2023 ESC指南：心内膜炎的管理

指南心血管内科· 心脏康复与其他 · 2023

Authors

Keywords

Council for Cardiology Practice, Council on Stroke Adult Congenital Heart Disease, Cardiovascular Surgery Guidelines, Antibiotics, Cardiac imaging, Cardiac implantable electronic device, Cardiac surgery, Complications, Computed tomography, Congenital heart disease, Diagnosis, Echocardiography, Endocarditis, Infection, Nuclear imaging, Positron emission tomography, Prevention, Prognosis, Prosthetic heart valve, Valve disease CHD, congenital heart disease, CIED, cardiovascular implanted electronic device, CT, computed tomography, HF, heart failure, IE, infective endocarditis, MRA, magnetic resonance angiography, NVE, native valve endocarditis, PVE, prosthetic valve endocarditis, TOE, transoesophageal echocardiography, TTE, transthoracic echocardiography IE, infective endocarditis, MRI, magnetic resonance imaging, PET/CT, positron emission tomography/computed tomography, TOE, transoesophageal echocardiography, TTE, transthoracic echocardiography

Abstract

Author/Task Force Member affiliations are listed in author information. 1 Representing the European Association of Nuclear Medicine (EANM) 2 Representing the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 3 Representing the European Association for Cardio-Thoracic Surgery (EACTS) ESC Clinical Practice Guidelines (CPG) Committee: listed in the Appendix. ESC subspecialty communities having participated in the development of this document: Associations: Association of Cardiovascular Nursing & Allied Professions (ACNAP), Association for Acute CardioVascular Care (ACVC), European Association of Cardiovascular Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), and Heart Failure Association (HFA).

# Tables of Recommendations

Tables of Recommendations

Recommendation Table 1 -Recommendations for antibiotic prophylaxis in patients with cardiovascular diseases undergoing oro-dental procedures at increased risk for infective endocarditis ..... 14 Recommendation Table 2 -Recommendations for infective endocarditis prevention in high-risk patients .

.. 16

Recommendation Table 3 -Recommendations for infective endocarditis prevention in cardiac procedures .

Recommendation Table 4 -Recommendations for the Endocarditis Team .

.. 18

Recommendation Table 5 -Recommendations for the role of echocardiography in infective endocarditis .

.. 22

Recommendation Table 6 -Recommendations for the role of computed tomography, nuclear imaging, and magnetic resonance in infective endocarditis . .. 38 Recommendation Table 11 -Recommendations for outpatient antibiotic treatment of infective endocarditis .

.. 40 Recommendation Table 12 -Recommendations for the main indications of surgery in infective endocarditis (native valve endocarditis and prosthetic valve endocarditis

.. 44

Recommendation Table 13 -Recommendations for the treatment of neurological complications of infective endocarditis .

.. 45

Recommendation Table 14 -Recommendations for pacemaker implantation in patients with complete atrioventricular block and infective endocarditis .

.. 60

Recommendation Table 22 -Recommendations for the use of antithrombotic therapy in infective endocarditis .

.. 62

List of tables

.. 10

Table 5 General prevention measures to be followed in patients at high and intermediate risk of infective endocarditis .

.. 13

Table 6 Prophylactic antibiotic regime for high-risk dental procedures 14 Table 7 Members of the Endocarditis Team .

Table 8 Cardiac and non-cardiac risk factors .

Table 9 Investigation of rare causes of blood culture-negative infective endocarditis .

.. 20

Table 10 Definitions of the 2023 European Society of Cardiology modified diagnostic criteria of infective endocarditis .

.. 24

Table 11 Antibiotic treatment of blood culture-negative infective endocarditis .

.. 37

Table 12 Features favouring a non-mechanical valve substitute in the setting of surgery for acute infective endocarditis .

.. 50

Table 13 Factors associated with an increased rate of relapse of infective endocarditis .

.. 67

List of figures

.. 15

Figure 3 Management of patients with infective endocarditis: positioning of the Endocarditis Team .

.. 17

Figure 4 Microbiological diagnostic algorithm in culture-positive and culture-negative infective endocarditis .

.. 56

Figure 14 Concept of patient-centred care in infective endocarditis . 64

Abbreviations and acronyms

[18F]FDG

1. Preamble

Guidelines evaluate and summarize available evidence, with the aim of assisting health professionals in proposing the best diagnostic or therapeutic approach for an individual patient with a given condition. Guidelines are intended for use by health professionals and the European Society of Cardiology (ESC) makes its Guidelines freely available.

ESC Guidelines do not override the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient or the patient's caregiver where appropriate and/or necessary. It is also the health professional's responsibility to verify the rules and regulations applicable in each country to drugs and devices at the time of prescription, and, where appropriate, to respect the ethical rules of their profession.

ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated. ESC Policies and Procedures for formulating and issuing ESC Guidelines can be found on the ESC website (https://www.escardio.org/Guidelines).

The Members of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this

Classes of recommendations

Class I

Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective.

Conflicting evidence and/or a divergence of opinion about the usefulness/ efficacy of the given treatment or procedure.

Is recommended or is indicated

Wording to use Definition

Class III

Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful.

Is not recommended

Class IIb

Usefulness/efficacy is less well established by evidence/opinion.

May be considered

Class IIa Weight of evidence/opinion is in favour of usefulness/efficacy.

Should be considered

Class II

The selection procedure aimed to include members from across the whole of the ESC region and from relevant ESC Subspecialty Communities. Consideration was given to diversity and inclusion, notably with respect to gender and country of origin. The Task Force performed a critical evaluation of diagnostic and therapeutic approaches, including assessment of the risk-benefit ratio. The strength of every recommendation and the level of evidence supporting them were weighed and scored according to predefined scales as outlined below. The Task Force followed ESC voting procedures, and all approved recommendations were subject to a vote and achieved at least 75% agreement among voting members.

The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. Their declarations of interest were reviewed according to the ESC declaration of interest rules and can be found on the ESC website (http://www.escardio.org/Guidelines) and have been compiled in a report published in a supplementary document with the guidelines. The Task Force received its entire financial support from the ESC without any involvement from the healthcare industry.

The ESC Clinical Practice Guidelines (CPG) Committee supervises and co-ordinates the preparation of new guidelines and is responsible for the approval process. ESC Guidelines undergo extensive review by the CPG Committee and external experts, including members from across the whole of the ESC region and from relevant ESC Subspecialty Communities and National Cardiac Societies. After appropriate revisions, the guidelines are signed off by all the experts involved in the Task Force. The finalized document is signed off by the CPG Committee for publication in the European Heart Journal. The guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their writing. Tables of evidence summarizing the findings of studies informing development of the guidelines are included. The ESC warns readers that the technical language may be misinterpreted and declines any responsibility in this respect.

Off-label use of medication may be presented in this guideline if a sufficient level of evidence shows that it can be considered medically appropriate for a given condition. However, the final decisions concerning an individual patient must be made by the responsible health professional giving special consideration to:

• The specific situation of the patient. Unless otherwise provided for by national regulations, off-label use of medication should be limited to situations where it is in the patient's interest with regard to the quality, safety, and efficacy of care, and only after the patient has been informed and has provided consent. • Country-specific health regulations, indications by governmental drug regulatory agencies, and the ethical rules to which health professionals are subject, where applicable.

2. Introduction

Infective endocarditis (IE) is a major public health challenge. 1 In 2019, the estimated incidence of IE was 13.8 cases per 100 000 subjects per year, and IE accounted for 66 300 deaths worldwide. 2 Due to the associated high morbidity and mortality (1723.59 disability-adjusted life years and 0.87 death cases per 100 000 population, respectively), identification of the best preventive strategies has been the focus of research. 2, 3 Since the publication of the 2015 ESC Guidelines for the management of infective endocarditis, 4 important new data have been published mandating an update of recommendations. ] [7] [8] [9] [10] [11] Furthermore, the emerging and increasing antibiotic resistance among oral streptococci is of concern. The rate of resistance to azythromycin and clarithromycin is higher than that to penicillin. 12 4] [15] [16] [17] [18] It is likely that the increased use of diagnostic tools to diagnose IE is an important contributor to the increase in the incidence of IE. ] [22] Data on the contemporary characterization of patients with IE have been taken into consideration to update the recommendations on the diagnosis and management of patients with IE. 5, 19, [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] Furthermore, the recommendations on antibiotic therapy have been updated based on the susceptibility of various microorganisms defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints. 42 ] [45] [46] The main objective of the current Task Force was to provide clear and simple recommendations, assisting healthcare providers in their clinical decision-making. These recommendations were obtained by expert consensus after thorough review of the available literature (see Supplementary data, evidence tables online). An evidence-based scoring system was used, based on a classification of the strength of recommendations and the levels of evidence.

2.1. What is new

I C

Antibiotic prophylaxis is recommended in patients with ventricular assist devices.

Antibiotic prophylaxis may be considered in recipients of heart transplant.

IIb C Section 3. Recommendation Table 2 -Recommendations for infective endocarditis prevention in high-risk patients

Systemic antibiotic prophylaxis may be considered for high-risk patients undergoing an invasive diagnostic or therapeutic procedure of the respiratory, gastrointestinal, genitourinary tract, skin, or musculoskeletal systems.

IIb C Section 3. Recommendation Table 3 -Recommendations for infective endocarditis prevention in cardiac procedures

Optimal pre-procedural aseptic measures of the site of implantation is recommended to prevent CIED infections.

I B

Continued

Surgical standard aseptic measures are recommended during the insertion and manipulation of catheters in the catheterization laboratory environment.

Antibiotic prophylaxis covering for common skin flora including Enterococcus spp. and S. aureus should be considered before TAVI and other transcatheter valvular procedures.

IIa C

Section 5. Recommendation Table 5 -Recommendations for the role of echocardiography in infective endocarditis TOE is recommended when the patient is stable before switching from intravenous to oral antibiotic therapy.

I B Section 5. Recommendation Table 6 -Recommendations for the role of computed tomography, nuclear imaging, and magnetic resonance in infective endocarditis

Cardiac CTA is recommended in patients with possible NVE to detect valvular lesions and confirm the diagnosis of IE.

[18F]FDG-PET/CT(A) and cardiac CTA are recommended in possible PVE to detect valvular lesions and confirm the diagnosis of IE.

[18F]FDG-PET/CT(A) may be considered in possible CIED-related IE to confirm the diagnosis of IE.

IIa B

Cardiac CTA is recommended in NVE and PVE to diagnose paravalvular or periprosthetic complications if echocardiography is inconclusive.

Brain and whole-body imaging (CT, [18F]FDG-PET/ CT, and/or MRI) are recommended in symptomatic patients with NVE and PVE to detect peripheral lesions or add minor diagnostic criteria.

WBC SPECT/CT should be considered in patients with high clinical suspicion of PVE when echocardiography is negative or inconclusive and when PET/CT is unavailable.

Brain and whole-body imaging (CT, [18F]FDG-PET/ CT, and MRI) in NVE and PVE may be considered for screening of peripheral lesions in asymptomatic patients.

IIb B Section 7. Recommendation

TTE/TOE is recommended to rule out IE in patients with spondylodiscitis and/or septic arthritis with positive blood cultures for typical IE microorganisms.

More than 6-week antibiotic therapy should be considered in patients with osteoarticular IE-related lesions caused by difficult-to-treat microorganisms, such as S. aureus or Candida spp., and/or complicated with severe vertebral destruction or abscesses.

IIa C Section 10. Recommendation Table 16 -Recommendations for pre-operative coronary anatomy assessment in patients requiring surgery for infective endocarditis

In haemodynamically stable patients with aortic valve vegetations who require cardiac surgery and are high risk of CAD, a high-resolution multislice coronary CTA is recommended.

Invasive coronary angiography is recommended in patients requiring heart surgery who are high risk of CAD, in the absence of aortic valve vegetations.

In emergency situations, valvular surgery without pre-operative coronary anatomy assessment regardless of CAD risk should be considered.

Invasive coronary angiography may be considered despite the presence of aortic valve vegetations in selected patients with known CAD or at high risk of significant obstructive CAD.

IIb C Section 10. Recommendation Table 17 -Indications and timing of cardiac surgery after neurological complications in active infective endocarditis

In patients with intracranial haemorrhage and unstable clinical status due to HF, uncontrolled infection, or persistent high embolic risk, urgent or emergency surgery should be considered weighing the likelihood of a meaningful neurological outcome.

. Recommendation Table 18 -Recommendations for post-discharge follow-up

Patient education on the risk of recurrence and preventive measures, with emphasis on dental health, and based on the individual risk profile, is recommended during follow-up.

Addiction treatment for patients following PWID-related IE is recommended.

Cardiac rehabilitation including physical exercise training should be considered in clinically stable patients based on an individual assessment.

Psychosocial support may be considered to be integrated in follow-up care, including screening for anxiety and depression, and referral to relevant psychological treatment.

IIb C Section 12. Recommendation Table 19 -Recommendations for prosthetic valve endocarditis

Surgery is recommended for early PVE (within 6 months of valve surgery) with new valve replacement and complete debridement.

I C Section 12. Recommendation Table 20 -Recommendations for cardiovascular implanted electronic device-related infective endocarditis

Complete system extraction without delay is recommended in patients with definite CIED-related IE under initial empirical antibiotic therapy.

Extension of antibiotic treatment of CIED-related endocarditis to (4-) 6 weeks following device extraction should be considered in the presence of septic emboli or prosthetic valves.

Use of an antibiotic envelope may be considered in select high-risk patients undergoing CIED reimplantation to reduce risk of infection.

IIb B

Table 4 Revised recommendations

Recommendations in 2015 version Class Level Recommendations in 2023 version Class Level Section 3. Recommendation Table 1 -Recommendations for antibiotic prophylaxis in patients with cardiovascular diseases undergoing oro-dental procedures at increased risk of infective endocarditis

Recommendations in 2015 version Class Level Recommendations in 2023 version Class Level Section 3. Recommendation Table 1 -Recommendations for antibiotic prophylaxis in patients with cardiovascular diseases undergoing oro-dental procedures at increased risk of infective endocarditis

Antibiotic prophylaxis should be considered for patients at highest risk of IE:

(1) Patients with any prosthetic valve, including a transcatheter valve, or those in whom any prosthetic material was used for cardiac valve repair.

Antibiotic prophylaxis is recommended in patients with previous IE.

Antibiotic prophylaxis is recommended in patients with surgically implanted prosthetic valves and with any material used for surgical cardiac valve repair.

Antibiotic prophylaxis is recommended in patients with transcatheter implanted aortic and pulmonary valvular prostheses.

Antibiotic prophylaxis should be considered in patients with transcatheter mitral and tricuspid valve repair.

In non-S. aureus CIED-related endocarditis without valve involvement or lead vegetations, and if follow-up blood cultures are negative without septic emboli, 2 weeks of antibiotic treatment may be considered following device extraction.

IIb C

Removal of CIED after a single positive blood culture, with no other clinical evidence of infection, is not recommended.

III C

Section 12. Recommendation Table 21 -Recommendations for the surgical treatment of right-sided infective endocarditis

Tricuspid valve repair should be considered instead of valve replacement, when possible.

Surgery should be considered in patients with right-sided IE who are receiving appropriate antibiotic therapy and present persistent bacteraemia/sepsis after at least 1 week of appropriate antibiotic therapy.

Prophylactic placement of an epicardial pacing lead should be considered at the time of tricuspid valve surgical procedures.

Debulking of right intra-atrial septic masses by aspiration may be considered in select patients who are high risk of surgery.

[18F]FDG-PET, 18 F-fluorodeoxyglucose positron emission tomography; AVB, atrioventricular block; CAD, coronary artery disease; CIED, cardiovascular implanted electronic device; CoNS, coagulase-negative staphylococci; CT, computed tomography; CTA, computed tomography angiography; HF, heart failure; IE, infective endocarditis; i.v., intravenous; MRI, magnetic resonance imaging; NVE, native valve endocarditis; PET, positron emission tomography; PVE, prosthetic valve endocarditis; PWID, people who inject drugs; TAVI, transcatheter aortic valve implantation; TOE, transoesophageal echocardiography; TTE, transthoracic echocardiography; WBC SPECT/CT, white blood cell single photon emission tomography/computed tomography.

percutaneous techniques, up to 6 months after the procedure or lifelong if residual shunt.

Antibiotic prophylaxis is recommended in patients with untreated cyanotic CHD, and patients treated with surgery or transcatheter procedures with post-operative palliative shunts, conduits, or other prostheses. After surgical repair, in the absence of residual defects or valve prostheses, antibiotic prophylaxis is recommended only for the first 6 months after the procedure.

I C Section 4. Recommendation Table 4 -Recommendations for the Endocarditis Team

Patients with complicated IE should be evaluated and managed at an early stage in a reference centre, with immediate surgical facilities and the presence of a multidisciplinary 'Endocarditis Team', including an infectious disease specialist, a microbiologist, a cardiologist, imaging specialists, a cardiac surgeon and, if needed, a specialist in CHD.

Diagnosis and management of patients with complicated IE are recommended to be performed at an early stage in a Heart Valve Centre, with immediate surgical facilities and an 'Endocarditis Team' to improve the outcomes.

For patients with uncomplicated IE managed in a non-reference centre, early and regular communication with the reference centre and, when needed, visits to the reference centre should be made.

For patients with uncomplicated IE managed in a Referring Centre, early and regular communication between the local and the Heart Valve Centre Endocarditis Teams is recommended to improve the outcomes of the patients.

I B Section 5. Recommendation

Brain CT or MRA is recommended in patients with IE and suspected infective cerebral aneurysms.

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 registry 5 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 7] [148] [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 n 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 hen all microbiological assays are negative, the diagnosis of nonbacterial endocarditis should systematically be considered and assays for antinuclear antibodies as well as antiphospholipid syndrome (APLs) (anticardiolipin antibodies [immunoglobulin (Ig)G] and anti-β 2 -glycoprotein 1 antibodies [IgG and IgM] ) should be performed (although these antibodies may also be present in patients with proven IE). 161, 162 Pathological examination of resected tissue or embolic fragments remains the gold standard for IE diagnosis. All tissue samples that are excised during surgical valve debridement/resection must be collected in a sterile container without fixative or culture medium. Samples should be sent to the pathology department and the microbiology laboratory for the identification of microorganisms. On histological examination of excised valve tissue, patterns, and degrees of inflammation will vary depending on the infecting organism. Stains for bacteria, mycobacteria, and fungi may identify the microorganisms, and organism-specific immunohistochemical stains can be very useful for the final diagnosis. Importantly, histopathological analysis may facilitate the diagnosis of non-infectious causes of endocarditis, such as neoplastic and autoimmune causes. 160

5.3.3. Proposed strategy for a microbiological diagnostic algorithm in suspected infective endocarditis

A proposed diagnostic scheme is provided in Figure 4 . When there is clinical suspicion of IE and blood cultures remain negative at 48 h, consultation with the microbiologist is necessary. 156, 160 A suggested strategy is the use of a diagnostic kit including blood cultures for the suspected microorganism and when negative, systematic serological testing for C. burnetii, Bartonella spp., Aspergillus spp., L. pneumophila, Brucella spp., and M. pneumoniae, as well as rheumatoid factor, serological tests for APLs (anticardiolipin [IgG] and anti-β 2 -glycoprotein 1 [IgG and IgM] ), antinuclear antibodies, and anti-pork antibodies. Serological testing should be performed taking into consideration the clinical characteristics of the patients (i.e. Aspergillus spp. in severe immunocompromised patients), the local epidemiology, and being aware of the specificity of the tests. In addition, tissue or prosthetic material obtained at surgery must be subjected to systematic culture, histological examination, and 16S or 18S rRNA sequencing aimed at documenting the presence of organisms.

5.4. Imaging techniques

Evidence of lesions characteristic of IE are major diagnostic criterion. Echocardiography is the first-line imaging technique to diagnose IE and to assess the structural and functional damage of cardiac structures. Echocardiographic findings have prognostic implications, and help to guide decision-making and patient follow-up while receiving antibiotic therapy and during the peri-operative and post-operative periods. 163 In some clinical scenarios, other imaging modalities, such as CT, nuclear imaging, and MRI, are needed to confirm or exclude the diagnosis of IE, to characterize the extent of the cardiac lesions, and to diagnose extracardiac complications. They can also provide additional useful information for patient management. 137 Each of these techniques has its diagnostic strengths and weaknesses (see Supplementary data online, Table S2 ). The use of an optimal imaging strategy depends on the availability of, and expertise in, each technique, but when indicated a multimodality imaging approach is essential for patients with suspected IE and should be strongly encouraged by the Endocarditis Team. 21

5.4.1. Echocardiography

Transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE) are the first and key imaging techniques used to diagnose IE. Although echocardiography is widely accessible, significant variation in the use of TOE still exists. 164 Three-dimensional TOE and intracardiac echocardiography have also been shown to be useful for the diagnosis of IE and its complications. 165 However, the availability of intracardiac echocardiography is limited. Vegetation characteristics and size, perivalvular complications (abscess, pseudoaneurysm, new partial dehiscence of prosthetic valve), intracardiac fistula, and leaflet perforation are the main echocardiographic findings for the diagnosis and evaluation of local complications of IE (see Supplementary data online, Table S3 ). Importantly, vegetation size is a key metric that guides surgical indication, and vegetation size is defined as the maximal length of the vegetation. 166 When evaluating IE on native or prosthetic valves, TTE had low sensitivity but good specificity as compared with TOE. 166 OE is helpful in a wide range of clinical scenarios, due to limitations of TTE to diagnose perivalvular complications, small vegetations, PVE, and vegetations associated with CIED. TOE is strongly recommended in patients with an inconclusive TTE, in patients with a negative TTE and a high suspicion of IE, as well as in patients with a positive TTE, in order to document local complications. Repeating TTE and/or TOE should be considered during follow-up of uncomplicated IE, in order to detect new silent complications and monitor vegetation size. The timing and mode (TTE or TOE) of repeated examination depend on the initial findings, type of microorganism, and initial response to therapy. Echocardiographic imaging should be performed as soon as the IE diagnosis is suspected. The degree of valvular damage, the rate of peripheral embolic events, and the need for valve surgery increase with increasing time to initial echocardiographic assessment. 167 chocardiography should be repeated 5-7 days after an initial normal or inconclusive echocardiography, if the suspicion of IE remains high, and in patients with diagnosed IE at high risk of complications (e.g. aggressive microorganisms, prosthetic valves). 22, 165, 168, 169 here is uncertainty regarding whether echocardiography should be systematically performed in patients with bloodstream infections due to different bacterial species, or if there are strategies (microbiological or imaging) that allow the identification of patients at higher risk of IE.

1] [172] [173] The combination of microbiological parameters (type of microorganism and number of positive blood culture bottles) and cardiac-related risk factors (native valve disease, previous IE, prosthetic valve, and cardiac devices) may help identify the patients in whom echocardiography (TTE+TOE) is needed. 19, 174 173] [175] [176] [177] [178] The cut-off values of the various scores are provided in Supplementary data online, Table S4 .

5.4.2. Computed tomography

The indications for CT in patients with suspected or diagnosed IE include:

(i) Diagnosis of IE and cardiac complications. Cardiac CT is more accurate than TOE for diagnosing perivalvular and periprosthetic complications of IE (abscesses, pseudoaneurysms, and fistulae) and is recommended in both NVE and PVE if TOE is not conclusive or not feasible. 33, 168, 169 In addition, cardiac CT can significantly influence subsequent surgical decision-making. 20, 185, 186 chocardiography continues to be superior for detecting valvular lesions, particularly small vegetations ( < 10 mm) which remain underdiagnosed by CT, but also leaflet perforations and fistulae (see Supplementary data online, Table S3 ). 35, 168, 169 Cardiac CT should be acquired according to the recommendations of cardiac CT guidelines to ensure high diagnostic accuracy, and can be performed alone or in combination with PET. 187 ii) Detection of distant lesions and sources of bacteraemia. Whole-body and brain CT are useful for assessing IE systemic complications, including septic emboli. The detection of distant lesions adds a minor diagnostic criterion leading to a more conclusive diagnosis of definite or rejected IE, and can be relevant for decision-making. 188 CT angiography can detect mycotic arterial aneurysms complicating IE in almost any site of the vascular tree, 189, 190 including the central nervous system (CNS). Although MRI is superior to CT for diagnosing neurological complications, 191 CT may be more feasible in an emergency setting and is an acceptable alternative for the detection of neurological complications, with a sensitivity of 90% and specificity of 86% in the detection of ischaemic and haemorrhagic lesions. 192 Finally, CT can also detect the extracardiac sources of the bacteraemia, including early neoplastic lesions, that may be important for patient management, and which need to be ideally addressed prior to undergoing heart valve surgery. However, CT does not replace the specific test indicated for the diagnosis of the extracardiac source of bacteraemia (i.e. colonoscopy in colon neoplasms). (iii) Pre-operative assessment. Cardiac CT is a valuable alternative for non-invasive assessment of coronary artery disease (CAD) before cardiac surgery in patients with IE. 193 (iv) Alternative diagnosis. In patients in whom IE is ruled out, or even in doubtful patients with possible IE, an alternative diagnosis can be reached by whole-body CT, as it can help to detect alternative infectious foci. However, in these circumstances, an [18]FDG positron emission tomography/computed tomography (PET/CT) is the preferred imaging technique. 194

5.4.3. Magnetic resonance imaging

The roles of MRI in the diagnostic work-up of IE include:

(i) Diagnosis of IE and cardiac complications. The role of cardiac MRI to diagnose IE is limited by the low spatial resolution (as compared with cardiac CT) and the signal void generated by some prostheses impairing the assessment of prosthetic valve anatomy and function. 195, 196 ii) Diagnosis of neurological IE-related complications. MRI has higher sensitivity than CT for the diagnosis of neurological lesions and, hence, increases the likelihood of detecting neurological complications in patients with IE. Patients with IE might present CNS lesions in up to 60-80% of cases, 197 most of them corresponding to ischaemic lesions (50-80% of patients) that are often small and asymptomatic and do not impact on the decision-making. 198 9] [200] [201] The systematic performance of brain MRI has shown to directly impact the

I C

Performing an echocardiography should be considered in S. aureus, E. faecalis, and some Streptococcus spp. bacteraemia. 19, 149, 174 a B

B. Follow-up under medical therapy

Repeating TTE and/or TOE is recommended as soon as a new complication of IE is suspected (new murmur, embolism, persisting fever and bacteraemia, HF, abscess, AVB). 165, 166, 179

I B

TOE is recommended when patient is stable before switching from intravenous to oral antibiotic therapy. 43, 180

During follow-up of uncomplicated IE, repeat TTE and/ or TOE should be considered to detect new silent complications. The timing of repeat TTE and/or TOE depends on the initial findings, type of microorganism, and initial response to therapy. 165, 166, 179 a B

C. Intra-operative echocardiography

Cerebral microbleeds, found in 50-60% of patients with IE, are detected at gradient echo T2* sequences. 200, 202 ] [205] (iii) Diagnosis of spine lesions. MRI is the diagnostic modality of choice of spondylodiscitis and vertebral osteomyelitis with a diagnostic accuracy of 89-94%. MRI findings include vertebrae and disc oedema, paravertebral/epidural inflammation or abscess, bone erosion, and gadolinium enhancement of vertebrae and discs. 32, 206 It should be acknowledged that when MRI is performed too early, the rate of false-negative increases. 207

5.4.4. Nuclear imaging positron emission tomography/computed tomography (angiography) and single photon emission tomography/computed tomography

Technical specifications of these imaging techniques are in the Supplementary data online, Section S2. 2.2. The roles of nuclear imaging techniques in the diagnostic work-up of IE include:

(i) Diagnosis of IE and cardiac complications.

