Infective Endocarditis and Cardiac Implantable Electronic Device Infection: Clinical Guidelines

List of Abbreviations

ABT – antibiotic therapy

AV – arteriovenous

AVF – arteriovenous fistula

ALT – alanine aminotransferase

aPTT – activated partial thromboplastin time

AST – aspartate aminotransferase

APS – antiphospholipid syndrome

HIV – human immunodeficiency virus

CHD – congenital heart disease

CIED*** – cardiac implantable electronic device – includes options for PM*** (single-chamber implantable pacemaker, rate-unresponsive***; single-chamber implantable pacemaker, rate-responsive***; dual-chamber implantable pacemaker, rate-unresponsive***; dual-chamber implantable pacemaker, rate-responsive***; dual-chamber implantable pacemaker, rate-responsive, MRI-conditional***; triple-chamber (biventricular) implantable pacemaker***) and options for ICD*** (single-chamber implantable cardioverter-defibrillator***; dual-chamber implantable cardioverter-defibrillator***; triple-chamber (biventricular) implantable cardioverter-defibrillator***)

TPM*** – temporary pacemaker

G– – Gram-negative

VSD – ventricular septal defect

ASD – atrial septal defect

ЕОК – European Society of Cardiology

EU – European Union

GI – gastrointestinal tract

RRT – renal replacement therapy

ICD*** – implantable cardioverter-defibrillator (single-chamber implantable cardioverter-defibrillator***; dual-chamber implantable cardioverter-defibrillator***; triple-chamber (biventricular) implantable cardioverter-defibrillator***)

ИМ – myocardial infarction

EIA – enzyme immunoassay

IE – infective endocarditis

CIED IE*** – cardiac implantable electronic device infective endocarditis

PVE – prosthetic valve endocarditis

NVE – native valve endocarditis

CAG – coronary angiography (MSS: coronarography)

CNIE – culture-negative infective endocarditis

CT – computed tomography (MSS: brain computed tomography; spinal computed tomography (one region); spinal computed tomography with multiplanar and three-dimensional reconstruction; soft tissue computed tomography; chest computed tomography; mediastinal computed tomography; abdominal computed tomography; retroperitoneal computed tomography; abdominopelvic computed tomography; female pelvic computed tomography; male pelvic computed tomography; cardiac computed tomography)

CT angiography – computed tomography angiography (MSS: computed tomography coronary angiography; cerebral computed tomography angiography with intravenous bolus contrast enhancement, thoracic aorta computed tomography angiography, abdominal aorta computed tomography angiography)

Contrast-enhanced CT – computed tomography with intravenous contrast administration (MSS: brain computed tomography with contrast enhancement; cerebral computed tomography angiography with intravenous bolus contrast enhancement; soft tissue computed tomography with contrast; spinal computed tomography with contrast enhancement (one region); chest computed tomography with intravenous bolus contrast enhancement; chest computed tomography with intravenous bolus contrast enhancement, multiplanar and three-dimensional reconstruction; mediastinal computed tomography with intravenous bolus contrast enhancement; abdominal computed tomography with intravenous bolus contrast enhancement; abdominopelvic computed tomography with intravenous bolus contrast enhancement; female pelvic computed tomography with contrast; female pelvic computed tomography with intravenous bolus contrast enhancement, multiplanar and three-dimensional reconstruction; male pelvic computed tomography with contrast; cardiac computed tomography with contrast)

Russian Ministry of Health – Ministry of Health of the Russian Federation

MD – medical device

INR – international normalized ratio

MRA – magnetic resonance angiography

MRI – magnetic resonance imaging (MSS: brain magnetic resonance imaging; spinal magnetic resonance imaging (one region); soft tissue magnetic resonance imaging; joint magnetic resonance imaging (one joint); chest magnetic resonance imaging; lung magnetic resonance imaging; cardiac and great vessel magnetic resonance imaging; mediastinal magnetic resonance imaging; abdominal magnetic resonance imaging; retroperitoneal magnetic resonance imaging; pelvic magnetic resonance imaging)

Contrast-enhanced MRI – magnetic resonance imaging with intravenous contrast administration (MSS: brain magnetic resonance imaging with contrast enhancement; intracranial vessel magnetic resonance angiography; contrast-enhanced magnetic resonance angiography (one region); spinal magnetic resonance imaging with contrast enhancement (one region); soft tissue magnetic resonance imaging with contrast enhancement; joint magnetic resonance imaging (one joint) with contrast enhancement; chest magnetic resonance imaging with intravenous contrast enhancement; cardiac magnetic resonance imaging with contrast enhancement; abdominal magnetic resonance imaging with intravenous contrast enhancement; retroperitoneal magnetic resonance imaging with intravenous contrast enhancement; pelvic magnetic resonance imaging with intravenous contrast enhancement)

MSCT – multislice computed tomography (MSS: spiral computed tomography of the lungs; ECG-gated spiral computed tomography of the heart; female pelvic spiral computed tomography; male pelvic spiral computed tomography)

Contrast-enhanced MSCT – multislice computed tomography with intravenous contrast administration (MSS: abdominal spiral computed tomography with intravenous bolus contrast enhancement, multiplanar and three-dimensional reconstruction; female pelvic spiral computed tomography with intravenous bolus contrast enhancement; male pelvic spiral computed tomography with intravenous bolus contrast enhancement)

MV – mitral valve

MIC – minimum inhibitory concentration

NBTE – non-bacterial thrombotic endocarditis

LMWH – low-molecular-weight heparins (ATC Heparin group)

NMU — nomenclature of medical services

AKI – acute kidney injury

ICU – intensive care unit

SPECT/CT – single-photon emission computed tomography (MSS: single-photon emission computed tomography combined with computed tomography of the inflammatory site)

PT – prothrombin time (MSS: determination of prothrombin (thromboplastin) time in blood or plasma)

RRT – regular hemodialysis

PI – prothrombin index

RIE – right-sided infective endocarditis

AVP*** – prosthetic heart valve (cardiac aortic valve bioprosthesis***, mechanical bileaflet aortic valve prosthesis***, mechanical bileaflet aortic valve prosthesis / biological polymer aortic prosthesis***, cardiac aortic valve xenograft bioprosthesis***, transcatheter aortic heart valve bioprosthesis with a stent frame***, mitral valve bioprosthesis***, mechanical bileaflet mitral valve prosthesis***, tricuspid valve bioprosthesis, cardiac pulmonary valve bioprosthesis***, transcatheter cardiac pulmonary valve bioprosthesis***)

PCR – polymerase chain reaction

RT-qPCR – real-time polymerase chain reaction with hybridization-fluorescence detection of assay results

PPM*** – permanent leads for implantable pacemakers (single-chamber implantable pacemaker without rate response***; single-chamber implantable pacemaker, rate-responsive***; dual-chamber implantable pacemaker without rate response***; dual-chamber implantable pacemaker, rate-responsive***; dual-chamber implantable pacemaker, rate-responsive, MRI-compatible***; triple-chamber (biventricular) implantable pacemaker***)

PET/CT – positron emission tomography (MHS: positron emission tomography for detection of inflammatory foci; whole-body positron emission tomography with tumor-tropic radiopharmaceuticals; positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals; positron emission tomography combined with computed tomography for detection of inflammatory foci; positron emission tomography combined with computed tomography using contrast-enhanced tumor-tropic radiopharmaceuticals; contrast-enhanced myocardial positron emission tomography combined with computed tomography)

¹⁸F-FDG PET/CT – positron emission tomography (PET) with fludeoxyglucose [18F]

RCTs – Randomized Controlled Trials

CRT – cardiac resynchronization therapy (cardiac resynchronization therapy implantable pacemaker (triple-chamber (biventricular) implantable pacemaker***; cardiac resynchronization therapy implantable cardioverter-defibrillator (triple-chamber (biventricular) implantable cardioverter-defibrillator***)

RF – rheumatoid factor

DM – diabetes mellitus

SLE – systemic lupus erythematosus

SCr – serum creatinine (MHS: determination of blood creatinine level)

GFR – glomerular filtration rate

eGFR CKD-EPI – estimated glomerular filtration rate calculated by the CKD-EPI formula

HF – heart failure

ESR – erythrocyte sedimentation rate

VG – vascular graft (synthetic blood vessel prosthesis***)

AIDS – acquired immunodeficiency syndrome

CRP – C-reactive protein (MHS: determination of C-reactive protein level in blood serum)

CVD – cardiovascular disease

TG – triglycerides

TIA – transient ischemic attack

TAVI – transcatheter aortic valve implantation (MHS: endovascular aortic valve replacement)

TV – tricuspid valve

TTE – transthoracic echocardiography (MHS: echocardiography, three-dimensional echocardiography)

PE – pulmonary embolism

LCE – level of confidence of evidence

US – ultrasound examination (MHS: soft tissue ultrasound (one anatomical zone); pleural cavity ultrasound; lung ultrasound; comprehensive abdominal ultrasound; retroperitoneal ultrasound; comprehensive pelvic ultrasound (transvaginal and transabdominal))

GRS – grade of recommendation strength

AF – atrial fibrillation

RF – risk factor

CKD – chronic kidney disease

CRHD – chronic rheumatic heart disease

LDL-C – low-density lipoprotein cholesterol

CHF – chronic heart failure

CVD – cerebrovascular disease

CVC – central venous catheter

PCI – percutaneous coronary intervention

TEE – transesophageal echocardiography (MHS: transesophageal echocardiography, intraoperative transesophageal echocardiography)

ECG – electrocardiogram (MHS: electrocardiography recording)

PM*** – pacemaker (single-chamber implantable pacemaker, non-rate-responsive***; single-chamber implantable pacemaker, rate-responsive***; dual-chamber implantable pacemaker, non-rate-responsive***; dual-chamber implantable pacemaker, rate-responsive***; dual-chamber implantable pacemaker, rate-responsive, MRI-conditional***; triple-chamber implantable pacemaker [biventricular]***)

EchoCG – echocardiographic study (MSM: echocardiography)

CoNS – coagulase-negative staphylococci

CKD-EPI – ChronicKidneyDiseaseEpidemiology Collaboration

D-dimer – MSM: determination of blood D-dimer concentration

HACEK – Haemophilus, Aggregatibacter, Cardiobacterium hominis, Eikenella corrodens, Kingella

MSSA – methicillin-sensitive Staphylococcus aureus

MRSA – methicillin-resistant Staphylococcus aureus

NT-proBNP – N-terminal pro-B-type natriuretic peptide (MSM: assay of N-terminal pro-B-type natriuretic peptide level in blood)

NYHA – New York Heart Association

PCT – procalcitonin (MSM: assay of blood procalcitonin level)

** – the drug is included in the list of vital and essential drugs

*** – medical device implanted when providing medical care under the state guarantee program for free medical care to citizens

# – medicinal product for medical use used inconsistently with the indications for use, contraindications, routes of administration, and doses contained in the instructions for use of the medicinal product

Terms and Definitions

Vegetation – a mass composed of fibrin, platelets, and microorganisms, attached to a valve leaflet, endocardium, or intracardiac device. The term was introduced by Jean-Nicolas Corvisart.

Community-acquired infective endocarditis – infective endocarditis with symptoms developing within ≤48 hours of hospital admission in patients with no history of healthcare-associated infective endocarditis criteria [1].

Secondary infective endocarditis – infective endocarditis developing against the background of congenital, degenerative, and other structural changes of the endocardium (prosthetic valves, intracardiac devices).

Evidence-based medicine – the conscientious, explicit, and judicious use of current best evidence (clinical research results) in making decisions about the care of individual patients, integrating clinical expertise with patient values and preferences.

Disease – a condition arising from the impact of pathogenic factors, representing a disruption of body function, working capacity, and ability to adapt to changing environmental conditions, accompanied by concurrent changes in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

Bacterial isolate – a pure culture of a specific bacterial species isolated from a biological specimen.

Infective endocarditis (IE) – an infectious and inflammatory cardiovascular disease caused by direct invasion of microorganisms (bacteria, fungi) into the endocardium of valve structures, surfaces of foreign materials located in the blood flow pathway (prosthetic valves, intracardiac devices) or, less frequently, the mural endocardium, resulting in polypoid-ulcerative changes of the affected heart structures with their functional insufficiency; accompanied by systemic inflammation, bacteremia, progressive heart failure, cardiogenic embolisms, and immune-complex extracardiac manifestations.

Infective endocarditis associated with intravenous (IV) drug use – infective endocarditis caused by intravenous use of psychoactive substances (within the past 3 months), without an alternative source of infection [1].

Infective endocarditis associated with implanted cardiac electronic devices (ICED***) – infective endocarditis/intracardiac infection localized on the structures of implanted cardiac devices and/or adjacent areas of the endocardium [1].

Healthcare-associated infective endocarditis – infective endocarditis with symptoms developing later than 48 hours after hospital admission, or IE with symptoms developing earlier than 48 hours after admission in patients who resided in nursing homes/care facilities, or received intravenous injections, hemodialysis, or chemotherapy within 30 days prior to symptom onset, or were treated in an intensive care unit within 90 days prior to symptom onset [1].

Outcome – any potential result arising from exposure to a causative factor, preventive or therapeutic intervention, or all established changes in health status resulting from an intervention [2].

Clinical trial – any investigation conducted in human subjects to discover or verify the clinical and/or pharmacological effects of investigational products, and/or to identify any adverse reactions to investigational products, and/or to study absorption, distribution, metabolism, and excretion of investigational products with the object of ascertaining their safety and/or efficacy [3].

Conflict of interest – a situation in which a medical or pharmaceutical worker, while exercising their professional activities, has a personal interest—whether acting directly or through a company representative—in obtaining material gain or another advantage that influences or may influence the proper performance of their professional duties due to a contradiction between the personal interest of the medical or pharmaceutical worker and the interests of the patient.

Culture-positive infective endocarditis (CPIE) – infective endocarditis in which a typical microorganism or one consistent with infective endocarditis is identified in the blood by microbiological (culture) methods.

Culture-negative infective endocarditis (CNIE) – infective endocarditis in which no growth of causative microorganisms is obtained in the blood by microbiological (culture) methods [1].

Left-sided native valve infective endocarditis (LNVIE) – infective endocarditis of native mitral and/or aortic heart valves, or mural infective endocarditis in the left heart chambers [1].

Left-sided prosthetic valve infective endocarditis – infective endocarditis of prosthetic mitral and/or aortic heart valves [1].

Medicinal products – pharmacological agents in the form of dosage forms used for the prevention, diagnosis, and treatment of disease, for rehabilitation, and for the preservation, prevention, or termination of pregnancy.

Non-bacterial thrombotic endocarditis (marantic endocarditis, Libman-Sacks endocarditis, verrucous endocarditis, NBTE) – sterile vegetations consisting of fibrin and platelet aggregates that typically form on intact heart valves in various pathological conditions (cancer, antiphospholipid syndrome, systemic lupus erythematosus, autoimmune diseases, hypercoagulability, tuberculosis, uremia, AIDS, etc.) [4, 5].

Nosocomial infective endocarditis – infective endocarditis whose symptoms develop in patients later than 48 hours after hospital admission [1].

Medical intervention – types of medical examinations and/or procedures performed by a medical worker or other personnel authorized to engage in medical activities regarding a patient, which affect the physical or mental state of a person and have a preventive, diagnostic, therapeutic, rehabilitative, or research focus, as well as artificial termination of pregnancy.

Mycotic aneurysm (infective aneurysm) – an aneurysm developing as a result of embolism of the vasa vasorum of arteries by bacterial clusters or thromboarteritis (thrombophlebitis) of a vessel in septic diseases.

Uncontrolled infection – a condition accompanied by persistent infection or sepsis despite ongoing antibacterial therapy, and/or a local infection that does not respond to antibacterial therapy, and/or an infection caused by resistant or highly virulent organisms [6].

Acute infective endocarditis – infective endocarditis characterized by pronounced intoxication and systemic inflammation, rapid development (within 1-2 weeks) of valvular regurgitation, more frequently developing on intact heart valves and caused by highly virulent microorganisms (S. aureus, group B streptococci).

Acute kidney injury (AKI) – an increase in SCr by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours; or an increase in SCr to more than 1.5 times baseline (known or presumed to have occurred within the prior 7 days); or urine output <0.5 mL/kg/h for 6 hours.

Patient – an individual who is receiving medical care or who applies for medical care regardless of the presence of a disease and their condition.

Primary infective endocarditis – infective endocarditis occurring in the absence of congenital, degenerative, or other structural changes of the endocardium (including prosthetic heart valves, intracardiac devices, etc.).

Persistent infection – a condition including fever and positive blood cultures 7 days after treatment with recommended antibacterial therapy [6].

Repeat infective endocarditis – a repeat episode of infective endocarditis caused by a different pathogen or the same pathogen more than 6 months after the previous episode [1].

Subacute infective endocarditis – infective endocarditis characterized by moderately severe systemic inflammation and intoxication with the development of valvular regurgitation later than 3-4 weeks after the onset of fever; more frequently develops on altered heart valves, usually caused by viridans group streptococci or enterococci.

Late left-sided prosthetic valve infective endocarditis – infective endocarditis of prosthetic mitral and/or aortic heart valves developing more than 12 months after valve surgery [1].

Right-sided infective endocarditis (RIE) – infective endocarditis of the right heart chambers, predominantly the tricuspid and pulmonary valves [1].

Janeway lesions – painless erythematous macules on the palms and soles resulting from hemorrhages, infiltration, and necrotic changes in capillaries and arterioles.

Lukin's spots – petechial rashes on the conjunctiva, oral mucosa, and eyelid folds.

Roth's spots – round retinal hemorrhages with a pale center near the optic disc.

Working group on the development/updating of clinical guidelines – a team of specialists working together and in a coordinated manner to develop/update clinical guidelines and bearing joint responsibility for the results of this work.

Early left-sided prosthetic valve infective endocarditis – infective endocarditis of prosthetic mitral and/or aortic heart valves developing within 12 months after valve surgery [1].

Reinfection in infective endocarditis – a repeat episode of infective endocarditis caused by a different pathogen less than 6 months after the previous episode [1].

Relapse of infective endocarditis – a repeat episode of infective endocarditis caused by the same pathogen less than 6 months after the previous episode [1].

Syndrome – a stable set of several symptoms with a single pathogenesis.

Condition – changes in the body arising in connection with the action of pathogenic and/or physiological factors and requiring medical care.

Transient bacteremia – time-limited circulation of bacteria in the bloodstream without a focus of infection.

Osler's nodes – painful erythematous nodules on the palmar aspects of the fingertips and toes.

Level of certainty of evidence (LCE) – the degree of certainty that the estimated effect of a medical intervention is true [7].

Level of recommendations confidence (LRC) – the degree of certainty in the reliability of the intervention effect and in the fact that following the recommendations will bring more benefit than harm in a specific situation [7].

Fixed-dose drug combination – a combination of two or more different classes of drugs in a single tablet.

Strain – a group of isolates differing from other members of a given bacterial species, but indistinguishable from one another by phenotypic and genetic characteristics.

Empiric antibacterial therapy – antibacterial therapy prescribed before microbiological test results are obtained.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Infective endocarditis (hereinafter – IE) – an infectious and inflammatory disease of the valvular endocardium, mural endocardium, and intracardiac artificial devices, caused by invasion of microorganisms (bacteria, fungi), with the development of polypoid-ulcerative lesions of cardiac structures, proceeding with systemic inflammation, progressive heart failure, systemic emboli, and immune-complex manifestations.

Active infective endocarditis – infective endocarditis with persistent fever, positive microbiological (culture) blood test for sterility, or histologically confirmed active inflammatory process in a valve obtained intraoperatively, or infective endocarditis in a patient receiving antibacterial therapy (ABT) for IE, or in the presence of any pathomorphological evidence of active infective endocarditis [1].

Latent infective endocarditis – infective endocarditis first diagnosed in the postoperative period based on pathomorphological examination results [8].

Intracardiac device infection – infection associated with implanted intracardiac devices, including pacemakers***, cardioverter-defibrillators***, and cardiac resynchronization therapy pacemakers / cardiac resynchronization therapy defibrillators. The devices have intravascular and external parts, and the infection can affect all structures: the pulse generator, leads, heart structures around the leads, as well as various combinations thereof. When the intracardiac part of the device is involved in the infectious process, CIED-related IE*** develops.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Etiology

IE is a multi-etiological disease. Currently, more than 130 pathogens are known to cause the disease: bacteria and fungi, a list that expands annually. The etiological structure of IE depends on the country's economic status and the development of medical care. Thus, developing countries retain a historically established association of IE with a predominance of streptococcal etiology, while developed countries show dangerous growth trends in staphylococcal and enterococcal IE. Typical pathogens of IE are Gram-positive cocci: staphylococci S. aureus (17-43%), coagulase-negative staphylococci (CoNS 7-13%), enterococci (9-16%), streptococci, including S. bovis (2-10%), viridans group streptococci (9-26%), representatives of the HACEK group (0.3-3.5%), including Haemophilus spp.(Haemophilus parainfluenzae, etc.), Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae), fungi (3-7%) [9]. Much less commonly, IE is caused by Gram-negative non-HACEK bacteria, anaerobic bacteria, and multiple pathogens simultaneously. Rare pathogens of IE include Coxiella burnetii, Bartonella spp., Chlamydia spp., Legionella spp. [10, 11]. The etiology of IE depends on its form and situations predisposing to bacteremia: in congenital heart disease (CHD) and rheumatic heart disease (RHD), the pathogens are frequently streptococci, including the viridans group, enterococci, S. aureus, in early prosthetic valve IE – Staphylococcus epidermidis, S. aureus, Gram-negative pathogens, and fungi; in late prosthetic valve IE – coagulase-negative staphylococci, enterococci, viridans group streptococci, S. aureus; in intravenous drug users, up to 68% of IE cases are caused by Staphylococcus aureus [more frequently methicillin-susceptible Staphylococcus aureus (MSSA)], as well as P. aeruginosa, enterococci, C. albicans; in pacemaker (PM***) IE, the most frequent pathogens are Staphylococcus aureus and Staphylococcus epidermidis [9, 11, 12]. Infection S. aureus or CoNS is associated with a more severe course of IE and high mortality (25-50%), whereas infection with viridans group streptococci, conversely, carries a low risk of mortality [12]. Mortality in fungal IE reaches 36-40%, and in IE caused by Gram-negative microorganisms – up to 24% [11].

Pathogenesis

Infection of the endocarditis occurs via direct colonization and invasion from the bloodstream during bacteremia, including transient bacteremia. Asymptomatic bacteremia in humans is most commonly caused by representatives of the oral microflora. At the same time, bacteremia occurs not only after dental procedures, but much more frequently during daily activities such as tooth brushing and flossing, especially in individuals with poor oral hygiene. The entry of microorganisms into the bloodstream is facilitated by skin infections and trauma, burns, chronic inflammatory diseases or tumors of the intestine, urogenital system, and intravenous drug use. Bacteremia is observed during many invasive medical procedures. The most frequent causative agents of bacteremia in non-dental medical interventions are S. aureus, CoNS, and enterococci.

It is believed that in its undamaged state, the endocarditis is resistant to infection. Degenerative processes (fibrosis, calcinosis), turbulent blood flow occurring in valvular heart disease, and mechanical damage during the implantation of any CIED*** can cause micro-damages to the endocardium followed by the formation of microscopic thrombi. Circulating microorganisms attach to their surface and multiply, overcoming the body's defense mechanisms. Endocardial inflammation in the absence of mechanical damage can also serve as an adhesive surface for certain circulating microorganisms. Currently, IE is considered a unique model of thrombo-inflammatory endocardial disease, reflecting the close relationship between the hemostatic system and innate immunity, which is termed "immunothrombosis". Immunothrombosis is a physiological process of activation of the endothelial, platelet, and plasma links of hemostasis, leading to the release of neutrophil extracellular traps (NETs) that serve to capture and destroy bacteria entering the bloodstream [13]. In the pathogenesis of CIED*** infection, the initiating step is the formation of a bacterial biofilm on the surface of intracardiac foreign materials.

