aware of the clinical suspicion of IE. Automated machines perform continuous monitoring of bacterial growth, which ensures quick provision of reports to physicians. When a positive blood culture is identified, presumptive identification is based on Gram staining. This information is immediately given to clinicians in order to adapt empirical antibiotic therapy. Complete identification is routinely achieved the same day or the following day with current methodology (e.g. matrix-assisted laser desorption ionization time-of-flight mass spectrometry [MALDI-TOF MS]), but may require a longer time for fastidious or atypical organisms. Since there is a long delay between blood culture sampling and definitive identification of the organism responsible for the bacteraemia and antibiotic susceptibility testing, many improvements have been proposed to speed up the process of detection and identification. One of the most recent procedures for rapid bacterial identification is based on peptide spectra obtained by MALDI-TOF MS.152 However, despite technical developments and the progress toward rapid susceptibility testing using MALDI-TOF MS, the gold standard for susceptibility testing is still the determination of the minimal inhibitory concentrations (MICs) to select appropriate antibiotic therapy, which needs to be performed following validated, standardized methodology.153

5.3.2 Blood culture-negative infective endocarditis

Blood culture-negative infective endocarditis (BCNIE) refers to IE in which no causative microorganism can be grown using the usual blood culture methods. The frequency of BCNIE as the cause of IE is highly variable and often poses considerable diagnostic and therapeutic dilemmas.154,155 Blood culture-negative IE most commonly arises as a consequence of previous antibiotic administration, underlying the importance of performing blood cultures prior to antibiotic therapy, particularly in patients with known risk factors for IE. Withdrawal of antibiotics and repeating blood cultures may be required in stable patients with subacute symptoms, no evidence of local or distant complications, and receiving a very short course of antibiotics. Blood culture-negative IE can also be caused by fungi or fastidious bacteria, notably obligatory intracellular bacteria. Isolation of these microorganisms requires culturing on specialized media, and their growth is relatively slow. Depending on local epidemiology,156 systematic serological testing for Coxiella burnetii, Bartonella spp., Aspergillus spp., Mycoplasma pneumoniae, Brucella spp., and Legionella pneumophila should be proposed,157 followed by specific polymerase chain reaction (PCR) assays for Tropheryma whipplei, Bartonella spp., and fungi (Candida spp., Aspergillus spp.) from blood and the tissue (Table 9).158 In addition, 16S and 18S ribosomal ribonucleic acid (rRNA) sequencing from tissue is routinely performed in most laboratories and may provide a microorganism diagnosis in BCNIE. For patients with prosthetic valve BCNIE, molecular imaging technique fluorescence in situ hybridization combined with 16S rRNA-gene PCR and sequencing improved the conventional cultural diagnostic methods in 30% of cases.159 Next-generation sequencing of plasma microbial cell-free deoxyribonucleic acid (DNA) may facilitate a rapid diagnosis of IE in the future.160 When all microbiological assays are negative, the diagnosis of nonbacterial endocarditis should systematically be considered and assays Downloaded from academic.oup.com/eurheartj/article/44/39/3948/7243107 by guest on 07 October 2026