[18F]FDG-PET/CT and white blood cell (WBC) single photon emission computed tomography (SPECT)/CT are recommended in suspected PVE in cases of inconclusive echocardiography. The most recent meta-analysis showed 86% sensitivity and 84% specificity for [18F]FDG-PET/CT in PVE. 129 dditional evidence demonstrating the incremental diagnostic value of [18F]FDG-PET/CT and WBC SPECT/CT is summarized in the Supplementary data online, Section S2.2.2; [210] [211] [212] White blood cell SPECT/CT is an alternative nuclear imaging technique for the diagnosis of IE, when PET/CT is unavailable and inexperienced centres. 99m Technetium-hexamethylpropyleneamine oxime (99mTc-HMPAO)-SPECT/CT helped to reduce the number of misdiagnosed IE cases classified in the 'possible IE' category by the modified Duke criteria by 27%. 216 n cases of NVE, the sensitivity of PET/CT and SPECT/CT is low (about 31%) but with a higher specificity (around 98%). 211 In NVE, the diagnosis of IE cannot be excluded in the absence of abnormal [18F]FDG uptake. 217 The more frequent presence of valve vegetations in comparison with paravalvular involvement in NVE compared with PVE leads to reduced inflammatory response and subsequently lower [18F]FDG and WBC uptake. 9] [220] Electrocardiogram (ECG)-gated PET may further improve the diagnostic accuracy. 221 ombining PET/CT acquisition with a CT angiography (PET/CTA) allows the detection of metabolic findings ([18F]FDG uptake distribution and intensity) and anatomical findings (IE-related lesions) within a single imaging procedure, resulting in the clinical clarification of indeterminate findings and change in the management of the patients. 22, 211 Such investigations may be particularly helpful in complex settings, such as patients with CHD 222, 223 and/or aortic grafts. 22, 224 i) Detection of distant lesions and sources of bacteraemia.

Whole-body [18F]FDG-PET/CT imaging is particularly useful in patients with a suspicion or proven IE to identify distant lesions, mycotic aneurysms, and the portal of entry of the infection. 225, 226 eptic emboli are typically located in the spleen, lungs (in rightsided IE), and kidneys, and metastatic infections in the intervertebral discs and/or the vertebral bone (spondylodiscitis) as well as in muscles and joints (septic arthritis) and liver. 211, 227, 228 [18F] FDG-PET/CT is less suited to detect cerebral septic embolism and mycotic aneurysms of intracerebral arteries due to the high physiological uptake of [18F] FDG in the brain. [231] [232] [233] [234] [235] [236] Recommendation Table 6 -Recommendations for the role of computed tomography, nuclear imaging, and magnetic resonance in infective endocarditis

Recommendations

Class a Level b

Cardiac CTA is recommended in patients with possible NVE to detect valvular lesions and confirm the diagnosis of IE. 33, 168, 169 I B

[18F]FDG-PET/CT(A) and cardiac CTA are recommended in possible PVE to detect valvular lesions and confirm the diagnosis of IE. 22, 129, 209, 210, [237] [238] [239]

Cardiac CTA is recommended in NVE and PVE to diagnose paravalvular or periprosthetic complications if echocardiography is inconclusive. 20, 168, 169, 185, 186

00,210,213,240,241

[215] [216] IIa C

5.5. Diagnostic criteria

Since 2000, clinical, microbiological, and imaging findings have been integrated in the modified Duke criteria (see Supplementary data online, Table S6 ), which have demonstrated an overall sensitivity of 80% for IE. 151 However, the clinical presentation of IE can be highly variable and some major limitations of the modified Duke criteria have become clear, particularly when prosthetic material is present (PVE, aortic grafts, cardiac devices, CHD). In these situations, echocardiography can be normal or inconclusive in up to 30% of cases despite the presence of IE. [242] [243] [244] Therefore, the 2015 ESC diagnostic criteria introduced a multimodality imaging approach (echocardiography, cardiac/ whole-body CT, cerebral MRI, [18F]FDG-PET/CT, and WBC SPECT/ CT) to improve the diagnostic yield. 123, 125, 126, 212

5.5.1. Modifications for the diagnosis of infective endocarditis

The current 2023 ESC Guidelines for the management of endocarditis introduce the following modifications for IE diagnosis:

(i) Changes to the major and minor diagnostic criteria (Table 10 ). • ≥2 positive blood cultures of blood samples drawn > 12 h apart.

• All of 3 or a majority of ≥4 separate cultures of blood (with first and last samples drawn ≥1 h apart).

(ii) Imaging positive for IE:

Valvular, perivalvular/periprosthetic and foreign material anatomic and metabolic lesions characteristic of IE detected by any of the following imaging techniques:

• Echocardiography (TTE and TOE).

• Cardiac CT.

• [18F]-FDG-PET/CT(A).

• WBC SPECT/CT.

Minor criteria (i) Predisposing conditions (i.e. predisposing heart condition at high or intermediate risk of IE or PWIDs) a

(ii) Fever defined as temperature > 38°C

(iii) Embolic vascular dissemination (including those asymptomatic detected by imaging only):

• Major systemic and pulmonary emboli/infarcts and abscesses.

• Haematogenous osteoarticular septic complications (i.e. spondylodiscitis).

• Mycotic aneurysms.

• Intracranial ischaemic/haemorrhagic lesions.

• Conjunctival haemorrhages.

• Janeway's lesions. (IV) Immunological phenomena:

• Glomerulonephritis.

• Osler nodes and Roth spots.

• Rheumatoid factor.

(V) Microbiological evidence:

• Positive blood culture but does not meet a major criterion as noted above.

• Serological evidence of active infection with organism consistent with IE.

IE Classification (at admission and during follow-up)

Definite:

• 2 major criteria.

• 1 major criterion and at least 3 minor criteria.

• 5 minor criteria.

Possible:

• 1 major criterion and 1 or 2 minor criteria.

• 3-4 minor criteria.

Rejected:

• Does not meet criteria for definite or possible at admission with or without a firm alternative diagnosis.

© ESC 2023

[18F]-FDG-PET/CT, 18 F-fluorodeoxyglucose positron emission tomography; CT(A), computed tomography (angiography); HACEK, Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella; IE, infective endocarditis; Ig, immunoglobulin; PWID, people who inject drugs; TOE, transoesophageal echocardiography; TTE, transthoracic echocardiography; WBC SPECT/CT, white blood cell single photon emission tomography/computed tomography. a For detailed explanation of predisposing conditions, please see Section 3.

(ii) Specific diagnostic algorithms to support decision-making, especially in the recommended sequence of imaging techniques (Figures 5 6 7 ). (iii) CIED-related IE is considered a right-sided endocarditis for diagnostic purposes and is included in the diagnostic algorithms, but its definitions and recommendations for management can be found in Section 12 and are in accordance with the specific European Heart Rhythm Association (EHRA) consensus on CIED infections. 130 peat blood cultures if negative or doubtful Repeat TTE/TOE within 5-

ESC Guidelines

The reasons to justify the changes in the diagnostic criteria include:

##### 5.5.1.1. Major criteria -microbiology

5.5.1.1. Major criteria -microbiology

Enteroccus faecalis should be acknowledged as a typical endocarditis bacterium, regardless of the place of acquisition or the source of infection. Currently, the modified Duke criteria fail to identify 30% of E. faecalis definite IE. Using data from a prospective study of 344 patients with E. faecalis bacteraemia evaluated with echocardiography, Dahl et al. demonstrated that designating E. faecalis as a 'typical' endocarditis pathogen significantly improved the sensitivity to correctly identify definite IE, from 70% to 96%. 245 major diagnostic criterion. Definitions of the anatomic and metabolic features of the infective lesions can be found in the Supplementary data online, Table S5 .

##### 5.5.1.2. Major criteria -imaging

5.5.1.2. Major criteria -imaging

(ii) Abnormal prosthetic or periprosthetic uptake (intense focal or heterogeneous) detected by [18F]FDG-PET/CT or WBC SPECT/CT should be considered a major criterion for PVE, irrespective of the interval from surgery (see Supplementary data online, Figure S1 ). Published data support that intense focal or heterogeneous patterns is associated with a final diagnosis of infection, while post-operative inflammatory changes can be persistent more than 3 months after surgery, as noted in the previous guidelines. However, these inflammatory changes can be differentiated from infection even after recent valve implantation. 246 Therefore, a consensus of experts has concluded that the need for a time interval prior to investigation is questionable, but accurate imaging interpretation by proper interpretation criteria is mandatory. 233, 236 5.1. 3

##### . Minor criteria

. Minor criteria

Distant IE-related lesions include all lesions that can result from embolic events and from haematogenous seeding of bacteria. These lesions can be suspected due to specific symptoms or can be incidentally detected on imaging techniques. Spondylodiscitis is the most frequent osteoarticular infective complication in patients with IE. 247, 248 5. 5.1. 4

##### . Microbiological criteria

. Microbiological criteria

Molecular biology (16S/18S rRNA PCR sequencing) in cardiac tissue or embolic material has increased the diagnostic performance of IE with negative blood culture. The sensitivity ranges between 41% and 96% and the specificity is very high, ranging between 90% and 100%. 249 peat blood cultures if negative or doubtful Repeat TTE/TOE within 5-

##### 5.5.1.5. Infective endocarditis classification

5.5.1.5. Infective endocarditis classification

Infective endocarditis classification has been added to the 2023 ESC criteria. Possible IE cases include the combination of 1 major and 1 or 2 minor criteria. Infective endocarditis classification should be applied by the Endocarditis Team at admission and later at follow-up, taking into account the complete clinical, microbiology, imaging, and surgical information to establish the final diagnosis.

It is important to acknowledge that these new criteria should be prospectively validated.

5.5.2. The new 2023 European Society of Cardiology diagnostic algorithms

The diagnosis of IE is based on clinical suspicion, blood cultures, and imaging findings. Echocardiography is usually the first imaging technique to diagnose IE, although the use of other techniques, either for the diagnosis of cardiac involvement (cardiac CT, [18F]FDG-PET/CT, or WBC SPECT/CT), or for the diagnosis of distant lesions (cerebral MRI, wholebody CT, and/or PET/CT), is encouraged. In the presence of prosthetic valves and CIED, echocardiography is particularly limited and the aforementioned imaging techniques are strongly recommended. Adapted diagnostic algorithms for suspected IE in NVE, PVE, and CIED are displayed in Figures 5 6 7 , respectively.

If non-invasive techniques are negative and the suspicion of infective aneurysm remains, invasive angiography should be considered.

IIa B Section 12. Recommendation Table 20 -Recommendations for cardiovascular implanted electronic device-related infective endocarditis

Routine antibiotic prophylaxis is recommended before device implantation.

Antibiotic prophylaxis covering S. aureus is recommended for CIED implantation.

I A

TOE is recommended in patients with suspected cardiac device-related infective endocarditis with positive or negative blood cultures, independent of the results of TTE, to evaluate lead-related endocarditis and heart valve infection.

TTE and TOE are both recommended in case of suspected CIED-related IE to identify vegetations.

In patients with NVE or PVE and an intracardiac device with no evidence of associated device infection, complete hardware extraction may be considered.

Complete CIED extraction should be considered in case of valvular IE, even without definite lead involvement, taking into account the identified pathogen and requirement for valve surgery.

Continued ESC Guidelines

3. Prevention

3.1. Rationale

The development of IE usually requires several conditions, including the presence of predisposing risk factors (i.e. a surface/structure that could be colonized by bacteria), pathogens entering the bloodstream, and the competence of the host's immune response. The role of predisposing risk factors has been recently underscored by Thornhill et al. 47 Predisposing risk factors conveying a moderate and high risk of IE had an incidence of 280 and 497 cases per 100 000 subjects per year, respectively. 47 ] [50] The oral cavity is colonized by relevant commensal flora, including oral group streptococci, and represents an important entry port. Oral surgery procedures (including all extractions, periodontal surgery, implant surgery, and oral biopsies) and dental procedures that involve manipulation of the gingival or periapical region of the teeth are considered at high risk of causing bacteraemia. 11, 48, 49, 51 uccessful antibiotic prophylaxis assumes that reducing the bacteraemia associated with medical procedures will lead to a reduced risk of IE. ] [54] [55] [56] [57] [58] [59] [60] However, systematic use of antibiotic prophylaxis has been questioned based on several considerations, the most important being the lack of randomized clinical trials (RCTs) demonstrating the efficacy of antibiotic prophylaxis prior to medical procedures in preventing IE. Such trials would entail enrolment of a very large number of individuals and prolonged follow-up, making the feasibility of such studies improbable. Furthermore, since the standard of care for high-risk individuals is antibiotic prophylaxis (to date, mostly before invasive oro-dental procedures), there may not be sufficient equipoise to perform such RCTs. Finally, the costs of performing such trials have been considered unacceptable. 61 To overcome these limitations, population-based studies Complete hardware removal should be considered on the basis of occult infection without another apparent source of infection.

In cases of possible CIED-related IE or occult Gram-positive bacteraemia or fungaemia, complete system removal should be considered in case bacteraemia/fungaemia persists after a course of antimicrobial therapy.

In cases of possible CIED-related IE with occult Gram-negative bacteraemia, complete system removal may be considered in case of persistent/relapsing bacteraemia after a course of antimicrobial therapy.

When indicated, definite reimplantation should be postponed if possible, to allow a few days or weeks of antibiotic therapy.

If CIED reimplantation is indicated after extraction for CIED-related IE, it is recommended to be performed at a site distant from the previous generator, as late as

Right ventricular dysfunction secondary to acute severe tricuspid regurgitation non-responsive to diuretics.

Persistent vegetation with respiratory insufficiency requiring ventilatory support after recurrent pulmonary emboli.

Large residual tricuspid vegetations ( > 20 mm) after recurrent septic pulmonary emboli.

Patients with simultaneous involvement of left-heart structures.

I C Section 12. Recommendation Table 22 -Recommendations for the use of antithrombotic therapy in infective endocarditis

Interruption of antiplatelet therapy is recommended in the presence of major bleeding.

Interruption of antiplatelet or anticoagulant therapy is recommended in the presence of major bleeding (including intracranial haemorrhage).

have evaluated the efficacy of antibiotic prophylaxis using bacteraemia as a surrogate of IE. [16] [17] [18] 52, 62 However, the relationship between bacteraemia and IE is not straightforward. Bacte aemia may be caused by daily activities such as tooth brushing, flossing, and chewing, and although these constitute low-level bacteraemia, they occur repetitively and may therefore outweigh the risk of bacteraemia associated with dental procedures. 48, 49 A meta-analysis of 36 studies, including 21 trials that investigated the effect of antibiotic prophylaxis on the incidence of bacteraemia following dental procedures, demonstrated that antibiotic prophylaxis is effective in reducing the incidence of bacteraemia, but did not lead to a statistically significant protective effect against IE in casecontrol studies. 52 Additionally, the potential risk of anaphylaxis, 63 or other adverse side effects in a small minority of patients, and the fact that a widespread use of antibiotics may be associated with antibiotic resistance, are areas of concern. 57, 58, [64] [65] [66] [67] While some studies did not demonstrate significant increases in IE-related hospitalizations and death rates after scaling down antibiotic prophylaxis indications, [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] others showed an increase in the incidence of IE among individuals at moderate and high risk of IE. 13, 26, 59, [78] [79] [80] [81] A meta-analysis including 16 studies reporting over 1.3 million cases of IE has shown that restricting antibiotic prophylaxis to only high-risk individuals has not resulted in an increase in the incidence of streptococcal IE in a North American population (despite the fact that it was unable to draw that conclusion for other populations). 18 In contrast, a systematic review including multiple nationwide population-based studies in Europe has shown a 4% per year rise in the incidence of IE. 82 These contrasting results may be explained by differences in the methodology of the studies (retrospective, population-or health-system-based studies that relied on claims data or epidemiological observations to estimate the incidence of IE), greater disease diagnosis with the use of newer imaging technologies, lack of microbiological data, and the lack of specific International Classification of Diseases codes for oral streptococci. 83 Recently, it has been shown that antibiotic prophylaxis in high-risk individuals was associated with a significant reduction of IE after invasive dental procedures (particularly extractions and oral surgical procedures). 11, 51 After careful consideration of all the new studies published after 2015, the present Task Force decided to revise and update the risk categories for IE, strengthening the recommendation of antibiotic prophylaxis, clarifying the definition of the population at risk, and considering the advances in transcatheter valve interventions.

3.2. Populations at risk of infective endocarditis

The groups of individuals at high risk of IE in whom antibiotic prophylaxis is recommended or should be considered include the following: as compared with patients with NVE, regardless of the pathogen. 87, 88 Furthermore, mitral and aortic bioprostheses may be associated with increased risk of IE as compared with mechanical prostheses, 89, 90 and bioprostheses are being implanted in an ever-increasing proportion of patients requiring valve replacement therapy. 2] [93] [94] In terms of transcatheter mitral and tricuspid valve interventions, the data on the risk of IE are limited. 95 Patients with septal defect closure devices, left atrial appendage closure devices, vascular grafts, vena cava filters, and central venous system ventriculo-atrial shunts are considered within this risk category in the first 6 months after implantation. 96 iii) Patients with congenital heart disease (CHD) (not including isolated congenital valve abnormalities) are at increased risk of IE. 8, 47, [97] [98] [99] The cumulative incidence over time is influenced strongly by the improved long-term survival of children with CHD into adulthood. 98 Indeed, there are now more adults living with CHD than children with CHD. 100 The overall incidence rate of IE among adult patients with CHD is 27-44 times that reported for contemporary adults of the general population (1.33 cases per 1000 persons per year) 8 while in children with CHD the incidence of IE is 0.41 cases per 1000 persons per year. 101 CHD groups at increased risk include those with untreated cyanotic CHD, and those whose surgery includes prosthetic material, including valved conduits or systemic to pulmonary shunts. 8, 47, 97 The risk of post-operative IE for CHD patients undergoing transcatheter atrial or ventricular septal defect closure with devices or surgery with non-valve-related prosthetic material is also increased, but predominantly for the first 6 months after surgery. 8 (iv) Patients with ventricular assist devices as destination therapy are also considered at high risk because of associated morbidity and mortality, and prophylaxis is also recommended in such patients. 102 Patients at intermediate risk of IE include those with: (i) rheumatic heart disease (RHD); (ii) non-rheumatic degenerative valve disease; (iii) congenital valve abnormalities including bicuspid aortic valve disease; (iv) cardiovascular implanted electronic devices (CIEDs); and (v) hypertrophic cardiomyopathy. 47, 103, 104 Some epidemiological data suggest that certain conditions stratified as intermediate risk are associated Table 5 General prevention measures to be followed in patients at high and intermediate risk of infective endocarditis with a higher risk of IE compared with the background population, 47, 90, 103 but further studies are required. In patients at intermediate risk of IE, antibiotic prophylaxis is not routinely recommended and may be considered on an individual basis. However, p evention measures (Table 5 ) are strongly encouraged in these patients. 7 Most of the IE in recipients of solid organ transplant is nosocomial. A recent systematic review of patient-level data including 57 heart transplant patients has shown that IE occurs frequently during the first year post-transplant, and the most common pathogen is S. aureus followed by Aspergillus fumigatus. 105 Oral streptococci are a very infrequent cause of IE, making the value of antibiotic prophylaxis after invasive orodental procedures questionable. Ho ever, IE in this group of patients is associated with very high mortality, particularly in patients with fungal IE. In contrast, other series that include a larger proportion of noncardiac solid organ transplant patients have shown that the pathogens are more frequently from the Staphylococcus spp. and the mortality seems to be similar to that of patients without solid organ transplant. 106, 107

(i)

3.3. Situations and procedures at risk

3.3.1. Dental procedures

Antibiotic prophylaxis is recommended in patients at high risk of IE undergoing at-risk dental procedures and is not currently recommended in other situations. At-risk dental procedures include dental extractions, oral surgery procedures (including periodontal surgery, implant surgery, and oral biopsies), and dental procedures involving manipulation of the gingival or periapical region of the teeth (including scaling and root canal procedures). 49, 108 The use of dental implants raises concerns about potential risk due to foreign material at the interface between the buccal cavity and blood, but available data remain very limited. 109 So far there is no evidence to contraindicate implants in all patients at risk and the indication should be discussed on an individual basis. Implant placement procedures, and invasive dental procedures on established implants, however, should be covered by antibiotic prophylaxis in those at high risk of IE. Once dental implants are placed in high-risk patients, professional dental hygiene and follow-up should be performed at least twice yearly under antibiotic cover, when indicated.

The main target for antibiotic prophylaxis is oral streptococci. Table 6 summarizes the main regimens of antibiotic prophylaxis recommended before dental procedures. ] [112] Accordingly, this Task Force does not recommend the use of clindamycin for antibiotic prophylaxis.

3.3.2. Non-dental procedures

No convincing evidence has been brought forward on the relationship between bacteraemia resulting from a non-dental procedure and risk of subsequent IE. However, observational studies reported that, compared with patients with IE not undergoing an invasive procedure,

Recommendation Table 1 -Recommendations for antibiotic prophylaxis in patients with cardiovascular diseases undergoing oro-dental procedures at increased risk for infective endocarditis

General prevention measures are recommended in individuals at high and intermediate risk for IE.

Antibiotic prophylaxis is recommended in patients with previous IE. 47, 84, 86

[89]

[93] [94]

Antibiotic prophylaxis is recommended in patients with ventricular assist devices. 102

Antibiotic prophylaxis should be considered in patients with transcatheter mitral and tricuspid valve repair. 95

IIa C

] [107] IIb C

Antibiotic prophylaxis is not recommended in other patients at low risk for IE. several invasive non-dental medical procedures were associated with increased risk of IE, including cardiovascular interventions, skin procedures and wound management, transfusion, dialysis, bone marrow puncture, and endoscopic procedures. 6, 11, 51 For this reason, an aseptic operational environment should be ensured during all these procedures to minimize the risk of IE. As previously indicated, it is very unlikely that an RCT on antibiotic prophylaxis for IE will be performed in the foreseeable future. However, at-risk patients have longer survival due to the advent of newer medical and device-based medical therapies.

In addition, the ageing general population with their accumulating number of co-morbidities has an increased risk of surgical therapy, if IE occurs. For these reasons, this Task Force no longer felt that a class III recommendation for antibiotic prophylaxis in high-risk patients undergoing non-dental medical procedures (see Recommendation Table 2 ) was appropriate, despite the limitations of observational data used to support this class IIb recommendation.

3.3.3. Cardiac or vascular interventions

In all patients undergoing implantation of a prosthetic valve, any type of prosthetic graft/occluder device or CIED, peri-operative antibiotic prophylaxis is recommended due to the increased risk and adverse outcome of an infection. 6 The most frequent microorganisms underlying early (1 year after surgery) surgical PVE are coagulase-negative staphylococci (CoNS) and S. aureus. Pre-operative screening of nasal carriage for S. aureus is recommended before elective cardiac surgery or transcatheter valve implantation to treat carriers using local mupirocin and chlorhexidine.

3.4. Patient education

Preventing IE also depends on preventive measures other than antibiotic prophylaxis. People at risk should be educated to maintain good dental and skin hygiene, to look out for signs of infection and, when ESC Guidelines experiencing fever of unknown origin, report to their physician that they are at risk, in which case clinicians should consider screening for IE before initiating antibiotics.

Education of high-risk patients to prevent infective endocarditis

Use of non-medical language, visual aids, digital tools, repetition, and teach back methods all aid the patients' comprehension and is encouraged. 115 National cardiology societies should be encouraged to develop specific IE cards for patient awareness (Figure 2 ).

4. The Endocarditis Team

9] [40] [41] [122] [123] [124] [125] [126] Establishing multidisciplinary endocarditis teams according to the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association Guidelines 4, 127, 128 has resulted in earlier and more accurate diagnosis of the primary disease and its complications, 5, 22, 31, 40, 129 uniform antibiotic treatment, 36, 40, 123 and optimized timing for surgical intervention. 36, 37, 40, 123 ] [132] [133] [134] [135] Furthermore, the clinical presentation may vary significantly depending on the characteristics of the host and virulence of the microorganism. Accordingly, the concept of the Endocarditis Team needs to embrace a multidisciplinary approach that must adapt according to the patient's clinical needs and the local epidemiology to ensure prompt diagnosis and treatment.

The members of the Endocarditis Team should include the specialists with direct involvement in the diagnostic and therapeutic processes (Table 7 ), and may vary depending on the type of centre. In the

Recommendation Table 2 -Recommendations for infective endocarditis prevention in high-risk patients

Recommendation Table 3 -Recommendations for infective endocarditis prevention in cardiac procedures

Recommendations

Class a Level b

Pre-operative screening for nasal carriage of S. aureus is recommended before elective cardiac surgery or transcatheter valve implantation to treat carriers. 113, 114

I A

] [118]

Optimal pre-procedural aseptic measures of the site of implantation is recommended to prevent CIED infections. 119

I B

Periprocedural antibiotic prophylaxis is recommended in patients undergoing surgical or transcatheter implantation of a prosthetic valve, intravascular prosthetic, or other foreign material. 120

I C

Elimination of potential sources of sepsis (including of dental origin) should be considered ≥2 weeks before implantation of a prosthetic valve or other intracardiac or intravascular foreign material, except in urgent procedures. • Cardiac imaging experts.

IIa C

Continued

• Cardiovascular surgeons.

• Infectious disease specialist (or internal medicine specialist with expertise in infectious diseases). • Microbiologist.

• Specialist in outpatient parenteral antibiotic treatment.

Adjunct specialities

• Radiologist and nuclear medicine specialist.

• Pharmacologist.

• Neurologist and neurosurgeon.

• Nephrologist.

• Anaesthesiologists.

• Critical care.

• Multidisciplinary addiction medicine teams.

• Geriatricians.

• Social worker.

• Nurses.

• Pathologist.

Heart Valve Centre, a centre having all diagnostic and therapeutic resources to treat IE, the core members of the Endocarditis Team should include cardiologists, cardiovascular surgeons, infectious disease specialists (or internal medicine specialists with expertise in infectious diseases), and microbiologists. Furthermore, for specific clinical questions, cardiologists/surgeons with expertise in CIED extraction, HF, and CHD; pathologists; critical care specialists; cardiac anaesthesiologists; interventional cardiologists; neurologists and neurosurgeons; pharmacologists; radiologists and nuclear medicine specialists; nephrologists; geriatricians; and multidisciplinary addiction medicine teams (psychiatrists, nurses, and social work specialists providing counselling) are crucial adjuncts that should be available onsite for consultation. Specific subgroups of complex and high-risk patients are frequently assessed by the Endocarditis Team. The decision-making process may involve difficult decisions regarding continuation of therapy, and legal counsel may therefore be required. ESC Guidelines multimodality imaging are key in the Endocarditis Team. In addition, radiology and nuclear medicine specialists with expertise on clinical cardiovascular imaging should be available whenever indicated. 22, 31, 129 The Endocarditis Team must meet on a frequent basis and work with standard operating procedures and the clinical governance arrangements defined locally. 128, 136 Although the decision of timing is left to the discretion of the local team, a weekly meeting is to be considered. In Referring Centres, i.e. those without a cardiovascular surgical team, the treating physician diagnosing IE should consult with a specialist in infectious diseases (or an internal medicine specialist with expertise in infectious diseases) and the microbiologist. 136 In addition, a cardiologist with expertise in valvular heart disease and cardiac imaging should be present to provide the initial and subsequent evaluations with echocardiography. Information of the strains of the isolated microorganisms, usually kept for 7-15 days, should be provided to the Heart Valve Centre if requested.

Communication between Referring Centres and the Heart Valve Centres should be facilitated with digital solutions that enable reliable data sharing. Early referral to the Heart Valve Centre for further diagnostic testing and clinical management should be available when deemed necessary (Figure 3 ). When there is evidence of failure to respond to the antibiotic therapy or there are complications related to valvular tissue destruction, the Referring Centre should consult the Heart Valve Centre. The Endocarditis Team of the Heart Valve Centre should share protocols with the physicians from the referring hospitals and should facilitate their continuing education. 136 critical aspect of the Endocarditis Team decision-making process is defining when a patient must be transferred to a Heart Valve Centre to expedite advanced diagnostics and therapy. The indications for transfer are comprehensive, to facilitate interhospital communication and avoid delaying therapy to improve prognosis.