The increase in the size of vegetations is associated with the further deposition of fibrin, microorganisms, and blood cells involved in inflammation on their surface. Active infection spreads to the adjacent connective tissue of the heart, leading to its destruction, which manifests as perforation and rupture of valve cusps, rupture of chordae tendineae, with the subsequent development of heart failure. Vegetations or their fragments are loosely attached to the endocardium and easily detach, which is why more than a third of patients develop embolic complications. Embolism can develop at any period of the disease, but is most commonly observed before the initiation of antibiotic therapy in the presence of large, mobile vegetations. Microorganisms fixed on the valves, bacteremia with massive influx of bacterial toxins and antigens into the bloodstream cause systemic inflammation and intoxication, as well as the production of antibodies (specific antibodies and a number of autoantibodies) and immune complexes (in 90-95% of patients with IE), which can lead to immunoinflammatory damage of the kidneys, skin vessels, and other organs and tissues [13].

1.3 Epidemiology of the Disease or Condition

On average, the incidence of IE is 3-10 per 100,000 population, with a global upward trend in recent decades: according to the Global Burden of Disease study in 2019, 1.09 million cases of IE were registered, and the age-standardized rate was 13.8 per 100,000 population, which was 39.4% higher than the corresponding figure in 1990 (9.9 per 100,000 population) [11, 14, 15], increasing with age (in individuals over 50 years – 15.0 cases, and in individuals over 80 years – 22.0 cases per 100,000 population) [11, 16]. In recent years, there has been an increase in the number of hospitalizations for IE: from 1998 to 2019, from 26.6 to 50.0 cases per million (an 86% increase) [17]. In Russia, according to Rosstat data over the past 10 years, the number of IE cases treated in hospitals has not changed (2010 – 6,439; 2019 – 6,235), although in recent years there have been fluctuations associated with the unfavorable epidemiological situation (2020 – 4,422; 2021 – 3,057; 2022 – 4,873; 2023 – 4,690) [18]. According to official statistics in Russia in 2010-2020, in-hospital mortality from IE in hospitals was 23.11%, and in Moscow – 34.71% [18, 19]. The male-to-female ratio is 2:1. The increase in the incidence of IE is associated with an increase in the number of cardiac surgeries for heart defects, installation of CIED*** (pacemakers, ICDs, CRT), coronary artery bypass grafting, percutaneous interventions, and other invasive medical procedures (placement of vascular catheters or performance of therapeutic/diagnostic procedures). In Russia, a high proportion of IE associated with intravenous psychoactive substance use persists [4, 16].

In recent decades, the proportion of primary IE has been increasing (31–57.4%). Among heart diseases predisposing to the development of secondary IE, there is an increased role of prosthetic heart valves (21%) and degenerative heart valve disease in the elderly (15.7%). Patients with recurrent IE are more common (8.9–11% of cases), while the proportion of patients with prior rheumatic heart disease has decreased (12%) [4, 9, 11, 12, 16]. Isolated aortic valve involvement prevails in 38.7–55.8% of cases, and mitral valve involvement in 26–37% [9, 11, 19]. The frequency of tricuspid valve involvement in the general population is 2.6–5.3%, while in IE among drug users it rises to 59–82.7% [9, 11, 19, 20]. Multivalvular involvement, predominantly a combination of mitral and aortic valves, is detected in no more than 20% of cases [9, 11, 19].

The portal of entry of the infection can be identified in only 34–58.6% of patients with IE [11]. The following predisposing factors are distinguished: dental procedures – in 7.5–19% of patients (up to 26.1–37.2% in patients with congenital heart disease), skin infections (abscesses, streptococcal pyoderma) – 2–19.5%, urinary tract infections – 1.5–12.6%, iatrogenic causes, especially in patients with prosthetic valve IE [15] (intravascular catheters, diagnostic and therapeutic procedures) – 1–10.6%, and gastrointestinal diseases – 1.4–9% [11]. It is important to note the significant role of transient bacteremia, which is observed after tooth extraction in 40% of patients, after chewing in 38%, and after tooth brushing in 25% [15].

Mortality in IE remains high: in-hospital – 4–20%, 6-month – 27–32%, 1-year – 30–40%, and 5-year – up to 51% [9, 20–22].

1.4 Features of Coding the Disease or Condition

Other heart diseases (I33, I38), complications associated with cardiac and vascular devices, implants, and grafts (T82):

I33 – Acute and subacute endocarditis:

I33.0 – Acute and subacute infective endocarditis;

I33.9 – Acute endocarditis, unspecified;

I38 – Endocarditis, valve unspecified;

T85.7 Infection and inflammatory reaction due to other internal prosthetic devices, implants, and grafts

For non-infective endocarditis, code I39 can be used; however, since it is a complication of the underlying disease, this code cannot be considered as the underlying cause of death and cannot be registered under the "underlying disease" section of the post-mortem clinical and pathoanatomical diagnoses:

I39 – Endocarditis and heart valve disorders in diseases classified elsewhere:

I39.0 – Mitral valve disorders in diseases classified elsewhere;

I39.1 – Aortic valve disorders in diseases classified elsewhere;

I39.2 – Tricuspid valve disorders in diseases classified elsewhere;

I39.3 – Pulmonary valve disorders in diseases classified elsewhere;

I39.4 – Multiple valve disorders in diseases classified elsewhere;

I39.8 – Endocarditis, valve unspecified, in diseases classified elsewhere;

1.5 Classification of the disease or condition

IE is classified:

• by the side of the heart affected – left-sided and right-sided IE are distinguished [1];

• by the prior valve status – primary IE (developing on intact valves) and secondary IE (arising on valves already damaged and altered by various processes) [23];

• by the clinical course (determined by clinical manifestations and depending on the prior valve status, pathogen species, and the patient's immune response) – acute IE and subacute IE [24];

• by the history of IE – relapsing IE (a repeat episode of IE caused by the same microorganism less than 6 months after the initial infection) and recurrent IE (a repeat episode of IE caused by a different pathogen or the same pathogen 6 months or more after the initial infection) [1].

• IE is classified by the affected area of the endocardium [23]:

  - Native aortic valve IE

  - Native mitral valve IE

  - Native tricuspid valve IE

  - Native pulmonary valve IE

  - Multivalvular IE

  - Mural endocarditis IE

  - Mechanical/biological aortic valve prosthesis IE***

  - IE of a mechanical/biological mitral valve prosthesis***

  - IE of a mechanical/biological tricuspid valve prosthesis***

  - IE of a cardiac implantable electronic device lead (pacemaker***/ICD***/CRT)

  - IE of an atrial or ventricular septal defect patch

  - IE of a vascular graft (VG) (homograft/allograft) According to the acquisition mode, IE is classified into: healthcare-associated IE; nosocomial IE (symptom onset >48 hours after hospital admission); community-acquired IE, and injection drug use-associated IE (IE in an active injection drug user without other sources of infection) [1].

• According to the Duke criteria: definite, possible, rejected.

Cardiac implantable electronic device infection is classified as follows [25]:

• Isolated CIED pocket infection***: localized erythema, swelling, tenderness, local warmth in the pocket area with negative blood cultures.

• Isolated CIED pocket erosion due to infection: the device and/or leads protrude from the pocket with local signs of infection (pain, edema, erythema, local warmth).

• Bacteremia: positive blood cultures without local signs of infection of the CIED generator pocket***.

• CIED pocket infection with bacteremia: signs of local infection and positive blood cultures.

• CIED lead infection: vegetation on the CIED lead*** and positive blood cultures.

• CIED generator pocket infection with CIED IE (valvular/lead): signs of local infection, positive blood cultures, and vegetation on the lead, endocarditis, or heart valve.

• CIED IE*** without CIED generator pocket infection: positive blood cultures and vegetation on the lead, endocarditis, or heart valve.

• Latent bacteremia with probable CIED IE***: absence of an alternative source of infection, cessation of bacteremia after CIED removal***.

• Situations where CIED IE*** is not a definite diagnosis, but cannot be completely ruled out: isolated pocket infection in patients with CIED***

• Superficial surgical site infection: infection of the skin and subcutaneous tissue at the incision site without involvement of deeper tissues.

1.6 Clinical presentation of the disease or condition

Clinical symptoms of IE can be divided into several groups:

• Nonspecific general symptoms caused by systemic inflammation and bacteremia: fever (body temperature >38°C), chills, splenomegaly, weight loss.

• Cardiac manifestations caused by vegetation formation and destructive valve changes: new regurgitation murmur (systolic for mitral localization, protodiastolic for aortic localization, systolic for tricuspid localization), and heart failure—dyspnea, less commonly lower extremity edema.

• Extracardiac manifestations caused by cardiogenic embolisms (cerebral infarction, myocardial infarction, etc.) or immuno-inflammatory processes (Osler nodes, glomerulonephritis, vasculitis, arthritis, etc.).

Infective endocarditis remains a difficult 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 can present as an acute, rapidly progressive infection, or as a subacute or chronic disease with low-grade fever, or even the absence of fever and nonspecific symptoms that may be misleading or contribute to an erroneous initial assessment. Infective endocarditis may also present with complications mimicking a wide range of diseases, such as rheumatological, neurological, autoimmune disorders, or even malignancies, before the diagnosis of IE is established. Thus, suspicion of IE typically arises in the presence of fever with positive blood cultures in the absence of an alternative source of infection, especially in patients with one or more risk factors.

The initial clinical evaluation should include assessment of cardiac risk factors (previous infective endocarditis, valvular heart disease, prosthetic heart valves, presence of central venous or arterial catheters, implantable cardiac devices, congenital heart disease) and non-cardiac risk factors (central venous catheters, intravenous drug abuse, immunosuppression, recent dental or surgical procedures, recent hospitalizations, renal replacement therapy), favorable conditions for infection development, physical examination findings, including potential portals of entry for infection. Examination may reveal various symptoms and signs of infective endocarditis, but their absence should not be a reason to exclude the diagnosis because the overall sensitivity and specificity of clinical symptoms and signs are low. In the Euro-ENDO international registry on infective endocarditis, which also included the Russian Federation, fever (77.7%), new heart murmur (64.5%), and signs of congestive heart failure (27.2%) were the most frequent clinical manifestations [9]. Splenomegaly occurs in up to 26% of patients [15]. Embolic complications can be detected in 25.3% of patients, cardiac arrhythmias in 25.3% of patients, and conduction abnormalities in 11.5% [9, 11]. Some classic signs are rare, especially in severe IE caused by S. aureus, or in cases of prolonged subacute courses (mainly caused by Streptococcus spp.). Among vascular and immunological phenomena, the most frequent were splinter hemorrhages [9, 26–28], Roth spots, and glomerulonephritis. An atypical course of the disease may occur in elderly or immunocompromised patients [29–31].

A high degree of clinical suspicion and readiness to promptly perform necessary examinations to rule out/confirm IE at a sufficiently early stage should be developed by the physician, especially regarding high-risk patients. It is also extremely important to inform patients about their potential risk of developing IE and its possible symptoms, upon which they should immediately seek medical attention.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis of IE includes the following steps: eliciting complaints and taking medical history; repeated body temperature measurements; physical examination; laboratory and instrumental examinations: imaging and microbiological (culture) blood tests for sterility as the first stage, and search for complications as the second stage of examination (as indicated); ruling out alternative sources of infection if necessary; prognostic assessment at the time of diagnosis.

Diagnostic criteria

The diagnosis of IE is established based on the presence of criteria corresponding to the modified Duke criteria (2023) (Appendix A3/2) or anatomical findings during surgery or autopsy. The 2023 modified Duke criteria include clinical, instrumental parameters, and results of microbiological (culture) blood tests for sterility.

RCS I C (LeR C, LoE 5)

Comment. The global community has been using the Duke criteria for diagnosing IE since 1994. The latest modification was in 2023. The sensitivity of the criteria is 80% [6, 32]. One of the problems with the Duke criteria is their low diagnostic sensitivity in the early clinical stages of the disease, especially in prosthetic valve IE*** or pacemaker/ICD lead IE***. In these cases, echocardiography is uninformative in 30% of cases [33]. Therefore, the Duke criteria underwent further changes in 2023, associated with the modernization and expansion of imaging modalities (magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET/CT), single-photon emission computed tomography (SPECT/CT)) to improve the detection of diagnostic criteria: embolic events and inflammatory cardiac changes (pathological process in prosthetic valve IE***, CIED***, and in other complex situations), and improvement of etiological criteria with an expanded spectrum of typical IE pathogens.

Major and minor 2023 modified Duke criteria are distinguished for diagnosing IE (Appendix A3/2). Major IE criteria are divided into etiological diagnostic criteria (microbiological (culture) blood tests for sterility and antibody blood tests) and imaging criteria.

1. Positive microbiological testing for IE

(a) Typical IE pathogens from two separate blood cultures:

Oral streptococci, Streptococcus gallolyticus (formerly S. bovis), HACEK group, S. aureus, E. faecalis

(b) Microorganisms consistent with IE from persistently positive blood cultures:

• ≥2 positive blood samples drawn >12 hours apart

• all 3 or a majority of ≥4 separate blood cultures (with ≥1 hour between the first and last sample)

(c) A single positive blood culture for C. burnetii or phase 1 IgG antibody titre >1:800

2. Positive IE imaging:

Valvular, perivalvular/periprosthetic anatomical and metabolic lesions of prosthetic material characteristic of IE, detected by any of the following imaging modalities:

• Echocardiography (TTE and TEE)

• Cardiac CT

• 18F-FDG PET/CT

• Leukocyte-labeled SPECT/CT

RSC I B (LoE C, GoR 4)

Comments: The improvement and development of imaging techniques have led to better identification of endocardial involvement and the development of extracardiac complications of IE [35]. Thus, recent studies have shown that the use of CT/MSCT with/without contrast of the brain, spine, soft tissues, chest, abdomen, pelvis, and heart (see list of abbreviations for NMU), brain MRI, 18F-FDG PET/CT, and leukocyte-labeled SPECT/CT has improved the diagnosis of vascular phenomena such as emboli or mycotic aneurysms, as well as endocardial lesions. 18F-FDG PET/CT and leukocyte-labeled SPECT/CT have proven their importance in the diagnosis of CIED-IE*** and PVE-IE*** [36–38]. The addition of these imaging modalities has improved the sensitivity of the modified 2023 Duke criteria in complex cases. Furthermore, among the major 2023 Duke criteria for IE diagnosis, changes affected the etiological parameter: Enterococcus faecalis was recognized as a typical pathogen for IE. Data from a large study demonstrated that the inclusion of E. faecalis as a "typical" causative agent of IE significantly increased the sensitivity of the criteria for the correct identification of definite IE—from 70% to 96% [39].

The minor 2023 Duke criteria for IE include the following:

1. Predisposing conditions (i.e., predisposing heart conditions with high or moderate risk of IE or injection drug use)

2. Fever: temperature >38°C

3. Embolic complications (including asymptomatic ones detected by imaging only):

   • Major systemic and pulmonary emboli/infarctions and abscesses

   • Hematogenous osteoarticular septic complications (e.g., spondylodiscitis)

   • Mycotic aneurysms

   • Intracranial ischemic/hemorrhagic lesions

   • Conjunctival hemorrhages

   • Janeway lesions

4. Immunological criteria:

   • Glomerulonephritis

   • Osler nodes and Roth spots

   • Rheumatoid factor

5. Microbiological evidence:

   • Positive blood culture not meeting a major criterion

   • Serological evidence of active infection with an IE microorganism

RSC I B (LoE B, GoR 2)

Comments: Positive results of microbiological (blood culture) testing for sterility with antimicrobial susceptibility testing and clinical signs remain key to the diagnosis of IE. A carefully taken medical history with a special emphasis on identifying cardiac problems, predisposing social factors, and internal organ pathology is of great importance. It should be remembered that nowadays IE is characterized by a blurred, mild clinical presentation, often with a single predominant symptom and sometimes an entirely asymptomatic course. Therefore, searching for "silent" forms of vascular and immunological phenomena using modern diagnostic methods (MRI with/without contrast, CT/MSCT with/without contrast, or 18F-FDG PET/CT) is of particular importance. Rheumatoid factor is a simple and accessible marker associated with immunological phenomena. In cases of negative or uninformative/inconclusive microbiological (blood culture) tests for sterility, additional methods of etiological diagnosis are indicated. Molecular methods (polymerase chain reaction, sequencing, etc.) of blood samples, resected valve tissues, or embolic material have demonstrated high diagnostic efficacy for IE of unknown etiology. At the same time, sensitivity ranges from 41% to 96%, and specificity from 90% to 100% [42, 43]. Moreover, a large study showed that molecular biological methods are significantly less dependent on prior antibiotic therapy [44].

RCS I C (LeR C, LoE 5)

Comments. Appendices B1-B3 present diagnostic algorithms based on the modified 2023 Duke criteria for various types of IE—native valve IE, prosthetic valve IE, and cardiac implantable electronic device IE. Echocardiography and microbiological (blood culture) testing for sterility are of paramount importance in the diagnosis of IE. If the diagnosis of IE is stratified as "possible" or even "rejected" («not IE»), but a high level of clinical probability persists, echocardiography (using different techniques—serial transthoracic echocardiography (TTE)/transesophageal echocardiography (TEE)) and blood sample analysis (using additional methods such as polymerase chain reaction (PCR), immunochemical methods) should be repeated, and imaging modalities should be used to assess cardiac involvement (cardiac CT, 18F-FDG PET/CT, and leukocyte-labeled SPECT/CT) and search for asymptomatic embolic events (MRI with/without contrast, CT/MSCT with/without contrast, or 18F-FDG PET/CT). Etiological and instrumental methods play an important role in the diagnosis of IE, but they do not replace the clinical judgment of a multidisciplinary team (the "Endocarditis Team").

Pathomorphological data of the affected valve/CIED*** obtained during surgery/autopsy are the most reliable criteria for IE. The following pathomorphological criteria are distinguished:

❖ microorganisms demonstrated by microbiological (culture) examination of excised valve tissue or by histological examination of vegetations, fragments of vegetations in peripheral organs, or an intracardiac abscess sample, and/or

❖ pathomorphological changes in the tissues of the excised valve, vegetations, or intracardiac abscess, histologically confirming an active inflammatory process.

RCS I C (LeR C, LoE 5)

Comment. Examination of the removed valve is advisable in all cases. Vegetations are not always identified on valves in IE; therefore, areas of the valves suspected of involvement should undergo histological examination, with the nature of inflammation varying depending on the etiological agent. Identification of the pathogen from the valve tissue surface or from vegetations is essential for diagnosing IE and determining the need to continue antimicrobial therapy.

ESC I B (LoE C, GoR 4)

Comment. The "Endocarditis Team" includes a cardiologist, cardiovascular surgeon, infectious disease specialist, clinical laboratory diagnostics physician, bacteriologist or medical microbiologist, neurologist, neurosurgeon, clinical pharmacologist, functional diagnostics physician (Echocardiography, MRI, multislice computed tomography (MSCT), and radioisotope study methods), Appendix A3/4. In addition, other specialists may be involved in the "Endocarditis Team" if necessary, such as a nephrologist, geriatrician, narcologist/psychiatrist, and other specialists depending on the clinical situation at hand. The creation of multidisciplinary teams for IE management in accordance with current clinical guidelines has led to earlier and more accurate diagnosis of the underlying disease and its complications, uniformity in prescribing antibacterial therapy, and optimization of the timing of surgical intervention [45–49]. IE teams should meet regularly and work in accordance with standard operating procedures and current clinical guidelines. Consideration should be given to holding weekly meetings to discuss previously observed and newly admitted patients. In centers without an "Endocarditis Team", a heart team can be established, including, in addition to the attending physician, a cardiologist with experience in managing patients with IE, an infectious disease specialist and/or bacteriologist or medical microbiologist, and a clinical pharmacologist.

ESC I B (LoE C, GoR 5)

Comment. Managing these patients requires a very high level of physician qualification. Early discussion of IE patients with cardiovascular surgeons is considered mandatory in all cases of complicated IE (heart failure, cardiac abscesses, or embolic complications), as about half of IE patients undergo surgery during hospitalization. A team approach for managing IE patients has been implemented in European countries and is recommended with a Class IB level of evidence by the American Heart Association/American College of Cardiology guidelines for the management of patients with heart valve disease and the ESC guidelines for the management of IE [6, 35].

2.1 Complaints and Anamnesis

The main symptoms of IE are prolonged fever, typically accompanied by chills and night sweats, loss of appetite, and weight loss. Taking an anamnesis when IE is suspected must include information on the presence of: prior heart disease; prosthetic valves or intracardiac devices; factors associated with parenteral drug/substance use; invasive procedures (dental, soft tissue, major surgery, etc.); and the form of clinical manifestation.

RSC I B (LoE C, GoR 4)

RSC I C (LoE C, GoR 4)

Comment. Other symptoms are determined by the form of clinical manifestation, the so-called "masks of endocarditis": cardiological (myocardial infarction, rhythm disorders); neurological (cerebral infarction, meningitis, subarachnoid hemorrhage); renal (renal infarctions, abscesses, nephritis); anemia; vascular (hemorrhagic vasculitis, arterial embolism).

2.2 Physical Examination

ESC I C (LoE C, GoR 5)

RCS I C (LeR C, LoE 5)

Comment. In the largest European IE registry (EURO-ENDO, 2019), the most common clinical manifestations were fever (77.7%), heart murmurs (64.5%), and congestive heart failure (27.2%) [9]. Embolic complications were detected in 25.3% of patients, and cardiac conduction disturbances in 11.5%. Heart murmurs are found in 85% of patients, and at least 25% have embolic complications at the time of IE diagnosis. Classical signs of IE are less common. Emboli to the brain, lungs, or spleen are found in 30% of patients. IE frequently presents atypically. In intravenous drug users, infarction pneumonia is diagnosed in 60–80% of cases. An atypical clinical picture with a monosymptomatic course is frequently noted. In elderly or immunocompromised patients, IE has an insidious presentation, whereas in young individuals it presents with a vivid clinical picture [29–31].

ESC IIa B (LoE C, GoR 3)

Comment. The clinical picture varies widely (focal neurological deficit, headache, confusion, seizures), which is why visualization must be performed systematically to detect intracranial mycotic aneurysms in all cases of IE with neurological symptoms.

Musculoskeletal system involvement is among the frequent manifestations of IE. Musculoskeletal symptoms (arthralgia, myalgia, back pain) frequently occur in IE. Rheumatological manifestations may be the first sign of IE and cause diagnostic difficulties, particularly if typical manifestations of IE are masked or if high titers of infection-related antibodies are detected (e.g., a positive antineutrophil cytoplasmic antibody test). Arthralgia occurs in approximately 10% of patients, whereas myalgia occurs in 12–15%. Back pain develops in approximately 13% of cases. Low back pain is the most frequent symptom of IE in vertebral osteomyelitis. Peripheral arthritis occurs in approximately 14% of cases. The prevalence of spondylodiscitis in patients with IE ranges from 1.8 to 2.5%. Thus, for the timely diagnosis of IE, a high index of suspicion and a low threshold for performing necessary investigations are of great importance, especially in high-risk patient groups, such as those with congenital heart defects or prosthetic valves. Patient education regarding the risk of IE is also essential; patients should be aware of the initial and specific manifestations of the disease to seek medical attention in a timely manner.

2.3 Laboratory Diagnostics

Only a single marker—rheumatoid factor (RF)—may be used as an additional minor criterion to establish a diagnosis of IE. However, other laboratory markers are necessary to assess disease severity, inflammatory activity, diagnose complications, perform differential diagnosis with non-bacterial thrombotic endocarditis (NBTE), and diagnose comorbid conditions that affect treatment efficacy and the patient's quality of life.

ESC IC (RR S, ELD 5)

RCS I C (LeR C, LoE 5)

RCS I C (LeR C, LoE 5)

ESC IIa C (Level of Evidence C, Expert Consensus)

ESC IIa C (Level of Evidence C, Expert Consensus)

ESC IIa C (Level of Evidence C, Expert Consensus)

ESC IIa C (Level of Evidence C, Expert Consensus)

ESC IIa C (Level of Evidence C, Expert Consensus)

ESC IIa C (Level of Evidence C, Expert Consensus)

ESC IIa C (Level of Evidence C, Expert Consensus)

Comment. Aside from RF, which is one of the minor criteria for IE, none of these markers are diagnostically specific for IE, but they are actively used for risk stratification in surgical risk scores for IE, such as SCr clearance for EuroSCORE II (European System for Cardiac Operative Risk Evaluation). Laboratory data provide insight into the efficacy of ongoing therapy (inflammatory markers). Changes in SCr levels / estimated glomerular filtration rate (eGFR) are used to assess renal function in the context of nephropathy caused by the underlying disease, as well as to monitor the dosages of systemic antibacterial drugs, particularly those with nephrotoxic potential. CRP and PCT are the most widely evaluated biomarkers in randomized clinical trials on the rational use of systemic antibacterial drugs and in real-world clinical practice. Unfortunately, no single biomarker possesses sufficient accuracy for diagnosing sepsis or specificity for IE. Thus, the primary role of biomarkers is to facilitate initial risk stratification for an adverse prognosis in patients with IE and to monitor the response to antibiotic therapy.

ESC IIa C (Level of Evidence C, Expert Consensus)

Comment. A series of Russian and international studies have demonstrated the high prognostic value of calculated inflammatory indices in patients with IE. Hu W. et al. (2022, China) noted that SII is an independent predictor of embolic stroke in IE [OR 6.93 (95% CI 1.035–46.318), p = 0.046] [54]. Agus H.Z. et al. (2020, Turkey) showed via ROC analysis that the cutoff value of SII for predicting in-hospital mortality is 2314.0 (AUC 0.641, p = 0.019) with a sensitivity of 33% and a specificity of 91% [55]. A Russian cohort study by Kotova E.O. et al. (2023) demonstrated that a high risk of in-hospital mortality is associated with an NLR ≥ 20.0 [OR 9.5 (95% CI 1.83–49.37), p = 0.007], an SII ≥ 2314.0 [OR 5.86 (95% CI 1.98–17.28), p = 0.001], and a PLR ≤ 82.0 [OR 3.5 (95% CI 1.4–9.1), p = 0.01] [56].

2.3.1. Microbiological (culture) diagnostics

Culture-positive infective endocarditis

RCS I C (LeR C, LoE 5)

Comment. Three sets of microbiological blood cultures for sterility should be obtained as early as possible after the onset of clinical symptoms, preferably before initiating antibiotic therapy. If the patient is already receiving antibiotics, the diagnostic yield can be improved by drawing blood cultures immediately prior to the next systemic antibacterial dose, using commercial blood culture bottles. For sterility testing, at least 3 blood samples should be drawn with a 30-minute interval. Samples should be collected via peripheral venipuncture (not through a venous catheter due to the risk of contamination), strictly adhering to aseptic collection techniques. The sample volume depends on the blood culture bottles used, but for adults, it is typically 10 mL per bottle, with two bottles (for aerobic and anaerobic microorganisms) used per set. In the absence of an anaerobic medium, using two aerobic bottles per set is acceptable. A single positive blood culture result should be interpreted with caution when diagnosing IE. The microbiology laboratory must be notified of the clinical suspicion of IE. After 48–72 hours of antibiotic therapy, blood cultures for sterility should be repeated to assess treatment efficacy [60, 61].

RCS I C (LeR C, LoE 5)

Comment. Bacteremia in IE is almost constant and has two features: (i) there is no point in delaying blood collection until the peak body temperature is reached; (ii) almost all blood cultures during bacteremia are positive. To improve diagnostic quality, modern automated systems for microbiological (cultural) blood sterility testing are used, allowing the detection of growth of most significant IE pathogens. To minimize the impact of antibiotic therapy on the results of microbiological (cultural) blood sterility testing, temporary discontinuation of antibiotics for several days is possible (if the patient is stable) and/or the use of special vials containing sorbents for antimicrobial substances for microbiological (cultural) blood sterility testing. After microbial growth is detected in the vial, Gram staining must be performed and preliminary results reported to the physician. Next, identification of pathogens and determination of their susceptibility to antimicrobial chemotherapeutic agents must be performed. This procedure, from the delivery of vials to the laboratory to obtaining final test results, usually takes 2–3 days, but may take longer if slow-growing microorganisms are present [60, 61].

Not addressed in ESC guidelines (Level of Evidence C, Grade of Recommendation 5)

Culture-Negative Infective Endocarditis

Culture-negative infective endocarditis (CNIE) refers to IE for which no causative agent is detected by routine microbiological (cultural) blood sterility testing methods. It occurs in 7–35.4% of IE cases and represents a diagnostic and therapeutic challenge (Appendix B4).

RSC I C (LoE C, GoR 4)

Comment. CNIE is usually caused by prior antibiotic therapy (dictating the need to discontinue antibiotics and repeat microbiological (cultural) blood sterility testing ) or may be associated with difficult-to-culture or non-culturable microorganisms (e.g., certain micromycetes or bacteria whose isolation requires special media and/or is characterized by slow growth) [61, 65, 66].

RSC I C (LoE C, GoR 4)

Comment. For the diagnosis of CNIE, immunochemical methods are of great importance (primarily for detecting antibodies against Coxiella burnetii, Bartonella spp., Brucella spp.), as well as molecular methods (e.g., PCR). Species-specific PCR can be performed to detect a specific pathogen or, in the case of ineffective etiological diagnosis at previous stages, genus-specific PCR followed by species identification (to detect DNA of a wide range of microorganisms, including Streptococcus gallolyticus and Streptococcus mitis, Enterococcus spp., S. aureus, etc.). According to a large Russian study, adding PCR testing to the standard etiological diagnostic algorithm in patients with IE increased the detection rate of IE etiology by 30%, especially in prosthetic valve IE*** and cardiac implantable electronic device-related IE*** [43]. All cases of CNIE should be managed in collaboration with a clinical pharmacologist.

RCS I C (LeR C, LoE 5)

Comment. If NBTE is suspected, further examination for autoimmune diseases is necessary using methods to detect antinuclear antibodies or antiphospholipid syndrome [testing for blood alpha-1-glycoprotein (orosomucoid) levels, blood anticardiolipin antibodies, blood antiphospholipid antibodies, blood beta-2-glycoprotein antibodies, antinuclear antibodies to Sm antigen], and in patients with an established xenobiotic prosthesis (bioprosthetic cardiac aortic valve / xenomaterial aortic prosthesis***) – searching for markers of allergic response and antibodies to valve components [71, 72].

Pathological and Anatomical Examination of Biopsy (Surgical) Material of Valves/Artificial Material

Examination of the excised valve or embolus fragments remains the gold standard for diagnosing IE.

RSC I B (LoE C, GoR 4)

Comment. All tissue samples removed during the surgical procedure of cardiac valve excision for microbiological testing should be collected in a sterile container without fixative or nutrient medium. Cardiac valve material obtained during surgery must undergo pathological and anatomical examination of the biopsy (surgical) material, microbiological (cultural) sterility testing (medical service: microbiological (cultural) examination of cardiac valve biopsy specimen for aerobic and facultatively anaerobic microorganisms; microbiological (cultural) examination of cardiac valve bioprosthesis for aerobic and facultatively anaerobic microorganisms; microbiological (cultural) examination of biopsy specimen for mycelial fungi; microbiological (cultural) examination of biopsy specimen for yeast fungi) with determination of microorganism susceptibility to antimicrobial chemotherapeutic agents, combined with PCR diagnostics if necessary.

2.4 Instrumental Diagnostics

Imaging, in particular echocardiography, plays a key role in the diagnosis and management of a patient with IE. Echocardiography is also useful for assessing the prognosis of patients with IE and treatment dynamics, including after surgical intervention. Echocardiography is particularly useful for the initial assessment of embolism risk and IE treatment tactics. Transesophageal echocardiography (TOE) plays an important role both before and during surgery (intraoperative TOE). The evaluation of patients with IE is not limited to standard echocardiography alone. It may include targeted chest radiography, CT/MSCT, MRI, ¹⁸F-FDG PET/CT, or other functional imaging modalities.

2.4.1. Echocardiography

ESC I B (LOC B, LOE 1)

Comment. Three echocardiographic findings serve as major criteria for the diagnosis of IE: vegetation, abscess or pseudoaneurysm, and prosthetic valve dysfunction. The size of vegetations is of major importance and is a key indicator determining indications for cardiac surgery. Appendix A3/6 provides anatomical and echocardiographic definitions, and Appendix B5 presents the algorithm for performing echocardiography in suspected IE.

ESC I C (LOC C, LOE 5)

ESC I B (LOC B, LOE 1)

Comment. TOE is useful in a wide range of clinical scenarios due to the limitations of TTE in diagnosing perivalvular complications, small vegetations, prosthetic valve IE***, and vegetations associated with cardiac implantable electronic devices***. TOE is strongly indicated in patients with inconclusive TTE findings, patients with a negative TTE and high clinical suspicion of IE, and patients with a positive TTE to confirm local complications.

ESC I B (LOC B, LOE 1)

Comment. In diagnosing vegetations on native and prosthetic valves, the sensitivity of TTE is 70% and 50%, and of TOE is 96% and 92%, respectively. The specificity for both methods is approximately 90%.

ESC I C (LoE C, GoR 4)

Comment. In cases of initially negative findings, repeat TTE/TOE is performed 5–7 days later if clinical suspicion persists, or even earlier if S. aureus is detected [85]. Other imaging modalities should also be used in this situation (see Section 2.6.2–2.6.4). The detection of vegetations may be difficult in the presence of prior valvular heart disease (mitral valve prolapse, degenerative calcified areas), on prosthetic valves, with small (<2–3 mm) vegetations, recent embolization, and IE without vegetation formation. Diagnosis can be particularly challenging when CIED*** are involved in IE, even with TOE. A misdiagnosis of IE may occur due to the challenges of differentiating vegetations from thrombi, Lambl excrescences, valve leaflet prolapse, ruptured chordae tendineae, lupus (Libman-Sacks) lesions, strands and threads, primary APS, rheumatoid lesions, and degenerative valvular deposits. Therefore, echocardiographic findings should be interpreted with caution, taking into account the clinical presentation and the probability of IE.

ESC IIa B (CGR B, LOR 2)

Comment. For patients with bacteremia caused by S. aureus, E. faecalis, and certain streptococcal species echocardiography is indicated due to the frequent presence of IE in such situations, as well as the virulence of these pathogens and their destructive cardiac effects. In such patients, both modalities of echocardiography should be used in accordance with individual risk factors (RF) and the source of bacteremia.

ESC not specified (LoE C, GoR 4)

Comment. One of the most frequent skeletal complications of IE is the development of purulent vertebral osteomyelitis, frequently associated with streptococcal or staphylococcal infection.

ESC I C (CGR B, LOR 1)

Comment. TOE should also be performed in patients with a positive TTE result to rule out local complications.

ESC I B (LOC B, LOE 1)

Comment. The sensitivity of TTE for the diagnosis of abscesses is approximately 50%, compared with 90% for TOE. The specificity is greater than 90% for both methods [87]. Small abscesses are difficult to identify, especially in the early stages of the disease, in the postoperative period, and in the presence of a prosthetic valve. IE should always be suspected when paraprosthetic regurgitation is detected, even in the absence of echocardiographic signs of IE [76].

ESC IIa B (CGR B, LOR 1)

Comment. Serial echocardiography is mandatory to detect complications and assess response to therapy.

ESC IIa B (CGR C, LOR 5)

ESC I C (CGR C, LOR 5)

RSS I B (CGR C, LOR 5)

ESC I B (CGR C, LOR 5)

Comment: The results of the largest clinical trial investigating the feasibility of switching patients with IE from intravenous systemic antibiotic therapy to oral antibiotic regimens demonstrated the safety and efficacy of this strategy in stable patients with left-sided IE. One of the switching criteria was the absence of structural and functional cardiac changes on echocardiography.

ESC I C (LoE C, GoR 4)

RSS IIa B (CGR B, LOR 2)

Comment. Real-time 3D TOE allows the analysis of 3D cardiac volumes from any possible perspective. A recent study demonstrated that conventional TOE underestimates vegetation size, and that real-time 3D TOE is a more appropriate modality for analyzing vegetation morphology and size, offering superior assessment of embolic risk in IE compared with conventional TOE. Real-time 3D TOE is particularly useful in assessing perivalvular extension of infection, prosthetic valve dysfunction, and valve perforation. Although real-time 3D TOE is increasingly performed alongside conventional TOE in clinical practice, this method should currently be considered complementary to standard echocardiography in most situations.

2.4.2. Computed tomography

ESC I B (LoE A, GoR 2)

Comment. ECG-gated cardiac CT is used in patients with IE to detect abscesses/pseudoaneurysms with diagnostic accuracy equivalent to that of TOE, and even superior regarding information on perivalvular extension, including pseudoaneurysm anatomy, abscesses, and fistulae.

RSS I B (CGR B, LOR 2)

ESC not specified (LoE C, GoR 4)

ESC I B (CGR A, LOR 1)

Comment. When assessing prosthetic valve dysfunction, ECG-gated cardiac CT is equivalent or superior to echocardiography for detecting prosthesis-related vegetations, abscesses, pseudoaneurysms, and dysfunction. However, large comparative studies of these two modalities have not been performed, and echocardiography should be performed first.

ESC I B (LE R, LoE 5)

Comment. MRI is known to have higher sensitivity than CT for detecting brain injury in patients with IE. Nevertheless, performing CT is more appropriate and practical for critically ill patients, especially if MRI is unavailable.

ESC I B (LE R, LoE 5)

Comment. CT angiography of the cerebral vessels provides complete visualization of intracranial vessels with a sensitivity of 90% and specificity of 86%, carries a low contrast load, and does not pose the risk of permanent neurological deficit associated with conventional digital subtraction angiography [111]. If subarachnoid and/or intraparenchymal hemorrhage is detected, other vascular imaging methods (e.g., angiography [internal carotid artery angiography, external carotid artery angiography, common carotid artery angiography]) may be required to confirm or exclude a mycotic aneurysm if it is not detected on cerebral CT angiography. Contrast-enhanced CT/MSCT has high sensitivity and specificity for diagnosing splenic, cerebral, and other organ abscesses; however, the differential diagnosis with infarction is sometimes problematic. Contrast-enhanced CT/MSCT provides rapid and high-quality results in imaging the systemic arterial bed. Detailed multiplanar 3D contrast-enhanced angiographic reconstruction allows for vascular mapping, identification and description of peripheral IE vascular complications, and dynamic follow-up.

RSC IIa C (LoE C, GoR 4)

ESC IIb B (LoE C, GoR 4)

2.4.3. Magnetic resonance imaging

ESC IIb B (LoE C, GoR 4)

Comment. MRI has a higher sensitivity for detecting cerebral consequences of IE compared to CT. Various studies utilizing MRI for diagnosing cerebral complications during the acute phase of IE detected pathology in 60–80% of cases. Despite neurological symptoms, most abnormalities were ischemic in nature (in 50–80% of cases), with small focal lesions predominating over larger infarct cores. In less than 10% of patients, other lesions were detected: parenchymal or subarachnoid hemorrhages, abscesses, and mycotic aneurysms. Repeat brain MRI contributes to the diagnosis of IE since it is included in the minor diagnostic criteria according to the Duke classification in patients with brain involvement but absence of neurological symptoms. In one study, MRI-diagnosed signs increased the number of patients with a confirmed diagnosis of IE by 25%, thereby improving diagnostics in initially uncertain situations. Cerebral microbleeds are detected in 50–60% of patients, present as small areas of hemosiderin deposition, and are considered small vessel disease. The insufficient degree of correlation between microbleeds, as well as differences in their predictive value, suggest that their cause is not embolic. Although IE and the presence of microbleeds are strongly interrelated, they should not be considered a Duke minor criterion [119].

ESC I B (LoE C, GoR 4)

Comment. Brain MRI primarily reveals abnormalities in IE patients with neurological symptoms. The sensitivity of MRI is higher than that of CT in determining the primary lesion, particularly regarding cerebral infarction, transient ischemic attack (TIA), and encephalopathy. MRI can also detect additional cerebral lesions that are not clinically apparent. Brain MRI does not affect the diagnosis of IE in patients with neurological symptoms, as they already meet one Duke minor criterion; however, MRI may influence the treatment strategy, particularly the timing of surgery. In patients without neurological symptoms, MRI indicates brain lesions in at least half of the cases, predominantly ischemic areas. Brain MRI provides a better understanding of lesion patterns in IE patients with neurological symptoms, whereas its impact on establishing the diagnosis of IE is more pronounced in cases of uncertainty and absence of neurological symptoms.

ESC IIb B (LoE C, GoR 5)

Comment. Abdominal MRI detects abnormalities in one-third of evaluated patients, predominantly splenic involvement. Ischemic lesions are most frequent, while hemorrhagic and abscess-forming lesions are less common. Parenchymal organ abnormalities detected on abdominal MRI do not fundamentally alter the IE diagnosis when brain MRI findings are taken into account.

ESC IIa B (CGR C, LOR 4)

Comment. Brain CT with or without intravenous contrast is performed most frequently; however, contrast-enhanced (with gadolinium-based paramagnetic contrast agents) or unenhanced brain MRI has higher sensitivity.

ESC IIa B (CGR A, LOR 2)

ESC I B (LE R, LoE 5)

Comment. A rare complication of IE is the development of myocarditis, often associated with myocardial abscess or immune complex-mediated injury, frequently leading to arrhythmias and heart failure, which determine an adverse prognosis.

ESC I B (LE R, LoE 5)

Comment: Spinal MRI is the method of choice for diagnosing spondylodiscitis and vertebral osteomyelitis with a diagnostic accuracy of 89–94%. MRI findings include vertebral and intervertebral disc edema, paraspinal/epidural inflammation or abscess, bone erosion, and increased gadolinium-based contrast agent (paramagnetic contrast agents) enhancement in the vertebrae and intervertebral discs. However, it should be noted that performing spinal MRI too early increases the rate of false-negative results.

2.4.4. Nuclear diagnostic imaging methods

ESC I B (LoE A, GoR 1)

Comment. With the introduction of hybrid equipment for conventional nuclear imaging [e.g., SPECT/CT and PET/CT], radioisotope technologies are considered an important complementary method for patients with suspected IE and diagnostic difficulties. SPECT/CT is based on the evaluation of the accumulation of autologous radiolabeled leukocytes (¹¹¹In-oxine or ^99mTc-hexamethylpropyleneamine oxime (INN: Technetium [99mTc] exametazime)) in inflammatory foci over time on early and late scintigrams. PET/CT is usually performed one hour after intravenous injection of ¹⁸F-FDG; the radiopharmaceutical agent (diagnostic radiopharmaceuticals) is taken up in vivo by activated leukocytes, monocyte-macrophages, and CD4 ⁺ T lymphocytes accumulating in foci of infection. There are several reports of promising results using radiolabeled leukocyte SPECT/CT and ¹⁸F-FDG PET/CT in IE. Additional data provided by these methods help reduce the rate of missed IE cases classified as "possible IE" according to the 2023 ESC criteria and also allow the detection of peripheral embolic events. Radiolabeled leukocyte SPECT/CT and ¹⁸F-FDG PET/CT are most informative for prosthetic valve IE and cardiac implantable electronic device-related IE. In cases of native valve IE, the sensitivity of radiolabeled leukocyte SPECT/CT and ¹⁸F-FDG PET/CT is low (about 31%), but with high specificity (about 98%) [130]. In native valve IE, the diagnosis of IE cannot be excluded in the absence of abnormal fluorodeoxyglucose (18F) uptake on PET/CT. The more frequent presence of valve vegetations compared to paravalvular lesions in native valve IE versus prosthetic valve IE leads to a lower inflammatory response and, consequently, lower uptake of fluorodeoxyglucose and leukocytes. However, the advantage of ¹⁸F-FDG PET/CT is its ability to detect embolic complications in IE, which increases diagnostic accuracy [131].

ESC I B (LE R, LoE 1)

Comment. A number of large Russian and foreign studies and meta-analyses have demonstrated high sensitivity and specificity for [18F] FDG-PET/CT in prosthetic valve IE [135, 136]. A limitation to the use of ¹⁸F-FDG PET/CT is the localization of septic emboli in the brain due to the high level of uptake of this diagnostic radiopharmaceutical by cortical cells, as well as the fact that lesions in this area are typically smaller than 5 mm, which is at the threshold of the method's spatial resolution. The results of ¹⁸F-FDG PET/CT must be interpreted with caution if cardiac surgery was recently performed, as the postoperative inflammatory response may lead to a non-specific increase in ¹⁸F-FDG uptake in the early postoperative period. The optimal timing for ¹⁸F-FDG PET/CT is 3 months or more after surgery. Active thrombosis, soft atherosclerotic plaques, vasculitis, primary cardiac tumors, metastases of non-cardiac tumors to the heart, postoperative inflammation, and foreign body reactions also increase ¹⁸F-FDG uptake, leading to false results.

ESC IIb B (LoE C, GoR 4)

ESC IIa C (LoE B, GoR 2)

Comment. Radiolabeled leukocyte SPECT/CT is more specific for detecting IE and foci of infection than ¹⁸F-FDG PET/CT and should be preferred in all situations where high specificity is required. Disadvantages of radiolabeled leukocyte scintigraphy include the need for in vitro radiolabeling of leukocytes, a longer procedure time compared to PET/CT, and a slightly lower spatial resolution and proton detection efficiency than PET/CT. An additional advantage of ¹⁸F-FDG PET/CT may be monitoring the response to antibiotic therapy in patients with established IE.

ESC I B (LoE C, GoR 4)

ESC IIb B (LoE C, GoR 4)

ESC not specified (LoE C, GoR 4)

2.5 Other Procedures

2.5.1. Electrocardiography

RCS I C (LeR C, LoE 5)

2.5.2. Abdominal ultrasound (comprehensive) and/or renal ultrasound

RSC I C (LoE C, GoR 4)

2.5.3. Coronary angiography

RSS I C (LE C, LoE 5)

Comment. If there are vegetations on the aorta that can be damaged and dislodged by instruments during CAG, or when emergency surgery is required, CT coronary angiography can be used to rule out coronary artery disease in hemodynamically stable patients.