5. Diagnosis

The diagnosis of IE is based on a clinical suspicion supported by consistent microbiological data and the documentation of IE-related cardiac lesions by imaging techniques. Evidence of involvement of cardiac valves (native or prosthetic) or prosthetic intracardiac material is a major diagnostic criterion of IE. Echocardiography is the first-line diagnostic imaging technique. Other imaging modalities such as CT, nuclear imaging, and magnetic resonance imaging (MRI) are currently part of the diagnostic strategy of suspected IE, given their ability to provide key information to confirm IE diagnosis, to assess local IE complications as well as IE-related distant lesions, and to identify the original source of bacteraemia in patients who develop secondary IE. 137 Beyond diagnosis of IE, imaging findings also have prognostic implications.

5.1. Clinical features

Infective endocarditis remains a diagnostic challenge due to its variable clinical presentation. In general, a diagnosis of IE should be considered in all patients with sepsis or fever of unknown origin in the presence of risk factors. Infective endocarditis may present as an acute, rapidly progressive infection, but also as a subacute or chronic disease with low-grade, or even no fever, and non-specific symptoms that may mislead or confuse initial assessment. Infective endocarditis can also present with a complication mimicking a wide range of medical conditions that may prompt evaluation of other diseases, such as rheumatological, neurological, and autoimmune disorders, or even malignancy, before reaching a diagnosis of IE. Therefore, high suspicion for IE is generally driven by fever and positive blood cultures in the absence of an alternative focus of infection, especially in patients with one or more risk factors. Early involvement of the Endocarditis Team to guide management is highly recommended.

The initial clinical assessment should include evaluation of cardiac and non-cardiac risk factors (Table 8 ), supportive clinical context, and physical examination findings including potential portals of entry. Physical examination may reveal a variety of clinical signs. However, the absence of clinical signs alone should not exclude IE since the overall sensitivity and specificity of the clinical signs are low.

In the European Infective Endocarditis Registry (EURO-ENDO), fever (77.7%), cardiac murmur (64.5%), and congestive HF (27.2%) were the most frequent clinical presentations. 5 Embolic complications were detected in 25.3% of patients and cardiac conduction abnormalities were found in 11.5%. Some classical signs, such as peripheral stigmata, are less frequently observed, but may still be observed in severe infections caused by S. aureus and in cases of subacute endocarditis (mainly caused by Streptococcis spp.). However, vascular and immunological phenomena, such as splinter haemorrhages, 138 Roth spots, and

Recommendation Table 4 -Recommendations for the Endocarditis Team

Recommendations

Class a Level b

122, 123, 125, 126

] 122, 123, 125, 126 glomerulonephritis, remain common. The main symptoms and signs observed in the EURO-ENDO registry are shown in the Supplementary data online, Table S1 . 0] [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

6. Prognostic assessment at admission

The in-hospital mortality rate of patients with IE has remained largely unchanged over the past two decades, ranging from 15% to 30%. 5, 145, 250, 251 Several patient characteristics, often occurring simultaneously, have been shown to confer an increased risk of death in IE. The rapid identification of patients at the highest risk may offer the opportunity to change the course of the disease (i.e. with urgent or emergency surgery) and improve prognosis. Predictors of poor outcome on admission of patients with IE are specified in the Supplementary data online, Section S3.1; Table S7 .

7. Antimicrobial therapy: principles and methods

7.1. General principles

Successful treatment of IE relies on microbial eradication by antimicrobial drugs. Surgery contributes by removing infected material. 3] [254] Aminoglycosides synergize with cell wall inhibitors (i.e. beta-lactams and glycopeptides) for bactericidal activity and are useful for shortening the duration of therapy (e.g. oral streptococci) and eradicating problematic organisms. However, the side effects of aminoglycosides should be taken into consideration and currently the combination of ampicillin with ceftriaxone has demonstrated effective in treating IE caused by E. faecalis irrespective of the presence of high-level aminoglycoside resistance (HLAR) and minimizing the risk of nephrotoxicity. 255, 256 ne major hindrance to drug-induced killing is bacterial antibiotic tolerance. Tolerant microbes are not resistant (i.e. they are still susceptible to growth inhibition by the drug) but escape drug-induced killing and may resume growth after treatment discontinuation. Slow-growing and dormant microbes display phenotypic tolerance towards most antimicrobials (except rifampin to some extent). They are present in vegetations and biofilms (complex communities of bacteria residing within an exopolysaccharide matrix that adheres to a surface, e.g. in PVE), 257 and justify the need for prolonged therapy to fully sterilize infected heart valves. Some bacteria carry mutations rendering them tolerant during both active growth and stationary (dormant) phases. 258, 259 Bactericidal drug combinations are preferred to monotherapy against tolerant organisms (e.g. the combination of ampicillin and ceftriaxone in IE caused by E. faecalis).

Drug treatment of PVE should last longer (≥6 weeks) than that of NVE (2-6 weeks) but is otherwise similar. In staphylococcal PVE, the regimen should include rifampin whenever the strain is susceptible, even if some recent data have shown no differences in outcomes between patients with PVE treated with rifampin vs. those treated without. 260, 261 n NVE needing valve replacement by a prosthesis during antibiotic therapy, the post-operative antibiotic regimen should be that recommended for NVE, not for PVE. In both NVE and PVE, the duration of treatment is based on the first day of effective antibiotic therapy (negative blood culture in the case of initial positive blood culture), not on the day of surgery. A new full course of treatment should only start if valve cultures are positive.

Finally, there are important considerations in these recommendations:

(i) Only published antibiotic efficacy data from clinical trials and cohort studies in patients with IE (or bacteraemia if there are no IE data) have been considered in these guidelines. Data from experimental IE models have not been taken into account. A recent systematic review evaluating the existing evidence about clinical benefits and harms of different antibiotic regimens used to treat patients with IE has shown that there is limited and low-to very low-quality evidence to make strong conclusions on the comparative effects of different antibiotic regimens on cure rates or other relevant clinical outcomes and, therefore, there is not enough evidence to support or reject any regimen of antibiotic therapy for the treatment of IE. 262 ,263 (ii) These guidelines have adopted the MIC breakpoints included in the 2022 EUCAST clinical breakpoint tables. 42 The EUCAST breakpoints are used to categorize results into three susceptibility categories:

• Susceptible, standard dosing regimen: a microorganism is categorized as such, when there is a high likelihood of therapeutic success using a standard dosing regimen of the agent. • Susceptible, increased exposure: a microorganism is categorized as such when there is a high likelihood of therapeutic success because exposure to the agent is increased by adjusting the dosing regimen or by its concentration at the site of infection. • Resistant: a microorganism is categorized as such when there is a high likelihood of therapeutic failure even when there is increased exposure.

The term exposure is defined as a function of how the mode of administration, dose, dosing interval, infusion time, as well as distribution and excretion of the antimicrobial agent, will influence the infecting organism at the site of infection. The local laboratories are responsible for the use of appropriate methods and interpretative criteria and quality control of the test results (MIC) while the clinicians are responsible for adjusting the level of exposure by modifying the dosing strategy (individual dose, frequency of dosing, mode of administration [oral or intravenous (i.v.)]). 42 ii) Oral antimicrobial therapy. The POET trial has changed the paradigm of i.v. antibiotic treatment for IE. 43 For more than 60 years it had been considered that antibiotics should always be given intravenously. The POET trial has shown that after an initial phase of i.v. treatment, up to 20% of patients could complete the treatment by oral antibiotic therapy (see Section 7. 13.1). 43 Therefore, as indicated in Figure 8 , the antibiotic treatment of IE has two phases.

The first phase can last up to 2 weeks of hospital i.v. treatment using combinations of rapidly bactericidal antibiotics to destroy planktonic bacteria. 257 In this initial phase, cardiac surgery should be performed if indicated, infected foreign bodies should be removed, and cardiac as well as extracardiac abscesses should be drained. After this period, clinically stable patients can end the antibiotic treatment at home with i.v. (OPAT) or oral antibiotic regimens for up to 6 weeks in order to eliminate the dormant (resting) bacteria and prevent relapses. (iv) Aminoglycosides are not recommended in staphylococcal NVE because their clinical benefits have not been demonstrated, but they can increase renal toxicity. 255, 264 When they are indicated in other conditions (e.g. resistant oral streptococci), 265 aminoglycosides should be given for no longer than 2 weeks to reduce nephrotoxicity. 266 v) Rifampin should be used only in foreign body infections such as PVE after 3-5 days of effective antibiotic therapy, once the bacteraemia has been cleared. The rationale supporting this recommendation is based on the likely antagonistic effect of the antibiotic combinations with rifampin against planktonic/replicating bacteria, 267 and the synergy seen against dormant bacteria within the biofilms and prevention of rifampinresistant variants. 268 New evidence based on a small, retrospective study has questioned this approach and needs further validation. 260 vi) Daptomycin has been recommended for treating staphylococcal and enterococcal endocarditis. 269 When daptomycin is indicated, it must be given at high doses (10 mg/kg once daily) 270 and combined with a second antibiotic (beta-lactams or fosfomycin in beta-lactam allergic patients) to increase activity and avoid the development of resistance. 271 It should be noted the use of fosfomycin is associated with increased risk of acute HF and renal failure due to the high load of sodium while the use of daptomycin has been associated with eosinophilic syndromes in up to 15% of patients. 272, 273 ases of antibiotic treatment of infective endocarditis S8 .

ESC Guidelines (vii) The antibiotic regimens need to adapt to the local circumstances and the availability of antibiotics. (viii) Data on the efficacy of long-term antibiotic suppressive therapy in patients with IE who do not undergo cardiac surgery are limited to small and heterogeneous series with various antibiotic regimens. 184, 274 In a small series of Gram-positive bloodstream infections and IE, dalbavancin (500 mg weekly or 1000 mg biweekly regimens) has been shown effective. 274, 275 Relapses are not infrequent. 184

7.2. Penicillin-susceptible oral streptococci and Streptococcus gallolyticus group

Oral streptococci include the groups mitis, sanguinis, anginosus, salivarius, downei, and mutans (see Supplementary data online, Figure S2 ). 276 he remaining streptococci isolated outside of the oral cavity are classified into either the Streptococcus gallolyticus (former bovis) or pyogenic groups. Recommended regimens against susceptible (susceptible standard dosing regimen and increased exposure) streptococci are summarized in Recommendation Table 7 . 4, [277] [278] [279] The cure rate is expected to be > 95%. In uncomplicated cases of NVE, short-term 2-week therapy can be administered by combining penicillin or ceftriaxone with gentamicin or netilmicin. 280, 281 Gentamicin and netilmicin can be given once daily in patients with IE due to susceptible streptococci and normal renal function. 1] [282] In patients with documented allergy to penicillin, desensitization is recommended. If desensitization cannot be performed, patients allergic to beta-lactam should receive cephalosporins (in non-anaphylactic reaction) or vancomycin, keeping in mind that a beta-lactam is superior to glycopeptides. Teicoplanin has been proposed as an alternative, 4 starting with loading doses (6 mg/kg/12 h for 3 days) and followed by 6-10 mg/kg/day. Loading is critical because the drug is highly bound (≥98%) to serum proteins and penetrates slowly into vegetations. 283 However, only limited retrospective studies have assessed its efficacy in streptococcal IE. 284 After 10-14 days of therapy, OPAT or outpatient oral antibiotic therapy should be considered.

7.3. Oral streptococci and

Streptococcus gallolyticus group susceptible, increased exposure or resistant to penicillin

The incidence of these resistant streptococci is increasing. Large strain collections have reported > 30% of resistant S. mitis and Streptococcus oralis. 285 etrospective series provide the evidence for the recommendations on antibiotic treatment of IE caused by penicillin-resistant oral streptococci and S. gallolyticus. 6] [287] [288] [289] [290] In penicillin-resistant cases, aminoglycoside treatment must be given for ≥2 weeks and short-term therapy regimens are not recommended. There is very limited experience with daptomycin in IE caused by resistant isolates. 265, 291 After 10-14 days of therapy, OPAT or outpatient oral antibiotic therapy should be considered if clinically stable (see Section 7.13).

Recommendation Table 7 -Recommendations for antibiotic treatment of infective endocarditis due to oral streptococci and

Allergy to beta-lactams

In patients with NVE due to oral streptococci and S. gallolyticus and who are allergic to beta-lactams, vancomycin for 4 weeks is recommended using the following doses:

I C Adult

7.4. Streptococcus pneumoniae, β-haemolytic streptococci (groups A, B, C, and G)

Infective endocarditis due to Streptococcus pneumoniae has become rare. It is associated with meningitis and pneumonia in up to 30% of cases, [293] [294] [295] [296] which requires special consideration in cases with penicillin resistance. Treatment of penicillin-susceptible strains is similar to that of oral streptococci (see Recommendation Table 7 ), except for the use of short-term 2-week therapy, which has not been thoroughly investigated. The same holds true for penicillin-susceptible increased exposure or resistant strains without meningitis, although for resistant strains some authors recommend high doses of cephalosporins (e.g. cefotaxime or ceftriaxone) or vancomycin. 295 In cases with meningitis, penicillin must be avoided because of its poor penetration into the cerebrospinal fluid, and should be replaced with ceftriaxone or cefotaxime alone, or in association with vancomycin according to the antibiotic susceptibility pattern. 297, 298 After 10-14 days of therapy and when meningitis is not associated, OPAT or outpatient oral antibiotic therapy should be considered if clinically stable (see Section 7.13).

Infective endocarditis due to group A, B, C, or G streptococci, including the Streptococcus anginosus group (S. constellatus, S. anginosus, and S. intermedius) is relatively rare. 299, 300 Group A streptococci are uniformly susceptible to beta-lactams, whereas other serogroups may display some degree of resistance. Infective endocarditis due to group B streptococci was once associated with the peripartum period, but it now occurs in all adults, especially the elderly. Groups B, C, and G streptococci and S. anginosus induce abscesses that require adjunctive surgery. 300 Mortality from group B PVE is very high and cardiac surgery is recommended. 301 Antibiotic treatment is similar to that of oral streptococci (see Recommendation Table 7 ), except that short-term (2 weeks) therapy is not recommended and gentamicin should be given for 2 weeks.

7.5. Granulicatella and Abiotrophia (formerly nutritionally variant streptococci)

Granulicatella and Abiotrophia induce IE with a prolonged course and are associated with large vegetations ( > 10 mm), and consequently with high rates of complications and valve replacement (around 50%). 302, 303 This is possibly due to delayed diagnosis and treatment. [304]

7.6. Staphylococcus aureus and coagulase-negative staphylococci

Staphylococcus aureus is usually responsible for acute and destructive IE, 305 whereas CoNS can induce more protracted valve infections. 306, 307 Of note, the addition of an aminoglycoside in staphylococcal NVE is no longer recommended because it increases renal toxicity. 264, 308 Short-term (2-week) and oral treatments have been proposed for uncomplicated right-sided native valve methicillinsusceptible S. aureus (MSSA) IE (see also Section 12. 4.2), but these regimens cannot be applied to left-sided IE. For penicillin-allergic patients with MSSA IE, penicillin desensitization can be attempted in stable patients or cefazolin can be used since vancomycin is inferior to betalactams. 309 If beta-lactams cannot be given, where available, daptomycin should be chosen and given in combination with another effective antistaphylococcal drug to increase activity and avoid the development of resistance. 310 Staphylococcus lugdunensis is mostly methicillinsusceptible and can be treated with cloxacillin.

Staphylococcus aureus PVE carries a very high risk of mortality ( > 45%), 305, 312, 313 and often requires early valve replacement. 5] [316] [317] [318] The rationale supporting this recommendation is based on the antagonistic effect of the antibiotic combinations with rifampin against planktonic/replicating bacteria as has been demonstrated in foreign body infection models and clinically in prosthetic orthopaedic and vascular infections. 319 However, a recent study has shown that the addition of aminoglycosides to a regimen containing vancomycin or cloxacillin plus rifampicin in S. aureus PVE was not associated with a better outcome. 320 In addition, the risk of nephrotoxicity associated with the use of aminoglycosides should be taken into consideration. Adding rifampin to the treatment of staphylococcal PVE is standard practice despite the weak evidence. 261, 321 The potential side effects and drug interactions of rifampin should also be considered. In patients with PVE who are allergic to penicillin, daptomycin can be given combined with ceftaroline or fosfomycin or with gentamicin (for 2 weeks) plus rifampin for at least 6 weeks. After 10-14 days of therapy, OPAT or outpatient oral antibiotic therapy should be considered if clinically stable (see Section 7.13).

7.7. Methicillin-resistant staphylococci

Methicillin-resistant S. aureus (MRSA) produces low-affinity penicillinbinding proteins (PBPs), which confer cross-resistance to most betalactams. 6] [327] [328] The prevalence of MRSA causing IE that is susceptible with increased exposure or resistant to vancomycin ranges between 19% and 34%. In addition, among patients with IE caused by MRSA, those isolates with a population analysis profile MIC ≥4 mg/L were associated with treatment failure defined by persistent bacteriaemia for ≥7 days or MRSA-attributable mortality. 325 Nephrotoxicity is of concern when using trough monitoring of levels of vancomycin as a surrogate marker of the area under the curve relative to the MIC (AUC/MIC). Therefore, it is recommended to use a target of AUC/ MIC between 400 and 600 mg*h/L (assuming an MIC of 1 mg/L) that should be achieved with 48 h of therapy. 329 When the MIC is > 1 mg/ L, the probability of achieving an AUC/MIC ≥400 is unlikely. In that clinical scenario, changing therapy should be considered due to the high risk of nephrotoxicity with higher doses of vancomycin. Daptomycin is a lipopeptide antibiotic approved for S. aureus bacteraemia and right-sided IE. 330 Cohort studies of S. aureus and CoNS IE have shown that daptomycin is at least as effective as vancomycin, 327, 328 and, in two cohort studies of MRSA bacteraemia with high vancomycin MICs ( > 1 mg/ L), 331, 332 daptomycin was associated with better outcomes (including survival) compared with vancomycin. 7] [328] However, in a randomized trial including 352 patients with MRSA bacteraemia, daptomycin or vancomycin combined with i.v. flucloxacillin, cloxacillin, or cefazolin did not result in a significant reduction of the primary composite endpoint of mortality, persistent bacteraemia, relapse, or treatment failure as compared with daptomycin or vancomycin alone. 328 The study was stopped prematurely before recruiting the target number of patients (n = 440) due to increased incidence of acute kidney injury in the combination therapy arm and, therefore, the results should be interpreted with caution.

Other alternatives include fosfomycin plus imipenem, 336 ceftaroline, 337 quinupristin-dalfopristin with or without beta-lactams, 338, 339 beta-lactams plus oxazolidinones (linezolid), 340 beta-lactams plus vancomycin, 341 and high doses of trimethoprim/sulfamethoxazole and clindamycin. 342, 343 hese clinical and therapeutic scenarios warrant collaborative management with the Endocarditis Team including an infectious disease specialist, since the evidence is based on very small populations.

Recommendation

In patients with NVE due to methicillin-susceptible staphylococci who are allergic to penicillin, cefazolin for 4-6 weeks is recommended using the following doses: In patients with NVE due to methicillin-resistant staphylococci, daptomycin combined with cloxacillin, ceftaroline or fosfomycin may be considered using the following doses: Cefazolin can replace cloxacillin only in patients with non-immediate-type hypersensitivity reactions to penicillin. f High doses of ceftaroline may be associated with risk of leucopaenia after 2 weeks. Ceftaroline can replace cloxacillin only in patients with non-immediate-type hypersensitivity reactions to penicillin. g In patients with heart failure, the high load of sodium associated with the use of fosfomycin can lead to acute heart failure. h Serum vancomycin concentrations should achieve 10-15 mg/L at pre-dose (trough) level, although some experts recommend to increase the dose of vancomycin to 45-60 mg/kg/day i.v. in 2 or 3 divided doses to reach serum trough vancomycin levels (Cmin) of 15-20 mg/L as in staphylococcal endocarditis. However, vancomycin dose should not exceed 2 g/d unless serum levels are monitored and can be adjusted to obtain a peak plasma concentration of 30-45 μg/mL 1 h after completion of the i.v. infusion of the antibiotic.

7.8. Enterococcus spp.

Enterococcal IE is primarily caused by E. faecalis (90% of cases) and less often by Enterococcus faecium (5% of cases), or other species. 350 nterococcal IE poses two major problems. ] [353] [354] [355] [356] [357] Penicillin-susceptible strains are treated with penicillin G or ampicillin (or amoxicillin) combined with gentamicin. However, ampicillin (or amoxicillin) is preferred since the MIC is two to four times lower than that of penicillin G. Gentamicin resistance is frequent in both E. faecalis and E. faecium (up to 75%). 358, 359 An aminoglycoside MIC > 128 mg/L (HLAR) is associated with the loss of bactericidal synergism with cell wall inhibitors, and aminoglycosides should not be used in such conditions.

There have been two important advances in recent years. First, in several cohort studies of E. faecalis IE including hundreds of cases, it was observed that ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for non-HLAR E. faecalis IE. The combination of ampicillin plus ceftriaxone was also associated with a beneficial safety profile, due to the lack of nephrotoxicity. 355, 360, 361 Therefore, this is the combination of choice for treating NVE and PVE caused by HLAR E. faecalis. This double beta-lactam therapy is not effective against E. faecium and the experience in the treatment of other enterococcal species is very limited. Second, the total daily dose of gentamicin can be given in a single daily dose instead of the 2 or 3 divided doses previously recommended, and the length of the treatment with gentamicin for non-HLAR E. faecalis IE may be safely shortened from 4-6 weeks to 2 weeks, reducing the rates of nephrotoxicity to very low levels. 266, 362, 363 ] [366] [367] Beta-lactam or vancomycin resistance is mainly observed in E. faecium. Since dual resistance is rare, beta-lactam might be used against vancomycin-resistant strains and vice versa. Varying results have been reported with quinupristin-dalfopristin (not active against E. faecalis), linezolid, daptomycin, teicoplanin, and tigecycline. 353, 365, 368 aptomycin 10-12 mg/kg/24 h, always combined with beta-lactams (ampicillin, ertapenem, or ceftaroline) or fosfomycin in order to prevent the development of daptomycin resistance, is the best option for treating multidrug-and vancomycin-resistant enterococcal IE. 369 Recommendation Table 9 -Recommendations for antibiotic treatment of infective endocarditis due to Enterococcus spp.

Beta-lactam and gentamicin-susceptible strains

In patients with NVE due to non-HLAR Enterococcus spp., the combination of ampicillin or amoxicillin with ceftriaxone for 6 weeks or with gentamicin for 2 weeks is recommended using the following doses: option. 370 [372] [373]

7.9.2. Non-Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella species

The ICE cohort reported non-HACEK Gram-negative bacteria in 49 of 2761 (1.8%) IE cases. 279, 374 Recommended treatment is early surgery plus prolonged (6 weeks) therapy with bactericidal combinations of beta-lactams and aminoglycosides, sometimes with additional quinolones or cotrimoxazole. 375, 376 In vitro bactericidal tests and monitoring of serum antibiotic concentrations may be helpful. Because of their rarity and severity, these conditions should be discussed by the Endocarditis Team.

7.10. Blood culture-negative infective endocarditis

0] [381] [382] [383] Treatment of Whipple's IE remains highly empirical. Successes have been reported with long-term therapy ( > 1 year). 384 In cases of CNS involvement, sulfadiazine 1.5 g/6 h orally must be added to doxycycline. An alternative therapy is ceftriaxone (2 g/24 h i.v.) for 2-4 weeks or penicillin G (2 million U/4 h) and streptomycin (1 g/24 h) i.v. for 2-4 weeks followed by cotrimoxazole (800 mg/12 h) orally. Trimethoprim is not active against T. whipplei. Consultation with the Endocarditis Team, including an infectious disease specialist, is recommended.

7.11. Fungi

Fungi are most frequently observed in PVE and in IE affecting PWID or immunocompromised patients. 386 Candida and Aspergillus spp. predominate, the latter resulting in BCNIE. 387, 388 Mortality is very high ( > 50%), and treatment necessitates combined antifungal administration and with a low threshold for surgery. 278, 387, 388 Antifungal therapy for Candida IE includes an echinocandin at high doses or liposomal amphotericin B (or other lipid formulations) with or without flucytosine. for Aspergillus IE, voriconazole is the drug of choice. Some experts recommend the addition of an echinocandin or amphotericin B. 278, [387] [388] [389] [390] Suppressive longterm treatment with oral azoles (fluconazole and voriconazole) is recommended, sometimes lifelong. 278, 388, 389 Consultation with the Endocarditis Team including an infectious disease specialist is recommended.

7.12. Empirical therapy

Treatment of IE should be started promptly. Three sets of blood cultures should be drawn at 30-minute intervals before initiation of antibiotics. 391 he initial choice of empirical treatment depends on several considerations: (i) Previous antibiotic therapy. (ii) IE in a native valve or a prosthesis (and if so, when surgery was performed [early vs. late PVE]). (iii) The place of the infection (community, nosocomial, or nonnosocomial healthcare-associated IE) and knowledge of the local epidemiology, especially for antibiotic resistance and specific genuine culture-negative pathogens. (iv) Cloxacillin/cefazolin administration is associated with lower mortality rates than other beta-lactams, including amoxicillin/clavulanic acid or ampicillin/sulbactam, 392 and vancomycin for empirically treating MSSA bacteraemia/endocarditis. 309, 393 However, recently amoxicillin/clavulanic acid or ampicillin/sulbactam might be an effective empirical treatment for MSSA bacteraemia when de-escalated to cloxacillin or cefazolin within 96 h from the index blood culture. 394 ative valve endocarditis and late PVE regimens should cover staphylococci, streptococci, and enterococci. If the patient was receiving antibiotic therapy, the empirical therapy should include different antibiotics. CoNS should be empirically covered in PVE but not in NVE. Early PVE or healthcare-associated IE regimens should cover methicillin-resistant staphylococci, enterococci and, ideally, non-HACEK Gram-negative pathogens. Once the pathogen is identified (usually within 24 h), the antibiotic treatment must be adapted to its antimicrobial susceptibility pattern. It should be emphasized that the empirical treatment should be changed to targeted therapy once the organism is identified within 24-48 h.

7.13. Outpatient parenteral or oral antibiotic therapy for infective endocarditis

Outpatient parenteral antibiotic treatment or step-down outpatient oral antibiotic treatment is used to consolidate antimicrobial therapy once critical infection-related complications are under control (e.g. 7] [398] [399] When feasible, early hospital discharge and OPAT helps to alleviate the effects of infection and prolonged hospitalization especially in the elderly. 400 In the initial phase of IE treatment, standard i.v. treatment is administered according to recommendations for specific microorganisms. Once the clinical condition of the patient is stable, OPAT or stepdown outpatient oral antibiotic treatment is a safe alternative to in-hospital i.v. treatment in selected patients. 43, 399 Patients may reach such stability at various points in their disease course but, when criteria for stability are reached, the patient may then be switched to OPAT or alternatively to an oral therapy at hospital discharge. The OPAT regime consists of the same antibiotic combinations administered in the acute phase if possible.

The 5-year outcomes from the POET trial showed continued effectiveness of oral antibiotic therapy as compared with i.v. antibiotic therapy for IE in selected patients. 401 Hence, clinical stability will then differentiate IE courses into two phases:

(i) Critical phase where at least 10 days of i.v. treatment is required: at this time point, OPAT has a restricted indication. (ii) Continuation phase (beyond 10 days of therapy and 7 days post-surgery), where OPAT/step-down oral therapy may be feasible.

Supplementary data online, Table S8 summarizes the salient questions to address when considering OPAT/step-down oral therapy for IE.

Recommendation Table 10 -Recommendations for antibiotic regimens for initial empirical treatment of infective endocarditis (before pathogen identification) a

Class b Level c

In In addition to the patient being medically stable, general considerations for suitability for OPAT include assessment of the patient's home environment and self-care capabilities. Adherence to treatment and follow-up visits are also crucial for a beneficial outcome of outpatient treatment and the healthcare provider-patient relationship is important for ensuring proper and continued treatment and maintenance of infection control.