2.5.4. Targeted chest X-ray

RCS I C (LeR C, LoE 5)

2.5.5. Prognostic assessment at admission

ESC IIa B (LE C, LoE 4)

Comment. The prognosis of IE is influenced by four main risk factors: patient characteristics, presence or absence of cardiac and extracardiac complications, IE etiology, and echocardiographic criteria (Appendix A3/7). When three risk factors are present, the risk reaches 79%. Advanced age, prosthetic valve involvement, heart failure, septic shock, cerebral complications, history of hemodialysis, paravalvular complications (especially abscess), and S. aureus infection are the strongest predictors of poor in-hospital prognosis [147, 148]. Furthermore, patients with persistently positive blood cultures 48–72 hours after initiation of antibiotic therapy are also at high risk of adverse outcomes and will derive significant benefit from early surgery. Timely cardiac surgery is an independent predictor of survival in IE, particularly in high-risk patients and those with uncontrolled infection and/or heart failure [149]. Among patients requiring emergency or urgent surgery, advanced age, impaired renal filtration function, prosthetic valve IE, septic shock, persistent infection, paravalvular complications, and multi-valve involvement are predictors of an adverse prognosis. Several surgical risk scoring systems have been developed, but none are widely used in routine clinical practice.

ESC I B (LE C, LoE 5)

Comment. The availability of an "Endocarditis Team" is preferred.

ESC IIa B (LE C, LoE 4)

Comment. Persistence of positive blood cultures 48–72 hours after initiation of antibiotic therapy indicates poor infection control and is considered an independent risk factor for in-hospital mortality.

2.5.6. Perioperative risk assessment in patients with infective endocarditis

RCS I C (LeR C, LoE 5)

Comment. Few studies have focused on the use of operative risk assessment scores in IE; therefore, there is currently no single standardized method for assessing perioperative risk. The indications for perioperative risk assessment in IE are clear and presented in Appendix A3/8, but their practical application is based more on the patient's clinical status, while comorbidities and surgical risk are not accounted for.

ESC I C (LOE B,等级 2)

Comment. In routine practice, the EuroSCORE II and the STS Short-term/Operative Risk Calculator are most commonly used to assess the risk of perioperative complications in cardiac surgery; these scores were developed and validated primarily for coronary artery bypass grafting and surgical treatment of valvular heart disease. The EuroSCORE II evaluates the following parameters: age, sex, comorbidities, renal dysfunction, IE activity, and planned surgical intervention. The STS Short-term/Operative Risk Calculator evaluates the following parameters: scope of surgery, demographic and laboratory parameters, pharmacotherapy, comorbidity, IE activity, bad habits, and cardiopulmonary disease. Specific risk scores for perioperative complications in IE patients have been developed by: (1) the Society of Thoracic Surgeons based on a database of 13,617 patients, and (2) De Feo et al. for native valve (NV) IE based on data from 440 patients. Comparative studies of the prognostic value of these two scores in IE patients after surgical treatment are of limited value due to the small sample size (146 patients), and further research is needed. Independent predictors of operative and long-term mortality include: preoperative use of inotropic agents (cardiac glycosides, non-glycoside cardiotonic agents) and intra-aortic balloon counterpulsation, as well as the presence of acute kidney injury (AKI) requiring renal replacement therapy (RRT).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Antibacterial therapy

3.1.1. General principles of antibacterial therapy

ESC IB (Level of Evidence C, Grade of Recommendation 5)

ESC IB (Level of Evidence C, Grade of Recommendation 5)

Comment. Microbial tolerance is the primary reason for prolonged antibiotic therapy. Tolerant microorganisms may be susceptible to systemic antibacterial drugs and fail to multiply during antibiotic therapy, yet resume growth immediately upon treatment completion. Typically, such microorganisms reside within vegetations and biofilms in PVE***. This necessitates prolonging antibiotic therapy to 6 weeks or longer for complete eradication of the pathogen. A combination of bactericidal systemic antibacterial drugs is preferable to monotherapy against tolerant microorganisms.

RCS I C (LeR C, LoE 5)

Comment. The starting point for determining the duration of antibiotic therapy (ABT) should be considered the first day of effective ABT (negative blood culture given a positive initial microbiological (cultural) blood sterility test prior to ABT prescription).

RCS I C (LeR C, LoE 5)

Comment. The day of surgery serves as the starting point for determining the duration of antibiotic therapy.

ESC III (LOE C, LOD 2)

ESC IB (LOE C, LOD 2)

Comment. In patients with staphylococcal NV IE, the administration of aminoglycosides showed no benefits but increased the incidence of renal complications. Aminoglycosides exhibit synergy with beta-lactam antibacterial drugs, penicillins (ATC J01C), cephalosporins, carbapenems, monobactams, and glycopeptide antibiotics, and may be useful as a short course complementary to antibiotic therapy for treating infections caused by certain streptococci and for eradicating challenging microorganisms such as enterococci.

ESC IIb C (CGR C, LOR 4)

Comment. This recommendation on the appropriateness of delayed administration is based on the potential antagonism of rifampicin** with other antibiotics against bacteria that are in the active replication phase (during bacteremia). At the same time, rifampicin** exhibits synergy with the same antibiotics, but against "dormant" bacteria within biofilms.

WhiteCoat Pro IIa C

(LOE B, LOD 2) – daptomycin**

(LOE C, LOD 5) – fosfomycin**

Comment. European guidelines indicate the use of daptomycin** only in high doses (≥10 mg/kg once daily) and in combination with other systemic antibacterial drugs to enhance activity and prevent the development of drug resistance [165].

RSC IIa C (LoE C, GoR 4)

RCS I C (LeR C, LoE 5)

RCS I C (LeR C, LoE 5)

RSC I C (LoE C, GoR 4)

Comment. AKI is a frequent complication of IE that can worsen the prognosis. The onset of AKI is independently associated with the risk of in-hospital mortality and postoperative events. AKI develops in approximately 6–30% of cases. Causes of AKI include: (1) immune complex and vasculitic glomerulonephritis; (2) renal infarction, primarily due to septic embolism, occurring at any stage of the disease; (3) hemodynamic failure secondary to heart failure, severe sepsis, or following cardiac surgery; (4) acute interstitial nephritis associated with the toxicity of aminoglycosides, vancomycin** (synergy with aminoglycosides), and even high doses of broad-spectrum penicillins; and (5) nephrotoxicity of contrast agents used in imaging. AKI requiring dialysis in IE dictates an unfavorable disease prognosis [167–171]. Appendix A3/9 presents the dosage adjustments of systemic antibacterial drugs in patients with renal and hepatic impairment.

3.1.2. Antibacterial therapy for streptococcal endocarditis

(For treatment regimens and dosage schedules, see Appendix A3/10)

ESC IB (LoE C, GoR 4)

Comment. #Gentamicin** and #netilmicin should be administered once daily [155, 166].

ESC IC (RR S, ELD 5)

ESC IIa C (Level of Evidence C, Expert Consensus)

Comment. The rationale for using a loading dose is determined by the high degree of plasma protein binding (≥98%).

ESC IB (Level of Evidence C, Grade of Recommendation 5)

ESC IB (Level of Evidence C, Grade of Recommendation 5)

Comment. The duration of therapy should be at least 4 weeks. Reducing the duration of treatment to 2 weeks has not been studied in patients with IE caused by S. pneumoniae.

RSC I C (LoE C, GoR 4)

Comment. When IE is combined with meningitis, the prescription of beta-lactam antibiotics and penicillins should be avoided due to their poor penetration across the blood-brain barrier; #ceftriaxone**, cefotaxime**, or vancomycin** should be prescribed instead.

RSC IIa C (LoE C, GoR 4)

Comment. This patient group has a very high mortality rate, and in the absence of contraindications, priority is given to surgical treatment.

RCS I C (LeR C, LoE 5)

RSC I C (LoE C, GoR 4)

• In patients with uncomplicated IE caused by Granulicatella spp. and Abiotrophia spp., without concomitant meningitis, it is recommended to consider switching to an oral antibacterial regimen in accordance with Appendix A3/17 at 10–14 days from the start of effective therapy [96; 401].

ESC IB (LoE B, GoR 2

3.1.3. Antibacterial therapy for staphylococcal endocarditis

(For the choice of therapy regimens and dosing regimens, see Appendix A3/11).

• In stable patients without complications, it is advisable to consider switching to outpatient oral therapy after 10–14 days of therapy [96] (Appendix A3/17).

ESC IB (LoE B, GoR 2)

RSC III C (LoE C, GoR 3)

RSC IIa B (LoE B, GoR 2)

Comment. Such therapy regimens cannot be used for prosthetic valve infective endocarditis.

ESC IIa C (Level of Evidence C, Expert Consensus)

Comment. Vancomycin** is less effective against MSSA than oxacillin** or cefazolin** (if susceptible) and should not be routinely prescribed in such cases. Desensitization should be performed by an allergist-immunologist or a clinical pharmacologist.

ESC IIa C (LoE C, GoR 4)

ESC IIb C (LoE B, GoR 3)

ESC I B (LE R, LoE 5)

ESC I B (LE C, LoE 5)

Comment. This recommendation regarding the feasibility of delayed administration is based on the potential antagonism of rifampicin** with other systemic antibacterial drugs against bacteria in the active multiplication phase (during bacteremia). At the same time, rifampicin** exhibits synergy with the same drugs against dormant bacteria within biofilms.

ESC IIB (LoE C, GoR 5)

ESC IIC (LoE C, GoR 4)

Comment: In all cases, the MIC of vancomycin for the pathogen should be determined. The use of vancomycin** is advisable if the MIC does not exceed 1 mg/L. At higher MIC values, effective concentrations of vancomycin** may not be achieved with therapeutic doses. An effective concentration is considered to be one at which the ratio of the area under the vancomycin** pharmacokinetic curve to the MIC is 400–600 mg*h/L. If the vancomycin** MIC for the pathogen is higher than 1 mg/L, other therapeutic options should be preferred.

ESC IIC (LoE C, GoR 4)

ESC IB (LoE C, GoR 5)

Comment. Combination with beta-lactam antibacterial drugs (J01C beta-lactam antibacterials, penicillins; J01D other beta-lactam antibacterials) and possibly fosfomycin** increases daptomycin** binding to cell membranes by reducing the surface positive charge for native valve IE, and with #gentamicin** and rifampicin** for prosthetic valve IE***.

CGR B, LEV 2 – for fosfomycin** with imipenem+cilastatin**, vancomycin**, #ceftobiprole medocaril**

CGR C, LEV 4 – for #ceftaroline fosamil** and #linezolid**

CGR B, LEV 3 – for #Co-trimoxazole [Sulfamethoxazole+Trimethoprim]** and clindamycin**

No ESC recommendation

Comment. It should be noted that combining vancomycin or daptomycin with cefazolin may increase the probability of acute kidney injury.

Experimental data and limited clinical observations indicate a potential role for #moxifloxacin** in the treatment of staphylococcal endocarditis [200, 201]. Complex cases of staphylococcal infection should be discussed with a clinical pharmacologist; #ceftaroline fosamil** is a cephalosporin with anti-MRSA activity (ATC – Other cephalosporins and penems); in a study of #ceftaroline fosamil** use in 125 patients with IE of staphylococcal etiology, the drug was prescribed as second- or third-line therapy after ineffective regimens involving vancomycin**, #linezolid**, daptomycin**. Another anti-MRSA cephem #ceftobiprole medocaril was studied in complicated staphylococcal bacteremia, including IE, in 189 patients in a randomized clinical trial, demonstrating comparable efficacy to daptomycin. Decisions regarding regimens for which infective endocarditis is not a registered indication (#co-trimoxazole**, #linezolid**, #ceftaroline fosamil**, #moxifloxacin**, #tigecycline**, #ceftobiprole medocaril) must be made by the hospital's Endocarditis Team and formalized in accordance with locally approved procedures.

3.1.4. Antibacterial therapy for enterococcal endocarditis

Features of enterococcal endocarditis include: reduced susceptibility to the bactericidal action of systemic antibacterial drugs, and the need for prolonged administration (up to 6 weeks) aimed at eradication using combinations of systemic antibacterial drugs. In cases of IE caused by E. faecium, therapeutic options may be limited (for antibiotic selection recommendations and dosing regimens, see Appendix A3/12).

ESC IB (CUA C, LOE 3)

Comment. The combination of ampicillin** with #ceftriaxone** is no less effective as a treatment regimen than the combination of ampicillin** with #gentamicin**, while carrying a lower risk of nephrotoxicity; therefore, this regimen is considered preferred [207]. As an alternative in the absence of ampicillin, administration of Ampicillin+[Sulbactam]** at a dose of 3 g every 6 h IV infusion may be considered [58], although its administration does not provide the recommended daily dose of ampicillin for adults.

RSC III C (CGR C, LEV 3)

Comment. Enterococcal strains with high-level resistance to aminoglycosides are associated with the loss of bactericidal synergy with other systemic antibacterial drugs. Aminoglycosides are not recommended in such cases.

ESC I B (LE C, LoE 5)

ESC IB (LoE C, GoR 5)

Comment. Such combinations must be prescribed in conjunction with a clinical pharmacologist. Decisions regarding the administration of regimens for which infective endocarditis is not a registered indication (#linezolid**, #ceftaroline fosamil**, #ceftobiprole medocaril**, #moxifloxacin**, #tigecycline**, etc.) must be made by the hospital's Endocarditis Team and formalized in accordance with locally approved procedures.

ESC IB (LoE C, GoE 4)

3.1.5. Antibacterial therapy for Gram-negative endocarditis

RSS I C (LE C, LoE 5)

RSS I C (LE C, LoE 5)

RSS I C (LE C, LoE 5)

RSC IIa C (CGR C, LEV 5)

RSC IIa C (CGR C, LEV 5)

Comment. The choice of antibiotic therapy regimen for healthcare-associated IE is determined by microbiological testing results, or for empirical therapy, by taking into account local resistance data for key pathogens. Each such case should be discussed by the Endocarditis Team, including a clinical pharmacologist, due to the rarity and complexity of patient management. Therapeutic drug monitoring of systemic antibacterial drug concentrations in blood serum (A09.05.035 Blood drug level testing) may be useful in such situations.

3.1.6. Antibacterial therapy for fungal endocarditis

RSC I B (CGR B, LEV 3)

Comment. Fungal IE most commonly occurs in intravenous drug users and immunocompromised patients, as well as long-term hospitalized patients receiving broad-spectrum antibiotic therapy. It is typically caused by Candida spp. and Aspergillus spp. Mortality in this variant of the disease reaches 50%.

(CGR C, LEV 4) – for #micafungin**, #caspofungin**, fluconazole**, voriconazole**.

(CGR C, LEV 5) – for #amphotericin B**, for #amphotericin B [lipid complex] and #Amphotericin B [liposomal].

RSC I C

RSC I C (LoE C, GoR 4)

RSC IIa C (CGR C, LEV 5)

RSS I C (LE C, LoE 5)

3.1.7. Antibacterial therapy for culture-negative endocarditis

(Appendix A3/13)

• Management of patients with CIED-IE is recommended to be discussed with the "Endocarditis Team" [150].

RSS I C (LE C, LoE 5)

3.1.8. Empirical antibacterial therapy for infective endocarditis

(Appendix A3/14)

RSC I C (LoE C, GoR 5)

RSC I C (LoE C, GoR 5)

Comment. In the presence of subacute native valve IE, to empirically cover S. aureus, Streptococcus spp., Enterococcus spp., and HACEK, the combination of ampicillin + [sulbactam]** or ceftriaxone with #vancomycin** may be prescribed as an alternative [153, 208].

RSS I C (LE C, LoE 5)

RSS I C (LE C, LoE 5)

3.1.9. Outpatient antibacterial therapy for infective endocarditis

Outpatient antibiotic therapy may serve as the second stage of treatment following inpatient care in selected clinical situations. Two options are possible: continuation of parenteral antibiotic therapy outside the hospital or administration of oral therapy.

RSC IIa C (LoE C, GoR 4)

Comment. Outpatient parenteral antibiotic therapy is used for the consolidation of antimicrobial treatment once critical complications are brought under control (e.g., perivalvular abscesses, acute heart failure, septic emboli, and stroke). There are two phases during antibiotic therapy: the critical phase—the first two weeks, when outpatient antibiotic therapy is limited; and the continuation phase—after 2 weeks of therapy, when outpatient antibiotic therapy may be considered. Outpatient therapy can only be considered if patient adherence is assured. Detailed indications are provided in Appendix A3/15.

RSC IIa C (LoE A, GoR 2)

Comment. The results of a randomized multicenter trial investigating the efficacy and safety of partial oral antibiotic therapy (POET 2016) in patients with IE (predominantly left-sided prosthetic valve IE) have been published, demonstrating that outpatient antibiotic therapy is non-inferior to intravenous antibiotic therapy. Criteria for switching to oral therapy and potential treatment regimens are presented in Appendix A3/16 and Appendix A3/17. Oral IE therapy may have limitations due to lower adherence, potential fluctuations in drug concentrations resulting from lower bioavailability compared to parenteral administration, particularly in cases involving resistant pathogens.

3.2. Antithrombotic therapy in patients with infective endocarditis

There are no specific indications for antithrombotic therapy in IE.

ESC I C (LoE C, GoR 5)

Comment. The risk of intracranial hemorrhage may be elevated in patients already receiving oral anticoagulants (antithrombotic agents) at the time of IE diagnosis, particularly in prosthetic valve IE*** caused by S. aureus [227, 228].

ESC IIa C (CARR C, LER 5)

Comment. Recommendations for managing anticoagulant therapy in IE are based on a low level of evidence, and decisions should be made on an individual basis by the "Endocarditis Team". The role of bridging therapy with unfractionated heparin** or its low molecular weight derivatives (e.g., nadroparin calcium/enoxaparin sodium**/dalteparin sodium) has not been studied in IE, but may have a rational basis in certain situations. If warfarin** is used, mandatory monitoring of the international normalized ratio (INR) is required

ESC IIa C (CARR C, LER 5)

ESC III C (LoE C, GoR 4)

Comment. Thrombolysis is contraindicated and sometimes leads to severe intracranial hemorrhages, but thrombectomy (medical service nomenclature: endovascular aspiration thrombectomy) may be an alternative in certain patients with ischemic stroke associated with IE.

The most frequent conduction disturbances in patients with IE are atrioventricular blocks, often associated with aortic and mitral valve involvement and linked to an unfavorable prognosis. Newly detected arrhythmias in patients with IE often indicate the development of perivalvular or coronary embolic complications and portend a poor prognosis. Atrial fibrillation may be one of the initial manifestations of IE or a complication thereof, and it is associated with a high risk of embolic events, heart failure, and an adverse prognosis.

RCS I C (LeR C, LoE 5)

Comment. Identified risk factors for embolic events in patients with atrial fibrillation and IE include age, diabetes mellitus, history of embolic events, vegetation length, and S. aureus infection.

RSC III C (LoE A, GoR 2)

Comment. Evidence does not support initiating antithrombotic therapy in patients with IE, despite positive results from experimental studies [231]. Some cohort studies suggest a possible reduction in the frequency of embolic events [232] or the development of IE in subgroups of patients already receiving such therapy [233], but data remain conflicting [234, 235].

3.3 Surgical Treatment

3.3.1. General principles of surgical treatment for infective endocarditis

ESC IA (LoE C, SoR 5)

Comment: Indications for cardiac surgery in left-sided native or prosthetic valve IE include: progressive heart failure [6, 58]; uncontrolled persistent infection (persistent bacteremia despite adequate antibiotic therapy for >7 days; ongoing signs of locally uncontrolled infection – increase in vegetation size, abscess formation, pseudoaneurysms or fistulae, new AV block despite adequate antibiotic therapy [4, 6, 58, 236, 237]; high embolic risk (mobile vegetations, prior emboli, vegetation size >1 cm) [6, 58]; IE caused by fungi or highly virulent organisms [6, 58].

ESC I B (LoE C, GoR 5)

Comment: Indications for cardiac surgical treatment of right-sided IE are: right ventricular dysfunction, secondary to acute severe tricuspid regurgitation with poor response to medical therapy [6, 58]; persistent infection (persisting vegetation size or vegetation >2 cm despite adequate antibiotic therapy; IE caused by difficult-to-treat multidrug-resistant pathogens) [6, 58]; recurrent septic embolism of the pulmonary artery [6, 58].

ESC III C (LoE C, GoR 4)

Comment: Patients operated on for IE associated with drug abuse have a low risk of in-hospital mortality, but high rates of readmission, recurrent infection, and septicemia. Ongoing drug addiction leads to decreased postoperative survival [238, 239]. There are also major challenges in the postoperative management of this patient group, including lack of support from physicians and the healthcare system [240]. To minimize the risk of reinfection and improve short- and long-term surgical outcomes in this patient group, an interdisciplinary approach is required, establishing communication between surgeons and addiction experts for the joint management of both the acute infection and substance use disorder [239–242].

ESC I B (LE R, LoE 5)

ESC not stated (LoE B, GoR 3)

ESC not stated (LoE C, GoR 4)

3.3.2. Indications and Timing of Surgery in Patients with Left-Sided Infective Endocarditis and Heart Failure

ESC IB (Level of Evidence C, Grade of Recommendation 5)

ESC IB (LoE C, GoR 4)

RSC I B (LoE A, GoR 2)

Comment. In patients with IE and heart failure, in-hospital and long-term mortality with conservative therapy is 31% and 53%, respectively. Cardiogenic shock is the most severe form of heart failure, manifested by hemodynamic instability and tissue hypoperfusion leading to irreversible organ damage and death. Operative mortality in left-sided active IE is expectedly high (9.4%), but significantly lower than mortality with conservative therapy (31.3%) [246]. At the same time, surgical treatment of IE with heart failure is associated with increased 1-year and long-term survival [241, 246, 253, 254]. However, despite recommendations for early intervention, in clinical practice, surgery is performed in less than half (44%) of patients with IE and heart failure, mainly due to surgical risk deemed unacceptable by physicians (age, comorbidities, left or right ventricular dysfunction, multiorgan failure, septic complications, severe baseline condition) [246]. Early diagnosis of IE, detection of signs of heart failure, determination of biomarkers and predictors of heart failure progression before hemodynamic deterioration and complications occur, and early referral of patients to cardiac surgery centers allow for earlier consideration of surgical treatment to prevent complications and reduce mortality [246, 249–252, 255].

3.3.3. Indications and Timing of Surgery in Patients with IE and Uncontrolled Infection

ESC IB (LoE C, GoR 4)

ESC IB (Level of Evidence A, Class of Recommendation 2)

ESC IC (Level of Evidence C, Grade of Recommendation 4)

3.3.4. Indications and Timing of Surgery in Patients with IE and Embolic Events

RSC I B (LoE C, GoR 4)

Comment. The brain and spleen are the most frequent sites of embolism in left-sided IE, whereas pulmonary embolism is common in right-sided IE and cardiac implantable electronic device-related IE*** [263].

ESC I A (BRP C, LoE 4)

ESC IIA (LoE C, GoR 4)

Comment. Patients with vegetation size >10 mm, mobile vegetations, and staphylococcal IE have a high risk of embolism. The risk of embolic events is high during the first 2 weeks of antibiotic therapy. For this reason, the benefit of surgery for the prevention of embolism is highest during the first 2 weeks of antibiotic therapy.

ESC IB (LoE C, GoR 5)

RSC IIa C (LoE C, GoR 4)

Comment. The question regarding the tactics and sequence of treatment for patients with infective endocarditis (IE) and preoperative pulmonary complications remains a subject of debate. Pulmonary disease in right-sided IE / CIED-associated IE occurs as a result of septic embolism, which in some patients leads to pulmonary embolism, pulmonary infarction, abscess, and pleural empyema. Most experts recommend surgical treatment for right-sided IE with pulmonary complications when indications are present [241, 269]. In left-sided IE, pulmonary involvement is associated with a septic complication (bacteremia) and the development of a systemic inflammatory response, clinically manifested as pneumonia, vasculitis, and diffuse alveolar hemorrhage, while direct infection of the lung can cause pneumonia [263]. Surgical treatment in this case is associated with progressive respiratory failure, a high risk of mortality, and an adverse outcome [270]. Management of this category of patients includes antibiotic therapy (ABT), supportive care, and, when indicated, drainage of pleural effusions, abscesses, and other surgical interventions on the lung tissue [4].

3.3.5. Indications and Timing of Surgery in Patients with Infective Endocarditis Complicated by Neurological Events and Other Embolisms

Neurological complications in IE occur in 10–40% of patients, are associated with vegetation embolism, and may be asymptomatic or clinically manifest as transient ischemic attack (TIA), ischemic/hemorrhagic stroke, brain abscess, meningitis, and toxic encephalopathy. Therapeutic strategies for patients with IE and neurological complications are presented in Appendix B6.

ESC IB (LoE C, GoE 5)

ESC IB (LoE C, GoE 5)

Comment: Infectious (mycotic) aneurysms result from septic arterial embolism either intraluminally or into the vasa vasorum, followed by the spread of infection. They are typically thin-walled, easily damaged, and prone to rupture/bleeding. There are no established predictors of bleeding from mycotic aneurysms and, unlike non-infectious aneurysms, their size does not correlate with the likelihood of rupture. Intracranial localization of mycotic aneurysms is the most frequent, occurring in 2–4% of cases, which is likely an underestimate since the majority of them are asymptomatic.

ESC IIa C (CGR C, LOR 5)

ESC IB (LoE C, GoE 4)

ESC IC (LoE A, GoE 2)

ESC IIa C (LoE A, GoE 2)

Comment. Several retrospective studies report the benefits of early surgery (within 2 weeks) after hemorrhagic stroke without further worsening of neurological outcomes. In patients in whom surgery is delayed, repeat CT or MRI of the brain and cerebral vessels should be performed 1–2 weeks after intracranial hemorrhage (or earlier in case of clinical deterioration) to assess the stability of cerebral findings and potentially reassess the timing of surgery. Therapeutic strategies for patients with IE and neurological complications are presented in Appendix B6.

RSC I B (LoE C, GoR 4)

Comment. The timing of surgery in IE with neurological complications remains controversial. Early surgery may lead to conversion to hemorrhagic stroke as a result of systemic heparinization during cardiopulmonary bypass (CPB) or exacerbation of ischemic stroke due to intraoperative hypotension. Delayed surgery may lead to recurrent embolic episodes and recurrent neurological stroke. In patients with ischemic embolic complications, mortality and recurrence rates of IE are similar between early and delayed surgery groups [248, 276]. At the same time, in patients with stroke, early surgical intervention in acute endocarditis is not associated with an increased stroke rate [275]. Therapeutic strategies for patients with IE and neurological complications are presented in Appendix B6.

ESC IB (CQR A, LOR 2)

• In patients with IE and mycotic aneurysms, the management strategy for aneurysms should be determined by a multidisciplinary team (Endocarditis Team) [150].

RSS I C (LE C, LoE 5)

Comment. Some infectious aneurysms may resolve with antibiotic therapy (ABT), whereas others require surgical and endovascular interventions depending on the visibility of rupture, the vascular arterial bed, and the patient's clinical status. The management of patients with IE and intracranial mycotic aneurysms is determined by the presence of neurological complications, the likelihood of aneurysm rupture, and the dynamics of their size during ABT. Intracranial infectious aneurysms complicated by rupture must be treated immediately, surgically or endovascularly. Uncomplicated aneurysms should be monitored using imaging methods while on ABT. If the aneurysm decreases in size or resolves completely, intervention becomes unnecessary. However, if the aneurysm increases in size or remains unchanged, the patient will likely require intervention.

• In patients with IE and large symptomatic mycotic intracranial aneurysms, as well as part of preoperative preparation, it is recommended to consider neurosurgical or endovascular intervention [277].

ESC I C (LoE C, GoR 4)

RSC I B (LoE C, GoR 4)

Comment. Splenectomy is indicated for splenic rupture or abscess and should be performed before valve surgery or simultaneously. When surgical risk is high, percutaneous drainage of the splenic abscess can be an alternative (MHI: drainage of a splenic abscess using video-endoscopic technologies) to reduce bacterial load, perform microbiological (culture) examination of the explanted material (MHI: microbiological (culture) examination of purulent discharge for aerobic and facultatively anaerobic microorganisms; microbiological (culture) examination of abscesses for aerobic and facultatively anaerobic microorganisms) and select appropriate ABT prior to elective surgery [280].

3.3.6 Surgical approaches and choice of valve replacement in patients with infective endocarditis

RSC I B (LoE A, GoE 2)

RSC I B (LoE C, GoE 4)

Comment. In complicated IE, preference is given to allografts because they possess hemostatic properties, good hemodynamic function, and a low risk of thrombotic complications, and can be used in combined lesions of the anterior mitral valve leaflet, while the "free root" implantation technique allows the abscess cavity to be excluded from the bloodstream [286–289]. In some patients with IE, particularly children, the Ross procedure may be considered [290, 291].

RSC I B (LoE C, GoR 4)

REC I B (LoE A, GoR 2)

RSC I B (LoE C, GoR 4)

Comment. Defects of the fibrous ring and leaflets can be repaired with an autopericardial or xenopericardial patch. The results of valve-sparing interventions show a low rate of infection recurrence, and in cases of tricuspid valve IE, they avoid the implantation of a right ventricle-to-pulmonary artery bioprosthetic conduit and inevitable long-term degeneration [298]. Clinical outcomes can be improved by focusing on early surgery, prior to extensive valve destruction, to ensure a durable repair and improve long-term outcomes [299].

REC III C (LoE C, GoR 4)

Comment. Reconstructive interventions for IE and extensive destruction of the heart valve apparatus (e.g., destruction and deficiency of the anterior mitral leaflet) do not show advantages in survival and infection recurrence; there are likely other factors determining the outcome, such as infectious pathogens, comorbidities, and cardiac dysfunction [299, 301].

ESC IIa C (LoE C, GoR 5)

REC IIa C (LoE C, GoR 4)

RSS I B (CGR C, LOR 5)

RSC I B (LoE C, GoR 4)

Comment. Patients with stroke are at significant risk of hemorrhagic transformation when a mechanical prosthesis is implanted due to the need for anticoagulant therapy [306]. The risk of infectious endocarditis, including reinfection, is significantly higher in patients with a biological heart valve prosthesis [307, 308].

3.3.7. Perioperative management of patients with infective endocarditis, anesthetic management

• In patients with IE, extracardiac foci of infection are recommended to be eliminated prior to cardiac surgery [293].

RSC I B (LoE C, GoE 4)

• All patients with IE admitted to the hospital for surgical treatment are recommended to undergo an acid-base balance and blood gas analysis (pH, BE, pCO2, PO2, Lac – capillary/arterial/venous blood samples) to assess the severity of hypoxemia and the degree of metabolic disorders [4, 41].

REC IIa C (LoE C, GoR 5)

• All patients with IE admitted to the hospital for surgical treatment are recommended to undergo a coagulogram (exploratory hemostasis screening) (aPTT, PT, prothrombin index, blood D-dimer concentration, blood fibrinogen level, blood antithrombin III activity), and INR determination to predict the risk of perioperative bleeding and blood loss volume [4, 41].

REC IIa C (LoE C, GoR 5)

• All patients with IE admitted to the hospital for surgical treatment are recommended to determine ABO blood groups, Rhesus antigen D (Rh factor), phenotype for C, c, E, e, Cw, K, k antigens, and irregular red blood cell antibodies to address the issue of transfusing type-specific red blood cell components of donor blood [4, 41].

REC IIa C (LoE C, GoR 5)

• All patients with IE admitted to the hospital for surgical treatment are recommended, as part of premedication, to be prescribed anxiolytics on the evening before surgery to reduce emotional stress and ensure sedation and emotional stability. Opioids and/or benzodiazepine derivatives are used for premedication before transferring the patient to the operating room to provide sedation and emotional stability [309].

REC IIa C (LoE C, GoR 5)

Comment. Evening before surgery: benzodiazepine derivatives in individual dosages. Before transfer to the operating room: intramuscular trimeperidine** and/or diazepam**/midazolam**. Drugs that increase heart rate should be excluded from premedication.

• All patients with IE admitted to the hospital for surgical treatment are recommended to use the following for intraoperative analgesia: propofol**, benzodiazepine derivatives, halogenated hydrocarbons. Fentanyl** (for premedication before surgery), diazepam** (as part of preparation for surgery) [309].

RSC I C (LoE C, GoR 5)

• During cardiac surgery, either intravenous anesthesia based on propofol** and fentanyl** or combined anesthesia using halogenated hydrocarbons and fentanyl** at all stages of surgery can be used [309, 310].

REC IIa C (LoE A, GoR 2)

Comment. The following drugs are used for intraoperative analgesia: midazolam**/diazepam**/propofol** and fentanyl**, sodium oxybutyrate**, and halogenated hydrocarbons can be used in combination with intravenous fentanyl** in calculated dosages. A multicenter RCT revealed no differences in clinical outcomes when using total intravenous anesthesia based on propofol** and fentanyl** versus combined anesthesia using halogenated hydrocarbons and fentanyl** during cardiac surgery [310].

• All patients with IE admitted to the hospital for surgical treatment are recommended to receive opioids in age-appropriate dosages for analgesia in the early postoperative period [309].

RSC I C (LoE C, GoR 5)

Comment. Drugs used for postoperative analgesia: first 24 hours after surgery – trimeperidine** or morphine** intramuscularly every 4–8 hours, NSAIDs. If special dispensers are available (e.g., syringe infusion pumps, etc.), patient-controlled analgesia with fentanyl** is effective. If severe pain persists, trimeperidine**/morphine**/fentanyl** as indicated.

3.3.8. Postoperative complications and postoperative follow-up of patients with infective endocarditis

• When managing patients after surgery for IE, it is necessary to follow the guidelines for managing patients after surgical correction of valvular heart disease, taking into account the specifics of IE and the duration of antibiotic therapy [311].

REC I B (LoE C, GoR 3)

Comment. Postoperative follow-up should be particularly careful due to the known in-hospital mortality of patients operated on for IE on an urgent or emergency basis. Mortality ranges from 10% to 20% in most studies.

Patients with IE after surgical treatment have a high risk of postoperative complications. The most frequent postoperative complications of IE include severe coagulopathy requiring treatment with coagulation factors; resternotomy due to bleeding or cardiac tamponade; AKI requiring RRT; stroke; low cardiac output syndrome; pneumonia; and atrioventricular block following radical resection of an aortic root abscess requiring the placement of permanent leads for permanent cardiac pacemakers (PPM). If death occurs in the postoperative period, the cause of death is most often multifactorial.

Patients with IE after surgical treatment remain at risk for complications after hospital discharge. The most frequent complications include reinfection, HF, the need for reoperation, and death.

• In patients with IE, especially after surgical treatment, it is recommended to determine the presence of risk factors associated with an increased rate of disease recurrence [312, 313].

RSC I B (CGR B, LEV 3)

Comment. The risk of infection recurrence in IE survivors is 2–6%. Two variants of recurrent IE are distinguished: relapse and reinfection. Although there are no clear definitions of these clinical situations in the literature, the term "relapse" refers to a repeated episode of IE caused by the same microorganism, whereas "reinfection" denotes infection with a new microorganism. Risk factors associated with an increased frequency of relapses are listed in Appendix A3/20. Relapses usually develop due to inadequate duration of the initial treatment and persistence of the focus of infection. In cases of insufficient treatment duration or an incorrect antibiotic therapy regimen, the relapse should be treated for an additional 4–6 weeks, depending on the microorganism and its susceptibility.

• Patients with a history of IE are recommended to be classified as being at high risk for IE development and should undergo strict prophylactic measures (see Appendices A3/21–A3/24) [8].

ESC I B (LOE C, EL 4)

Comment. IE reinfection occurs most frequently in intravenous drug users (especially during the first year), after prosthetic valve IE***, in patients on chronic hemodialysis, and in those with multiple IE risk factors. Patients with reinfection following a previous episode of IE have a poor prognosis. Patients with reinfection have a higher risk of death and the need for valve replacement. Paravalvular destruction is associated with a higher rate of recurrence and higher operative mortality.

3.4. Management of patients with infective endocarditis in specific clinical settings

3.4.1. Prosthetic valve infective endocarditis

ESC I B (LoE C, GoR 4)

Comment. Due to differences in the microbiological profile, early PVIE (within 1 year) and late PVIE (more than 1 year after surgery) are distinguished. The main causative agents of early PVIE are staphylococci, fungi, and Gram-negative bacteria. The main causative agents of late PVIE are staphylococci, streptococci, S. bovis, and enterococci [316].

ESC I B (LOE C, EL 4)

ESC I B (LoE A, GoR 2)

Comment. Radioisotope imaging, ¹⁸F-FDG PET/CT, has been included as a new major Duke criterion for the diagnosis of PVIE [316].

ESC I C (LoE C, GoR 4)

ESC I C (LoE C, GoR 5)

ESC IIa B (LOE C, EL 4)

3.4.1.1 Infective endocarditis in patients after transcatheter aortic valve implantation (TAVI)

The incidence of prosthetic valve endocarditis after TAVI is 2.4–2.7% [325]. The risk of PVIE is higher during the first year after the procedure and is presumably associated with technical and intraoperative complications. Risk factors for PVIE include male sex, tracheal intubation, chronic kidney disease, and the use of a transfemoral approach [326, 327]. The most frequent causative agents are enterococci [316].

Diagnosis of PVIE after TAVI is challenging, and many cases remain undiagnosed due to a lack of data and clinical experience [328].

Clinical manifestations are non-pathognomonic or entirely absent, especially in elderly patients. TTE or TEE is informative in only 60% of cases (with large vegetations obstructing the stent-valve lumen). In cases of small vegetations, ultrasound diagnostics are unable to identify calcium/vegetations located within the stent-valve frame. In uncertain cases, positron emission tomography using [18F]FDG PET/CT is informative, as it allows the detection of abnormal metabolic activity [248, 316]. However, nuclear imaging methods can be used if more than 3 months have passed since valve prosthesis implantation [320].

RCS I C (LOE C, EL 3)

Comment. In cases of stent-valve PVIE, open cardiac surgery is performed in 22% of cases, while the remaining patients are treated conservatively. Mortality is 16.7% in the surgical treatment group and 37.4% in the antibiotic therapy group [75].

RCS I C (LOE C, EL 4)

REC IIa C (LoE C, GoR 4)

Comment. Surgical endovascular interventions can be performed no earlier than 1–3 months after the initiation of effective antibiotic therapy and cured PVIE confirmed by imaging methods.

RSC I B (LoE C, GoR 4)

Comment. In the early stages of reoperation, endothelialization of the stent-valve frame is incomplete, which facilitates easy explantation of the prosthesis [332]. In most cases, prosthesis explantation is associated with a high risk of left ventricular outflow tract injury and the need for interventions on the ascending aorta [248].

3.4.2. Infective endocarditis associated with implantable cardiac electronic devices

Infection of implanted cardiac electronic devices (CIEDs) is a severe condition associated with high mortality. The increasing rate of CIED implantation is accompanied by a growing proportion of older patients with multiple comorbid conditions. This leads to a risk of CIED infection, including the development of IE. The incidence of CIED infection is 1.9 per 1,000 device-years, with a higher probability of infection for ICDs compared to permanent pacemakers. The diagnostic algorithm for CIED pocket infection or CIED-associated systemic infection is presented in Appendix B7.

RCS I C (LOE C, EL 4)

Comment. Localized infection is defined as infection confined to the device pocket itself and is clinically suspected when local inflammatory signs are present in the generator pocket, including erythema, local warmth, fluctuation, wound dehiscence, erosion, tenderness, and purulent discharge. CIED-related IE is defined as infection spreading along leads, valve leaflets, or the endocardial surface.

Risk factors for CIED*** infection are associated with two main aspects: patient-related risk factors and implantation procedure-related risk factors. Patient-related factors include acute kidney injury (AKI), glucocorticoid therapy, congestive heart failure (CHF), hematomas, diabetes mellitus, or the use of anticoagulants (B01A Antithrombotic agents). Procedure-related risk factors include the type of surgical intervention, the site of the intervention, the use of a periprocedural temporary pacemaker, failure to use perioperative antibiotic prophylaxis, fever within 24 hours prior to implantation, and the surgeon's experience. The most common causative agents of CIED-associated IE are staphylococci (60–80%), predominantly CoNS. Methicillin resistance among staphylococci varies across studies, but a low frequency of methicillin-resistant CoNS has been shown for individuals with no history of contact with healthcare facilities, whereas a high level of methicillin resistance in CoNS is associated with healthcare-associated infections. Polymicrobial infection occasionally involves even a single CoNS species. Corynebacterium spp., Propionibacterium acnes, Gram-negative bacteria, and Candida spp. are rarely encountered in CIED infections [333–335]. Diagnosis of CIED IE remains challenging due to the masked clinical presentation and imaging difficulties. The clinical picture of CIED IE is characterized by a predominance of respiratory and rheumatic syndromes, and local signs of infection. CIED IE should be suspected in any CIED patient presenting with fever of unknown origin. Fever is often absent or mild, especially in the elderly. As with other forms of IE, blood cultures for sterility and echocardiography are the cornerstones of diagnosis. S. aureus bacteremia may be the sole manifestation of a CIED infection.

ESC I C (LoE C, GoR 5)

ESC I C (LoE C, GoR 5)

ESC I B (GРR C, LоE 4)

Comment. Echocardiography plays a pivotal role in CIED IE and is useful for diagnosing both lead vegetations and valve involvement, assessing tricuspid regurgitation, measuring vegetations, and monitoring following lead extraction. TEE has higher sensitivity and specificity for diagnosing lead-associated endocarditis. Performing both examinations is indicated when CIED IE is suspected. The diagnostic algorithm for CIED pocket infection or CIED-associated systemic infection is presented in Appendix B7.

ESC IIb C (LoE C, GoR 4)

ESC IIb C (LoE C, GoR 4)

Comment. A standard echocardiographic examination does not rule out CIED IE. In complex cases, labeled leukocyte SPECT/CT and ¹⁸F-FDG PET/CT can be utilized as supplementary methods in the diagnosis of CIED IE and related complications, including septic pulmonary emboli/abscesses.

RCS I C (LOE C, EL 4)

Comment. The Duke criteria are difficult to apply to such patients due to low sensitivity. Modified Duke criteria were specifically developed, incorporating local signs of infection and pulmonary embolism as major criteria.

ESC I C (LoE C, GoR 4)

Comment. Since most infections are related to staphylococci in one way or another, and approximately 50% of these are methicillin-resistant, vancomycin** should be used for empiric therapy. Daptomycin**, approved for the treatment of right-sided IE and S. aureus bacteremia, is a promising drug for treating CIED infection. The duration of therapy should be 4–6 weeks in most cases. At least 2 weeks of parenteral administration is indicated after the removal of all infected devices in patients with bloodstream infection. Patients with persistent bacteremia (positive blood cultures for sterility > 24 h) despite CIED removal and appropriate antimicrobial therapy should receive parenteral drugs for at least 4 weeks.

ESC IIa C (LoE C, GoR 4)

Comment. In cases of definite CIED IE, medical therapy alone is associated with higher mortality and a greater risk of relapse.

ESC IIa C (LoE C, GoR 4)

ESC IIa C (LoE C, GoR 4)

ESC IIa C (LoE C, GoR 4)

ESC I B (LoE C, GoR 4)

Comment. Considering the risks of open surgery, transvenous lead extraction is the preferred method. It is important to remove all hardware to prevent recurrent infection. In experienced centers, procedural mortality is 0.1–0.6%. Typical ICD*** leads are harder to remove than traditional pacemaker leads, which are usually removed by simple manual traction. Pulmonary embolism resulting from the detachment of vegetations during extraction occurs frequently, especially when vegetations are large. However, these episodes are often asymptomatic, and percutaneous extraction remains the recommended method even in cases of large vegetations, as the overall risks are higher with surgical removal.

ESC IIb C (LoE C, GoR 4)

ESC IIa C (LoE C, GoR 4)

ESC I C (LoE C, GoR 4)

Comment. The first step prior to reimplantation is a reassessment of the indications for CIED placement. In a significant number of cases, reimplantation is unnecessary.

ESC I C (LoE C, GoR 4)

Comment. Immediate reimplantation should be avoided due to the risk of reinfection [333, 335, 356, 358]. Blood culture results for sterility must be negative for at least 72 hours prior to placing a new device. In cases of documented residual valvular infection, implantation should be delayed for at least 14 days.

ESC IIb C (GРR A, LоE 3)

ESC III C (LoE C, GoR 4)

Comment. Temporary pacing carries a risk of subsequent CIED*** infection, and its use should be avoided whenever possible. In pacemaker-dependent*** patients, the temporary use of actively fixated leads connected to external devices is described as "bridging," which enables early mobilization while reducing the risk of CIED***-related adverse events [361–363].

ESC I B (LOE C, EL 4)

Comment. Vancomycin**, #teicoplanin (400–800 mg 1–2 IV administrations) [367] may be considered instead of cefazolin** in centers with high staphylococcal resistance to oxacillin**, as well as in high-risk patients or in case of contraindications to cephalosporins.

ESC IIa C (Level of Clinical Evidence C, Grade of Recommendation 5)

ESC IIa C (Level of Clinical Evidence C, Grade of Recommendation 5)

ESC IIb C (LoE C, LoR 5)

ESC IIa C (Level of Clinical Evidence B, Level of Scientific Evidence 3)

ESC III (Level of Clinical Evidence A, Level of Scientific Evidence 2)

3.4.3. Infective endocarditis in the intensive care unit

Patients with IE may be admitted to the intensive care unit (ICU) for a number of reasons requiring intensive monitoring, controlled hemodynamic support, and personalized management of cardiac and multiorgan failure. First, due to the development of IE complications, such as septic, cardiogenic, or combined shock, acute heart failure, and a number of embolic (primarily cerebral) and non-embolic complications. Second, following surgical treatment for IE for further monitoring in the ICU [6, 258, 372]. Mortality in IE requiring ICU admission remains particularly high at 20–42% [9, 372–374]. ICU patients are characterized by a high risk of nosocomial infections, which also determines the risk of nosocomial IE, especially in the elderly and/or in the presence of implanted electronic (pacemakers, cardioverter-defibrillators, cardiac resynchronization therapy devices) and non-electronic (e.g., central venous catheters) devices [6, 244]. The causative pathogens of IE in the ICU are predominantly S. aureus (80–90%), Str. viridans (26%), and other streptococci (19%). In recent years, there has been a significant increase in the incidence of IE caused by Enterococcus spp. (11%) and coagulase-negative staphylococci [372, 375, 376]. A growing problem of IE in the ICU is Gram-negative flora and fungal IE (usually Candida spp.). Overall, the following features of IE can be noted in ICU patients [6, 258, 372, 377]:

— Indications for ICU transfer in most cases are sepsis, septic shock, respiratory failure, embolic complications

— In addition to IE, a number of other conditions competing with the diagnosis of IE are frequently observed, such as sepsis, heart failure, acute kidney injury, and others

— A masked clinical presentation of IE and reduced sensitivity of the Duke criteria, which are not validated for ICU patients, patients with nosocomial IE, and patients with CIED-IE***

— Reduced sensitivity of echocardiography in the diagnosis of IE, especially transthoracic echocardiography during mechanical ventilation with positive end-expiratory pressure

— Low reliability of blood culture results for sterility due to the necessity of early antimicrobial therapy initiation

— High frequency of IE caused by S. aureus, coagulase-negative staphylococci (e.g., S. epidermidis), and E. faecalis. The risk of bloodstream infection caused by resistant and (hyper-)virulent Gram-negative pathogens (e.g., Klebsiella spp.).