7.13.1. Parenteral and oral step-down antibiotic treatment

Stability criteria are essential and timing in the clinical planning the patient's course, especially TOE, becomes key (Figure 9 ). Stability criteria include blood samples, clinical parameters, and TOE. 43 PAT has been shown to be a safe treatment in IE for stable patients who are suitable for home treatment.

The patient, and preferably also a caregiver, should be educated carefully in the disease and how to monitor/observe for signs of infection, including daily temperature and other signs of disease progression or complications. In addition, regular post-discharge evaluation is required (nurse once per day, responsible physician 1-3 times per week). For patients receiving OPAT, regular i.v. catheter inspection and care by a healthcare professional should be provided. If the patient is not sufficiently able to self-monitor, and has no close caregivers, added surveillance is required by involved staff and home treatment should generally be carefully considered in such cases.

Certain combinations of two oral antibiotics should be used for oral step-down treatment (see Supplementary data online, Table S9 ).

7.13.2. Other considerations for outpatient oral or parenteral antimicrobial therapy

In the OPAT programme, patients continue with the same antibiotics that are administered in the acute phase in once-daily regimens, or with infusion pumps if antibiotics should be administered intermittently, 43 ESC Guidelines or in continuous infusion. Dalbavancin is a glycopeptide antibiotic with a very long half-life that can be administered weekly. There is previous positive experience in sensitive Gram-positive IE, although the most effective administration schedule is not clear. 274, 402 The recommended prescription is 1.5 g as a loading dose followed by 0.5-1 g weekly until completing 6 weeks of antibiotic treatment.

Although the evidence is weak, another option (in addition to the combinations listed in the Supplementary data online, Table S9 ) for staphylococcal IE is the combination of i.v. cotrimoxazole (sulfamethoxazole 4800 mg/day and trimethoprim 960 mg/day in 4-6 doses) plus i.v. clindamycin (1800 mg/day in 3 doses) during the first week followed by only oral cotrimoxazole for 5 weeks. 343

8. Indications for surgery and management of main infective endocarditis complications

Infective endocarditis is associated with certain risks and complications that can only be controlled with surgical intervention. Despite the risks of surgery in these patients, current evidence suggests that surgical treatment may generate a survival advantage of up to 20% in the first year. 403, 404 There are three main reasons to undergo surgery in the setting of acute IE: HF, uncontrolled infection, and prevention of septic embolization (in particular, to the CNS) (Figure 10 ).

A significant proportion of surgical procedures for IE are performed on an urgent basis. The Task Force has defined urgent surgery as that requiring intervention within 3-5 days, although unnecessary delays should be avoided once the indication for urgent surgery is established. Some cases require emergency surgery (within 24 h), irrespective of the pre-operative duration of antibiotic treatment. A third group requires surgery non-urgently, i.e. within the same hospital admission. In cases where the infective component can be completely healed with antibiotic treatment alone, both timing and indications for treatment of residual valve dysfunction follow the conventional guidelines for valve treatment. 128

8.1. Pre-operative risk assessment

The risk of surgical therapy during the active phase of IE can be significant. It is heavily influenced by pre-existing co-morbidities and current organ function, but should not be limited by one risk factor alone (e.g. age or liver function). 405, 406 The decision to operate should therefore be made by the Endocarditis Team (see Section 4), 167 considering urgency of the patient's clinical condition, peri-operative risk, the potential to recover from the infection, and the patient's associated long-term prognosis. 403, 404 here are several scoring systems that predict mortality after general (i.e. non-IE) cardiac surgery and which are in routine clinical use. 407, 408 0] [411] [412] [413] [414] Some of these scoring systems are web-based and free of charge (e.g. the AEPEI risk calculator https://www.endocardite.org/index.php/calculateurs/score-demortalite-post-chirurgie-aepei). 6] [417] In addition, none of these scoring systems are used in daily clinical routine. Therefore, prospective surgical scoring systems with better precision need to be developed, particularly for determining operative futility in prohibitively high-risk patients.

A significant proportion of patients with clear indications for surgery for IE may have multiple risk factors or other reasons that lead to surgery not being performed, and these patients have the worst prognosis. 184, 403 Conversely, high-risk but salvageable patients may not be offered life-saving operations on the basis of perceived unacceptable risk, and this is especially true in the elderly (see Section 12.2). The complex decision of not offering surgery when indicated should therefore be made in the setting of an Endocarditis Team with experienced surgical input. 418 Determining when operative management for a specific patient is futile requires compassionate multidisciplinary insight along with consideration of the patient's and family's wills (see Section 13.2).

8.2. Heart failure

8.2.1. Heart failure in infective endocarditis

Heart failure is the most frequent complication of IE and the main indication for urgent and emergency surgery for IE. 419 1] [422] [423] [424] [425] are mainly caused by congestion and may vary from mild dyspnoea to severe and rapidly worsening dyspnoea, orthopnoea, pulmonary oedema, and cardiogenic shock. ] [422] [423] [424] [425] Leaflet perforation and rupture, as well as mitral chordal rupture, lead to new severe valvular regurgitation or worsening of pre-existent valvular regurgitation and subsequent acute HF. Other less common causes of HF include intracardiac fistulae, interference of the vegetation mass with leaflet opening and closure, or myocardial infarction from vegetations embolizing into the coronary arteries. Patients with rightsided IE complicated by HF present with symptoms of right heart congestion, as discussed in Section 12. 6.

New-onset HF is the predominant clinical presentation in IE patients, whereas worsening of pre-existing HF is less frequent. Cardiogenic shock can be the first presentation in up to 5% of cases, of which half of such patients develop cardiogenic shock within 72 h of admission for IE. 424 ] [428] [429] [430] Even though in-hospital mortality rates increase with the severity of HF presentation, the survival benefit of surgical treatment vs. medical therapy is more pronounced among patients with NYHA functional class III-IV symptoms. 420 TTE provides important information on the severity of the haemodynamic consequences of valve dysfunction. New onset of elevated filling pressures, pulmonary hypertension, and/or pericardial effusion may lead to urgent or emergency recommendation for surgery. 163 Biomarkers such as B-type natriuretic peptide and troponin have been associated with poor prognosis in IE. 431, 432 Patients who are discharged after treatment of IE require subsequent follow-up (see Section 11). Heart failure is more likely to develop during follow-up in IE patients who are discharged with valvular regurgitation than in those without regurgitation, particularly if mitral regurgitation is present. 433

8.2.2. Indications and timing of surgery in the presence of heart failure in infective endocarditis

Timing of surgical intervention in patients with IE (Figure 10 ) complicated by HF should be decided by the Endocarditis Team, although surgery should not be delayed by Endocarditis Team discussions in patients requiring emergency operations. The presence of HF leads to recommendation for surgery in the majority of patients and is the principal indication for urgent surgery in IE patients. 429, 434 Emergency surgery should be performed in patients with new-onset NYHA class IV HF symptoms, pulmonary oedema, and/or cardiogenic shock, irrespective of the status of infection or length of antibiotic treatment and when considered non-futile intervention. Urgent surgery is indicated in patients with milder forms of HF (NYHA class II-III) and severe valve regurgitation or echocardiographic signs of haemodynamic compromise (elevated end-diastolic left ventricular pressure, high left atrial pressure, or moderate and severe pulmonary hypertension), or large vegetations. In patients without haemodynamic compromise, i.v. antibiotic therapy and strict clinical and echocardiographic observation are first indicated, and surgery can be temporarily delayed. However, it should be emphasized that early surgery is a good option for patients with surgical indications and low risk of surgery. 403, 404

8.3. Uncontrolled infection

Uncontrolled infection is one of the most common complications of IE and is the second most frequent indication for surgery. 5 Uncontrolled infection is considered to be present when there is: (i) persistent infection or sepsis despite antibiotic therapy; (ii) signs of local infection that do not respond to antibiotic therapy; or (iii) infection with resistant or very virulent organisms.

8.3.1. Septic shock and persistent infection

Septic shock, defined as vasopressor requirement to maintain a mean arterial pressure of 65 mmHg or greater and serum lactate level greater than 2 mmol/L in the absence of hypovolaemia, 435 is a highly lethal complication of IE and occurs in ∼5-10% of patients. 425, 436 Risk factors for septic shock include S. aureus and Gram-negative bacteria, persistent bacteraemia, nosocomial acquisition, acute renal failure, diabetes mellitus, CNS emboli, and large vegetations. 147, 436 Surgery is associated with a significant reduction in early and 1-year mortality for patients with IE and septic shock. 425, 436 Urgent surgery is therefore recommended in patients with IE and persistent sepsis or septic shock despite adequate antibiotic therapy, in which surgery is non-futile.

The definition of persistent infection is somewhat arbitrary and consists of fever and persistent positive cultures after 7 days of appropriate antibiotic treatment. It has been demonstrated that persistent blood cultures 48-72 h after initiation of antibiotics are an independent risk factor for hospital mortality. 437 In many cases of persistent infection, antibiotics alone are insufficient to eradicate the infection. Surgery is therefore indicated for persistent infection when extracardiac abscesses (splenic, vertebral, cerebral, or renal) and other potential causes of positive cultures and fever (infected lines and embolic complications) have been excluded. Persistent fever may also be caused as an adverse reaction to antibiotics. 438

8.3.2. Locally uncontrolled infection

Signs of locally uncontrolled infection include increasing vegetation size, abscess formation, the creation of pseudoaneurysms and/or fistulae, and new atrioventricular block (AVB). The incidence of perivalvular extension ranges from 10% to 30% in NVE with higher incidences found in patients with PVE. 5, 439 Perivalvular complications and abscess formation are more frequent in aortic valve than mitral valve IE, and may be higher in patients with bicuspid vs. tricuspid aortic valves. 440 In aortic valve IE, perivalvular extension occurs most frequently in the mitral-aortic intervalvular fibrosa, 441 whereas perivalvular abscesses are usually located posteriorly or laterally in mitral valve IE. 442 Persistent fever and infection, new AVB, chest pain, new heart murmur, recurrent embolism, or HF may indicate perivalvular extension. The diagnosis should be confirmed by TOE, which is more sensitive and specific than TTE. 443 However, mitral annular calcification may obscure small regions of mitral perivalvular extension, particularly in the posterior aspects of the mitral annulus. Cardiac CT has been shown to be an accurate alternative imaging procedure for the evaluation of perivalvular extension of infection, and PET/CT imaging may be particularly helpful in cases of PVE (see Section 5. 4. 4.

8.3.3 Indications and timing of surgery in the presence of uncontrolled infection

Surgery should be considered for uncontrolled infection when antibiotic therapy is ineffective and extracardiac sources are ruled out. Reports in the literature demonstrate that surgery for uncontrolled infection in IE has the potential to improve 1-year survival by 15-20%. 403, 429, 444 3. 3

.1. Persistent infection

Uncontrolled infection is present in the form of persistent infection when blood cultures remain positive for > 1 week or persistent sepsis despite appropriate antimicrobial therapy and when other causes of bacteraemia have been excluded. Not performing surgery for uncontrolled infection is associated with significantly increased mortality. 444

##### 8.3.3.2. Locally uncontrolled infection

8.3.3.2. Locally uncontrolled infection

Uncontrolled infection is also present if signs of local progression, i.e. increasing vegetation size or perivalvular involvement, are observed during follow-up imaging. 5, 420, 421, 445, 446 Surgery should be performed urgently (within 3-5 days) in such cases. Rarely, when there are no other reasons for surgery and fever is easily controlled with antibiotics, small abscesses or pseudoaneurysms can be treated conservatively under close clinical and echocardiographic follow-up. 429, 444

##### 8.3.3.3. Infection with resistant or virulent organisms

8.3.3.3. Infection with resistant or virulent organisms

Microorganisms causing endocarditis that are unlikely to be controlled with current antimicrobial therapy include fungi, 447, 448 multiresistant bacteria (e.g. MRSA or vancomycin-resistant enterococci) and, in rare cases, non-HACEK Gram-negative bacteria. S. aureus should also be included in this group due to its fast progression and ability to cause local tissue destruction and abscess formation, 5, 449 specifically, if a favourable early response to antibiotics is not achieved. 305, 312, 449 The presence of these organisms should lead to discussions within the Endocarditis Team and urgent surgery. 385, 450

8.4. Prevention of systemic embolism

8.4.1. Incidence of embolic events in infective endocarditis

Embolic events are frequent and potentially life-threatening complications of IE related to the migration of cardiac vegetations. 451, 452 The brain and spleen are the most frequent sites of embolism for left-sided IE, while pulmonary embolism is frequent in right-sided and pacemaker lead IE (see Section 12). Stroke may be the first clinical manifestation of IE, and is a severe complication that is associated with increased morbidity and mortality. 451, 453, 454 Embolic events may be clinically silent in up to 50% of patients with IE. 198 Emboli affecting the splenic or cerebral circulation are frequently asymptomatic, and are diagnosed by noninvasive imaging. 197, 200 Although whole-body CT imaging (i.e. chest, abdomen, and pelvis) is frequently performed during the work-up for surgery, diagnosis and management of patients is infrequently altered as a result of these investigations. 194 However, cerebral CT may affect clinical decision-making and outcomes when surgery is considered. 452 mbolic risk in IE is high, with 20-50% of patients being affected. 452, 455 The highest incidence of embolic strokes can be observed in the days around the initial diagnosis of IE, 456 and embolic events are often what leads to the initial diagnosis of IE. Embolic risk is highest the day after therapy initiation, and is 10-20 times higher on the day before and after the start of antibiotic treatment compared with 2 weeks before and after. 456 6] [457] The benefits of surgery to prevent embolism may therefore be greatest during the early stages of therapy, when embolic risk is at its highest.

8.4.2. Predicting the risk of embolism

Predicting the risks of embolization is important for decision-making in IE. Echocardiography plays a key role in identifying potentially embolic structures in the heart, 429, 455, 456, 458 although predicting the time point of embolization remains difficult. Several factors are associated with increased risk of embolism including the size and mobility of vegetations, 455, 456, [458] [459] [460] the location of the vegetation on the mitral valve, 455 the increasing or decreasing size of the vegetation under antibiotic therapy, 455 particular microorganisms (especially S. aureus, 455 S. gallolyticus, 461 and Candida spp. 450 ), previous embolism, 455 multivalvular involvement, 458 and biological markers. 462 Among these, the size and mobility of the vegetations are the most important independent predictors of new embolic events. 459, 460, 463 A recent study, however, demonstrated that vegetation size was predictive of worse outcomes only when present with other indications for surgery (i.e. HF or uncontrolled infection). 464 Staphylococcal endocarditis is also a risk factor for embolization, [465] [466] [467] [468] which is particularly important because the incidence of S. aureus IE is increasing. 78, 469 Risk of neurological complications is particularly high in patients with very large vegetations ( > 30 mm in length). 451 dditional factors may need to be taken into account and it may be helpful to use an embolic risk calculator. 470 S. aureus infection, previous embolism, vegetation length, age, diabetes, and the presence of atrial fibrillation have been identified as specific risk factors for embolism. 470

8.4.3. Indications and timing of surgery to prevent embolism in infective endocarditis

Surgical removal of potentially embolic material from the heart may prevent new or additional embolic events. Given the imminent risk and high rates of embolization in patients with mobile and large vegetations, 5, 451, [455] [456] [457] 460, 471 surgery should be considered urgently (within 3-5 days) in such patients. A prosp ctive randomized trial in young, low-risk patients assessed the effects of early surgery in patients with large vegetations and streptococcal IE. 471 Although there was no difference in all-cause mortality at 6 months between the early surgery and conventional treatment groups, the risk of embolization was significantly reduced with early surgery. Non-randomized observational analyses including patients at higher risk also suggest that early surgery may be beneficial in patients with a high likelihood of embolization, 428, 459, 472, 473 and that initial conservative treatment is associated with increased mortality. 474, 475 However, prosthetic dehiscence has also been associated with early surgery in patients with S. aureus IE. 429 Individualized decision-making is required to balance the risk of surgery, which is also influenced by pre-operative neurological events or other co-morbidities. 5, 453 The main indications and the timing of surgery to prevent embolism based on the currently available literature are given in Recommendation Table 12 and Figure 10 .

9. Other complications of infective endocarditis

9.1. Neurological complications

Neurological manifestations may occur before or after the diagnosis of IE is established and recurrent events can also take place later in the course of IE. 451 The possibility of IE should be considered in patients who present with stroke, meningitis, or brain abscess. Unexplained fever accompanying a stroke in a patient with valvular disease should trigger the suspicion of IE with blood cultures taken prior to empirical antibiotic therapy.

Symptomatic cerebrovascular complications occur in up to 35% of patients with IE, 145, 198, 451, 452 whereas silent cerebrovascular complications (including ischaemia and microhaemorrhage) occur in up to 80% of patients. 200, 204, 403 Clinical presentation is variable, but ischaemic stroke and transient ischaemic attack are the most common presentations. 479 ther manifestations include haemorrhage (intracerebral, subarachnoid), meningitis, brain abscess, encephalopathy, and infectious aneurysms. Focal neurological symptoms are present in ∼40% of affected patients, and nonfocal presentations occur in approximately one-third.

S. aureus IE is more frequently associated with neurological complications compared with IE caused by other microorganisms. Vegetation size and mobility also correlate with embolic risk.

Neurological complications are associated with excess mortality, as well as long-term morbidity, particularly in the case of stroke. 480 rompt diagnosis of IE and early initiation of the antibiotic therapy are pivotal to preventing neurological complications. Early cardiac surgery in high-risk patients is key to preventing embolization of vegetations. 471, 481 ] [483] Mechanical thrombectomy may be considered within time limits in selected cases. 484 If mechanical thrombectomy is performed, the retrieved embolic material must be sent off for pathological and microbiological analyses. Neurosurgery or endovascular therapy is recommended for large infective aneurysms, especially when a continuous growth, despite optimal antibiotic therapy or ruptured intracranial infective aneurysms, is observed. 485 he use of anticoagulation in patients with left-sided IE does not seem to have an effect on the risk of stroke, cerebrovascular haemorrhage, or mortality at 10 weeks and, therefore, continuation of anticoagulation in patients with left-sided IE and with a pre-existing indication for the use of anticoagulants is recommended in the absence of other contraindications. 486 Substitution from oral anticoagulation to heparin in such patients is generally preferred in case of cerebral bleeding or indication for early surgery.

Following a neurological event, the indication for cardiac surgery must be balanced against the peri-operative risk and post-operative prognosis of the patient. Randomized studies are impractical and cohort studies suffer from bias that can only be partially compensated for by statistical methods. The majority of publications demonstrate lower risk of secondary haemorrhagic conversion of uncomplicated ischaemic lesions than the risk of recurrent embolism under antibiotic treatment. Therefore, the available evidence supports early surgery in such patients (see Section 10.4).

Recommendation Table 13 summarizes the recommended management of neurological complications in IE; considerations for cardiac surgery after neurological complications are discussed in Section 10. 4.

Recommendation Table 12 -Recommendations for the main indications of surgery in infective endocarditis (native valve endocarditis and prosthetic valve endocarditis) a

Urgent d surgery may be considered in aortic or mitral IE with vegetation ≥10 mm and without severe valve dysfunction or without clinical evidence of embolism and low surgical risk. 460, 463, 465, 473, 478 b B

9.1.1. The role of cerebral imaging in infective endocarditis

Cerebral imaging is mandatory when neurological complications of IE are suspected. Evaluation should include MRI with and without gadolinium, or CT with and without contrast if MRI is not possible. 487 Vascular imaging should not be performed routinely, and CTA or magnetic resonance angiography (MRA) is probably sufficient for screening when infective aneurysm is suspected. Catheter angiography should be performed in patients in whom an infective aneurysm was diagnosed on CTA or MRA, in patients with an acute brain haemorrhage, or if the suspicion of aneurysm remains despite negative non-invasive techniques, and if mechanical thrombectomy is considered. 488 n patients without neurological symptoms, cerebral MRI often detects 'silent' lesions such as microbleeds. 204 The lack of association with parenchymal haemorrhage and the absence of post-operative neurological complications in patients with microbleeds suggest that microbleeds should not postpone surgery when indicated. 489

9.2. Infective aneurysms

An infective (mycotic) aneurysm is a rare but potentially devastating complication of IE. Infective cerebral aneurysms may be asymptomatic, cause headaches, seizures, or focal symptoms, and may progress to a potentially lethal rupture. They are associated with subarachnoid, intracerebral, and intracranial haemorrhage, 201 particularly when the patient is anticoagulated. The true incidence of infective cerebral aneurysms may be underdiagnosed as vascular imaging modalities are not systematically performed in asymptomatic patients. In 168 patients who underwent cerebral angiography with a diagnosis of IE or infected left ventricular assist device were retrospectively reviewed and infective aneurysms were present in 9% of patients. 488 Another series using CTA identified infective aneurysms in up to 32% of patients with left-sided IE. 492 Digital subtraction angiography (DSA) remains the gold standard diagnostic test for the detection of infective aneurysms. 487 The sensitivity of CTA and MRA progressively increases with the size of the aneurysm. In a large study including 142 patients, the sensitivity for detection of infective aneurysms smaller than 5 mm was 57% for CTA and 35% for MRA, compared with respective 94% and 86% sensitivities for the detection of aneurysms of 5 mm or larger. 493 Compared with the sensitivity of DSA, the sensitivities of CTA and MRA for detecting infective aneurysms are inferior. 488, 490 Therefore, in patients with IE and high suspicion of infective aneurysms in whom CTA or MRA are negative, DSA may be considered. 490, 494 6] [497] [498] Therefore, management should be discussed among the members of the Endocarditis Team and tailored to individual clinical situations. Shi et al. 496 reported that in patients with unruptured infective cerebral aneurysms, antibiotic treatment may have similar outcomes to invasive treatment. However, interventional treatment should be considered in cases of ruptured infective aneurysms or unruptured infective aneurysms that do not respond to antibiotic therapy. 485, 495 ndovascular therapy is highly successful and associated with low morbidity compared with microsurgical and medical management. 487, 499 A systematic review including 499 patients with infective cerebral aneurysms reported a 36% rate of aneurysm rupture. 495 ndovascular surgical and conservative therapies were performed in an approximately equal number of patients. Among patients undergoing valve surgery in this series, only 15% underwent cardiac surgery before aneurysm treatment whereas 85% underwent cardiac surgery after aneurysm treatment. 495 rgency of cardiac surgery plays a pivotal role in decision-making regarding the type of invasive treatment. Compared with neurosurgical clipping that requires a craniotomy and often at least 2-week delay prior to procedure, cardiovascular surgery can be performed on the same day as endovascular treatment. 485, 487, 496, 499 Finally, endovascular treatment of infective cerebral aneurysms prior to heart valve surgery may be considered, even if no rupture is documented. 499

9.3. Splenic complications

Splenic complications associated with IE range from asymptomatic infarction 500 and abscess formation 501 through to splenic rupture and cardiovascular collapse. 502 Splenic infarcts are common (∼20% of patients in the EURO-ENDO registry) and very often asymptomatic. 5 p to 5% of splenic infarcts can progress to abscess formation. 503 ersistent or recurrent fever, abdominal pain, and persistent bacteraemia are suggestive for the presence of such complications. Patients with suspected splenic complications should be evaluated with ultrasound, abdominal CT, MRI, or PET/CT. 504 reatment of splenic complications includes conservative medical therapy with appropriate antibiotics for splenic infarction or for antibiotic-responsive abscesses, although antibiotic penetration may be poor in these circumstances. When an abscess is large, splenectomy may be considered, but the timing of splenectomy in relation to heart valve surgery needs careful assessment. 505 Splenectomy and heart valve surgery are seldom performed in the same operative episode. 506 plenectomy is usually performed prior to valve surgery due to concerns of dissemination and reinfection of the heart valve.

Recommendation Table 13 -Recommendations for the treatment of neurological complications of infective endocarditis

Brain CT or MRA is recommended in patients with IE and suspected infective cerebral aneurysms. 490

Neurosurgery or endovascular therapy is recommended for large aneurysms, those with continuous growth despite optimal antibiotic therapy, and ruptured intracranial infective cerebral aneurysms. 485

If non-invasive techniques are negative and the suspicion of infective aneurysm remains, invasive angiography should be considered. 488

In embolic stroke, mechanical thrombectomy may be considered if the expertise is available in a timely manner. 484

Thrombolytic therapy is not recommended in embolic stroke due to IE. 481, 491 III C

Nevertheless, one case series reported that it is safe to address the splenic abscess with splenectomy after valve repair. 502 Alternatives to open splenectomy, i.e. percutaneous drainage 507 and/or laparoscopic surgery, 508 may be considered in patients with high surgical risk.

After splenectomy, vaccination against encapsulated microorganisms (S. pneumoniae, N. meningitis, and Haemophilus spp.) is recommended.

9.4. Myocarditis and pericarditis

The actual prevalence of acute myocarditis in the setting of IE is unknown. Myocarditis will usually present in the form of acute HF and/ or ventricular arrhythmias indicating myocardial involvement in the inflammatory process most likely mediated by an immune mechanism.

] [511] Pericarditis is an infrequent complication of IE. In one retrospective series of 95 patients with aortic valve IE, 19% developed pericarditis usually related to ring abscess formation. The same authors also described a 12% rate of pericarditis associated with mitral valve IE. 512, 513 The pathophysiological mechanisms most commonly involved in IE-related pericarditis are the extension of inflammation from an infective aneurysm of the aortic root or valve ring abscess, an embolus in an extramural coronary artery, or the rupture of an infective aneurysm. In a recent large series of NVE, pericardial effusion was observed in 7.8% of patients and was associated with a higher risk of HF during admission. After adjusting for possible confounders, patients did not have a higher rate of surgery, and the presence of pericardial effusion was not associated with a higher in-hospital or 1-year mortality. 513

9.5. Heart rhythm and conduction disturbances

Due to the critical anatomical relationship between heart valves and the conduction system, AVB may complicate the clinical presentation of IE. The atrioventricular node (AVN) and His bundle lie in close proximity to the insertion of the septal leaflet of the tricuspid valve, the aortic root (below the non-coronary and right coronary cusps), and the mitral annulus. 514 A paravalvular abscess of these valves, especially of the aortic valve, may lead to AVB, and new electrocardiographic AVN conduction abnormalities are indicative of a paravalvular extension of the infection. In the EURO-ENDO registry, conduction abnormalities were observed at diagnosis in 11.5% of patients, including first-degree AVB in 8.1%, second-degree AVB in 0.6%, and third-degree AVB in 2.8% of cases. 5 New-onset AVB caused by local extension of IE (i.e. abscess) is an indication for urgent cardiac surgery.

Atrioventricular block may not only occur as a complication of paravalvular extension of the infection, but it may also develop as a consequence of valve surgery. In a series of 444 patients who survived cardiac surgery for IE, 515 12.8% of patients required pacemaker implantation for AVB. Multivariable analysis identified that prolonged pre-operative PR and QRS intervals, S. aureus infection, presence of aortic root abscess, tricuspid valve involvement, and prior valvular surgery were independently associated with the need for post-operative pacemaker implantation.

Pacemaker implantation should be considered in patients with surgery for valvular endocarditis and complete AVB if one or more of these risk factors is present. 515

9.6. Musculoskeletal manifestations

9.6.1. Osteoarticular infective endocarditis-related infections

Metastatic bone or joint IE-related lesions are relatively frequent due to the spread of the pathogen through the bloodstream and its subsequent tissue implantation. Although these lesions are considered an IE-related distal lesion or complication because infected valves are a continuous source of bacteraemia, it is often impossible to determine whether the primary infection is the valve or the osteoarticular infection. Overall, the incidence of osteoarticular infection among patients with IE is 6-8%, including bones, joints, and vertebral discs. 5, 145, 247, 516 9] [520] In general, the rate of IE is 10 times higher in patients with known spondylodiscitis. ] [519] [520] [521] [522] [523] The most common symptom of spondylodiscitis is back pain, although only 4% of patients with IE and back pain have spondylodiscitis. 32, 522 An MRI should be performed to accurately diagnose spondylodiscitis. Computed tomography can detect indirect signs of spondylodiscitis: loss of disc height, erosion/destruction of the endplates and vertebral bodies, and paravertebral soft tissue phlegmonous changes or abscess. 206 Whole-body [18F]FDG-PET/CT can also identify spondylodiscitis. 30, 32, 524 Indeed, spondylodiscitis is frequently detected as an incidental finding when PET/CT is performed for the diagnosis of PVE. Imaging techniques can also be helpful in guiding biopsies to obtain material for cultures in cases of suspected IE with negative blood cultures. 206 ntibiotic treatment adapted to the antimicrobial susceptibility pattern is appropriate for most cases of spondylodiscitis. The outcome is usually favourable with the 4-to 6-week IE treatment course. Prolonged therapy is necessary in patients with IE caused by difficult-to-treat microorganisms, such as S. aureus or Candida spp., or in those with epidural or perivertebral abscesses. 523, 525 In patients with neurological deficits or severe spinal instability, the indication for Recommendation Table 14 surgical spinal treatment should be considered. 526 In patients with urgent indication for cardiac surgery, the presence of these lesions does not contraindicate the cardiac intervention. Spondylodiscitis does not appear to worsen the prognosis of patients with IE but delaying the diagnosis of IE in patients with spondylodiscitis is associated with poor prognosis. 248 ,517-520

9.6.2. Rheumatological manifestations

The pathogenesis of rheumatological manifestations and musculoskeletal symptoms in IE is not well established. The probable immunologicalinflammatory aetiology of this clinical presentation is supported by a variety of antibodies and laboratory markers, the sterility of the synovial fluid, and the rapid resolution without sequelae. 527 Myalgia and back pain are reported in 12-15% of cases. Arthralgia occurs in ∼10% of patients, sometimes sequentially affecting several joints. Slightly less often are symptoms of peripheral arthritis preferentially involving the major and proximal joints at the lower extremities. 5, 145, 182, 516 acroiliitis is less frequently observed (1% of cases) as well as polymyalgia rheumatic-like syndrome with pain and morning stiffness of the shoulders and hips, proximal muscle weakness (0.9% of cases), and cutaneous leucocytoclastic vasculitis (purpuric skin lesions, 3.6% of cases). 182, 527, 528 Rheumatological manifestations and musculoskeletal symptoms show rapid and complete resolution with antibiotics and their presence does not impact on the prognosis of IE. 182, 529

9.7. Acute renal failure

2] [533] [534] Additionally, renal failure is an independent predictor of poor outcome after cardiac surgery. 417 owever, acute renal failure should not be a reason to delay cardiac surgery. The EURO-ENDO registry reported that in patients with IE, acute renal failure was the second most common complication with an incidence of almost 18%. 5 Some single-centre studies that specifically reported on the incidence of acute renal failure (using standardized criteria) in patients with IE reported that any degree of acute renal failure from mild to severe might be observed in 40-69% of cases. 532, 535, 536 evere renal failure requiring haemodialysis has been reported in 6% of patients with IE and it is associated with a very high risk of mortality (40%). 537 everal factors may be responsible for the onset or worsening of renal dysfunction: (i) immune complex and vasculitic glomerulonephritis; (ii) renal infarction due to septic emboli; 538, 539 (iii) haemodynamic impairment in patients with HF; (iv) antibiotic and other drug toxicity (notably related to aminoglycosides, vancomycin, nafcillin, amoxicillin, oxacillin, concomitant use of non-steroidal anti-inflammatories, and/ or high dose loop diuretics); and (v) nephrotoxicity of contrast agents used for diagnostic imaging techniques. 417, 531, 534, 535, 537, 540 o reduce the incidence of acute renal failure, nephrotoxic antibiotics should be avoided if possible or, if not possible, serum levels (aminoglycosides and vancomycin) as well as creatinine should be closely monitored, and the optimal dose of medication should be periodically re-evaluated and discussed with the Endocarditis Team and a pharmacologist. 536 Loop diuretics should also be used cautiously and other potentially nephrotoxic drugs, such as non-steroidal anti-inflammatories, should be avoided. 536 Similarly, the use of nephrotoxic contrast agents for diagnostic imaging techniques should be carefully evaluated and avoided when possible.

In patients with IE and a reduced glomerular filtration rate, contrast enhanced abdominal ultrasound or MRI are reasonable tests to diagnose embolization as cause of renal function impairment. 541

10. Surgical therapy: principles and methods

Surgery has been demonstrated to be an independent predictor of survival in many retrospective studies of IE patients under various clinical conditions and offers a potential curative therapy to select patient groups. 5, 250, 403, 404, 421, 436 Optimal management of such patients may lead to lower peri-operative complication rates and further potential benefits of surgical therapy.

10.1. Pre-operative and peri-operative management 10.1.1. Coronary angiography

When cardiac surgery becomes necessary in IE, assessment of coronary anatomy is recommended (see Recommendation Table 16 ). Classically, pre-operative coronary angiography is recommended for men > 40 years, post-menopausal women, and in those with one or more cardiovascular risk factors or history of CAD. 128 The presence of aortic valve vegetations may preclude invasive coronary angiography due to the risk of iatrogenic embolization. 542, 543 However, some studies have demonstrated the safety of performing invasive coronary angiography in the presence of aortic valve vegetations, particularly in patients without very large and mobile vegetations. 193, 544 Alternatively, coronary CTA can be used to rule out significant coronary obstructions. Furthermore, surgery may need to be conducted without detailed information on coronary anatomy in certain clinical conditions, particularly emergencies. Of note, a recent study questioned the need for coronary artery bypass grafting of non-critical lesions at the time of surgery for IE and suggested that such concomitant intervention may have a negative impact on peri-operative outcomes. 545

Recommendation Table 15 -Recommendations for patients with musculoskeletal manifestations of infective endocarditis

Class a Level b MRI or PET/CT is recommended in patients with suspected spondylodiscitis and vertebral osteomyelitis complicating IE. 30, 32, 206, 524

] [520] [521] 523

10.1.2. Extracardiac infection

Extracardiac foci may be treated prior to valve surgery, during the valve operation, or post-operatively, dependent on the urgency of cardiac surgery. Regardless of the timing of intervention, infective foci need to be eradicated before completion of antibiotic therapy in order to avoid cardiac valve reinfection.

10.1.3. Intra-operative echocardiography

Intra-operative TOE provides contemporaneous assessment of the extent of infection prior to valve repair/replacement. Extent of infection, stability of known vegetations, re-assessment of previously uninvolved heart valves, and biventricular function are routinely performed with intra-operative TOE. Intra-operative TOE post-surgical repair is mandatory to determine the immediate result and establish a baseline for follow-up comparisons. 547

10.2. Other intra-operative considerations

Specific peri-operative management considerations are necessary in all IE patients undergoing valve surgery, particularly in those following stroke (see Section 10.3). Pre-operative antibiotic therapy must be continued intra-operatively, and doses may need to be repeated in case of prolonged operations or major bleeding. Although the pharmacokinetics of antibiotic therapy is altered during cardio-pulmonary bypass (CPB), adjustment of doses is rarely required. 548 In general, ongoing IE antibiotic treatment offers appropriate surgical site infection prophylaxis. However, when the antibiotic treatment for IE does not fully cover normal surgical prophylactic treatment, conventional prophylaxis should be added. Intra-operative bleeding management is often complicated by marked coagulopathy in patients with IE, particularly those undergoing surgery during persistent sepsis. The management of hypotension and vasoplaegia is particularly challenging in patients presenting with septic shock, and accompanying vasoplaegia tends to worsen significantly during CPB. Norepinephrine is frequently used as first-line therapy for septic shock, followed by vasopressin or terlipressin in cases of resistant vasoplaegia. 549 Methylene blue may be used as a rescue agent in patients who are unresponsive to these measures, but mortality rates are high for such patients. 550 etrospective studies have suggested that the use of haemoadsorbent filters during CPB may decrease the negative effects associated with cytokine cascade activation. 551 A recent RCT of haemoadsorption during cardiac surgery in IE patients, however, failed to demonstrate any beneficial effects with regards to adverse events or end-organ function. 552

10.3. Surgical approach and techniques

Surgery for IE aims to remove infected structures followed by reestablishment of anatomy and haemodynamic function. With regards to the involved heart valve(s), repair or replacement is carried out based on the extent of destruction, acuity of disease, and patient characteristics. 553 Appropriate collection and labelling of tissue samples for pathological, microbiological, and molecular biological analyses are necessary to help guide antibiotic treatment.

Aortic valve replacement is usually required for aortic IE. Aortic valve repair is very uncommon in the acute situation but may be performed for isolated aortic regurgitation after healed endocarditis. In mitral IE, leaflet perforations with preserved free margin and chordae tendinae may be treated with patch repair, particularly in the setting of subacute or healed IE. Although mitral valve repair is feasible in more complex mitral IE involving the annuli, the leaflet free edge, and/or chordae, evidence showing the feasibility and durability of such repair techniques is scarce. 554, 555 A large registry on mitral repair vs. replacement in IE was limited by the lack of information on severity of IE, different patient group profiles, and significantly higher incidence of staphylococcal endocarditis in the mitral valve replacement group. 556 Therefore, it cannot be concluded that mitral valve repair is superior to replacement due to the high probability of selection bias. Valve preservation in acute IE should only be attempted if a durable repair is anticipated and complete eradication of infected tissue can be achieved. However, valve repair may be necessary in children, where valve replacement options are more limited.

Invasion of the aortic annuli may create shallow defects (very limited abscess or small pseudoaneurysms) that are still amenable to conventional valve replacement surgery. When disease progresses into an extensive aortic root abscess or periannular destruction, aortic root replacement is usually required. In experienced centres, the use of allografts has been preferred as they have the advantage of adapting to irregular surfaces and provide haemostatic advantages with very good haemodynamic function and low thrombo-embolic risk, and can be used to repair concomitant lesions of the anterior mitral valve leaflet. 557, 558 Additionally, allografts and stentless bioprostheses can be beneficial in small aortic roots and are associated with low reinfection rates. However, experience is generally limited to single-centre case series and there is no clear evidence of superiority of one valve substitute over the other. 559 In very selected patients and children in particular, the Ross operation (pulmonary valve autotransplantation) may be considered for aortic root IE. 128 The use of patches to cover abscess cavities and prevent extensive resection and reconstruction is discouraged in aortic root IE as it may be associated with recurrences, periprosthetic leaks, and pseudoaneurysm formation. After exclusion from the circulation, abscess and pseudoaneurysm cavities are left to drain into the pericardial cavity.

When periannular infection of the aortic root extends into the intervalvular fibrosa body, complex surgical reconstructions are required and are frequently the only option to achieve patient survival. The reported

Recommendation Table 16 -Recommendations for pre-operative coronary anatomy assessment in patients requiring surgery for infective endocarditis

In haemodynamically stable patients with aortic valve vegetations who require cardiac surgery and are high risk for CAD, a high-resolution multislice coronary CTA is recommended. 185, 546

Invasive coronary angiography is recommended in patients requiring heart surgery who are high risk for CAD, in the absence of aortic valve vegetations.

In emergency situations, valvular surgery without pre-operative coronary anatomy assessment regardless of CAD risk should be considered. 543, 545 a C

Invasive coronary angiography may be considered despite the presence of aortic valve vegetations in selected patients with known CAD or at high risk of significant obstructive CAD. 193, 543, 544 b C pooled peri-operative survival rate of such surgical technique is 84%. 560 ven more extensive repairs may be required for cases involving the intervalvular fibrosa, central fibrous body, and mitral valve, with or without fistulation to the right-side chambers. These operations are technically complex and require a surgeon who is very experienced in IE, which may not be available in every cardiovascular surgery department. Exceptionally, heart transplantation has been utilized for carefully selected patients without other surgical options. 561

10.3.1. Choice of valve prosthesis

Many patient characteristics are taken into account when deciding the type of valve prosthesis to implant in a given patient with IE. ] [564] [565] [566] Beyond the patient characteristics that apply in the non-IE setting, 128 and the ability of the patient to participate in decision-making, especially for emergency surgery (Table 12 ). In the absence of specific contraindications for a particular valve substitute, patient preferences should determine the final decision.

10.4. Timing of surgery after ischaemic and haemorrhagic stroke

There is a general trend of offering early surgery in IE in light of the improved operative outcomes and survival benefits observed with operative management. 451, 567 For patients who have suffered a neurological injury, however, the optimal timing of surgery remains to be defined. 568 There are no RCTs specifically assessing this clinically relevant issue and contemporary evidence arises from observational studies. 415, 454, 473, 569, 570 eurological exacerbation may occur during surgery or early postoperatively due to the altered physiology conditions during and immediately after cardiac repair. 571 Several peri-operative variables should be addressed in order to lower the risk of neurological deterioration and haemorrhagic transformation post-stroke (see Supplementary data online, Table S10 ).

The risk of neurological exacerbation during surgery needs to be balanced against that of delaying a cardiac operation. 1] [572] [573] [574] [575] [576] [577] [578] A more common situation occurs when surgery is considered for the prevention of recurrent embolism after stroke, due to the presence of large vegetations ( > 10 mm). In patients that have suffered a transient ischaemic attack, the risk of surgery is usually low and surgery should be performed without delay. For patients with ischaemic stroke, multiple observational data exist supporting a non-delayed (urgent) intervention, unless the neurological status is poor (i.e. coma or extensive damage leading to poor functional prognosis). 573, 578 Involvement of an expert neurology/neurosurgical specialist will help in risk assessment discussions.

The risk of post-operative haemorrhagic conversion after preoperative stroke is reported in the range of 2-7%. 453, 579 Remarkably, bleeding transformation after cardiac surgery can also occur in patients with silent pre-operative cerebral embolisms, with similar frequency as in patients with overt neurological deficits. Unfortunately, these events cannot currently be accurately predicted prior to surgery. When haemorrhagic transformation occurs, it is associated with high mortality (40%) and may require rescue neurointerventional or neurosurgical treatment to control bleeding or allow cerebral decompression by means of craniectomy. 577, 580 everal retrospective studies report benefits of early surgery (within 2 weeks) after haemorrhagic stroke without further compromising neurological outcomes. 574, 581, 582 Decisions should be taken on a case-by-case basis by the Endocarditis Team, including a neurologist, and should be adapted to the mechanism of intracranial haemorrhage and its severity including intracranial haemorrhage volume measurement and National Institutes of Health Stroke Scale Score (NIHSS) score (see Figure 11 ). 495 In patients in whom surgery is delayed, repeat CT or MRI imaging should be performed 1-2 weeks following intracranial haemorrhage (or earlier in the case of clinical deterioration) in order to assess stability of the cerebral finding and potentially re-assess timing of surgery. The timing of surgery after intracranial haemorrhage is controversial and an area where further evidence is urgently required.

10.5. Post-operative complications

Post-operative management of patients with IE may be challenging due to pre-operative multiorgan involvement and often complex surgical procedures. The risk of in-hospital mortality associated with IE surgery remains high (10-20%), particularly in patients > 75 years of age, usually due to co-morbidities and complications of IE. Further research should focus on methods to lower surgical mortality.

The most frequent serious post-operative complications are coagulopathy requiring extensive use of blood products and clotting factors, re-exploration of the thorax due to bleeding/tamponade, haemodialysis, stroke, or cerebral haemorrhagic transformation of prior cerebrovascular lesions, low cardiac output syndrome, respiratory complications and tracheostomy, prolonged hospital stay, and need for a permanent pacemaker. 515, 585, 586 When mortality occurs, the cause of death is often multifactorial. Post-mortem examination is helpful for determining the cause of death, further understanding of disease process, teaching purposes at academic environments, and quality control.

Recommendation Table 17 -Indications and timing of cardiac surgery after neurological complications in active infective endocarditis

After a transient ischaemic attack, cardiac surgery, if indicated, is recommended without delay. 454, 468

[572] [573] [574] [575] [576] [577] [578]

Following intracranial haemorrhage, delaying cardiac surgery > 1 month, if possible, with frequent re-assessment of the patient's clinical condition and imaging should be considered. 571

In patients with intracranial haemorrhage and unstable clinical status due to HF, uncontrolled infection or persistent high embolic risk, urgent or emergency surgery should be considered weighing the likelihood of a meaningful neurological outcome.

10.6. Management of antithrombotic therapy after surgery

The management of antithrombotic therapy early after surgery for IE may need to be altered when compared with non-IE clinical scenarios (see also Section 12 .10). 128 This is mainly due to known increased risk of intracranial haemorrhage after cerebral embolism. Restrictive or tailored use of antiplatelet and antithrombotic agents after surgery are key to avoid further complications, 203, 587 which is more feasible in patients who received bioprosthetic valve prostheses or valve repair operations than after mechanical valve replacement surgery.

11. Outcome after discharge: follow-up and long-term prognosis

Following in-hospital treatment, patients should be followed-up for the occurrence of main post-discharge complications, including recurrence of infection, HF, need for valve surgery or additional intervention, stroke, need for renal replacement therapy, psychological complications, and death. 86, 588, 589

11.1. Recurrences: relapses and reinfections

0] [591] [592] [593] [594] [595] However, it has been shown that reinfections have worse outcomes as compared with relapses. 592 igure 12 illustrates the diagnostic paths to differentiate relapse from reinfection. 596 nceptually, relapse refers to a repeat episode of IE caused by the same microorganism and represents a failure of treatment due to insufficient duration of initial treatment, sub-optimal choice of initial antibiotics, or a persistent focus of infection. 592 Conversely, reinfection is related to patients' clinical and immunological profiles, describes an infection caused by a different microorganism usually more than 6 months after the initial episode, 4, 596 and is associated with worse outcome. 592 The differentiation between relapse and reinfection needs to be interpreted with caution, however, as a long time period from initial infection suggests reinfection even in the presence of the same strain. Contemporary data report low rates of relapse, 86 most probably reflecting improved management of these patients. Relapse should be treated with i.v. v. antibiotics for an additional 4-6 weeks, depending on the causative microorganism and its antibiotic susceptibility, and cardiac surgery should be considered. It is also important to consider that antibiotic resistance may develop over time. Factors associated with an increased rate of relapse are listed in Table 13 . 588, 595, 597 n surgically managed NVE, the risk of IE recurrence is no different when comparing valve replacement and valve repair. 84, 598 0] [601] However, the most recent Danish registry study reports increased risk of IE recurrence associated with biological vs. mechanical prostheses. 84 artial oral vs. i.v. antibiotic treatment of IE, as well as OPAT vs. hospital-based antibiotic treatment in select stable patients, is not associated with an increased risk of recurrent IE. 43, 396, 399, 602 Notably, residual vegetation after treatment for IE also did not show increased association with recurrence of IE, 602 although this result should be interpreted with caution. Patients with relapse or reinfection IE should be managed as indicated in Sections 7 and 8 (if complicated IE).

Same species isolated

11.2. First year follow-up

Patients discharged after the first episode of IE should remain under close surveillance for potential long-term complications. A partnership between cardiologists, infectious disease specialists, cardiac surgeons, general practitioners, and dentists is encouraged to improve patient care and reinforce prophylaxis measures. In medically treated patients, residual valve dysfunction may worsen, or structural valve deterioration may progress, despite bacteriological cure. To monitor the risk of development of secondary HF, an initial clinical evaluation and baseline TTE should be performed at the completion of antimicrobial therapy and repeated if a change in the clinical condition occurs. Clinical re-assessment should be performed one or more times in the first year and yearly thereafter depending on the individual risk profile. The need for late valve surgery is relatively low, ranging from 3% to 11%. 27, 588, 592 Blood testing for inflammatory markers (i.e. WBC, C-reactive protein, procalcitonin) should be performed early after finishing antimicrobial treatment and repeated thereafter when clinically indicated. 592 Due to the increased risk of relapse for virulent microorganisms, blood cultures are encouraged within the first week after finishing treatment.

The early period after discharge might be challenged by slow physical and mental recovery. 603, 604 Patients' and families' concerns should be addressed during follow-up. Supporting the family may indirectly support the patient during recovery and reduce the psychological burden. Cardiac rehabilitation, including physical exercise training and patient education, may be beneficial, and has been shown to be safe and feasible in stable patients at a minimum of 2 weeks after surgery for left-sided IE. 605 Physical training should start as early as possible and can be adapted post-sternotomy with isolated lower-limb training. Adherence is improved if the delay to training is minimized, and rebuilding muscle mass and reducing frailty should be a priority.

Patients, and their caregivers, should be informed of their risk of IE recurrence and be educated on preventive measures and selfmonitoring. In particular, patients should be educated that new onset of fever, chills, or other signs of infection mandate immediate evaluation, including procurement of blood cultures before empirical use of antibiotics, and that contact with the Heart Valve Centre is mandatory in case of suspected recurrent IE. Good oral health maintenance, preventive dentistry, and advice about skin hygiene, including advice on tattoos and skin piercing, are mandatory. Deficiencies in dental surveillance contribute to the continuous gradual increase in the incidence of IE, which underlines the need for repeating the principles of IE prevention at each follow-up visit. In PWID patients, follow-up care should include a strategy for addiction treatment, involve relevant addiction specialists before hospital discharge, and possibly including medication for opioid-use disorder. 606, 607

11.3. Long-term prognosis

10, 611 Impact of referral bias, however, should be taken into consideration. 612 The main predictors of long-term mortality are age, co-morbidities, PWID, double valve infection, recurrences of IE, and HF, especially when cardiac surgery cannot be performed. 588, 589, 592, 593, 613 Compared with an age-and sex-matched general population, patients that survived a first episode of IE have significantly worse survival when suffering relapses or reinfections. 589, 614 his excess mortality is especially high within the first few years after hospital discharge and can be explained by late complications such as HF, risk of recurrences, and higher patient vulnerability. 589, 611 In fact, most recurrences of IE and late cardiac surgeries occurred during this period of time. 589, 592, 611

12. Management of specific situations

12.1. Prosthetic valve endocarditis

Prosthetic valve endocarditis is the most severe form of IE and occurs in 1-6% of patients with valve prostheses, 615 with an incidence of 0.3-1.2% per patient-year. 5, 420, 616, 617 PVE accounts for 20-30% of all cases of IE, 618 and may be more common after biological than after mechanical valve replacement surgery. 619, 620 PVE was observed in 21% of cases of IE in a French survey, 618 in 26% of cases in the Euro Heart Survey, 419 and in 20% of cases in the ICE-PCS. 621 Real-world

Addiction treatment for patients following PWID-related IE is recommended. 606, 607 C

Cardiac rehabilitation including physical exercise

training should be considered in clinically stable patients based on an individual assessment. 605, 609 a C

Psychosocial support may be considered to be integrated in follow-up care, including screening for anxiety and depression, and referral to relevant psychological treatment. 605, 609 b C observational studies demonstrated stable rates of IE, but a remarkable increase in PVE between 1998 and 2013. 80 Recently, a further increase in PVE cases (31%) was observed in the EURO-ENDO registry. 5 PVE is still associated with difficulties in diagnosis, determination of the optimal therapeutic strategy, and poor prognosis.

12.1.1. Definition and pathophysiology

A distinction is commonly made between early PVE and late PVE based on the time since valve surgery, because of significant differences in the microbiological profiles between these two groups. 622 However, the time to IE onset is prognostically less important than the connection of IE to the peri-operative period or to specific pathogens. Prosthetic valve endocarditis with an onset in the peri-operative period involves mainly S. aureus, Staphylococcus epidermidis, or nosocomial microorganisms, such as Gram-negative pathogens or fungi. Late PVE more commonly mimics the pattern of NVE, which is mostly represented by streptococcal and staphylococcal infections. 623 S. aureus is more commonly observed in patients with mechanical valves, while alphahaemolytic streptococci, enterococci, and CoNS are more common in patients with bioprosthetic valves. 624 PVE due to Mycobacterium chimaera is an uncommon form of nosocomial infection that can result from contaminated CPB heater-cooler systems. Such infections present many months after the index operation and can therefore be challenging to identify, and are associated with high mortality. 625 he pathogenesis of PVE differs according to both the type of contamination and the type of prosthetic valve (see Supplementary data online, Section S6.1).

12.1.2. Diagnosis

Diagnosis is more difficult in PVE than in NVE. Clinical presentation is frequently atypical, particularly in the early post-operative period, in which fever and inflammatory syndromes are common in the absence of macroscopic alterations of the prosthesis on cardiac imaging. However, persistent fever should trigger the suspicion of PVE. As in NVE, diagnosis of PVE is based mainly on the results of echocardiography and blood cultures. However, both are associated with a sensitivity of only 60% for the definite diagnosis of endocarditis. 212 lthough TOE is mandatory in suspected PVE (Figure 6 ), its diagnostic value is lower than in NVE. Identification of a new periprosthetic leak is a major criterion of IE and urges additional imaging modality to confirm the diagnosis (see Section 5). 533, 626 Recently, nuclear techniques, particularly [18F]FDG-PET/CT, have been shown to improve the diagnostic accuracy of the Duke criteria and increase sensitivity. 34, 209 ombinations of different imaging techniques such as cardiac CT, nuclear imaging, and TOE, improve diagnostic accuracy and provide relevant information in terms of prognosis. 33, 627 In select cases of suspected PVE, and non-diagnostic results for the above-listed exams, intracardiac echocardiography may be considered.

12.1.3. Prognosis and treatment

A high in-hospital mortality rate of 20-40% has been reported in PVE. 628, 629 Compared with NVE, PVE is associated with increased inhospital mortality and morbidity as well as reduced long-term survival. 88, 630 Several factors have been associated with poor prognosis in PVE, including older age, diabetes mellitus, healthcare-associated infections, and early PVE. 312 Among the different causative organisms, staphylococcal or fungal infection seem to be more aggressive, whereas enterococcal infections are associated with similar mortality but higher recurrence rates. 628 Haemodynamic instability, multivalvular involvement as well as involvement of the aortomitral fibrosa have been associated with worse outcomes. It is noteworthy that the most important risk factor for recurrent IE and mortality is withholding surgery despite an obvious indication. 5 he best therapeutic option in PVE is still debated. Although surgery is generally considered the best option when PVE causes severe prosthetic dysfunction or HF, in the EURO-ENDO registry it was performed in only 73% of patients with PVE despite a clear indication for surgical treatment. 5 In a single-series study of 523 PVE patients, early surgery was a large independent predictor of early and 1-year survival. 631 Conversely, after adjustment for differences in clinical characteristics and survival bias, early valve replacement was not associated with lower mortality compared with medical therapy in a large international cohort. 421 In this series, however, surgery was beneficial in the subgroup of patients with the strongest indications for surgery including valve regurgitation, vegetation, and dehiscence or paravalvular abscess/fistula formation. 421 Therefore, a surgical strategy is recommended for PVE in high-risk subgroups identified by prognostic assessment, i.e. PVE complicated with HF, severe prosthetic dysfunction, abscess, or persistent fever. ] [634] However, patients who are initially treated medically require close follow-up because of the risk of late events and the higher risk of relapse or valvular dysfunction.

Surgery for PVE follows the general principles outlined for NVE. However, the reoperation setting and the higher incidence of periprosthetic tissue destruction increase the complexity of the procedure. Meticulous and radical debridement of the infected material, including the original prosthesis, suture, and pledgets, is recommended. The type of valve substitute used for PVE follows the same recommendations as for NVE (see also Section 10. 3

.1).