— More frequent presence of intravascular implanted devices (central venous catheter, temporary/permanent pacemaker)

RSC I C (LoE C, GoR 5)

Comment. The clinical manifestation of IE in ICU patients can be atypical and have several important features. Clinical signs may be "masked" by comorbid conditions and intensive care modalities. Thus, fever may be explained by a competing nosocomial infection, signs of embolic neurological complications may be obscured due to sedation, and renal and other organ damage may be interpreted as a systemic manifestation of multiorgan failure in the setting of septic shock. The Duke criteria were recently modified to account for the emergence of new risk factors and diagnostic methods [6, 316]. It should be noted that they are validated exclusively for left-sided native valve IE outside the ICU [378]. It is very likely that the diagnostic accuracy of the Duke criteria in ICU patients is significantly lower, especially in prosthetic valve IE and cardiac implantable electronic device IE [316, 372].

ESC IIb B (LoE C, GoR 5)

Comment: Transthoracic echocardiography has low sensitivity for IE in ICU patients [6]. Extreme caution should be exercised regarding the following signs of systemic and especially multifocal embolism*: brain, splenic, and periparticular abscess(es), arthritis, epidural abscess, psoas abscess, osteomyelitis (spondylitis), and multiple concurrent soft tissue phlegmons and abscesses. IE should not be excluded in the absence of visible valvular or extravalvular vegetations and alternative primary sources of infection. When performing echocardiography, attention should be paid to potential signs of IE such as thickening of the valve leaflet(s), newly developed regurgitation, and paravalvular changes [316, 372, 377].

RSC IIa B (Level of Clinical Evidence C, Level of Scientific Evidence 4)

Comment. The diagnostic utility of transthoracic echocardiography may be reduced due to lung hyperinflation and limited acoustic windows during invasive or non-invasive mechanical ventilation with positive end-expiratory pressure. In addition, hemodynamic problems may occur when turning ICU patients in shock onto their side. The sensitivity of transthoracic echocardiography for detecting native valve vegetations is 60–70% [372, 377], but for vegetations smaller than 5–6 mm, CIED-IE***, and prosthetic valve IE, it is significantly lower at 40–50%. Therefore, transesophageal echocardiography serves as the method of choice in ICU patients generally, and especially in prosthetic valve IE, CIED-IE***, and particularly in the presence of an established central venous catheter [379]. Negative transesophageal echocardiography results can serve as an additional argument to search for an alternative diagnosis and modify the antibiotic therapy regimen.

ESC I B (LE R, LoE 5)

ESC I B (LE R, LoE 5)

Comment. Antimicrobial therapy and indications for surgical treatment in patients with IE are described in the relevant sections of the clinical guidelines. Patients with IE in the ICU have the highest mortality rate among those operated on for IE. Decision-making regarding the management strategy for such patients, when indications and contraindications for cardiac surgery coexist, is complex and must be made in the context of multidisciplinary teamwork among specialists from various fields ("Endocarditis Team"), taking into account the severity of the patient's condition and comorbid factors, primarily the presence of sepsis and septic shock [380, 381].

3.4.4. Right-sided infective endocarditis

Right-sided IE (RIE) accounts for ∼5–34.6% of all IE cases [11, 19, 382, 383]. Risk factors for right-sided IE include patients with congenital heart disease (see Chapter 3.4.5.), patients with central venous catheters and CIED*** (see Chapter 3.4.2.), as well as immunocompromised patients, for example, those with HIV infection and substance use disorder. The etiological factor of RIE is most often staphylococcal infection. S. aureus is found in 38–70% of patients with RIE, with a rising trend in the frequency of MRSA and polymicrobial infection.

Rind-sided IE most commonly involves the tricuspid valve — up to 90–100% in IE among people who use drugs and in 56.4–82% of patients who do not use drugs [384–386]. Other possible localizations of right-sided IE include: CIED leads***, pulmonary valve, Eustachian valve, Thebesian valve, other minor congenital anomalies of the right atrium, and mural involvement. Right-sided heart involvement is occasionally observed in combination with mitral or aortic valve lesions [387, 388]. In-hospital mortality for RIE is 5–15%. Typical manifestations of RIE include fever, bacteremia, and multiple septic cardiogenic pulmonary emboli, which manifest as chest pain, cough, hemoptysis, and dyspnea. Septic multilobar embolic pneumonia develops in 65–100% of patients, characterized by bilateral lung involvement and the detection on radiography of multiple rapidly changing focal infiltrates with abscess formation and subsequent cyst-like cavity development [11, 107]. Isolated right-sided heart failure can be caused by either pulmonary hypertension or severe tricuspid regurgitation or obstruction, but is observed rarely.

ESC IC (LoE C, GoR 5)

ESC IIbC (Level of Evidence C, GR 4)

ESC IC (Level of Evidence C, Quality of Evidence 4)

ESC IC (RR S, ELD 5)

Comment. Empirical antibiotic therapy includes beta-lactamase-resistant penicillins, #vancomycin**, or daptomycin**, depending on the local prevalence of MRSA, in combination with #gentamicin**. If the patient uses pentazocine, an antibiotic with antipseudomonal activity should be added (Systemic antibacterial drugs). If the patient uses "brown heroin in lemon juice," there is a high probability of Candida spp. infection (non-albicans species), and therefore antifungal treatment should be added. As soon as the etiology of IE is verified, antibiotic therapy should be adjusted.

ESC IC (LoE C, GoR 4)

Comment. A two-week course of oxacillin** without #gentamicin** is effective for patients with isolated tricuspid valve IE only if all criteria from the following list are met: MSSA infection; good response to treatment; absence of pleural empyema and embolic complications of infection; absence of cardiac and extracardiac complications; absence of prosthetic valve infection or combination with left-sided IE; vegetation size less than 20 mm; absence of immunosuppression (CD4 less than 200 cells/µL) with or without AIDS.

ESC IB (CoE A, LOE 1)

Comment. Due to limited bactericidal activity, poor penetration into vegetations, and increased drug elimination in intravenous drug users, glycopeptide antibiotics (#vancomycin**) should not be used in a short course. The standard 4–6-week regimen should be used in the following situations: slow clinical or microbiological response (more than 96 h); RIE complicated by right-sided heart failure, vegetations greater than 20 mm, acute respiratory failure, septic seeding outside the lungs (including pleural empyema), or extracardiac complications, e.g., acute kidney injury syndrome; antibiotic therapy other than penicillinase-resistant penicillins; substance use with severe immunosuppression (CD4 less than 200 cells/µL) with or without AIDS; or associated left-sided IE.

ESC IIb B (CGR B, LOR 3)

Comment. If the standard intravenous route is not feasible, RIE caused by S. aureus in substance users can be treated orally with #ciprofloxacin** (750 mg twice daily) combined with rifampicin** (300 mg twice daily), provided the IE is uncomplicated, caused by an S. aureus strain susceptible to both drugs, and close monitoring of patient adherence to treatment is possible.

RSC IIa B (LoE B, GoR 2)

Comment. The efficacy of daptomycin**, non-inferior to standard therapy in treating S. aureus infections including RIE, has been confirmed in a randomized controlled trial. Most authors recommend using high doses of #daptomycin** (10 mg/kg/24 h) and combining daptomycin** with fosfomycin** to prevent the development of resistance to this drug. Glycopeptide antibiotics (e.g., vancomycin**) or daptomycin** are the drugs of choice for MRSA infections [92, 392]. #Vancomycin** may have lower efficacy in infections caused by S. aureus isolates with a #vancomycin** MIC above 1 µg/mL. In these cases, daptomycin** is the drug of choice.

RSC I C (LoE C, GoR 5)

Comment. Indications for surgical treatment of RIE have limitations associated with the low social compliance of substance-using patients and the high risk of IE recurrence in them.

ESC I B (LE R, LoE 5)

ESC IIa C (CARR C, LER 5)

ESC I B (LoE C, GoR 5)

ESC IIa C (CARR C, LER 5)

ESC I C (LoE C, GoR 5)

RSC I C (LoE C, GoR 5)

Comment: Cardiac surgery in HIV-infected intravenous drug users with IE does not worsen the prognosis of either IE or HIV infection.

RSC I C (LoE C, GoR 5)

ESC IIa B (RRR C, LVE 5)

ESC IIa C (RRR C, LVE 5)

ESC IIb C (LoE C, GoR 5)

Comment. Tricuspid valve repair is performed more frequently than replacement [407]. Tricuspid valve repair may also be associated with better short- and long-term outcomes than replacement in right-sided IE, particularly regarding recurrent infection and the need for reoperation [383, 404]. Bioprostheses are used in most cases of tricuspid valve replacement. In exceptional cases, valvulectomy without prosthetic replacement can be performed; however, it may be associated with severe postoperative right ventricular HF, especially in the presence of pulmonary hypertension. In such cases, valve replacement can be performed once the infection has resolved in patients who have stopped using drugs. If pulmonary valve replacement is necessary, it is preferable to use a homograft, or, if that is not possible, a xenograft.

3.4.5. Infective endocarditis in patients with congenital heart disease

Although the incidence of congenital heart disease (CHD) remains relatively constant, the total population of individuals with CHD is steadily growing due to increased survival following childhood CHD surgery and increased life expectancy in adults with CHD. The presence of CHD, even after correction, is recognized as a lifelong potential substrate for IE; however, the risk of IE depends on the type of CHD. Large-scale studies in this patient category are extremely sparse; only retrospective study data are available, often associated with specific selections in specialized centers, which are difficult to extrapolate to the general population. The prevalence of IE in CHD is 15–140 times higher than in the general population (with the highest rate originating from a highly specialized center). The incidence of IE is lower in children (0.04% per year) than in adults with CHD (0.1% per year). The prevalence of CHD in patients with IE varies (possibly due to selection biases) from 2% to 60%, with a slight male predominance.

ESC IB (LoE B, LoR 3)

Comment. CHD with hemodynamically significant abnormalities, such as a bicuspid aortic valve, carries a higher risk of developing IE. However, CHD may consist of a complex of abnormalities, each contributing to the overall risk of IE. For example, the incidence of IE is significantly higher in patients with VSD when associated with aortic regurgitation.

The etiology, clinical presentation, complications, and diagnostic criteria for IE do not differ from those of IE associated with acquired heart defects. However, in CHD, right-sided IE occurs more frequently than in IE associated with acquired heart defects.

ESC IB (LoE C, GoR 4)

Comment. Timely oral cavity sanitation, dental and skin hygiene, as discussed in Appendix A3/22–A3/23, play a significant role. However, there is an issue with patient education (especially among patients not followed up at CHD centers) regarding awareness of IE and the necessity of IE prevention within the CHD population. Cosmetic tattooing and piercing (at least in the area of the tongue and mucous membranes) should be avoided in this group.

ESC IB (LoE C, GoR 4)

ESC IB (LoE C, GoR 4)

Comment. Complex anatomy and the presence of prosthetic materials can reduce the detection rate of vegetations and other signs of IE, making TOE preferable, especially in adults. Negative findings do not exclude the diagnosis.

RSC I C (LoE C, GoR 5)

RSC I C (LoE C, GoR 5)

RCS I C (LOE C, EL 4)

RCS I C (LOE C, EL 4)

Comment. The prognosis in patients with IE and CHD is better than in the general population of IE patients with acquired heart defects. IE in CHD has a mortality rate of 6–15%. This better prognosis compared to acquired pathology may be related to a higher proportion of RIE or higher quality care in specialized CHD centers. Surgical correction of CHD reduces the risk of IE if performed without residual defects. Implantation of artificial valves for CHD correction increases the risk of developing IE.

3.4.6. Infective endocarditis during pregnancy

Managing a female patient during pregnancy is always challenging for a physician due to altered hemodynamics and cardiovascular physiology, which can mimic heart disease and alter the clinical presentation [415, 416]. The incidence of IE during pregnancy is approximately 0.006% [417]. The prevalence of IE in patients with heart disease is 0–1.2% and is higher in women with mechanical prosthetic valves (mechanical bileaflet aortic valve prosthesis***, mechanical bileaflet mitral valve prosthesis***) [418–421]. Therefore, IE during pregnancy is rarely verified and is either a complication of a pre-existing valve defect or the result of intravenous drug use. Standard antibiotic therapy regimens can be used in pregnant women at any gestational age, given the high risk of mortality in cases of delayed initiation and inadequate therapy. Evidence of fetal toxicity has been published only based on experimental studies for fluoroquinolones and tetracyclines. Beta-lactam antibacterial drugs—penicillins or other beta-lactams—are the safest and most well-studied in terms of fetal safety. Published literature contains no data on adverse outcomes for the pregnant woman and the fetus from the use of vancomycin**, but the total number of observations is small. The prescription of antibiotic therapy for the treatment of pregnant women with IE must be carried out for vital indications by a multidisciplinary team including obstetrician-gynecologists, infectious disease specialists, and a clinical pharmacologist. The decision must be made individually and documented in accordance with local regulations.

ESC I B (LE R, LoE 5)

ESC III B (LoE C, GoR 5)

ESC I B (LE R, LoE 5)

Comment. IE is associated with a high rate of both maternal and fetal mortality. Maternal mortality in IE reaches 33% (in most cases due to heart failure or embolism), and fetal mortality is about 29% [417]. Close attention should be paid to any pregnant woman presenting with unexplained fever and a heart murmur.

ESC I B (LE R, LoE 5)

ESC I B (LE R, LoE 5)

ESC I B (LE R, LoE 5)

REC IIa C (LoE C, GoR 5)

ESC IB (C-EO, LoE 5)

Comment. Timely diagnosis and selection of the correct treatment strategy (antibiotic therapy/surgical treatment) reduce the risk of maternal and fetal death.

ESC IB (C-EO, LoE 5)

ESC I B (LE R, LoE 5)

ESC IIbC (LoE C, GoR 5)

Comment. If there are vital indications, the administration of any necessary classes of systemic antibacterial drugs should be considered.

ESC IIbC (LoE C, GoR 5)

REC IIa C (LoE C, GoR 5)

RCS I C (LOE C, EL 4)

RSC I C (LoE C, GoR 5)

Comments: Prompt detection of IE and appropriate treatment are essential to reduce the risk of both maternal and fetal death [417].

3.4.7. Infective Endocarditis in Immunocompromised Patients and Organ Transplant Recipients

ESC none (C-EO, LoE 4)

Comments: The incidence of IE in solid organ transplant recipients ranges from 1% to 2%. These patients tend to be younger and have a higher prevalence of comorbidities (especially renal and hepatic disease) compared to patients with IE without solid organ transplants. Among solid organ transplant recipients with IE, kidney transplants are the most common (72%), followed by liver (17%) and pancreas (8%). The most frequent site of IE is the aortic valve, followed less frequently by the mitral valve. Right-sided IE is rare. Such patients may also present with abnormal localization of vegetations—in the atrial or ventricular regions without valvular involvement (so-called mural IE). Hospital-acquired and healthcare-associated IE are common forms. The etiological profile remains traditional: the most frequent pathogen is S. aureus (34%), followed less frequently by Enterococcus spp. (17%) and Streptococcus spp. (11%). Cardiac surgery in patients with IE and solid organ transplants is performed less frequently than in patients with IE without solid organ transplants. The outcomes of IE in solid organ transplant recipients do not differ from those in patients with traditional forms of IE, which is likely due to the patients' younger age and frequent contact with the healthcare system, leading to earlier diagnosis and treatment of IE. However, a number of studies indicate that the presence of immunosuppressive therapy in patients with IE and solid organ transplants generally has a negative impact on the course of IE.

ESC none (B-EO, LoE 3)

Comments: IE in heart transplant recipients accounts for 10% of patients with solid organ transplants and IE. Among 57 heart transplant recipients who developed IE, the most frequent causative pathogen was S. aureus (26%), followed by Aspergillus fumigatus (19%) and E. faecalis (12%). The mean time to the onset of IE after heart transplantation was 8 years, with the mitral valve being most frequently affected, followed by mural IE and tricuspid valve IE. All-cause mortality in this patient group was high (45%), with the worst prognosis seen in fungal IE. Heart transplant recipients with IE were rarely referred for cardiac surgery (35%). It should be remembered that an individual antibiotic regimen protocol may require modification due to drug-drug interactions [427]. In solid organ transplant recipients, monitoring blood concentrations of immunosuppressants is essential. The absence of therapeutic drug monitoring may lead to a risk of excessive immunosuppression and worsening renal function. Aminoglycosides, erythromycin, and clarithromycin** are contraindicated due to the high risk of renal interactions when administered concomitantly with calcineurin inhibitors [428]. In some cases, solely in consultation with a cardiovascular surgeon from the organ and/or tissue transplantation department, short-term discontinuation of antimetabolites (immunosuppressants) (mycophenolate mofetic**, mycophenolate mofetil**, azathioprine**) or mammalian target of rapamycin (mTOR) inhibitors (everolimus**, sirolimus) may be considered in severe infections [428].

No ESC recommendation (LoE C, LoQ 4)

Comment: Immunosuppressants should not be discontinued in the perioperative period. However, the immunosuppressive therapy protocol may be adjusted in consultation with the transplant surgeon of the organ and/or tissue transplantation surgical department. In some cases, a single morning dose of a calcineurin inhibitor may be omitted on the day of surgery to minimize renal dysfunction associated with dehydration. Immunosuppression must be continued postoperatively. If oral administration is not feasible, conversion to intravenous forms of immunosuppressants is indicated [428].

ESC IIb C (LoE C, GoR 5)

Comments: See Section 5. Prevention and dispensary monitoring, medical indications, and contraindications for preventive methods

ESC none (C-EO, LoE 4)

Comments: The advent of combination antiretroviral therapy has led to a decrease in the risk of acquired immunodeficiency syndrome (AIDS), but people living with HIV remain a vulnerable population for IE. The incidence of IE in people living with HIV has declined over the past two decades. A retrospective study conducted in Spain showed a decrease in IE incidence 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. Similarly, a United States registry reported a decrease in IE incidence from 148 in 2007 to 112 in 2017. Patients living with HIV who develop IE are aging, with an increasing prevalence of substance abuse and comorbidities. Notably, patients with HIV and IE have a higher incidence of coronary artery disease, prior valve surgery, cardiac implantable electronic device (CIED) infection, and hemodialysis. The most common causative pathogens of IE were Staphylococcus spp. (the majority being S. aureus), followed by Streptococcus spp., Gram-negative bacilli, and Enterococcus spp. Importantly, over the past two decades, the frequency of CoNS as a cause of IE has decreased, whereas the frequency of streptococci, Gram-negative bacteria, enterococci, and fungi has increased. Community-acquired IE has become the most common form, while healthcare-associated IE has significantly declined. IE outcomes in patients with HIV have improved over the years (from 23.9 to 5.5 deaths per 100,000 patient-years).

3.4.8. Infective endocarditis in patients receiving maintenance hemodialysis

This variant of the disease belongs to the group of healthcare/hospital-associated IE. The prevalence of IE in patients undergoing maintenance hemodialysis (MHD) is 2.9%, which is 50–180 times higher than in the general population [431]. This is due to the presence of several additional risk factors for IE in patients with stage V CKD requiring renal replacement therapy (RRT): recurrent bacteremia due to permanent vascular access use, heart valve calcification secondary to calcium-phosphate metabolism disorders, immunosuppression in uremic patients, and comorbidity [432]. "Dialysis" endocarditis is characterized by high in-hospital and 1-year mortality rates, exceeding those in the non-dialysis population [431, 432]. The unfavorable prognosis with a high frequency of early and late mortality emphasizes the need for early diagnosis and treatment of IE in MHD patients, identification of susceptible individuals, and development of prevention strategies [431, 433].

ESC none (C-EO, LoE 4)

Comment: The source of bacteremia and subsequent heart valve infection in MHD patients is primarily the vascular access. The risk of IE on MHD is increased with the use of central and permanent dialysis catheters, and is lower when arteriovenous fistulas (AVF) and arteriovenous (AV) grafts are used as vascular access [147]. AVF is considered a safer option compared to a central venous catheter (CVC) as it demonstrates a lower rate of bacteremia. However, high blood flow velocities through an AVF (1,500 mL/min or more) can create turbulent flow capable of potentially damaging the endocarditis, especially in patients with pre-existing valvular heart disease. This hypothesis requires further investigation, as direct evidence is lacking in the literature.

No ESC recommendation (LoE B, LoQ 2)

Comment: The etiology of IE in MHD patients has certain differences from IE in the general population. Staphylococcus aureus (predominantly MSSA, but with an increasing role of MRSA) is the primary cause of bacteremia in MHD patients (up to 75% of cases) [147] due to pathogen entry into the bloodstream from the skin during vascular access manipulation, as well as nasal carriage. Enterococci rank second [431, 433]. Predominantly left-sided localization of IE is driven by high pressures in the left heart chambers, which promotes damage to the mitral and aortic valves in patients with end-stage renal disease (ESRD); pulmonary hypertension and hypervolemia are also hemodynamic risk factors for IE [434]. Right-sided IE is less common than left-sided IE in MHD patients, but more frequent than in the general population. In the pathogenesis of right-sided heart IE (low-pressure system), important factors include the inflow of infected blood from vascular access devices, endothelial damage of large veins, atrial endocarditis, and tricuspid valve involvement by an implantable port/infusion/injection catheter***, as well as micro-damage to the endothelium and valve caused by air bubbles due to turbulent blood flow within the tubing and dialyzer circuits [434, 435].

No ESC guideline (LoE C, GoR 5)

No ESC guideline (LoE C, GoR 5)

Comment. The 2023 ESC guidelines place greater emphasis on the risks associated with RRT, the importance of screening, and the optimization of the diagnostic approach to IE in such patients. There is currently insufficient evidence as to whether the 2023 International Society for Cardiovascular Infectious Diseases (ISCVID) IE criteria are fully applicable to patients with IE on RRT. Nevertheless, it is advisable to apply the generally accepted diagnostic approach to them. Valve visualization using TTE and TEE, positive blood culture results, and clinical evaluation should continue to serve as the basis for diagnosing IE in patients on RRT, alongside novel imaging modalities and etiological diagnostic methods [433].

No ESC guideline (LoE C, GoR 5)

Comment. Fluid removal during an RRT procedure can decrease cardiac chamber volumes and affect myocardial contractility, which is reflected in echocardiographic parameters such as end-diastolic volume (EDV), end-systolic volume (ESV), and left ventricular ejection fraction (LVEF) [437]. Correction of hypervolemia and reduction of pressure in the cardiac chambers alter the degree of functional valvular regurgitation. Echocardiographic parameters may therefore differ before and after the hemodialysis procedure. The nature of these changes depends on the baseline cardiovascular status, the volume of fluid removed, and the rate of its removal. Therefore, echocardiography—particularly for assessing not only organic valvular pathology, but also cardiac chambers, cardiac output, etc.—must be performed in a state of normohydration (within the first 24 hours after the procedure), including serial assessments.

No ESC guideline (LoE C, GoR 5)

Comment. In the absence of pathogen isolation, patients with IE on RRT should initially be prescribed systemic antibacterial drugs active against staphylococci/enterococci; subsequently, antibacterial therapy should be adjusted based on the pathogen data obtained and clinical efficacy.