Early PVE following valve replacement surgery is a separate entity associated with a high mortality rate, where conservative treatment with antibiotics is unlikely to lead to a cure and repeat surgery should be performed. 621, 635 Staphylococci, Cutibacteria, or similar species are the usual causative organisms. 622, 636

12.2. Endocarditis in the elderly

Characteristics of patients with IE have dramatically changed over recent decades, with an increasing prevalence and specific features of IE in the elderly population. 25, 145, 637, 638 In this population, enterococci and S. aureus are reported to be the most frequent aetiological agents. In addition, the higher presence of intracardiac prosthetic devices (CIED and valvular prosthesis/repair including TAVI devices) and increased incidence of healthcare-associated IE episodes are observed. 25, 637 Finally, a lower risk of embolic episodes has been observed in this subgroup. A number of studies have shown that cardiac surgery positively affects the clinical outcome of IE patients. Nevertheless, old age, comorbidities, and previous non-cardiac and cardiac procedures lead to surgical hesitancy by referring physicians, surgeons, and patients themselves. 642 Moreover, these characteristics also influence the outcome of this fragile cohort. 400, 433 As a result, less frequent performance of curative surgery and increased mortality are typical hallmarks of IE episodes in elderly as compared with the younger population. 640 In a recently published Swedish propensity analysis of IE patients from 2006 to 2017, the authors found that surgery was underused in the elderly and that 1-year mortality was significantly higher in elderly patients who did not undergo surgery. 641 In a sub-analysis of the ESC EORP EURO-ENDO registry, the indication for surgery was less often recognized (51% vs. 57%) and surgery was far less frequently performed when indicated (35% vs. 68%) in patients > 80 vs. < 80 years. However, mortality of surgically treated patients was remarkably similar in patients < 80 and > 80 years after propensity matching (19.7% vs. 20.0%). Age was also not demonstrated to be an independent predictor of mortality in this large prospective study. 640, 643 These findings suggest that performance of surgery in well-selected elderly patients is underutilized and may increase their chance of survival.

In elderly IE patients, functional and nutritional status are important predictors of outcomes. 400 When considering cardiac surgery in elderly patients, functional and nutritional status, and their associated risks, should be accurately explored through a comprehensive assessment by geriatricians. In addition, the earliest possible discharge home to facilitate the patient's functional recovery should be considered in this subgroup of patients.

12.3. Transcatheter prosthetic valve endocarditis 12.3.1. Endocarditis following transcatheter aortic valve implantation

The incidence of IE post-TAVI ranges from 0.3 to 1.9 per 100 patientyears, 94, 623, [644] [645] [646] [647] [648] which is similar to that reported following surgical aortic valve replacement in both observational studies and RCTs. 94, 623, 646, 647 One recent study, however, reported a lower incidence of PVE after TAVI compared with surgical prostheses. 649 1] [652] A modest decrease in the incidence of IE post-TAVI has been observed in recent years, particularly in the early period following the procedure, presumably related to multiple technical improvements, more streamlined procedures, and a reduction of periprocedural complications. 650, 652 , 652 12. 3.1.1. Diagnosis The diagnosis of IE post-TAVI is challenging. The stent frame of transcatheter valves, with a much higher amount of metal surrounding the valve leaflets compared with surgical prostheses, and the characteristics of TAVI patients (frequently elderly with multiple co-morbidities) may increase the diagnostic challenges in this population. The clinical presentation is frequently atypical, with fever lacking in 13-20% of patients. 623, 645, 650 6] 650 Some important aspects should be considered regarding TOE in patients with suspected IE post-TAVI: (i) no vegetations are detected in 38-60% of cases; 623, 645, 650, 651 (ii) vegetations are located in the stent frame of the transcatheter valve (and not on the valve leaflets) in 12% of cases, and this rate increases up to 19% in the presence of some self-expanding valve systems with a longer stent frame occupying the ascending aorta; 653 and (iii) the vegetations are located outside the transcatheter valve in about one-third of cases, mainly at the level of the mitral valve. 645, 650, 651 Nuclear imaging or CT have been useful to diagnose IE post-TAVI. 654, 655 The addition of [18F]FDG-PET/CT and/or CTA to the diagnostic work-up of IE in TAVI changed the final clinical diagnosis in 33% of patients. 655 Intracardiac echocardiography may also be useful for detecting vegetations in patients with suspected IE after TAVI and negative TOE. 165

##### 12.3.1.2. Prognosis and treatment

12.3.1.2. Prognosis and treatment

Prognosis and treatment of post-TAVI PVE is complicated by the fact that patients are older and have more co-morbidities than post-surgical PVE patients. About two-thirds of patients with IE post-TAVI exhibit at least one complication, with acute kidney injury and HF being the most frequent adverse events. 645, 646, 656 45, 652, 657 A higher patient risk profile, S. aureus, and the occurrence of IE complications have been identified as risk factors for increased mortality. 645, 652, 657 Antimicrobial therapy for IE post-TAVI is similar to that of PVE (see Section 7). Similar to surgical PVE, cardiac surgery is considered the best option in the presence of IE complications, particularly severe prosthetic failure or HF, but is infrequently performed. Surgery is performed in ∼20% of cases (ranging from 3.8% to 31.3%), 645, 652, 656 a much lower rate compared with NVE and surgical PVE. The characteris ics of the TAVI population, with often advanced age and high or prohibitive surgical risk, along with the potential difficulties associated with the removal of some transcatheter valve systems (particularly those with a large amount of stent frame, frequently adherent to the ascending aorta after a few months following the TAVI procedure) may play a role in the low rate of surgical interventions.

To date, all studies but one failed to demonstrate the potential benefit of surgery in IE post-TAVI patients, 442, 645, 652, 656, 658 but the relatively small sample size of the studies and the multiplicity of potential confounders when comparing to those patients not receiving surgical treatment precludes definite conclusions. The only study showing a beneficial effect of surgical intervention focused on those patients who had a local extension of the infection (i.e. abscess or fistula). 442 he decision to proceed with surgery in IE post-TAVI patients should be individualized, balancing the surgical risks and the prognosis of medical treatment alone. In cases with local extension of the infection, surgery may be recommended in the absence of a prohibitive surgical risk. In cases with healed IE and valve prosthesis dysfunction, repeat transcatheter therapy (valve-in-valve procedure) can be performed in select patients. 659 Such interventions should be performed at least 1-3 months after the healed endocarditis episode and following a negative follow-up TOE.

12.3.2. Endocarditis following transcatheter pulmonary valve implantation

The incidence of IE post-transcatheter pulmonary valve implantation (TPVI) ranges from 1.6 to 4.0 per 100 patient-years, 93,660-667 which seems to be higher than that reported following surgical pulmonary valve interventions (observational studies, no randomized data). 662, 663, 667, 668 While some studies suggest a higher risk associated with the use of bovine jugular vein valves, 662, 667, 669 a recent large multicentre study including different transcatheter valve systems did not observe differences between valve types. 665 The most consistent factors associated with an increased risk of IE following TPVI have been younger age, a previous history of IE, and a higher transvalvular residual gradient. 93, 663, 665 . 3

.2.1. Diagnosis

The diagnosis of IE in TPVI recipients may be challenging, and the use of intracardiac echocardiography and [18F]FDG-PET/CT has been shown to be useful in cases with a clinical suspicion and negative TTE/ TOE. 34, 93, 210, 660, 665, 670 [666] 12. 3

.2.2. Prognosis and treatment

New moderate or severe prosthetic valve stenosis occurs much more frequently (one-third to one-half of patients) in post-TPVI PVE than in aortic PVE, and the rate of surgical valve replacement therapy ranges from 26% to 56%. 93, 660, 661, 664, 665 The possibility of a transcatheter therapy (valve-in-valve intervention) for treating severe prosthesis dysfunction in cases with healed endocarditis or as an urgent treatment (balloon dilatation) in severe valve stenosis cases has also been reported. 660, 665 A valve-in-valve intervention should be delayed at least 1-3 months following antibiotic treatment of the endocarditis episode. The mortality rate related to the IE episode ranges from 0% to 11%. 93, 660, 661, 664, 665 This rate is much lower compared with TAVI patients, which is likely to be related to the younger and less co-morbid characteristics of the TPVI population.

12.4. Infective endocarditis affecting cardiac implantable electronic devices

Device-related infection is one of the most serious complications of CIED therapy and is associated with significant mortality and morbidity. 671

12.4.1. Definitions of cardiac device infections

A recent EHRA consensus document has published criteria for CIED infection. 130 Localized infections may be either superficial incisional infections (acute infection without involvement of the pocket or hardware) or isolated pocket infections (limited to the hardware in the pocket), and can be either acute or chronic. Systemic CIED infections may occur with or without pocket infection, and with or without visible vegetations on the tricuspid or pulmonary valves or pacing leads. Cardiovascular implanted electronic device-related IE is defined as evidence of CIED infection with clinical signs of pocket infection and/or imaging findings (lead vegetations, positive FDG-PET on the generator/leads etc.) which fulfil the criteria for valvular IE (see Section 5).

12.4.2. Pathophysiology and microbiology

Cardiovascular implanted electronic device-related IE occurs by two mechanisms. Local infection usually results from bacterial flora from the patient's skin that is introduced into the pocket at the time of incision despite surgical preparation. 672 ] [675] [676] Whereas CoNS are most frequently the cause of chronic pocket infection, the most frequent agents identified with bacteraemia in CIED infection are S. aureus and CoNS. 677, 678 Other causative organisms are Enterococcus spp., β-haemolytic streptococci, oral streptococci group, Cutibacterium acnes, and Corynebacterium spp. 674, 678, 679 More rarely, systemic infection is caused by Gram-negative (mainly P. aeruginosa or Serratia marcescens) 680 or polymicrobial agents, whereas systemic fungal infections (Candida spp. and Aspergillus spp.) 681 are exceptional.

12.4.3. Risk factors

Risk factors may be divided into patient-related, procedure-related, and device-related factors. 118 The PADIT (Previous procedure on same pocket; Age; Depressed renal function; Immunocompromised; Type of procedure) study randomized 19 603 patients undergoing CIED implantation to conventional treatment (pre-procedural cefazolin infusion) vs. different regimens of incremental treatment. 682 The primary outcome was 1-year hospitalization for device infection which was not significantly different between groups. A risk score for infection has been derived from the study (see Supplementary data online, Table S11 ) 683 and has been validated externally. 684 A web-based calculator is available (https://padit-calculator.ca). 683

12.4.4. Prophylaxis

Antibiotic prophylaxis to prevent CIED-related IE before interventions, such as dental, respiratory, gastrointestinal, or genitourinary procedures, is not warranted as the risk is very low.

Prevention of CIED infection at implantation hinges upon careful planning, pre-operative antibiotic prophylaxis, correction of modifiable risk factors, hygienic surgical environment and technique, ancillary measures in case of increased risk (e.g. use of an antibacterial envelope), and proper post-operative care.

Correction of modifiable risk factors includes general measures such as postponing the procedure in cases of fever or signs of infection and avoiding temporary pacing. Routine administration of prophylactic systemic antibiotics within 1 h of incision is the standard of care. 118 RCTs have used flucloxacillin (1-2 g i.v.) 117 and first-generation cephalosporins, such as cefazolin (1-2 g i.v.). 116 Vancomycin (1-2 g over 60-90 min) may be used in case of allergy to cephalosporins with other alternatives, including teicoplanin and clindamycin. 117 Coverage of MRSA should be guided by the prevalence in the implanting institution.

Haematoma is a major contributor to risk of infection, and all possible measures should be taken to avoid this complication. 685, 686 Another major risk factor is a revision with re-opening of the pocket (e.g. for lead repositioning). Technical aspects have recently been covered in detail in an EHRA consensus document on CIED implantation. 687 t is generally not recommended to wash the pocket with antibiotics, nor to administer antibiotic treatment post-operatively, as shown by the PADIT trial. 682 An antibiotic mesh envelope, which locally releases minocycline and rifampin for a minimum of 7 days and is fully absorbed in ∼9 weeks, may, however, be useful to reduce risk of infection in selected patients. The Worldwide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP-IT) showed that the mesh envelope significantly reduces the incidence of CIED infection in patients at increased risk (i.e. undergoing a pocket revision, generator replacement, system upgrade, or implantation of a cardiac resynchronization therapy [CRT]-implantable cardioverter defibrillator [ICD] ). 688 The number needed to treat was, however, high at 200, but is ∼50 in patients undergoing CRT reoperations (replacement/upgrade/revision) in a recent observational study. 689

12.4.5. Diagnosis

Clinical presentation of CIED-associated IE is similar to valvular IE with patients frequently presenting with fever, chills, and embolic events. Signs of pocket infection (swelling, tenderness, erythema, purulent discharge etc.) may or may not be present.

The probability that a positive blood culture in a CIED recipient represents underlying device infection depends on the organism type and duration of bacteraemia. Suspicion of CIED-associated IE should be particularly high in the event of S. aureus bacteraemia. 675 CIED infection is less likely with Gram-negative bacteraemia, and in these instances, the pocket usually shows signs of infection. TOE. b Taking into account the identified pathogen, procedural risk, and requirement for valve surgery. c At a distant site and postponed as long as possible (until signs and symptoms of infection have resolved and blood cultures are negative for > 72 h in the absence of vegetations and /or 'ghosts', or otherwise after > 2 weeks of negative blood cultures).

Transthoracic echocardiography and TOE are both recommended in the case of suspected CIED-related IE. [692] [693] [694] Intracardiac echocardiography may also be used to visualize vegetations, 695 and may be useful in patients in whom TOE is not possible. However, the absence of vegetations does not rule out IE, as these may be present on extracardiac segments of the lead which cannot be visualized. Repeating TTE and/or TOE within 5-7 days is recommended in case of initially negative examination when clinical suspicion of CIED-related IE remains high. It is important to note that fibrinous lead masses may be observed in asymptomatic CIED patients, and do not predict CIED-related IE over long-term follow-up. 696 iagnosis of CIED-related endocarditis by [18]FDG-PET/CT has good sensitivity and specificity, 129 and is particularly useful in the setting of possible CIED-related IE without signs of pocket infection. 238 Results should be interpreted with caution, however, if the CIED is recently implanted ( < 6 weeks). 130 hite blood cell SPECT/CT has also been used for diagnosing CIED infection but has limited availability. 216, 697 A chest X-ray or CT should be performed in all patients to evaluate the presence of pulmonary complications.

12.4.6. Antimicrobial therapy

Treatment of CIED infection involves early 698, 699 and complete removal of all parts of the system, combined with initial empirical antibiotic therapy directed at MRSA and Gram-negative bacteria, while awaiting identification of the pathogen. 130, 700, 701 Antibiotic treatment follows the recommendations indicated in Section 7. In exceptional cases where complete device removal is not possible, i.v. antibiotics for 4-6 weeks may be administered followed by close follow-up after interruption of antibiotic therapy or, alternatively, individualized long-term suppressive oral therapy.

12.4.7. Device extraction

When CIED and lead extraction is required, such procedures should be performed in centres with the corresponding expertise. Complete CIED removal is recommended for all patients with confirmed infection of the lead(s), as conservative treatment is associated with increased mortality. 678, 699 In patients with left-sided prosthetic heart valves and CIED infection, complete CIED removal combined with prolonged (4-)6 week antibiotic therapy may prevent left-sided valve infection. 130, 702 Complete CIED extraction should also be considered in case of valvular IE without definite lead involvement, taking into account the identified pathogens (Staphylococcus spp. infections may be more prone to seed the CIED), 673, 675, 676 procedural risk, and indication for valve surgery.

Complete device extraction should be considered even in the absence of vegetations in the setting of persistent or relapsing Gram-positive bacteraemia or fungaemia after a course of appropriate antibiotic therapy, if there is no other identified source (see Figure 13 ). 681 In all instances of lead extraction, procedural risk should be carefully evaluated taking into account lead dwell time, pacemaker dependency, patient frailty, and other co-morbidities within the process of shared decision-making. 703 ead extraction should be performed, without delay (i.e. within the first days of admission), as this has been shown to be associated with improved outcomes. 698, 699, 704 Percutaneous rather than surgical extraction is the preferred procedure, but requires specialized tools and should be performed in centres with expertise in this technique and with onsite surgical backup, due to the risk of life-threatening tamponade and vein laceration.

Large vegetations may be aspirated percutaneously before lead extraction to reduce risk associated with embolization. 705 Surgical lead extraction should be considered in case of large vegetations (e.g. > 20 mm) 679 and if aspiration is not available or is unsuccessful. Surgical removal is also the preferred technique if valve surgery is indicated.

Hardware retrieved from extraction, especially the lead tip, should be cultured. 706 Sonication has been shown to increase diagnostic yield. 707, 708

12.4.8. Device reimplantation

The indication for reimplantation should always be carefully evaluated and no part of the removed CIED system should be reimplanted. Quality of evidence regarding timing of reimplantation is poor. 709 eimplantation should be performed at a site distant from that of the previous generator, and delayed until signs and symptoms of local and systemic infection have resolved and blood cultures are negative for at least 72 h after extraction in the absence of vegetations or 'ghosts' (fibrous remnants after lead extraction, which have been associated with death and reinfection), 710 or after 2 weeks of negative blood cultures if vegetations were visualized. 701, 711 or patients with a high risk of sudden cardiac death, a wearable defibrillator is an option as a bridge to reimplantation. In pacemaker-dependent patients, an active-fixation lead may be introduced via the internal jugular vein and connected to an external pacemaker for up to 4-6 weeks, thereby preserving the contralateral side for definitive device reimplantation. 712 As an alternative to delayed reimplantation in pacemaker-dependent patients, an epicardial pacemaker may be implanted before lead extraction, although this strategy has been associated with a higher risk of device re-intervention. 713 Alternative devices such as leadless pacemakers 714 or subcutaneous ICD 715 may be implanted in selected patients if the risk of new infection is deemed high.

Recommendation Table 20 -Recommendations for cardiovascular implanted electronic device-related infective endocarditis

Antibiotic prophylaxis covering S. aureus is recommended for CIED implantation. 118

I A

[694]

Complete system extraction without delay is recommended in patients with definite CIED-related IE under initial empirical antibiotic therapy. 698, 699 B

Obtaining at least three sets of blood cultures is recommended before prompt initiation of empirical antibiotic therapy for CIED infection, 710 covering methicillin-resistant staphylococci and Gram-negative bacteria.

If CIED reimplantation is indicated after extraction for CIED-related IE, it is recommended to be performed at a site distant from the previous generator, as late as possible, once signs and symptoms of infection have abated and until blood cultures are negative for at least 72 h in the absence of vegetations, and negative for at least 2 weeks if vegetations were visualized. 701, 711

12.5. Infective endocarditis in patients admitted to intensive care units

Infective endocarditis is frequently associated with severe life-threatening cardiac and/or systemic complications and the number of patients requiring intensive care unit (ICU) admission has steadily been growing in recent years, as shown in a large retrospective study. 716 The need for ICU admission, advanced monitoring, vasoactive treatment, and organ support is most commonly prompted by the occurrence of septic shock, acute HF, and cardiogenic shock leading to multiorgan failure. 8] [719] Any IE patient requiring ICU admission should be urgently discussed within the Endocarditis Team.

In the largest multicentre retrospective series, focusing on critically ill IE patients with organ failure requiring ICU admission in France over an 18-year period, overall in-hospital mortality was 32%. 716 ultivariate analysis showed age, Simplified Acute Physiology Score (SAPS) II score, organ failure, stroke, and Staphylococcus spp. to be associated with an increased risk of death. In contrast, cardiac surgery, CIED, male gender, and Streptococcus spp. as the causative microorganism of IE, were associated with a better survival. 716 In another study that reported an even higher mortality (42%), four independent prognostic factors were identified: high SAPS II ( > 35 points) and Sequential Organ Failure Assessment ( > 8 points) scores, MRSA infection, and native valve IE. 718 Right-sided IE, which is more commonly associated with PWID, accounts for < 10% of IE cases but is associated with high mortality in patients needing ICU admission. 717

12.5.1. Causative microorganisms

The majority of retrospective series in the ICU setting point to Staphylococcus spp. as the main causative agent of IE episodes. Indeed, S. aureus has emerged as the most feared aetiological agent with the highest rates of complications and mortality, being responsible for up to 56% of IE cases in one observational study. 719 Streptococcus spp., Enterococcus spp., Gram-negative bacilli, and Candida spp. are less frequently reported. 718, 719 Identification of the infecting microorganism remains the mainstay of effective therapy in complicated IE cases. Hence, in patients with negative blood cultures, serological or molecular testing by PCR should be considered (see Section 5.3).

12.5.2. Diagnosis

The diverse nature, epidemiological profile, and presentation phenotype of IE in the ICU setting may hinder early diagnosis. In particular, pyrexial episodes suggestive of an alternative infective source and neurological manifestations, such as confusion, delirium, or focal symptoms may initially mislead the clinician from a diagnosis of IE.

The diagnosis of IE in ICUs follows the same modified criteria as in non-ICU patients (see Section 5). Transoesophageal echocardiography has a prominent role as a tool for diagnosis of IE and its complications in the ICU. 720

12.5.3. Management

Antimicrobial therapy and indications for surgery in patients with IE are described in Sections 7 and 10, respectively. Surgical therapy has been associated with an improved early and late outcome both in the general population and in patients admitted to ICUs. Although surgery is the treatment of choice in about one-half of patients, surgical therapy in ICU patients is characterized by more complex procedures with increased peri-operative mortality, as well as difficult post-operative care due to higher requirements of circulatory and pulmonary support. Five independent predictors of post-operative need for advanced circulatory support were found in one study of patients with IE: male sex, increased surgery duration, renal dysfunction (pre-operative estimated glomerular filtration < 60 mL/min/m 2 ), HF prior to surgery, and lower pre-operative platelet count. 721 xtracorporeal membrane oxygenation is occasionally required in patients post-surgery but is associated with poor outcomes. 722 ecision-making in ICU patients with IE should always be a product of consensus of the Endocarditis Team to determine the best management strategy. Pre-operative haemodynamic optimization and goal-directed therapy protocols including vasoactive drugs and mechanical circulatory support may be considered in these complex high-risk patients. 721

12.6. Right-sided infective endocarditis

Right-sided IE accounts for ∼5-10% of patients with IE, 723 but its frequency may be increasing as its risk factors are increasing in some countries. 133, 724 Risk factors for right-sided IE include patients with CHD, indwelling catheters, and CIED, as well as immunocompromised and PWID patients. Of these, PWID is an increasingly common risk Complete CIED extraction should be considered in case of valvular IE, even without definite lead involvement, taking into account the identified pathogen and requirement for valve surgery.

[675] [676] IIa C

Extension of antibiotic treatment of CIED-related endocarditis to (4-6) weeks following device extraction should be considered in the presence of septic emboli or prosthetic valves. 702

Use of an antibiotic envelope may be considered in select high-risk patients undergoing CIED reimplantation to reduce risk of infection. 688, 689 b B

In cases of possible CIED-related IE with occult Gram-negative bacteraemia, complete system removal may be considered in case of persistent/ relapsing bacteraemia after a course of antimicrobial therapy. 680, 690, 691 b C

Removal of CIED after a single positive blood culture, with no other clinical evidence of infection, is not recommended. 675

factor, 133, 723 while patients with indwelling vascular catheters have the worst prognosis. 725 IE of transcatheter pulmonary valves is covered in Section 12.2, whereas CIED-related right-sided IE is covered in Section 12. 3.

The most common microorganism causing right-sided IE is S. aureus, accounting for the majority of patients. 723, 726 The tricuspid valve is much more commonly infected than the pulmonary valve in patients with right-sided IE. 723, 727 Right-sided IE may also involve non-functional embryonic remnants of the right atrium (e.g. Eustachian valve). 723, 727 ight-sided IE rarely spreads to involve the left-sided cardiac structures, whereas spread from left-to right-sided structures is not uncommon. 728

12.6.1. Diagnosis and complications

Right-sided IE patients present with fever, bacteraemia, and pulmonary complaints (i.e. cough, chest pain, or haemoptysis). Right-sided HF may also occur due to tricuspid or pulmonary regurgitation, or to pulmonary hypertension induced by multiple pulmonary septic emboli. 133 iagnosis is most frequently confirmed by echocardiographic findings of vegetations on the tricuspid valve or, less frequently, pulmonary valve. Adequate evaluation of the tricuspid valve may be performed with TTE, due to the anterior location of the valve and the large vegetations frequently observed in right-sided IE. Transoesophageal echocardiography is frequently required, however, particularly for evaluation of the pulmonary valve or in patients with indwelling venous catheters or intracardiac devices. 729 Intracardiac echocardiography may also be helpful in select patients. Vegetations may be challenging to identify on the pulmonary valve even with TOE, especially in patients with a prosthetic valve in the pulmonary position. [18]FDG-PET imaging may be very helpful in such patients. 34, 730 Perivalvular abscess formation and invasion into surrounding structures is rarely seen in right-sided IE, unless it is a secondary consequence of left-sided IE. 728 CT is useful in order to identify concomitant pulmonary disease, including infarcts and abscess formation.

12.6.2. Endocarditis in people who inject drugs

Infective endocarditis in PWID is an increasing global phenomenon. 10, 132, 133, 141 Repeat i.v. injections result in contaminated particles that reach the tricuspid valve and right-heart chambers and can also lead to infection of left-heart structures, which is associated with worse prognosis. 614 PWID patients also have an increased rate of human immunodeficiency virus (HIV) and hepatitis than other patients with right-sided IE. 731 The majority of right-sided IE in PWID can be treated successfully with antibiotic therapy. Mortality rates of PWID are relatively low, even when surgery is required, probably due to the young patient age. 723 However, PWID have a markedly increased rate of IE recurrence, particularly in the first 6 months post-surgery. 133, 614, 723, 732

12.6.3. Prognosis and treatment

Right-sided IE is generally a more benign clinical entity than left-sided IE and can be medically managed in ∼90% of patients, with surgery reserved for those who fail medical therapy. 733 Patients with CIED-related right-sided IE have a worse prognosis as compared with non-CIED-related right-sided IE (see Section 12.4). 723 725 ight-sided IE in immunocompromised patients, particularly fungal infections, carries a very poor prognosis.

12. 6. 3.1. Antimicrobial therapy S. aureus and CoNS are the cause of right-sided IE in a large proportion of cases, with S. aureus predominating in PWID and CoNS being more common in patients with indwelling devices. 723, 726 MRSA rates may be increasing over time, particularly in PWID. 133 Right-sided IE due to Streptococcus spp. is unusual but can be observed in alcoholics and diabetics. P. aeruginosa and other Gram-negative organisms are rare causes of right-sided IE, while Candida albicans is mostly seen in immunocompromised patients.