No ESC guideline (LoE C, GoR 5)

Comment: Appendix A3/9 contains recommendations for the use of the most common systemic antibacterial drugs in patients with IE with decreased renal function, including instructions for their use in the presence of RRT. It should be noted that drug dosing is adjusted based on renal function and the dialysis modality. The administration of systemic antibacterial drugs is indicated immediately after dialysis to maintain an effective therapeutic concentration. Low plasma protein binding and a small molecular weight of a systemic antibacterial drug facilitate good drug elimination during hemodialysis/hemodialfiltration. Conversely, a high degree of protein binding significantly limits drug elimination by all dialysis methods. The use of high-flux membranes in hemodialfiltration facilitates the effective removal of a systemic antibacterial drug, such as daptomycin**, despite its high molecular weight. For systemic antibacterial drugs with a narrow therapeutic window (vancomycin** and aminoglycosides), it is necessary to monitor blood drug levels and account for nephrotoxicity if residual renal function is preserved [6, 439]. When choosing an antibacterial treatment regimen in patients with IE on RRT, one should be guided by the characteristics specified in the drug product labeling.

ESC not specified (LoE C, GoR 4)

Comment. Cardiac surgery is indicated in patients with IE on RRT when acute heart failure, uncontrolled infection, and a high risk of embolic complications are observed. Patients with IE on RRT have a higher risk of adverse outcomes from cardiac surgery. Nevertheless, refusing or delaying surgery when indicated worsens IE outcomes in patients on RRT [147, 439].

ESC not specified (LoE C, GoR 4)

Comment. Addressing vascular access in patients with IE on RRT requires an individualized approach in each specific case, as controlled studies on this issue are insufficient [147]. However, one should be guided by international guidelines formulated, inter alia, for the management of patients with vascular access infections/catheter-related bloodstream infections. Their development is associated with biofilm formation and often proves refractory to systemic antibacterial therapy. Immediate removal of the dialysis catheter is necessary in the event of fever lasting more than 48–72 hours, bacteremia, or sepsis [436]. When attempting to preserve a catheter in a patient with IE on RRT (e.g., in patients without alternative vascular accesses), prolonged antibiotic therapy and repeated echocardiographic examinations are indicated [440].

No ESC guideline (LoE C, GoR 5)

Comment: The Endocarditis Team must discuss and practically implement the management strategy for a patient with IE on RRT, including: the scope, dosages, and duration of antibacterial therapy; indications and timing for cardiac surgery; selection of the optimal vascular access/RRT modality; correction of anemia and metabolic disorders, etc.

ESC not specified (LoE C, GoR 4)

Comments: Prevention of IE in patients on RRT involves a combination of general and local measures. General IE prevention measures include adequate application of the renal replacement therapy modality (achieving target «dialysis dose» parameters, achieving and timely correcting the individual «dry weight» [patient weight at normohydration], proper nutrition, correction of anemia and calcium-phosphate metabolism disorders/prevention of valve calcification, etc.), eradication of chronic infection foci, regular bacteriological examination of the nasopharyngeal microflora, staphylococcal vaccination, quality control of dialysis fluids, and vascular access monitoring with patient education. Local measures for the prevention of IE and its recurrence in patients on RRT involve the preemptive creation of permanent (AVF/AV graft) vascular access prior to starting RRT, minimization of implantable intracardiac devices, skin preparation, and strict adherence to asepsis during vascular access use [441]. Antibacterial prophylaxis for IE during invasive medical procedures (dental and others) is carried out according to the rules described in the relevant section of the guidelines. The presence of dialysis per se is not classified as a very high-risk factor for recommending prophylactic systemic antibacterial drugs before invasive procedures, but this issue is decided on a case-by-case basis.

3.4.9. Non-bacterial thrombotic endocarditis (thrombotic, marantic, verrucous, Libman-Sacks)

According to autopsy studies, non-bacterial thrombotic endocarditis (NBTE) is a rare disease with a prevalence ranging from 1.1% to 1.6% [476]. Non-bacterial thrombotic endocarditis (NBTE) (also known as marantic endocarditis, verrucous endocarditis, or Libman-Sacks endocarditis) is characterized by the presence of sterile vegetations composed of fibrin and platelet aggregates on the heart valves. These vegetations are not associated with bacteremia or destructive valvular changes. It is crucial to differentiate true NBTE from blood culture-negative results for sterility in IE due to antibiotic therapy. NBTE is a condition associated with a range of diseases, such as cancer, systemic connective tissue diseases (e.g., systemic lupus erythematosus in the presence of antiphospholipid antibodies—the so-called Libman-Sacks endocarditis), autoimmune disorders, hypercoagulable states, septicemia, severe burns, or chronic diseases like tuberculosis, uremia, or AIDS. NBTE is a potentially fatal source of embolism. Embolism is frequently the first manifestation of the disease. According to a registry of patients with NBTE, 41% had cancer, 33% had SLE, and 36% had antiphospholipid syndrome (APS), with 21% of patients having both SLE and APS. Among patients with malignancies, the three most common types of cancer were lung adenocarcinoma, breast cancer, and pancreatic cancer. Stroke was the most common clinical presentation upon admission (60%), while heart failure 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 affected more frequently (62%) than the aortic valve (24%) [477].

ESC I C (LoE C, GoR 4)

Comment. It is fundamentally important to differentiate between NBTE and IE. The same diagnostic scheme is used as for IE. Diagnosing NBTE is challenging and is based on a high clinical suspicion in the context of disease progression that may be associated with NBTE, in the presence of a heart murmur upon auscultation, vegetations unresponsive to antibiotic therapy, or multiple systemic emboli.

ESC I C (LoE C, GoR 5)

Comment. Compared to transthoracic echocardiography, TEE has higher sensitivity and specificity in this category of patients. Libman-Sacks vegetations can have various shapes (sessile, tubular, or coalescing), with varying levels of echogenicity (heterogeneous or homogeneous), usually small, with a broad base and diverse forms, more friable, mobile, and frequently giving rise to embolic complications. They are rarely associated with valvular dysfunction and never associated with valvular perforation, which is an important method of differentiating them from bacterial IE [477]. They exhibit a weak inflammatory response at the attachment site, making them more mobile and prone to detachment. Following embolization, small remnants (up to 3 mm) can lead to false-negative echocardiographic findings. TEE should be ordered if there is a high suspicion of NBTE. Left-sided (mitral more often than aortic) and bilateral vegetations are more indicative of NBTE than IE [479]. When TEE is performed early, the prognosis of NBTE improves.

ESC: none (Leve of Evidence C, Level of Recommendations 5)

Comment. Immunochemical testing for antiphospholipid syndrome (i.e., lupus anticoagulant, alpha-1-glycoprotein (orosomucoid) in the blood, anticardiolipin antibodies in the blood, antiphospholipid antibodies in the blood, anti-beta-2-glycoprotein antibodies in the blood, antinuclear antibodies to the Sm antigen; at least one must be positive for the diagnosis of antiphospholipid syndrome in at least two tests 12 weeks apart) should be ordered for patients with recurrent systemic embolism or known systemic lupus erythematosus. However, it should be noted that laboratory data indicating a hypercoagulable state (e.g., lupus anticoagulant, anticardiolipin antibodies, and anti-β2-glycoprotein 1 antibodies, or DIC) may be present, but they are non-specific and may also be elevated in other IE patients with embolic events [71].

ESC: none (Leve of Evidence C, Level of Recommendations 5)

Comment. Blood culture testing for sterility must be performed several times to rule out IE, although blood cultures can also be negative in IE (e.g., after antibiotic therapy, in the HACEK group, fungal IE, etc.).

ESC I C (Level of Recommendations C, Level of Evidence 4)

Comment. The management of NBTE begins with the treatment of the underlying disease. If there are no contraindications, these patients should receive heparin sodium** or LMWH (e.g., nadroparin calcium/enoxaparin sodium**/dalteparin sodium) or warfarin**, although there is little evidence to support this strategy. In a randomized open-label multicenter study comparing rivaroxaban and warfarin in patients with APS, the use of rivaroxaban was associated with an increased rate of thromboembolic events and major bleeding [484]. Therefore, the use of direct oral anticoagulants (direct thrombin inhibitors and direct factor Xa inhibitors) is not indicated in patients with NBTE [6]. In thrombotic antiphospholipid syndrome, lifelong anticoagulant therapy with warfarin** is indicated to prevent thrombosis and thromboembolism.

ESC IIa C (CARR C, LER 5)

• In patients with NBTE and severe valvular regurgitation and/or large vegetations, it is recommended to consider surgical treatment to improve prognosis [6, 477].

ESC IIbC (LoE C, GoR 5)

RSS III C (Level of Recommendations C, Level of Evidence 5)

Comment: The development of IE is frequently associated with oncological diseases. IE can be a potential marker of occult cancer. A large Danish nationwide study detected 997 cancers among 8,445 patients with IE during a median follow-up of 3.5 years. A high incidence of abdominal cancer and hematological malignancies was revealed. IE caused by S. bovis/S. gallolyticus is frequently associated with colon cancer. Severe bacteremia has been shown to be associated with colon cancer, with the strongest association seen in S. bovis infections, particularly S. gallolyticus subspecies. S. bovis infection was associated with the presence of a gastrointestinal tumor, which in most cases turned out to be a colonic adenoma or carcinoma. However, it is still debated whether the association of S. bovis/S. gallolyticus IE with colorectal tumors is a consequence of gastrointestinal disease or if it contributes to the development of colorectal cancer.

REC IIa C (LoE C, GoR 4)

Comment. In the presence of S. bovis IE, proper microbiological classification is necessary. In cases of S. bovis/S. gallolyticus IE, it is important to rule out occult colon cancer during hospitalization. If no tumor is found, annual colonoscopy should be scheduled.

REC IIa C (LoE C, GoR 5)

Comment. ¹⁸F-FDG PET/CT may play a significant role in detecting gastrointestinal pathological activity to guide patients for colonoscopy. However, negative PET/CT results do not rule out colonic pathology.

3.5. Other treatment modalities

Specific pain management and dietary therapy are not required.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

The main objectives of comprehensive rehabilitation in patients with IE are to restore the body's functional capacity and psycho-emotional status to an optimal level, mobilize compensatory mechanisms, eliminate the consequences of surgical intervention, prevent IE recurrence and reinfection, disease complications, readmissions, reoperations, disability, and premature death.

REC IIa C (LoE C, GoR 5)

Comment. The rehabilitation program includes an educational module (informing and training patients on issues related to the disease and its medical and non-medical treatment), a psychosocial support module, and physical rehabilitation (physical training and recommendations for other types of physical activity); optimal medical therapy and properly planned follow-up are the guarantors of the effectiveness and safety of these measures [6, 443, 444–446].

REC IIa C (LoE C, GoR 5)

Comment. In the case of a stable disease course, "early" rehabilitation should be understood as starting – immediately after diagnosis establishment / upon first contact with the patient; in the case of surgery, acute illness, or exacerbation of a chronic condition – immediately after stabilization of vital functions (in the absence of other generally accepted contraindications).

RKO IIa C (LoE A, GoR 1)

Comment. Preoperative rehabilitation (prehabilitation) programs help reduce the time to endotracheal extubation after surgery, lower the likelihood of pulmonary complications, atrial fibrillation, and flutter, decrease hospital stay duration, and promote faster recovery of patients' physical function and higher adherence to outpatient rehabilitation and secondary prevention.

RKO IIa C (LoE C, GoR 5)

Comment. Patient education and training is an integral part of comprehensive cardiac rehabilitation. Implementation of educational programs helps increase treatment adherence, ensure timely diagnosis of IE recurrence or reinfection and late complications of the disease, and improve prognosis; however, their effectiveness in patients with IE has not been specifically studied in large trials. At the same time, explaining the nature of the disease, the benefits of the therapy (both medical and non-medical), and the risks of its absence or self-treatment is driven not only by medical considerations, but also by ethical and legal standards, according to which the patient must receive sufficient information to make an informed decision.

RKO IIa C (LoE A, GoR 2)

Comment. To reduce the risk of disease recurrence and the development of late complications, patients should be strongly advised to strictly maintain skin hygiene, and the undesirability of getting tattoos and piercings, especially with trauma to the oral mucosa, should be explained [6]. Patients with IE should be strongly advised to carefully maintain oral hygiene, systematically visit a dentist for oral health monitoring and timely treatment of detected conditions (dental caries, gingivitis, periodontitis), quit smoking, and limit the intake of simple carbohydrates and alcohol, which may contribute to their development [453]. Patients with IE should receive information on procedures for which antibiotic prophylaxis is necessary [454, 455].

RKO IIa C (LoE C, GoR 5)

Comment. The onset or progression of heart failure, IE recurrence, and reoperation are the most frequent late complications of IE that determine an unfavorable prognosis and premature death. The likelihood of an adverse outcome can be reduced if the patient seeks qualified medical care in a timely manner. Patients should be informed that the development of fever, chills, and other signs of infection, or the onset or progression of heart failure symptoms, requires mandatory and immediate medical attention.

RKO IIa C (LoE C, GoR 5)

Comment. A properly planned follow-up is an integral part of comprehensive cardiac rehabilitation and secondary prevention programs. It is precisely during follow-up that the efficacy and safety of the measures are assessed and the program is modified, which not only helps improve patient prognosis but also avoids unjustified tests.

REC IIa C (LoE C, GoR 5)

Comment. Currently, there is no definitive evidence of the benefits of participating patients with IE in long-term outpatient physical training programs. However, numerous positive effects of regular physical activity are well-known, including anti-inflammatory, antithrombotic, and antiarrhythmic effects, a favorable impact on the patient's psycho-emotional state, and an increase in physical capacity, among others [446, 457], which can be considered a rationale for these recommendations. Physical training should be initiated as early as possible [6]. The foundation of physical rehabilitation in cardiovascular patients is aerobic training (cardiorespiratory endurance training). Recommendations for physical activity and training parameters (type of exercise, intensity, duration, frequency) are determined individually, taking into account the patient's functional class, disease severity, and comorbid pathology [444, 457, 458]. The target level of physical activity should be the one recommended by the World Health Organization for healthy adults (over 18 years old) and patients with stable chronic conditions [459, 460]: (1) moderate-intensity aerobic cardiorespiratory endurance training (walking, swimming, cycling, etc.) for 150–300 minutes per week (or, in the absence of contraindications, high-intensity training for 75–150 minutes per week); (2) strength-oriented training (for muscle strength and endurance), as well as exercises improving flexibility, coordination, and postural stability – 2–3 days a week (at age ≥65 years – 3 or more days a week); (3) passive (sedentary) behavior (activity intensity ≤1.5 METs) should be avoided; even a small amount of physical activity is better than none; (4) prescribing physical activity as a therapeutic modality must follow prescription rules, specifying the therapeutic agent itself (type of physical exercise), its dose (exercise intensity), and the frequency and periodicity of "administration" – performing the respective type of exercise. These parameters are individual and depend on the patient's clinical and functional status [444, 458, 459].

5. Prevention and Dispensary Observation

Antibiotic prophylaxis of IE has been developed based on review studies and animal models; its purpose is to prevent bacteria from adhering to the endocardium during transient bacteremia following invasive procedures [461, 462]. Recurrent bacteremia is frequently detected during routine daily activities such as tooth brushing, flossing, or chewing gum, especially in patients with untreated dental conditions. The risk of IE is related more to the cumulative exposure to bacteremia throughout the day than to a single pronounced episode of bacteremia during dental procedures. Most case-control studies have not shown an association between invasive dental procedures and the development of IE [312, 463, 464]. The estimated risk of IE following dental interventions is very low. Antibiotic prophylaxis in this setting may prevent a small number of IE cases—approximately 1 in 150,000 interventions with, or 1 in 46,000 without, the use of systemic antibacterial drugs [312]. The use of systemic antibacterial drugs is associated with the risk of allergic and anaphylactic reactions. Widespread use of systemic antibacterial drugs may lead to the selection of antibiotic resistance.

ESC I C (CARR A, LER 2)

Comment. The use of antibiotic prophylaxis to prevent the onset or recurrence of IE is indicated for patients at high cardiovascular risk for this disease. These include patients with a prior history of IE, intracardiac foreign material (surgically implanted valve prostheses, including transcatheter aortic valve implantation, and any materials used for surgical heart valve repair), patients with cyanotic congenital heart disease (CHD), postoperative palliative shunts, conduits, or other prostheses, as well as patients with mechanical circulatory support devices (e.g., left ventricular assist devices) and heart transplant recipients with valvulopathy [6].

ESC III C (LOC A, LOR 2)

Comment. Antibiotic prophylaxis is not recommended in patients at moderate and low risk of IE. Patients at moderate/intermediate risk of IE include: patients with a history of acute rheumatic fever, patients with any heart defects (including bicuspid aortic valve, myxomatous degeneration/mitral valve prolapse, aortic stenosis), patients with uncorrected congenital heart disease, and those with pacemakers***/implantable cardioverter-defibrillators (ICDs)***. The low/negligible risk population for IE (no higher than in the general population) includes: surgically corrected ventricular septal defects, atrial septal defects, and patent ductus arteriosus (if more than 6 months have passed since surgery), a history of coronary artery bypass grafting, myxomatous degeneration/mitral valve prolapse without mitral regurgitation, physiological and functional heart murmurs, Kawasaki disease without valve dysfunction, and acute rheumatic fever without valve dysfunction.

ESC I C (CARR A, LER 2)

ESC I B (LOC C, LOR 4)

Comment. The main causative agents of IE associated with dental procedures are oral streptococci. Appendix A3/23 compiles the main antibiotic prophylaxis regimens prior to dental interventions. Fluoroquinolones and glycopeptide antibiotics are not indicated due to unproven efficacy and the potential for developing resistance to them. Cephalosporins should not be used if there is a history of anaphylaxis, angioedema, or urticaria to beta-lactam antibacterial drugs, penicillins, or ampicillin**, due to cross-hypersensitivity.

ESC III C (LOC A, LOR 2)

Comment. The use of dental implants raises concerns due to the potential risk of bacteremia. The Working Group's opinion is that there is no evidence against performing implantation in all high-risk patients. Indications should be discussed individually. Patients should be informed about the uncertainties and the importance of careful monitoring. Patient information is presented in Appendix A3/25.

ESC IIB C (LOC A, LOR 2)

Comment. Systemic antibacterial drugs active against staphylococci or the suspected/identified pathogen should be prescribed when performing procedures on infected respiratory tract tissues.

ESC IIb C (LOC A, LOR 2)

Comment. The antibiotic prophylaxis regimen should include agents active against enterococci, such as ampicillin**, amoxicillin**, or vancomycin** (only in patients with intolerance to beta-lactam antibacterial drugs (J01C Beta-lactam antibacterials, penicillins; J01D Other beta-lactam antibacterials)).

ESC III C (LOC A, LOE 2)

ESC III C (LOC C, LOE 5)

ESC IIb C (LoE A, GoR 2)

Comment. The antibiotic prophylaxis regimen should include agents active against staphylococci and beta-hemolytic streptococci.

Russian Society of Cardiology (RSC) I C (LOC C, LOE 3)

Comment. The increasing popularity of body piercing and tattooing among the population is a matter of concern, especially for individuals with congenital heart disease (CHD) who have an increased susceptibility to IE. The number of clinical cases of IE following piercing and tattooing is growing, particularly when tongue piercing is performed, although conclusive data on the incidence of IE after such procedures and the efficacy of antibiotic prophylaxis are lacking. Patients should be informed about the dangers of piercing and tattooing; these procedures should be discouraged not only in high-risk patients, but also in those with valvular heart disease. If performed, strictly sterile conditions must be ensured for these manipulations, although antibiotic prophylaxis remains unindicated.

ESC I B (LOC A, LOE 2)

Comment. During prosthetic valve implantation, implantation of any type of prosthesis, or pacemaker placement, the need for antibiotic prophylaxis should be evaluated due to the elevated risk of infection and adverse infectious outcomes. Indications for antibiotic prophylaxis to prevent local and systemic infections prior to cardiac and vascular interventions are outlined in Appendix A3/24. The microorganisms most frequently associated with early (less than 1 year postoperatively) prosthetic infections are CoNS and S. aureus. Prophylaxis should be initiated immediately prior to the procedure, repeated in the event of a delay, and completed within 48 hours afterward. A randomized trial demonstrated the efficacy of cefazolin** (1 g IV) in preventing local and systemic infection prior to CIED implantation*** [469]. It is strongly recommended that potential sources of odontogenic sepsis be eradicated at least two weeks prior to the implantation of a prosthetic valve or other intracardiac or intravascular foreign material, unless the latter procedure is emergent. In the case of transcatheter valve interventions, including transcatheter aortic valve implantation (TAVI), antibiotic prophylaxis should primarily target skin flora, as well as Enterococcus spp. and S. aureus.

ESC I A (LOC C, LOE 5)

ESC I A (LOC A, LOE 2)

ESC I C (Level of Recommendations C, Level of Evidence 4)

Comment. Healthcare-associated IE accounts for up to 30% of all IE cases and is characterized by increasing prevalence and an unfavorable prognosis [472, 473]. Although routine antibiotic prophylaxis prior to invasive procedures is not recommended, aseptic measures during venous catheter insertion and during any other invasive procedures, including outpatient ones, are mandatory to reduce the risk of this type of IE.

ESC I B (LOC C, LOE 5)

ESC IIa C (CGR C, LOR 5)

• All patients after recovering from IE are recommended lifetime follow-up by a cardiologist or, in the absence of a cardiologist, by a general practitioner or family physician to determine visit frequency, monitor compliance with prescribed recommendations, adjust therapy in a timely manner, assess cardiovascular risk, refer for additional investigations or sanatorium-resort treatment, and, if necessary, hospital admission [4, 6, 468, 471].

RSC I C (LoE C, GoR 5)

RSC I C (LoE C, GoR 5)

REC IIa C (LoE C, GoR 5)

REC IIa C (LoE C, GoR 5)

REC IIa C (LoE C, GoR 5)

REC IIa C (LoE C, GoR 5)

REC IIa C (LoE C, GoR 5)

RSC I C (LoE C, GoR 5)

RSC I C (LoE C, GoR 5)

RSC I C (LoE C, GoR 5)

6. Organization of Medical Care

Indications for hospitalization in a medical organization:

All patients with suspected infective endocarditis should be referred to a hospital exclusively on an emergency basis due to diagnostic difficulties, high risk of complications, the need for daily dynamic monitoring, and mandatory initiation of intravenous antibiotic therapy in the early stages [244]. There are no defined indications for planned hospitalization in patients with infective endocarditis.

Indications for patient discharge from a medical organization:

Patients with infective endocarditis should be discharged from the hospital upon clinical stabilization (including no signs of ongoing infection (sustained normal temperature for at least 48–72 hours; negative blood culture results for sterility), absence of heart failure decompensation, lack of echocardiographic criteria for hemodynamically significant valvular changes) and completion of the chosen treatment strategy (finished inpatient course of antibiotic therapy, no indications for emergency/urgent surgery) [244].

Other organizational technologies:

A patient-centered approach to managing patients with infective endocarditis has been convincingly proven, involving engagement and cooperation between medical staff and the patient's family at all stages of diagnosis, treatment, and recovery [6, 475].

7. Additional Information

None.