Empirical antimicrobial therapy depends on the suspected microorganism, the type of drug and solvent used by the PWID, and the infection location, 734 but S. aureus must be initially covered in all cases. Initial treatment consists of penicillinase-resistant penicillin, vancomycin, or daptomycin, depending on the local prevalence of MRSA, 735 in combination with gentamicin. If the patient is a pentazocine addict, an anti-Pseudomonas agent may also be required, as the use of recreational drugs may also entail infections with Gram-negative bacteria. 735 Very large vegetations and history of brown heroin use dissolved in lemon juice suggest infection for Candida spp. (not C. albicans), and therefore antifungal treatment should be added. 736 Antifungals may be necessary in selected PWID, particularly if immunocompromised. 737 nce the causative organisms have been isolated, therapy has to be adjusted. An RCT demonstrated that a 2-week treatment course may be sufficient and that aminoglycosides may be unnecessary. 738 717 wo-week treatment with oxacillin (or cloxacillin) without gentamicin is effective when:

(i) MSSA is the causative organism; (ii) There is good clinical and microbiological response to treatment ( > 96 h); 739 (iii) The vegetation size is ≤20 mm; and (iv) There is an absence of metastatic sites of infection or empyema and cardiac or extracardiac complications, 739, 740 prosthetic valve or left-sided valve infection, 741 and severe immunosuppression. 742 ycopeptides (vancomycin) should not be used in a 2-week treatment. 0] [741] [742] [743] [744] When the conventional i.v. route therapy is not possible, S. aureus right-sided IE in PWID may also be treated with oral ciprofloxacin (750 mg twice a day) plus rifampin (300 mg twice a day) if the strain is susceptible to both drugs, the case is uncomplicated, and patient adherence is monitored carefully. 745 Partial oral antibiotic treatment may also be beneficial for PWID with IE. 746 For organisms other than S. aureus, therapy in PWID does not differ from that in other patients. 12. 6. 3

.2. Surgery

The commonly accepted indications for surgical treatment of rightsided IE in patients who are receiving appropriate antibiotic therapy are (see Recommendation Table 19 ):

• Persistent bacteraemia after at least 1 week of appropriate antibiotic therapy. 10 Tight ventricular dysfunction secondary to acute severe tricuspid regurgitation non-responsive to diuretics. 479 Respiratory insufficiency requiring ventilatory support after recurrent pulmonary emboli. 747 Involvement of left-sided structures; 748, 749 and • Large residual tricuspid vegetations ( > 20 mm) after recurrent pulmonary emboli. 145, 471 Patients should be individually assessed by the Endocarditis Team. An isolated veg tion is not an indication for surgery. Patients with residual large vegetations frequently present with right-heart and/or respiratory failure, as well as persistent sepsis. 750 The common surgical strategies for tricuspid valve IE include valve repair, replacement and, less commonly, surgical valvectomy. 751 Tricuspid valve repair is more frequently performed than valve replacement in right-sided IE, although the extent of valve destruction may make repair impossible. 725, 752 Tricuspid valve repair may also be associated with better short-and long-term outcomes than replacement for right-sided IE, particularly with regards to recurrent infection and need for repeat surgery. 479, 723 When valve replacement for right-sided IE is required, bioprostheses are frequently preferred due to concerns with the management and risks of lifelong anticoagulation, especially in PWID, and the risks of thrombo-embolism for mechanical valves in the right heart. 726 Prophylactic placement of permanent epicardial leads should be performed at the time of tricuspid valve surgery for right-sided IE, particularly if heart block is present in the operating room to prevent damage of a replaced valve during subsequent transvenous lead displacement and to lower the risk of reinfection. 733 Recently, interest has been generated in the extraction of large vegetations using percutaneous extracorporeal circuitry for aspiration. 753 The main goals have been debulking of septic intracardiac masses, reducing the infectious load, and achieving clinical stability. 754

12.7. Infective endocarditis in congenital heart disease

Although the incidence of CHD is relatively constant, the overall population with CHD is constantly increasing due to increased survival following CHD surgery in childhood and increased longevity of adults with CHD. The presence of CHD, even after repair, is recognized as a lifelong potential substrate for IE. Congenital heart disease predisposes to IE via several mechanisms including turbulent non-laminar blood flow causing shear stress and endothelial damage, the presence of intracardiac foreign material such as prosthetic valves or CIED, cyanosis, and recurrent exposure to cardiac procedures. 98 here are marked variations in susceptibility to IE between CHD lesions. Some simple conditions, such as secundum atrial septal defect, patent ductus arteriosus, and pulmonary valve stenosis, carry a low risk of IE, while others, such as bicuspid aortic valve carry a somewhat increased risk. 8 However, CHD often presents with multiple cardiac lesions, each adding to the total risk of IE. 8, 756 In general terms, IE is more common in CHD with multiple defects and in patients with more complex CHD. 757 pecific high-risk conditions are prosthetic valves, including transcatheter valves, valve repair using a prosthetic ring, previous IE, any unrepaired cyanotic CHD, and any CHD repaired with prosthetic material for up to 6 months after the procedure, or lifelong if residual shunt or valvar regurgitation remains. 758 Contemporary studies confirm the relatively high risk of IE in CHD patients after valve surgery. 8, 47, 90, 759 Specific awareness is needed after TPVI (see Section 12.3.2). 666, 759, 760 The distribution of causative microorganisms does not differ from the pattern found in acquired heart disease, with Streptococcus spp. and Staphylococcus spp. being the most common strains. 98, 757, 761, 762 s in other groups, the diagnosis of IE is often made late, 757 highlighting the need to consider the diagnosis of IE in any CHD patient presenting with persisting fever or other signs of ongoing infection. Multiple blood cultures are essential before starting antibiotic treatment. The principal symptoms, complications, and basis for diagnosis do not differ from IE in general. However, in CHD right-sided IE is more frequent than in non-CHD-acquired cardiac disease.

Transthoracic echocardiography is sufficient in many cases to image the infectious lesions and their complications. However, complex anatomy and the presence of artificial material may reduce the rate of vegetation detection and other features of IE, thus favouring the addition of TOE, particularly in adults and larger children. Despite the improved sensitivity of TOE for the detection of IE, TOE may only perform similarly to TTE for anterior structures of the heart, such as the right ventricular outflow tract, or infected sites at distal structures, such as stents or other prosthetic material within branch pulmonary arteries. Hence, a negative study does not exclude the diagnosis of IE. In patients with prosthetic material advanced imaging such as [18F]FDG-PET/CT and PET/CTA, can increase the diagnostic accuracy. 223 n addition to the usual Endocarditis Team (see Section 4), multidisciplinary care of CHD patients with IE from diagnosis to treatment should be provided in specialized CHD centres with expertise in CHD cardiac imaging, CHD surgery, infectious disease, and intensive care. Surgical indications do not differ from those of acquired heart disease IE. 2] [763] [764] This better prognosis compared with acquired heart disease IE may reflect the higher proportion of right-heart IE, younger overall patient age, or the comprehensive care in CHD centres.

Primary prevention of IE in CHD patients and corresponding patient education is essential (see Section 3). 765

Recommendation Table 21 -Recommendations for the surgical treatment of right-sided infective endocarditis

Surgery is recommended in patients with right-sided IE who are receiving appropriate antibiotic therapy for the following scenarios:

Right ventricular dysfunction secondary to acute severe tricuspid regurgitation non-responsive to diuretics. 479

Persistent vegetation with respiratory insufficiency requiring ventilatory support after recurrent pulmonary emboli. 479, 755

Large residual tricuspid vegetations ( > 20 mm) after recurrent septic pulmonary emboli. 145, 471 C

Patients with simultaneous involvement of left-heart structures. 749

Tricuspid valve repair should be considered instead of valve replacement, when possible. 479

Prophylactic placement of an epicardial pacing lead should be considered at the time of tricuspid valve surgical procedures. 733

Debulking of right intra-atrial septic masses by aspiration may be considered in selected patients who are high risk for surgery.

12.8. Infective endocarditis in rheumatic heart disease

Infective endocarditis is a known complication of RHD, 766 and acute rheumatic fever (the antecedent of RHD) may even present with concomitant IE. 767 Of the 3343 participants enrolled in The Global Rheumatic Heart Disease Registry (REMEDY), 768 133 (2.4%) had a history of IE at enrolment, 769 and 20 (0.7%; 3.65 per 1000 patient-years) developed IE during the 27-month follow-up. 770 These participants were young with a median age of 28 years (interquartile range 18-40 years), 66.2% were women, and over 30% were children. The majority of the over 40 million patients with RHD 771 live in low-and middle-income countries and face socioeconomic and health-system barriers 772 to adequate prevention, early diagnosis, and advanced care and, therefore, are at particular risk of IE. 773 Global access to surgery for RHD and RHD-associated complications is extremely limited. 774 RHD patients presenting with fever, changing or new murmurs should be investigated for IE. 6] [777] [778] [779] [780] [781] [782] [783] [784] In those affected with oral bacteria-related IE linked to RHD, oral Streptococcus spp. was the main cause of IE associated with poor oral health status. 785 In RHD-endemic countries, IE in children is strongly linked to RHD, [786] [787] [788] and when causing HF, carries the highest case fatality rate. 789 IE is associated with enhanced risk of death among patients with RHD undergoing isolated mitral valve replacement (odds ratio 5.22, 95% confidence interval [CI], 1368-19 915; P = 0.008). 790 Pregnancy is a particularly high-risk period for women with RHD, with an increased risk of developing IE. 791, 792 [795] [796]

12.9. Infective endocarditis during pregnancy

8] [799] Maternal mortality approaches 18%, with most deaths relating to HF or an embolic event, while pre-term birth is reported at 55.7% and foetal mortality at 29%. 800 Recurrent infective complications can occur in up to 27% of women post-partum. 801 he diagnosis must be considered in pregnant women with unexplained fever and cardiac signs (especially tachycardia), new or changing cardiac murmurs, and peripheral signs of septic emboli. 802 ] [806] [807] The gravity of the condition requires the inclusion of gynaecologists, obstetricians, and neonatologists in the Endocarditis Team in any suspected cases, and a diagnosis and treatment plan should be formulated without delay, as this is key to saving the lives of mothers and infants. 799, 808, 809 Management can be challenging, especially when the pregnant patient warrants a cardiac operation under CPB. Although this poses a considerable risk to the foetus, urgent surgery when indicated should not be delayed. 799, 810

12.10. Infective endocarditis in immunocompromised patients

12.10.1. Solid organ transplant recipients

The incidence of IE in recipients of solid organ transplantation (SOT) ranges between 1% and 2%. 107 SOT recipients with IE are younger and have higher prevalence of co-morbidities (particularly renal and liver disease) compared with non-SOT patients with IE. Among the SOT patients with IE, the most common transplanted organ is the kidney (72%), followed by liver (17%), and pancreas (8%). 811 Similar to non-SOT patients, aortic followed by mitral IE are the most common forms of IE while right-sided IE is uncommon. Interestingly, SOT patients with IE more frequently have atrial or ventricular vegetations without valve involvement (mural IE). 107 In-hospital and healthcare-related IE are the most frequent causes of IE in recipients of SOT and the most frequent microorganism involved is S. aureus (34%), followed by Enterococcus spp. (17%), and Streptococcus spp. (11%). 107, 811 urgical valve repair/replacement is less frequently performed in SOT patients with IE as compared with non-SOT patients. Interestingly, the outcomes of IE in patients with SOT do not differ from those of non-SOT with IE. 107, 811 The reasons for the similar outcomes may rely on the younger age of the SOT patients, the frequent contact with the healthcare system which may lead to early diagnosis and treatment of IE, and the frequent involvement of infectious disease specialists in the care of hospitalized SOT patients. However, compared with SOT patients without IE, those who develop IE during the index transplant hospitalization have worse outcomes. 811 The high levels of immunosuppression probably negatively impact the IE course in these patients.

Heart transplant recipients represent 10% of SOT with IE patients. 811 Among 57 heart transplant recipients who developed IE, the most frequent organism was S. aureus (26%), followed by A. fumigatus (19%), and E. faecalis (12%). 105 The median time to IE presentation after heart transplant was 8 years and the mitral valve was the most frequently affected, followed by mural and tricuspid valve IE. All-cause mortality in this group of patients is high (45%), and fungal aetiology is associated with worse outcomes. Similar to other SOT recipients, heart transplant recipients were not frequently referred to surgery (35%). 105

12.10.2. Patients with human immunodeficiency virus

The advent of combined antiretroviral treatment has led to a reduction in the risk of developing acquired immune deficiency syndrome (AIDS) but people living with HIV remain a vulnerable population for IE. 812 The incidence of IE in people living with HIV has decreased over the last two decades. A retrospective study from Spain has shown a reduction in the incidence of IE from 18.2 per 100 000 patient-years between 1997 and 1999 to 2.9 events per 100 000 patient-years between 2000 and 2014. 813 Similarly, a registry from the United States of America reported a reduction in the incidence of IE from 148 in 2007 to 112 in 2017. 141 Patients living with HIV and presenting with IE are becoming older, and have a higher percentage of substance abuse and comorbidities. 141, 813 Of importance, the number of patients living with HIV who are admitted with IE have higher frequency of CHD, prior valve surgery, CIED infection, and haemodialysis. 141, 813 The most frequent microorganisms causing IE are Staphylococcus spp. (the majority of which is S. aureus), followed by Streptococcus spp., Gram-negative bacilli, and enterococci. It is important to note that over the last two decades, the frequency of CoNS as a cause of IE has decreased whereas the frequency of streptococci, Gram-negative bacilli, enterococci, and fungus has increased. 813 Community-acquired IE has become the most frequent form while healthcare-associated IE rates have significantly decreased over time.

The outcomes of IE in people living with HIV have improved over the years (from 23.9 to 5.5 deaths per 100 000 patient-years) and surgical treatment should follow the same indications as in patients without HIV. 813

12.10.3. Patients with neutropaenia

Neutropaenia is common in patients with haematological malignancies and in patients receiving chemotherapy for other malignancies, but is rare in patients presenting with IE. 814 Neutrophils play an important role in the pathogenesis of IE by producing layers of extracellular traps that entrap bacteria-platelet aggregates, leading to expansion of these aggregates, vegetation growth, and the destruction of tissues. 814 The diagnosis of IE can therefore be challenging in patients with neutropaenia, delaying the appropriate treatment, and worsening outcomes. Series reporting the clinical characteristics and outcomes of IE in patients with neutropaenia are anecdotal. 814 s in any other immunocompromised patient with IE, antibiotic and surgical treatment are the same as in patients without neutropaenia. It is important to take into consideration the side effects of some antibiotics which may worsen the neutropaenia, such as cloxacillin and ceftaroline. 815, 816

12.11. Antithrombotic and anticoagulant therapy in infective endocarditis

Infective endocarditis by itself is not an indication for antithrombotics or anticoagulants, and bleeding complications or stroke may in contrast justify discontinuation or interruption of such therapies. Indications for antithrombotic therapy or anticoagulants (e.g. atrial fibrillation, valve prostheses, ischaemic heart disease, prior stroke, etc.) are prevalent in the general population and, as a result, the clinician is often faced with the challenge of these therapies in patients presenting with IE, especially in cases where surgery is part of the treatment course. For patients with IE and stroke, thrombolytic therapy is not recommended (see Section 9.1). However, thrombectomy may be considered in selected cases with large vessel occlusion.

The level of evidence underlying the recommendations for antithrombotic and anticoagulant therapy in IE is low and should be discussed within the Endocarditis Team. Bridging with lowmolecular-weight heparin/unfractionated heparin instead of oral anticoagulants should be considered early on in the IE course, especially for patients in whom surgery is indicated. To date, no data support initiation of either antithrombotics nor anticoagulants for treatment or prevention of stroke in IE.

12.12. Non-bacterial thrombotic endocarditis

Non-bacterial thrombotic endocarditis (NBTE) is a rare condition with an incidence varying from 1.1% to 1.6% in patient-series from autopsy studies. 818, 819 Non-bacterial thrombotic endocarditis occurs in patients with a predisposing factor and/or a hypercoagulable state, such as systemic lupus erythematous (SLE), APLs (Libman-Sacks endocarditis), cancer (marantic endocarditis), disseminated intravascular coagulation (DIC), or various other chronic diseases (tuberculosis or autoimmune disease). 820, 821 Increased production of coagulation factors, of cytokines, and high tissue factor expression are potential mechanisms underlying NBTE in cancer patients. 822 n a recent contemporary registry, 41% of NBTE patients had cancer, 33% SLE, and 36% APLs, with 21% of patients having both SLE and APLs. 823 Among the patients with malignancies, the three most frequent cancers were lung adenocarcinoma, breast, and pancreatic cancer. Stroke was the most frequent clinical presentation at admission (60%), while HF was observed in 21% and acute coronary syndrome in 7% of patients. Transthoracic echocardiography was able to confirm the diagnosis in 45% of patients. The mitral valve was more often affected (62%) than the aortic valve (24%). 823 he diagnosis of NBTE remains challenging and should be suspected in patients presenting with systemic embolization and a predisposing factor (i.e. e. cancer, APLs, SLE). Laboratory findings of a hypercoagulable state (eg. lupus anticoagulant, anti-cardiolipin antibodies, and anti-β 2 -glycoprotein 1 antibodies or DIC) may be present, but are nonspecific and may also be demonstrated in other IE patients with embolic events. 162 chocardiography diagnosis should attempt to differentiate non-bacterial thrombotic vegetation from IE, Lambl excrescences, or fibroelastoma, or other benign intracardiac masses/tumours. 824 ibman-Sacks vegetations may present with various shapes (sessile, tubular, or coalescent), various levels of echogenicity (heterogeneously or homogeneously), could be nodular or protuberant, are generally located near the leaflet's edge of coaptation, and frequently have extensions to the mid and basal portions of the leaflet. They are rarely associated with valve dysfunction and never with valve perforation, which is an important method of differentiating from bacterial IE. 824 Compared with TOE, TTE has a lower sensitivity (63%), specificity (58%), negative predictive value (40%), and a moderate positive predictive value (78%) for the detection of NBTE. 823, 824 Compared with two-dimensional TOE, three-dimensional TOE provides additional information and allows a better characterization of the vegetation. 823 he treatment of the underlying cause (i.e. SLE or cancer) is crucial to prevent recurrent NBTE. Anticoagulant treatment should be considered in all patients and should be balanced against the individual

Recommendation Table 22 -Recommendations for the use of antithrombotic therapy in infective endocarditis

Interruption of antiplatelet or anticoagulant therapy is recommended in the presence of major bleeding (including intracranial haemorrhage). 482, 483

In patients with intracranial haemorrhage and a mechanical valve, reinitiating unfractionated heparin should be considered as soon as possible following multidisciplinary discussion. 817

In the absence of stroke, replacement of oral anticoagulant therapy by unfractionated heparin under close monitoring should be considered in cases where indication for surgery is likely (e.g. S.

aureus IE). 451, 817 a C Thrombolytic therapy is not recommended in patients with IE. patient's bleeding risk. 821 Patients may be anticoagulated with low-molecular-weight heparin, vitamin K antagonists, or unfractionated heparin. There are no data to support the use of direct oral anticoagulants in NBTE. In a randomized open-label multicentre study comparing rivaroxaban and warfarin in patients with thrombotic APLs, the use of rivaroxaban was associated with an increased rate of thrombo-embolic events and major bleeding. 825 The role of surgery is controversial and remains to be clarified. However, surgery should be considered in patients with severe valve dysfunction or with large vegetations. 823

12.13. Infective endocarditis and malignancy

There are limited data on the prevalence, clinical presentation, management, and outcome of IE in patients with malignancy. In a retrospective Japanese cohort study including 170 patients, 17.6% had active malignancy. 826 Compared with patients without malignancy, patients with malignancies were older, nosocomial IE was more frequent, and procedures before IE (non-dental, i.v. catheter insertion, invasive endoscopic, or genitourinary procedures) were more frequent. 826 Another recent study from the EURO-ENDO registry of 3085 patients with IE found a history of malignancy in 11.6% of patients. 827 Patients with a history of malignancy had a similar rate of theoretical indications for surgery, but surgery was performed less often in this group. Mortality was higher in the malignancy group with independent predictors for mortality being elevated creatinine > 2 mg/dL, congestive HF, and unperformed cardiac surgery when indicated. 827 In IE patients with concomitant cancer, indications for valve surgery should be discussed within the Endocarditis Team, including a cardio-oncologist and the oncologist in charge of the patient, in order to take into account the risks and benefits of surgery and cancer prognosis.

13. Patient-centred care and shared decision-making in infective endocarditis

13.1. What is patient-centred care and shared decision-making and why is it important?

5] [836] The majority of patients prefer sharing decisions about their own health, if they are sufficiently informed and prepared. 837, 838 Patient-centred care and shared decision-making have been shown to contribute to improved concordance between care providers and patients on treatment plans, as well as increased patient satisfaction, quality of life, and health outcomes. 830 ,839-843

13.2. Patient-centred care and shared decision-making in infective endocarditis

The severity of IE, the complex and comprehensive diagnostics and treatment, as well as the long illness trajectory, put special emphasis on patient-centred care and shared decision-making in IE (Figure 14 ). Quality of life appears to be impaired in IE survivors, with a significant number of patients developing symptoms of anxiety, depression, or even post-traumatic stress disorder following IE treatment. 604, 844 he time of diagnosis is often emotionally distressing to the patient and family, as they face a life-threatening condition and lengthy treatment. 845 uring the diagnostic and active treatment phase, healthcare providers should make every effort to minimize patient discomfort (e.g. related to symptoms and diagnostic procedures), and alleviate distress in both patient and family by providing support and comprehensive and timely information about the patient's condition, therapeutic options, and prognosis. Independent of the therapeutic strategy (i.e. surgical vs. conservative), patient-centred care is key to ensure a good physical and mental outcome during a lengthy treatment and hospitalization associated with IE. Maintaining continuity of care, when possible, by minimizing the number of providers the patient encounters and minimizing transfers between and within units, is all part of a patient-centred care approach. Allowing family visits at any time and providing the opportunity to uphold personal integrity and autonomy are important issues for patients. National patient organizations and associations may be an option for offering information and support to patients and their families.

The role of outpatient antimicrobial treatment options in IE should be discussed using a shared decision-making approach, involving the patient's partner or family if possible. The outpatient treatment should be in concordance with the patient's and family's preferences, also considering transportation and self-care abilities. To monitor possible complications, it is important to inform and educate patients and caregivers about the signs and symptoms of disease progression or recurrence.

The early period after discharge can be challenging for patients and their families, and patients report slow physical and mental recovery after IE, often extending longer than anticipated. 603, 604, 846, 847 Patient-centred care should therefore extend further than the clinical treatment at the hospital to ensure a good outcome after discharge. Though little research has explored patients' and families' needs for recovery and rehabilitation following IE, patients with heart disease report experiencing new and continuous challenges and a lack of knowledge and understanding after discharge, which should be addressed to optimize recovery. 848 t is recommended that a recovery plan is developed in collaboration with the patient and their caregivers and that the plan is reviewed and potentially adjusted following a short period after discharge. 849 hysical exercise should be recommended based on an individual assessment of functional capacity (guided by physicians and physiotherapists), and patient education and psychosocial support should address the main problems and concerns patients and families have. Importantly, patient education should also include information about the risk of recurrence and preventive measures described in Sections 3 and 11. Special consideration should be taken for patients with no close relatives. Self-support groups or mentors may be introduced to patients without support networks. Also, follow-up by telephone from the ward staff, until full recovery has been reached, may be an option.

A palliative approach aims to improve the quality of life of patients and their families who are facing problems associated with lifethreatening illness, which is relevant for many patients with IE. This approach includes a holistic, needs-based perspective with the aims of assessing and improving symptom management, communication, advanced care planning, as well as psychosocial and spiritual needs. 850

14. Sex differences

Female sex is less common in patients diagnosed with IE, being present in approximately one-third of cases; a finding that has been demonstrated in multiple IE patient subpopulations and across different regions. 5, 59, 723, 851, 852 The reason why female sex is observed less frequently in IE is unknown and deserves further investigation. Possible reasons include underdiagnosis of IE in women, referral bias in published studies, intrinsic protective mechanisms against IE in women, and decreased incidence of risk factors for IE in women (e.g. bicuspid aortic valve disease, previous heart valve replacement surgery), among others. A recent nationwide population study of individual patient-level linkage data of 7513 patients hospitalized for IE in Scotland, however, demonstrated roughly equal proportions of male and female patients throughout the 25-year study period. 27 4] [855] [856] However, men have a higher prevalence of other important risk factors including previous prosthetic valve replacement, periannular complications, CAD, and liver cirrhosis. 855 ome studies have demonstrated higher mortality rates for female patients with IE, 856 while others have demonstrated no differences in early and 1-year mortality rates between males and females. 853, 855, 857 he abovementioned population study from Scotland showed lower mortality rates for women during the study period. 27 lthough surgery has been demonstrated to be protective against mortality in several clinical scenarios (see Section 8), surgery is performed less frequently in female patients with IE. 855, 856 In a study using the National Inpatient Sample of 81 942 patients hospitalized for IE over an 11-year period, women were 43% less likely to undergo valve replacement surgery, a significant difference that remained after adjusting for confounding factors. 855 The reason for decreased surgery in female IE patients is unknown and requires further investigation.

Female sex has also been identified as an independent risk factor for mortality in prediction models for patients with IE undergoing surgery. 416 However, a single-centre study suggested that worse observed surgical outcomes in female patients with IE was related to their increased risk factors and severity of presentation, rather than gender per se. 854 In addition, a large multicentre registry of 4300 patients undergoing surgery for IE failed to identify female gender as an independent predictor of mortality. 852

15. Key messages Prevention:

• Populations at high risk of IE include patients with previous IE, patients with surgical or transcatheter prosthetic valves or post-cardiac valve repair, and patients with untreated CHD and surgically corrected CHD. • Prevention of IE comprise hygienic measures (including oral hygiene) for all individuals and antibiotic prophylaxis for patients at high risk of IE undergoing oro-dental procedures.

The Endocarditis Team:

• The diagnosis and management of patients with IE should be discussed with the Endocarditis Team, which includes healthcare professionals with the expertise to diagnose and treat IE and its complications. • Uncomplicated IE can be managed in a Referring Centre that remains in early and regular communication with the Endocarditis Team of the Heart Valve Centre. • Patients with complicated IE should be treated in the Heart Valve Centre, which must offer a wide range of ancillary specialty support including onsite cardiac surgery expertise.

Diagnosis:

• The diagnosis of IE is based on major criteria, which include positive blood cultures and valvular and perivalvular/periprosthetic anatomic and metabolic lesions detected on imaging, and on minor criteria which have been updated to include frequent embolic vascular dissemination including asymptomatic lesions detected by imaging only. • Clear diagnostic algorithms have been established to diagnose NVE, PVE, and right-sided IE.

Antimicrobial therapy -principles and methods:

• Successful treatment of IE relies on microbial eradication by antimicrobial drugs. Surgery contributes by removing infected material and draining abscesses.

• Antibiotic treatment of PVE should last longer (≥6 weeks) than that of NVE (2-6 weeks). • In both NVE and PVE, the duration of treatment is based on the first day of effective antibiotic therapy (negative blood culture in the case of initial positive blood culture), not on the day of surgery.

Indications for surgery and management of main infective endocarditis complications:

• There are three main reasons to undergo surgery in the setting of acute IE: HF, uncontrolled infection, and prevention of septic embolization. • While surgery during the acute phase of IE is usually performed on an urgent basis (i.e. the patient undergoes surgery within 3-5 days), some cases require emergency surgery (i.e. within 24 h), irrespective of the pre-operative duration of antibiotic treatment.

Other complications of infective endocarditis:

• Stroke may be the first presenting symptom in patients with IE.

Unexplained fever accompanying a stroke in a patient with risk factors for IE should trigger the suspicion of IE. • Epicardial pacemaker implantation should be considered in patients undergoing surgery for IE with complete AVB and other risk factors. • MRI or PET/CT are indicated in patients with suspected spondylodiscitis and vertebral osteomyelitis complicating IE.

Surgical therapy principles and methods:

• The indication to perform invasive coronary angiography or CTA prior to surgery for IE should be based on the presence of cardiovascular risk factors in patients with aortic valve IE. • Surgery should not be delayed in patients with non-haemorrhagic stroke and clear indications for surgery. In patients with significant pre-operative haemorrhagic stroke, a delay in operative management (≥4 weeks) is generally recommended. • The decision of not offering surgery when indicated should be made in the setting of an Endocarditis Team.

Outcome after discharge -follow-up and long-term prognosis:

• Relapse is a repeat episode of IE caused by the same microorganism and represents a failure of treatment, and mandates a search for a persistent focus of infection and an evaluation towards surgical therapy. • Reinfection is an infection caused by a different microorganism, usually more than 6 months after the initial episode. • Once antibiotic treatment has been completed, blood cultures should be performed. • Patients discharged after the first episode of IE should remain under close surveillance for potential long-term complications.

Management of specific situations:

• Antibiotic prophylaxis to prevent CIED-related IE before dental and other non-cardiac interventions is not warranted. • A single positive blood culture with no other clinical evidence of infection should not result in removal of the CIED. Complete CIED removal is recommended for all patients with confirmed infection of the lead(s). • The indication for CIED reimplantation should always be reevaluated and no part of the removed system should be reimplanted.

In pacemaker-dependent patients, an active-fixation lead may be introduced and connected to an external pacemaker for up to 6 weeks. • Surgical treatment of right-sided IE is indicated in patients with persistent bacteraemia, right ventricular dysfunction, recurrent septic pulmonary embolism and respiratory compromise, and involvement of left-sided structures. • Multidisciplinary care of CHD patients with IE, from diagnosis to treatment, should be provided in specialized CHD centres with expertise in CHD cardiac imaging, CHD surgery, and intensive care.

Patient-centred care and shared decision-making in infective endocarditis:

• In patients with IE, shared decision-making enables the integration of patients' preferences, values, and priorities to achieve a good treatment decision. • In patients with IE and without support networks or severely impacted by social determinants, a recovery plan developed in collaboration with the patient should be established, highlighting the information about the risk of recurrence and preventive measures.

Sex differences:

• Female sex is less common in patients diagnosed with IE, being present in approximately one-third of cases.

16. Gaps in evidence

• The majority of the recommendations with a level of evidence B are based on observational studies rather than single RCTs or meta-analyses from RCTs.

Prevention:

• In the intermediate or unknown risk condition groups, there is no evidence to recommend antibiotic prophylaxis. • There is currently no evidence to support the use of antibiotic prophylaxis after the implantation of a left atrial appendage occlusion device.

• More data on the accuracy of diagnosis of culture-negative IE using molecular biology techniques, or the determination of bacterial/fungal cell-free DNA in blood samples, is required.

• The indication of surgical treatment in patients with IE rely mainly on expert opinion based on observational studies. • RCTs are required to establish the indication and timing of surgery in patients with:

• Increased surgical risk.

• Large vegetations but without other indications for surgery.

• Cerebral emboli or bleeding.

• Patients with uncontrolled infection. • More data on the need and timing of coronary angiogram before endocarditis surgery. • There is a lack of information on timing and sequence of interventions in patients with multiple septic sources. • More data are needed on the efficacy and safety of vegetation extraction systems in right-sided IE.

• There is limited information on the safety and efficacy of mechanical thrombectomy in IE-related embolic strokes. • There are no prospective data on the timing and safety of splenectomy for splenic abscess, complicating IE in relation to surgical valve treatment.

• There is a significant need for scores to predict futility of surgical management in very high-risk patients. • There is a lack of data on the most appropriate anticoagulation regimen in patients with PVE complicated by haemorrhagic stroke.

Outcome after discharge: follow-up and long-term prognosis:

• Clinical trials are required to assess the efficacy of rehabilitation, including optimal timing, duration, methods, and components. • Data on patient-reported outcomes during short-and long-term follow-up are needed.

• Additional data on the incidence, characteristics, and outcomes of IE in patients treated with transcatheter valve therapies or left atrial appendage occluders are needed.

• There is an unmet clinical question on the efficacy and safety of surgical treatment of IE in patients previously treated with transcatheter valve therapies. • Randomized data on the timing of CIED reimplantation after device removal after CIED infection are needed. • There is a lack of evidence on whether or not CIED removal should be routinely performed in patients with left-sided IE. • Randomized data on surgery in right-sided IE are required.

Patient-centred care and shared decision-making in infective endocarditis:

• As no disease-specific evidence exists, data on patient-centred care and shared decision-making in IE is needed. • Data on how patient-centred care and shared decision-making in patients with social and mental health vulnerabilities can improve their outcomes are lacking. • Data on the effect of patient-centred care and shared decisionmaking interventions are required to implement effective strategies.

• Further data are required to determine why IE is less frequently observed, and why the outcomes are worse, in female patients. • The reasons for lower referral to surgery in female patients with IE as compared with male patients need to be determined and addressed.

Recommendations for antibiotic prophylaxis in patients with cardiovascular diseases undergoing oro-dental procedures at increased risk of infective endocarditis

General prevention measures are recommended in individuals at high and intermediate risk of IE.

Antibiotic prophylaxis is not recommended in other patients at low risk of IE.

III C

Recommendations for infective endocarditis prevention in high-risk patients

Antibiotic prophylaxis is recommended in dental extractions, oral surgery procedures, and procedures requiring manipulation of the gingival or periapical region of the teeth.

Recommendations for infective endocarditis prevention in cardiac procedures

Pre-operative screening for nasal carriage of S. aureus is recommended before elective cardiac surgery or transcatheter valve implantation to treat carriers.

Peri-operative antibiotic prophylaxis is recommended before placement of a CIED.

Optimal pre-procedural aseptic measures of the site of implantation are recommended to prevent CIED infections.

Periprocedural antibiotic prophylaxis is recommended in patients undergoing surgical or transcatheter implantation of a prosthetic valve, intravascular prosthetic, or other foreign material.

Recommendations for the treatment of neurological complications of infective endocarditis

Neurosurgery or endovascular therapy is recommended for large aneurysms, those with continuous growth despite optimal antibiotic therapy, and ruptured intracranial infective cerebral aneurysms.

Thrombolytic therapy is not recommended in embolic stroke due to IE.

Obtaining at least three sets of blood cultures is recommended before prompt initiation of empirical antibiotic therapy for CIED infection, covering methicillin-resistant staphylococci and Gram-negative bacteria.

If CIED reimplantation is indicated after extraction for CIED-related IE, it is recommended to be performed at a site distant from the previous generator, as late as possible, once signs and symptoms of infection have abated, and until blood cultures are negative for at least 72 h in the absence of vegetations, and negative for at least 2 weeks if vegetations were visualized.

Recommendations for the surgical treatment of right-sided infective endocarditis Surgery is recommended in patients with right-sided IE who are receiving appropriate antibiotic therapy for the following scenarios:

Recommendations for the use of antithrombotic therapy in infective endocarditis ESC Guidelines

|Outpatient parenteral antibiotic treatment should be||| |---|---|---|

|considered in patients with left-sided IE caused by|||

|Streptococcus spp., E. faecalis, S. aureus, or CoNS who|||

|were receiving appropriate i.v. antibiotic treatment for at least 10 days (or at least 7 days after cardiac surgery),|IIa|A|

|are clinically stable, and who do not show signs of|||

|abscess formation or valve abnormalities requiring|||

|surgery on TOE.|||

|Outpatient parenteral antibiotic treatment is not|||

||IIb|C| |---|---|---|

|Thrombolytic therapy is not recommended in embolic stroke due to IE.|III|C|

|Section 9.|||

|Immediate epicardial pacemaker implantation should be||| |---|---|---|

|considered in patients undergoing surgery for valvular IE|||

|and complete AVB if one of the following predictors of persistent AVB is present: pre-operative conduction|IIa|C|

|abnormality, S. aureus infection, aortic root abscess,|||

|tricuspid valve involvement, or previous valvular surgery.|||

|IIb|B| |---|---|

|possible, once signs and symptoms of infection have|I|C| |---|---|---|

|abated and until blood cultures are negative for at least|||

|72 h in the absence of vegetations, and negative for at|||

|least 2 weeks if vegetations were visualized.|||

|Section 12.|||

|No allergy to|Amoxicillin|2 g orally|50 mg/kg orally|| |---|---|---|---|---|

|penicillin or|Ampicillin|2 g i.m.|50 mg/kg i.v. or i.m.||

|ampicillin||or i.v.|||

||Cefazolin or|1 g i.m.|50 mg/kg i.v. or i.m.||

||ceftriaxone|or i.v.|||

|Allergy to|Cephalexin a,b|2 g orally|50 mg/kg orally||

|penicillin or|Azithromycin or|500 mg|15 mg/kg orally||

|ampicillin|clarithromycin|orally|||

||Doxycycline|100 mg|< 45 kg, 2.2 mg/kg||

|||orally|orally||

||||> 45 kg, 100 mg||

|i.m., intramuscular; i.v., intravenous.|i.m., intramuscular; i.v., intravenous.||||

|Patient with de nite infective endocarditis 2023 ESC diagnostic criteria||| |---|---|---|

||Start empirical antibiotic treatment||

|Admission to a Heart Valve Centre|Admission to a Referring Centre||

|Adjust antibiotic treatment according to blood culture results|||

|Endocarditis Team||Endocarditis Team|

|Cardiologists|Frequent communication|Cardiologists|

|Cardiovascular surgeons|Clinical, microbiological,|Infectious disease specialists|

|Infecious disease specialists|and imaging data sharing||

|Microbiologists|||

|Adjunct specialities|||

|Radiologists/nuclear|||

|medicine specialists Neurologists/|Complicated clinical evolution||

|neurosurgeons|Unstable haemodynamic condition under pharmacological||

|Intensive care specialists|and/or respiratory support||

|Geriatricians|Severe valvular regurgitation (clinical and echocardiographic||

|Nephrologists|criteria)||

|Nurses|Prosthetic valve endocarditis with or without prosthetic valve||

|Addiction medicine|dysfunction||

|teams|Stroke (ischaemic or haemorrhagic) with definite or possible IE||

||Extravalvular complications (abscesses, fistulae, etc.)||

||Positive blood cultures > 7 days under appropriate antibiotic||

||therapy||

|Establish indication and timing of|Embolism CIED-related infective endocarditis Aggressive or difficult-to-treat microorganisms (S. aureus,||

|cardiac surgery|Gram-negative bacilli, fungi)||

||Y|N|

|Consultation with|||

|outpatient antibiotic|||

|therapy team|||

|Brucella spp.|Serology, blood cultures, tissue culture,|| |---|---|---|

||immunohistology, and 16S rRNA||

||sequencing of tissue||

|C. burnetii|Serology (IgG phase l > 1:800), tissue||

||culture, immunohistology, and 16S rRNA||

|Bartonella spp.|Serology (IgG phase I > 1:800), blood||

||cultures, tissue culture, immunohistology,||

||and 16S rRNA sequencing of tissue||

|T. whipplei|Histology and 16S rRNA sequencing of||

||tissue||

|Mycoplasma spp.|Serology, tissue culture, immunohistology,||

|Legionella spp.|Serology, blood cultures, tissue culture,||

|Fungi|Serology, blood cultures, 18S rRNA||

|Mycobacteria (including Mycobacterium chimaera)|sequencing of tissue Specific blood cultures, 16S rRNA sequencing of tissue|© ESC 2023|

|Ig, immunoglobulin; rRNA, ribosomal ribonucleic acid.|Ig, immunoglobulin; rRNA, ribosomal ribonucleic acid.||

|TTE is recommended as the first-line imaging modality in suspected IE. 166,179|I|B| |---|---|---|

|TOE is recommended in all patients with clinical|||

|suspicion of IE and a negative or non-diagnostic|I|B|

|TTE. 166,178,179|||

|TOE is recommended in patients with clinical|||

|suspicion of IE, when a prosthetic heart valve or an|I|B|

|intracardiac device is present. 166,178,179|||

|Repeating TTE and/or TOE within 5-7 days is|||

|recommended in cases of initially negative or|||

|inconclusive examination when clinical suspicion of IE|||

|remains high. 178|||

|181|I|C| |---|---|---|

|D. Following completion of therapy|||

|TTE and/or TOE are recommended at completion of|||

|antibiotic therapy for evaluation of cardiac and valve morphology and function in patients with IE who did|I|C|

|not undergo heart valve surgery. 182-184|||

|Paediatric antibiotic dosage and route|||| |---|---|---|---|

|Penicillin G||||

|12-18 million c U/day i.v. either in 4-6 doses or continuously||||

|Amoxicillin|100-200 mg/kg/day c i.v. in 4-6 doses|||

|Ceftriaxone|100 mg/kg i.v. in 1 dose|||

|Gentamicin d|3 mg/kg/day i.v. or i.m. in 1 dose or 3 equally divided doses d|||

|Allergy to beta-lactams||||

|In patients allergic to beta-lactams and with IE due to oral streptococci and S. gallolyticus, vancomycin for 4 weeks in NVE or for 6||||

|weeks in PVE is recommended using the following doses: 292||||

|Adult antibiotic dosage and route Vancomycin e|30 mg/kg/day i.v. in 2 doses e|I|C|

|Paediatric antibiotic dosage and route||||

|Vancomycin e|30 mg/kg/day i.v. in 2 or 3 equally divided doses e|||

|Adult antibiotic dosage and route||||

|Penicillin G|12-18 million c U/day i.v. either in 4-6 doses or continuously|||

|Amoxicillin Ceftriaxone|100-200 mg/kg/day i.v. in 4-6 doses 2 g/day i.v. in 1 dose|I|B|

|Penicillin G|200 000 U/kg/day i.v. in 4-6 divided doses|||

|Amoxicillin|100-200 c mg/kg/day i.v. in 4-6 doses|||

|Ceftriaxone|100 mg/kg/day i.v. in 1 dose|||

|Standard treatment: 2-week duration (not applicable to PVE)||||

|2-week treatment with penicillin G, amoxicillin, ceftriaxone combined with gentamicin is recommended only for the treatment of||||

|non-complicated NVE due to oral streptococci and S. gallolyticus in patients with normal renal function using the following||||

|doses: 277,278||||

|Adult antibiotic dosage and route||I|B|

|Penicillin G|12-18 million Continued|||

|Adult antibiotic dosage and route|||| |---|---|---|---|

|Penicillin G|24 million U/day i.v. either in 4-6 doses or continuously|I|B|

|Amoxicillin|2 g/day i.v. in 6 doses|||

|Ceftriaxone|2 g/day i.v. in 1 dose|||

|Vancomycin e|30 mg/kg/day i.v. in 2 doses e||| |---|---|---|---|

|Vancomycin e|30 mg/kg/day i.v. in 2 doses e|||

|Vancomycin e Gentamicin d|30 mg/kg/day i.v. in 2 doses e 3 mg/kg/day i.v. or i.m. in 1 dose d|I|C|

|Paediatric antibiotic dosage and route Vancomycin e 30 mg/kg/day i.v. in 2 doses e Gentamicin d 3 mg/kg/day i.v. or i.m. in 1 dose d||© ESC 2023||

|IE, infective endocarditis; i.m., intramuscular; i.v., intravenous; NVE, native valve endocarditis; PVE, prosthetic valve endocarditis; U, units.||||

|Recommendations| |---|

|Daptomycin|10 mg/kg/day i.v. in 1 dose|||

|Cloxacillin c|12 g/day i.v. in 6 doses|IIb|C|

|OR|OR|||

|High-level aminoglycoside resistance d|High-level aminoglycoside resistance d||| |---|---|---|---|

|Adult antibiotic dosage and route|Adult antibiotic dosage and route|||

|Ampicillin|12 g/day i.v. in 4-6 doses|||

|Amoxicillin Ceftriaxone|200 mg/kg/day i.v. in 4-6 doses 4 g/day i.v. or i.m. in 2 doses|I|B|

|Paediatric antibiotic dosage and route|Paediatric antibiotic dosage and route|||

|Ampicillin|300 mg/kg/day i.v. in 4-6 equally divided doses|||

|Amoxicillin|100-200 mg/kg/day i.v. in 4-6 doses|||

|Ceftriaxone|100 mg/kg i.v. or i.m. in 2 doses|||

|Adult antibiotic dosage and route Beta-lactam I Vancomycin 30 mg/kg/day i.v. in 2 doses Gentamicin 3 mg/kg/day i.v. or i.m. in 1 dose|Adult antibiotic dosage and route Beta-lactam I Vancomycin 30 mg/kg/day i.v. in 2 doses Gentamicin 3 mg/kg/day i.v. or i.m. in 1 dose|C||

|Vancomycin|30 mg/kg/day i.v. in 2-3 equally divided doses|||

|Adult antibiotic dosage and route Gentamicin 3 mg/kg/day i.Ampicillin 300 mg/kg/day i.v. in 4-6 equally divided doses|Adult antibiotic dosage and route Gentamicin 3 mg/kg/day i.Ampicillin 300 mg/kg/day i.v. in 4-6 equally divided doses|355,360,361||

|Amoxicillin Fosfomycin|200 mg/kg/day i.v. in 4-6 doses 12 g/day i.v. in 4 doses|||

|Ampicillin Ceftaroline Ceftriaxone Ertapenem g|1800 mg/day i.v. in 3 doses 12 g/day i.v. in 4-6 doses 4 g/day i.v. in 2 doses 2 g/day i.v. or i.m. in 1 dose|I|B|

|Paediatric antibiotic dosage and route Daptomycin 10-12 mg/kg/day i.v. in 1 dose (age-adjusted) Ampicillin 300 mg/kg/day i.v. in 4-6 equally divided doses Fosfomycin 2-3 g/day i.v. in 1 dose Ceftaroline 24-36 mg/kg/day in 3 doses Gentamicin using the Ertapenem|Paediatric antibiotic dosage and route Daptomycin 10-12 mg/kg/day i.v. in 1 dose (age-adjusted) Ampicillin 300 mg/kg/day i.v. in 4-6 equally divided doses Fosfomycin 2-3 g/day i.v. in 1 dose Ceftaroline 24-36 mg/kg/day in 3 doses Gentamicin using the Ertapenem|||

|following doses: 355,360,361||||

|Amoxicillin|200 mg/kg/day i.v. in 4-6 doses|||

|Ceftriaxone|4 g/day i.v. in 2 doses|I|B|

|Gentamicin c|3 mg/kg/day i.v. or i.m. in 1 dose|||

|Brucella spp.|Doxycycline (200 mg/24 h)|Treatment success defined|| |---|---|---|---|

||plus cotrimoxazole (960 mg/|as an antibody titre < 1:60.||

||12 h) plus rifampin (300-|Some authors recommend||

||600 mg/24 h) for ≥3-6|adding gentamicin for the||

||months b orally|first 3 weeks||

|C. burnetii (Q|Doxycycline (200 mg/24 h)|Treatment success defined||

|fever agent)|plus hydroxychloroquine (200-|as anti-phase I IgG titre||

||600 mg/24 h) c orally ( > 18|< 1:400, and IgA and IgM||

||months of treatment)|titres < 1:50||

|Bartonella spp. d|Doxycycline 100 mg/12 h|Treatment success||

||orally for 4 weeks plus|expected in ≥90%||

||gentamicin (3 mg/24 h) i.v. for 2|||

||weeks|||

|Legionella spp.|Levofloxacin (500 mg/12 h) i.v.|Optimal treatment||

||or orally for ≥6 weeks or|unknown||

||clarithromycin (500 mg/12 h)|||

||i.v. for 2 weeks, then orally for 4|||

||weeks plus rifampin (300-|||

||1200 mg/24 h)|||

|Mycoplasma spp.|Levofloxacin (500 mg/12 h) i.v.|Optimal treatment||

||or orally for ≥6 months e|unknown||

|T. whipplei (Whipple's disease agent) f|Doxycycline (200 mg/24 h) plus hydroxychloroquine (200-600 mg/24 h) c orally for ≥18 months|Long-term treatment, optimal duration unknown|© ESC 2023|

|IE, infective endocarditis; Ig, immunoglobulin; i.v., intravenous.||||

|Adapted from Brouqui et al. 383|Adapted from Brouqui et al. 383|||

|a||||

|b Addition of streptomycin (15 mg/kg/24 h in 2 doses) for the first few weeks is optional.|b Addition of streptomycin (15 mg/kg/24 h in 2 doses) for the first few weeks is optional.|b Addition of streptomycin (15 mg/kg/24 h in 2 doses) for the first few weeks is optional.||

|c Doxycycline plus hydroxychloroquine (with monitoring of serum hydroxychloroquine|c Doxycycline plus hydroxychloroquine (with monitoring of serum hydroxychloroquine|c Doxycycline plus hydroxychloroquine (with monitoring of serum hydroxychloroquine||

|levels) is significantly superior to doxycycline. 385|levels) is significantly superior to doxycycline. 385|||

|d Several therapeutic regimens have been reported, including ampicillin or amoxicillin, (12 g/|d Several therapeutic regimens have been reported, including ampicillin or amoxicillin, (12 g/|d Several therapeutic regimens have been reported, including ampicillin or amoxicillin, (12 g/||

|24 h i.v.) or cephalosporins (ceftriaxone 2 g/24 h i.v.) combined with aminoglycosides||||

|(gentamicin or netilmicin).||||

||||Paediatric antibiotic dosage and route|Paediatric antibiotic dosage and route| |---|---|---|---|---|

||||Cefazolin|6 g/day i.v. in 3 doses|

||||Vancomycin e|40 mg/kg/day i.v. in 2-3 equally|

|patients with community-acquired NVE or late PVE (≥12 months post-surgery), ampicillin in||Gentamicin d|divided doses 3 mg/kg/day i.v. or i.m. in 3 equally divided doses|© ESC 2023|

|combination with ceftriaxone or with (flu)cloxacillin||BCNIE, blood culture-negative infective endocarditis; IE, infective endocarditis; i.m.,|||

|and gentamicin should be considered using the following doses: 255||intramuscular; i.v., intravenous; NVE, native valve endocarditis; PVE, prosthetic valve endocarditis.|||

|Adult antibiotic dosage and route|||||

|Ampicillin|12 g/day i.v. in 4-6 doses||||

|Ceftriaxone|4 g/day i.v. or i.m. in 2 doses||||

|(Flu)cloxacillin Gentamicin d|12 g/day i.v. in 4-6 doses 3 mg/kg/day i.v. or i.m. in 1 dose|IIa|C||

|Paediatric antibiotic dosage and route|||||

|Ampicillin|300 mg/kg/day i.v. in 4-6 equally||||

||divided doses||||

|Ceftriaxone|100 mg/kg i.v. or i.m. in 1 dose||||

|(Flu)cloxacillin|200-300 mg/kg/day i.v. in 4-6||||

||equally divided doses||||

|Gentamicin d|3 mg/kg/day i.v. or i.m. in 3 equally||||

|In patients with early PVE ( < 12 months|||||

|post-surgery) or nosocomial and non-nosocomial|||||

|healthcare-associated IE, vancomycin or daptomycin|||||

|combined with gentamicin and rifampin may be|||||

|considered using the following doses: 395|||||

|Vancomycin e|30 mg/kg/day i.v. in 2 doses||||

|Daptomycin|10 mg/kg/day i.v. in 1 dose||||

|Gentamicin d|3 mg/kg/day i.v. or i.m. in 1 dose|IIb|C||

|Rifampin|900-1200 mg i.v. or orally in 2 or||||

||3 doses||||

|Vancomycin e|40 mg/kg/day i.v. in 2-3 equally||||

|Rifampin|20 mg/kg/day i.v. or orally in 3||||

|Allergy to beta-lactams|||||

|In patients with community-acquired NVE or late|||||

|PVE (≥12 months post-surgery) who are allergic to|||||

|penicillin, cefazolin, or vancomycin in combination|||||

|with gentamicin may be considered using the|||||

|following doses:||IIb|C||

|Cefazolin|6 g/day i.v. in 3 doses||||

|Vancomycin Continued|||||

|Recommendations|Class a|Level b| |---|---|---|

|Outpatient parenteral or oral antibiotic treatment|||

|should be considered in patients with left-sided IE|||

|Immediate epicardial pacemaker implantation should|||

|be considered in patients undergoing surgery for|||

|valvular IE and complete AVB if one of the following|||

|predictors of persistent AVB is present:|IIa|C|

|pre-operative conduction abnormality, S. aureus infection, aortic root abscess, tricuspid valve involvement, or previous valvular surgery. 515||© ESC 2023|

|AVB, atrioventricular block; IE, infective endocarditis.|||

|CT, computed tomography; HF, heart failure; MRI, magnetic resonance imaging.|||

|Early surgery after a recent ischaemic stroke| |---|

|Evidence of intracranial bleeding|

|Woman of childbearing age|

|High likelihood of prolonged mechanical circulatory support|

|Advanced age or frailty|

|Poor or unknown medical compliance|

|Expected complicated and prolonged post-operative course|

|Patient preference|

|Surgery is recommended for early PVE (within 6 months of valve surgery) with new valve replacement and complete debridement. 621,635|I|C|© ESC 2023| |---|---|---|---|

|PVE, prosthetic valve endocarditis.||||

||Suspicion of CIED-related IE||| |---|---|---|---|

||Blood cultures|||

||TTE and TOE (or intracardiac echocardiography)|||

||[18F]FDG-PET/CT (or WBC SPECT) a|||

||(Class I)|||

||2023 ESC diagnostic criteria for IE|||

||Possible IE|||

|No IE|Repeat diagnostic tests within 7 days||Definite IE|

||Bacteraemia/fungaemia without other major criteria or source of infection|Antibiotic therapy covering MRSA and Gram-negative bacteria (Class I)||

||Persistent/relapsing|||

||bacteraemia/fungaemia|||

||Gram-negative|Gram-positive or fungaemia||

|(Class IIb)|(Class IIa)||(Class I)|

||CIED extraction|||

|No vegetations|Vegetations and/or|Septic emboli or||

|and non-S. aureus|S. aureus|prosthetic valve||

|2 weeks of antibiotics|4 weeks of antibiotics|6 weeks of antibiotics||

|(Class IIb)|(Class IIa)||(Class IIa)|

||CIED reimplantation c|||

|Allergy to beta-lactams|Allergy to beta-lactams||| |---|---|---|---|

|Adult antibiotic dosage and route Vancomycin 30 mg/kg/day i.v. in 2 doses|Adult antibiotic dosage and route Vancomycin 30 mg/kg/day i.v. in 2 doses|I|C|

|Gentamicin Adult antibiotic dosage and route 3 mg/I Penicillin G 24 million U/day i.v. either in 4-6 doses or continuously|B|||

|Gentamicin|3 mg/kg/day i.v. or i.m. in 1 dose|||

|Allergy to beta-lactams|Allergy to beta-lactams|||

|Adult antibiotic dosage and route Penicillin G 12-18 million U/day i.v. either in 4-6 doses or continuously Vancomycin 30 mg/kg/day i.v. in 2 doses Gentamicin 3 mg/kg/day i.v. or i.m. in 1 dose|Adult antibiotic dosage and route Penicillin G 12-18 million U/day i.v. either in 4-6 doses or continuously Vancomycin 30 mg/kg/day i.v. in 2 doses Gentamicin 3 mg/kg/day i.v. or i.m. in 1 dose|I|C|

|Amoxicillin Paediatric antibiotic dosage and route 100-200 mg/kg/day i.v. in 4-6 doses Ceftriaxone 2 g/day i.v. in 1 dose Vancomycin 30 mg/kg/day i.v. in 2 doses|I|B||

|Paediatric antibiotic dosage and route Gentamicin 3 mg/kg/day i.v. or i.m. in 1 dose|Paediatric antibiotic dosage and route Gentamicin 3 mg/kg/day i.v. or i.m. in 1 dose|||

|Penicillin G|200 000 U/kg/day i.v. in 4-6 divided doses|200 000 U/kg/day i.v. in 4-6 divided doses||

|Amoxicillin|100-200 mg/kg/day i.v. in 4-6 doses|100-200 mg/kg/day i.v. in 4-6 doses||

|Adult antibiotic dosage and route|Adult antibiotic dosage and route||| |---|---|---|---|

|(Flu)cloxacillin|12 g/day i.v. in 4-6 doses|||

|Cefazolin|6 g/day i.v. in 3 doses|||

|Rifampin Gentamicin|900 mg/day i.v. or orally in 3 equally divided doses 3 mg/kg/day i.v. or i.m. in 1 (preferred) or 2 doses|I|B|

|(Flu)cloxacillin|200-300 mg/kg/day i.v. in 4-6 equally divided doses|||

|Rifampin|20 mg/kg/day i.v. or orally in 3 equally divided doses|||

|Gentamicin|3 mg/kg/day i.v. or i.m. in 1 (preferred) or 2 doses|||

|Adult antibiotic dosage and route Cefazolin 6 g/day i.v. in 3 doses|Adult antibiotic dosage and route Cefazolin 6 g/day i.v. in 3 doses|I|B|

|||I|B|

|IE caused by methicillin-resistant staphylococci||||

|Vancomycin|30-60 mg/kg/day i.v. in 2-3 doses|I|B|

|Rifampin|20 mg/kg/day i.v. or orally in 2 or 3 divided doses|||

tamicin|3 mg/kg/day i.v. or i.m. in 1 (preferred) or 2 doses|||

|III|C| |---|---|

|I|B| |---|---|

|(ii) Uncontrolled infection||

|I|B|

|I|C|

|(iii) Prevention of embolism||

|[18F]||||

References

引用 / 出处

2023 ESC指南：心内膜炎的管理. 2023.