Criteria for Evaluating the Quality of Medical Care

Quality assessment criteria for primary health care provided to adults with infective endocarditis and intracardiac device infection (ICD-10 codes: I33, I38, I39, T85.7)

Quality assessment criteria for specialized medical care provided to adults with infective endocarditis and intracardiac device infection (ICD-10 codes: I33, I38, I39, T85.7)

References

Appendix A1. Working Group Composition

Steering Committee of the Working Group:

• Kobalava Zh.D., Corr. Member of RAS, Prof., D.Sc. (Moscow), RNMOT, RSC

• Demin A.A., Prof., D.Sc. (Novosibirsk), RNMOT, RSC

• Titov D.A., Ph.D. (Moscow), ACSV

• Kozlov R.S., Corr. Member of RAS, Prof., D.Sc. (Smolensk), IACMAC

Working Group:

• Artyukhina E.A., D.Sc. (Moscow), ARHS

• Boytsov S.A., Academician of RAS, Prof., D.Sc. (Moscow), RSC

• Golukhova E.Z., Academician of RAS, Prof., D.Sc. (Moscow), RSC, ACSV

• Gordeev M.L., Prof., D.Sc. (Saint Petersburg), RSC, ACSV

• Gudymovich V.G., Assoc. Prof., D.Sc. (Moscow), ACSV

• Demchenko E.A., D.Sc. (Saint Petersburg), RSC

• Drobysheva V.P., Prof., D.Sc. (Novosibirsk), RSC

• Domonova E.A., D.Sc. (Moscow), VSEPRMI

• Drapkina O.M., Corr. Member of RAS, Prof., D.Sc. (Moscow), RSC

• Zagorodnikova K.A., Ph.D. (Saint Petersburg), RSC

• Irtyuga OB, MD, PhD (Saint Petersburg), RSC

• Kalashnikov S.V., PhD (Moscow), CVSS

• Kakhktsyan P.V., Ph.D. (Moscow), ACSV

• Kirov M.Yu., Corr. Member of RAS, Prof., D.Sc. (Arkhangelsk), FAR

• Kuzkov V.V., Assoc. Prof., D.Sc. (Arkhangelsk), FAR

• Kotova E.O., D.Sc. (Moscow), RSC, RNMOT

• Lebedinsky K.M., Prof., D.Sc. (Moscow), FAR

• Medvedev A.P., Prof., D.Sc. (Nizhny Novgorod), ACSV

• Muratov R.M., Prof., D.Sc. (Moscow), ACSV

• Nikolaevsky E.N., Prof., D.Sc. (Samara), RSC, RNMOT

• Pisaryuk A.S., Ph.D. (Moscow), RSC, RNMOT

• Ponomareva E.Yu., Ph.D. (Saratov), RNMOT

• Popov D.A., Prof., D.Sc. (Moscow), IACMAC

• Rachina S.A., Prof., D.Sc. (Moscow), IACMAC

• Protsenko D.N., Assoc. Prof., D.Sc. (Moscow)

• Revishvili A.Sh., Academician of RAS, Prof., D.Sc. (Moscow), RSC, ARHS

• Reznik I.I., Prof., D.Sc. (Yekaterinburg), RSC, RNMOT

• Ryzhkova D.V., Prof., D.Sc. (Saint Petersburg), RSC, RSNM

• Sazonova Yu.V. (Saint Petersburg), RSC

• Safarova A.F., Prof., D.Sc. (Moscow), RSC, RNMOT

• Skopin I.I., Prof., D.Sc. (Moscow), ACSV

• Tazina S.Ya., Assoc. Prof., D.Sc. (Moscow), RSC

• Tyurin V.P., Prof., D.Sc. (Moscow), RNMOT

• Fedoseykina M.I. (Moscow), ACSV

• Chipigina N.S., Ph.D. (Moscow), RNMOT

• Shadrina U.M. (Saint Petersburg), RSC

• Shlyakhto E.V., Academician of RAS, Prof. (Saint Petersburg), RSC

• Shneider Yu.A., Prof., D.Sc. (Kaliningrad), ACSV

• Shostak N.A., Prof., D.Sc. (Moscow), RSC, RNMOT

The working group members confirmed no financial support/conflict of interest. In the event of a reported conflict of interest, the working group member(s) were excluded from discussions related to the area of conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

These Guidelines have been developed based on the 2023 European Society of Cardiology (ESC) Guidelines for the management of IE [6].

The Guidelines, based on the results of major epidemiological studies, RCTs, and meta-analyses, summarize and outline the core principles of managing patients with IE both generally and in specific clinical scenarios. The primary goal of the Guidelines is to facilitate decision-making when choosing the optimal treatment strategy for an individual patient with IE. Nonetheless, the final treatment decision must be made taking into account the individual features of the disease mechanisms and clinical course.

Target audience for these clinical guidelines:

1. Cardiologist

2. General Practitioner

3. General Practitioner (Family Doctor)

4. Neurologist

5. Cardiovascular Surgeon

6. Endovascular radiologist / X-ray endovascular diagnostic and treatment physician

7. Clinical Pharmacologist

8. Clinical Laboratory Diagnostics Physician

9. Infectious Diseases Physician

Due to the fact that the Russian Society of Cardiology (RSC) is a constituent of the European Society of Cardiology (ESC), and RSC members are also ESC members, all European guidelines are formulated with the participation of Russian experts who co-authored the guidelines. Thus, the existing ESC guidelines reflect the consensus of leading Russian and European cardiologists.

Accordingly, the formulation of national guidelines was carried out on the basis of the ESC guidelines, taking into account national specifics, examination and treatment features, and the availability of specific medical care. For this reason, during the development of the Russian clinical guidelines by the RSC, international recommendation classes were used, allowing assessment of the feasibility of guideline provisions and the levels of evidence for these classes (Tables A2/1 and A2/2).

In cases where European guidelines lacked classes and levels of evidence, but in the opinion of RSC experts these statements were extremely necessary for implementation or, conversely, strictly not recommended for use, RSC experts—based on the rules for formulating recommendation classes according to the European Society of Cardiology guidelines—assigned the classes and levels themselves. In such instances, the ESC designation is replaced with RSC classes and levels assigned by RSC experts.

In addition, a new grading system for levels of evidence (LoE) and grades of recommendation (GoR) for therapeutic, rehabilitation, preventive, and diagnostic interventions (Tables A2/3, A2/4, and A2/5) introduced in 2018 by the Center for Healthcare Quality Assessment and Control of the Russian Ministry of Health was added. Thus, the text of clinical practice guidelines developed by RSC experts simultaneously utilizes two grading scales (Tables A2/1, A2/2, A2/3, A2/4, A2/5).

Table A2/1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table A2/2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table A2/3. Grades of Recommendation (GoR) scale for methods of prevention, diagnostics, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Table A2/4. European Society of Cardiology (ESC) Classes of Recommendations scale

Table A2/5. European Society of Cardiology (ESC) Levels of Evidence scale

Procedure for updating clinical guidelines

The update mechanism for clinical guidelines provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific conditions, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3/1. Orders serving as the basis for drafting these guidelines

1. Order of the Ministry of Health of the Russian Federation No. 918n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Patients with Cardiovascular Diseases."

2. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Deadlines for the Development of Clinical Guidelines, Their Revision, the Standard Template of Clinical Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines"

3. Federal Law No. 61-FZ dated April 12, 2010, "On the Circulation of Medicines".

4. Federal Agency on Technical Regulating and Metrology. National Standard of the Russian Federation. GOST R 52379-2005. Good Clinical Practice. Moscow, 2005.

5. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation."

Appendix A3/2. 2023 ESC Modified Duke Criteria

Appendix A3/2. 2023 ESC Modified Duke Criteria

Major criteria

(i) Positive microbiological finding for IE

(a) Typical IE pathogens from two separate blood cultures:

Oral streptococci, Streptococcus gallolyticus (formerly S. bovis), HACEK group, S. aureus, E. faecalis

(b) Microorganisms consistent with IE from persistently positive blood cultures:

• ≥2 positive blood samples drawn >12 hours apart

• all 3 or a majority of ≥4 separate blood cultures (with ≥1 hour between the first and last sample)

(c) A single positive blood culture for C. burnetii or phase 1 IgG antibody titer >1:800

(ii) Positive imaging for IE:

Valvular, perivalvular/periprosthetic anatomical and metabolic lesions of prosthetic material characteristic of IE, detected by any of the following imaging modalities:

• Echocardiography (TTE and TEE)

• Cardiac CT

• [18F]-FDG-PET/CT

• Leukocyte-labeled SPECT/CT

Minor criteria

(i) Predisposing conditions (i.e., high- or moderate-risk predisposing heart conditions for IE or intravenous drug use)

(ii) Fever: temperature >38°C

(iii) Embolic complications (including asymptomatic ones detected by imaging only):

• Major systemic and pulmonary emboli/infarctions and abscesses

• Hematogenous osteoarticular septic complications (e.g., spondylodiscitis)

• Mycotic aneurysms

• Intracranial ischemic/hemorrhagic lesions

• Conjunctival hemorrhages

• Janeway lesions

(IV) Immunological criteria:

• Glomerulonephritis

• Osler's nodes and Roth spots

• Rheumatoid factor

(V) Microbiological evidence:

• Positive blood culture not meeting a major criterion

• Serological evidence of active infection with an IE organism

Abbreviations: IE – infective endocarditis, HACEK – Haemophilus parainfluenzae, H. aphrophilus, H. paraphrophilus, H. influenzae, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, K. denitrificans, Ig – immunoglobulin, 18F-FDG – fluorodeoxyglucose [18F], PET/CT – positron emission tomography/computed tomography, SPECT/CT – single-photon emission computed tomography/computed tomography, ESC – European Society of Cardiology, CT – computed tomography

Appendix A3/3. Diagnosis of infective endocarditis according to the 2023 ESC modified Duke criteria

Abbreviations: IE – infective endocarditis; ESC – European Society of Cardiology; ABT – antibiotic therapy

Appendix A3/4. Characteristics of the "Endocarditis Team"

Abbreviations: IE – infective endocarditis, HF – heart failure, CHD – congenital heart disease, MSCT – multislice computed tomography, MRI – magnetic resonance imaging, EchoCG – echocardiography, TEE – transesophageal echocardiography, ABT – antibiotic therapy.

Appendix A3/5. Recommendations for the detection of rare causative agents of blood culture-negative infective endocarditis

Abbreviations: Ig – immunoglobulin, PCR – polymerase chain reaction.

Appendix A3/6. Anatomical and echocardiographic criteria for infective endocarditis

Abbreviations: TTE – transthoracic echocardiogram, TEE – transesophageal echocardiogram.

Appendix A3/7. Predictors of poor prognosis in patients with infective endocarditis

Abbreviation: HACEK – Haemophilus parainfluenzae, H. aphrophilus, H. paraphrophilus, H. influenzae, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, K. denitrificans. PVE*** – prosthetic valve infective endocarditis, MV – mitral valve

Appendix A3/8. EuroSCORE II Perioperative Risk Assessment Scale

Note: the listed coefficients are substituted into the equation:

where B₀ is the logistic regression constant, B_i is the variability coefficient of X_i, for age X_i = 1 if the patient is younger than 60 years, X_i increases by 1 for each year after 60 (at 61 X_i =2, at 62 X_i =3, and so on). CABG – coronary artery bypass graft, MI – myocardial infarction, DM – diabetes mellitus, sPAP – systolic pulmonary artery pressure, GFR – glomerular filtration rate (calculated by Cockcroft-Gault), CPR – cardiopulmonary resuscitation, HF – heart failure, CCS – Canadian Cardiovascular Society, NYHA – New York Heart Association

http://www.euroscore.org/calc.html [152]

Appendix A3/9. Dosing of antibacterial drugs used for the treatment of infective endocarditis in patients with renal and hepatic impairment

* Percentages are relative to a single dose

** "+" – dose adjustment is required; in severe hepatic impairment, it is advisable to withhold the drug; "–" – no dosage change is required. Not used – contraindicated in liver dysfunction

Creatinine clearance in men can be calculated using the formula:

Creatinine clearance for women = 0.85 x creatinine clearance for men

Appendix A3/10. Recommendations for antibiotic therapy of infective endocarditis caused by viridans group streptococci or S. gallolyticus group

Note: ^a – class of recommendation, ^b – level of evidence, ^c – serum #gentamicin** concentration and renal function should be monitored once a week; serum #gentamicin** concentration before administering the daily dose should be less than 1 mg/L, and after administering the daily dose (peak, 1 hour after administration) 10-12 mg/L [493]; ^d – desensitization can be performed in stable patients. ^e – trough serum vancomycin** level should be 10-15 mg/L prior to the next dose; some experts suggest increasing the #vancomycin** dose to 45-60 mg/kg/day [4] IV in 2-3 divided doses to achieve a serum concentration of 15-20 mg/L as in staphylococcal IE. However, the #vancomycin** dose may exceed 2 g/day only if the peak #vancomycin** concentration does not exceed 30-45 mg/mL [4]. ^f – if isolates with a benzylpenicillin MIC >2 mg/L are detected, treat as for enterococcal IE.

Abbreviations: ESC – European Society of Cardiology, NVIE – native valve IE, PVIE*** – prosthetic valve infective endocarditis, LOR – level of recommendation, LOE – level of evidence, MIC – minimum inhibitory concentration.

Appendix A3/11. Recommendations for antibiotic therapy of staphylococcal infective endocarditis

Note: a – class of recommendation, b – level of evidence, c – #Co-trimoxazole [Sulfamethoxazole+Trimethoprim]** concentrations and renal function should be monitored once a week (twice a week in renal failure), d – trough serum concentration for vancomycin** in the range of 10-15 mg/L, determining the AUC/MIC ratio is more optimal. The AUC/MIC ratio for vancomycin** in MRSA infection should be 400-600 mg*h/L. e – rifampicin** increases the hepatic metabolism of many drugs, notably warfarin**. f – CKD determination once a week. Some experts suggest adding fosfomycin** (2 g every 6 hours IV) to enhance activity and prevent the development of resistance to daptomycin**. g – penicillin desensitization can be performed in stable patients;

Abbreviations: ESC – European Society of Cardiology, NVIE – native valve IE, PVIE*** – prosthetic valve infective endocarditis, LOR – level of recommendation, LOE – level of evidence, MIC – minimum inhibitory concentration.

Appendix A3/12. Recommendations for antibacterial therapy of enterococcal infective endocarditis

Note: ^a – class of recommendation, ^b – level of evidence, ^c – in case of high-level resistance to #gentamicin** (MIC >500 mg/L): if susceptible to streptomycin**, replace with #streptomycin** 15 mg/kg/day in 2 divided doses; ^с – in case of resistance to beta-lactam antibacterials (1) due to beta-lactamase production – replace ampicillin** with Ampicillin+[Sulbactam]**, (2) due to binding to penicillin-binding proteins PBP5 – use vancomycin**; ^c – in case of multidrug resistance (to beta-lactam antibacterials, #gentamicin**, and vancomycin**), it is possible to use (1) #daptomycin** 10 mg/kg/day with #ampicillin** 200 mg/kg/day IV in 4-6 divided doses, (2) #linezolid** 600 mg twice daily IV or orally ≥8 weeks [4].

Abbreviations: ESC – European Society of Cardiology, NVIE – native valve IE, PVIE*** – prosthetic valve infective endocarditis, LOR – level of recommendation, LOE – level of evidence, MIC – minimum inhibitory concentration.

Appendix A3/13. Guidelines for Antibiotic Therapy of Culture-Negative IE

Note: ^a – #doxycycline** with #hydroxychloroquine** (serum levels of #hydroxychloroquine** must be monitored) is superior in efficacy to #doxycycline** monotherapy, ^b – there are isolated studies with treatment regimens including aminopenicillins (ATC: broad-spectrum penicillins) (#ampicillin** 12 g/day IV) or third-generation cephalosporins (#ceftriaxone** 2 g/day) in combination with aminoglycosides (#gentamicin** or #netilmicin). Doses are similar to the treatment of streptococcal and enterococcal IE ^c – #levofloxacin** and #moxifloxacin** have greater activity against intracellular pathogens compared to #ciprofloxacin** ^d – Treatment of Whipple's disease remains empirical. Alternative therapy: #ceftriaxone** 2 g/day IV for 2–4 weeks or #benzylpenicillin** 2 million IU every 4 hours and #streptomycin** 1 g every 24 hours IV for 2–4 weeks, followed by #co-trimoxazole** 800 mg every 12 hours orally [4].

Abbreviations: Ig – immunoglobulin.

Appendix A3/14. Guidelines for Empirical Antibiotic Therapy

Note: ^a – class of recommendation, ^b – level of evidence, ^c – serum concentration monitoring for #vancomycin** and #gentamicin**. ^d – In cases of suspected subacute native valve IE, for empirical coverage of S. aureus, Streptococcus, Enterococcus, HACEK, a combination of ampicillin + [sulbactam]** with #vancomycin** may be prescribed [58, 504, 505].

Abbreviations: ESC – European Society of Cardiology, NVE – native valve infective endocarditis, PVE – prosthetic valve infective endocarditis, LoR – level of recommendation, LoE – level of evidence, MIC – minimum inhibitory concentration, BCNIE – blood culture-negative infective endocarditis, MRSA – methicillin-resistant S. aureus.

Appendix A3/15. Criteria determining the feasibility of transition to outpatient parenteral antibiotic therapy for infective endocarditis

Note: ^a – consult an infectious disease specialist for other pathogens, ^b – consultation with an infectious disease specialist is indicated for late prosthetic valve endocarditis, ^c – an Endocarditis Team is preferred, ^d – general practitioner (family physician) may visit the patient once a week if needed, EchoCG – echocardiography.

Appendix A3/16. Criteria for Switching to Oral Antibiotic Therapy

Abbreviations: ABT – antibiotic therapy; CRP – C-reactive protein, TTE – transthoracic echocardiography; TOE – transesophageal echocardiography; COPD – chronic obstructive pulmonary disease; DM – diabetes mellitus; GI – gastrointestinal; HF – heart failure; AKI – acute kidney injury.

Appendix A3/17. Potential Regimens for Oral Antibiotic Therapy

Abbreviations: CoNS – coagulase-negative staphylococci; MIC – minimum inhibitory concentration

Appendix A3/18. Indications and timing of surgery in left-sided native and prosthetic valve IE

Note: emergency surgery – within 24 hours, urgent – within several days, deferred – at least 1–2 weeks of antibiotic therapy, a – class of recommendation, b – level of evidence

Abbreviations: HACEK – Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus, Haemophilus influenzae, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, Kingella denitrificans, NVE – native valve infective endocarditis, PVE*** – prosthetic valve infective endocarditis, LGR – level of recommendation, LED – level of evidentiary data.

Appendix A3/19. Risk assessment calculator for embolic complications within 6 months in patients with infective endocarditis

Note: clinical, echocardiographic, and microbiological data must be collected upon admission in patients with IE.

Abbreviations: DM – diabetes mellitus, IE – infective endocarditis, AF – atrial fibrillation

Appendix A3/20. Factors associated with a high rate of infective endocarditis relapse

Abbreviations: IE – infective endocarditis, PVE*** – prosthetic valve infective endocarditis

Appendix A3/21. Predisposing heart conditions with the highest risk of infective endocarditis requiring antibiotic prophylaxis before high-risk procedures

Note: ^a – class of recommendation, ^b – level of evidence.

Abbreviations: IE – infective endocarditis, CHD – congenital heart disease, LoR – level of recommendation, LoE – level of evidence. [6]

Appendix A3/22. Non-specific preventive measures in high- and moderate-risk patients for infective endocarditis

Appendix A3/23. Recommended prophylaxis before high-risk dental procedures in high-risk patients for infective endocarditis

Cephalosporins should not be used in patients with anaphylaxis or angioedema after taking broad-spectrum penicillins or ampicillin** due to cross-sensitivity.

Appendix A3/24. Measures for the prevention of local and systemic infections before cardiovascular interventions

Note: ^a – class of recommendation, ^b – level of evidence.

Abbreviations: PPM*** – permanent pacemaker leads, ICD*** – implantable cardioverter-defibrillator, TAVI – transcatheter aortic valve implantation, LoR – level of recommendation, LoE – level of evidence.

Appendix A3/25. Patient Information Card

INFECTIVE ENDOCARDITIS PROPHYLAXIS

Patient Card

You received this card because you are at high risk for infective endocarditis (IE). The recommendations for IE prophylaxis specified in this patient card are based on the current Clinical Guidelines of the Russian Ministry of Health.

These guidelines were developed by experts from professional societies: the Russian Society of Cardiology, the Association of Cardiovascular Surgeons, the Russian Scientific Medical Society of Therapists, the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy, and the All-Russian Scientific and Practical Society of Epidemiologists, Microbiologists, and Parasitologists.

These recommendations do not change the fact that your predisposing heart condition increases the risk of developing IE. If you develop symptoms—such as fever unrelated to other causes—contact your attending physician immediately. If a blood culture microbiological test for sterility is required (in case of IE), it is extremely crucial that the physician performs this test before starting antibacterial drugs.

Antibacterial prophylaxis before dental procedures in patients at high risk for IE is necessary only in the following patient groups:

• Prosthetic heart valves, including transcatheter implantation and homografts

• Use of prosthetic material for heart valve repair, such as annuloplasty rings and chordal reconstruction

• Previous history of IE

• Congenital heart disease (CHD) only in the following cases:

  a. Any type of cyanotic CHD

  b. Any type of CHD for which surgical or percutaneous prosthetic material was used, up to 6 months after the procedure or lifelong if there is a residual shunt or regurgitation.

• Heart transplant recipients

Antibiotic prophylaxis for IE during dental procedures should be administered only for procedures involving manipulation of the gingival tissue or periapical region of the teeth, or perforation of the oral mucosa.

Antibiotic prophylaxis should NOT be performed for: routine local anesthetic injections, dental radiographs, removable prosthodontic or orthodontic appliances, braces, or minor trauma to the lips.

Antibiotic prophylaxis regimens for IE during dental procedures

Note: cephalosporins should not be used in patients with anaphylaxis or angioedema after taking penicillins or ampicillin** due to cross-sensitivity.

Respiratory, gastrointestinal, and genitourinary tract procedures, dermatological procedures: there is no evidence supporting the need for antibiotic prophylaxis during procedures such as gastroscopy, colonoscopy, bronchoscopy, uncomplicated vaginal delivery, etc. Antibiotic prophylaxis is indicated only when procedures are performed on infected tissues.

Nonspecific prophylaxis is of great importance and is indicated for all patients to prevent the development of IE:

• Strict skin and dental hygiene. Dental examination and treatment twice a year in high-risk patients and once a year in others

• Wound disinfection

• Eradication or suppression of chronic bacterial carriage: skin, urinary tract

• Antibacterial therapy for the treatment of any focus of bacterial infection

• Prohibition of uncontrolled use of antibacterial drugs without a prescription

• Avoid body piercing and tattooing

• Minimize the use of infusion catheters and invasive procedures whenever possible. Prefer peripheral catheters over central ones and systematically replace the peripheral catheter every 3–4 days. Strict adherence to the care of central and peripheral cannulation devices

Appendix B. Physician Action Algorithms

Appendix B1. Native Valve Infective Endocarditis Diagnostic Algorithm

Abbreviations: IE – infective endocarditis, TTE – transthoracic echocardiography, TEE – transesophageal echocardiography, MRI – magnetic resonance imaging, CT – computed tomography, 18F-FDG – fluorodeoxyglucose [18F], PET/CT – positron emission tomography, SPECT/CT – single-photon emission computed tomography, CIED*** – cardiac implantable electronic device, PE – pulmonary embolism

Appendix B2. Prosthetic Valve Infective Endocarditis Diagnostic Algorithm

Abbreviations: IE – infective endocarditis, TTE – transthoracic echocardiography, TEE – transesophageal echocardiography, MRI – magnetic resonance imaging, CT – computed tomography, ¹⁸F-FDG – fluorodeoxyglucose [18F], PET/CT – positron emission tomography, SPECT/CT – single-photon emission computed tomography, CIED*** – cardiac implantable electronic device, PE – pulmonary embolism

Appendix B3. Intracardiac Device-Related Infective Endocarditis Diagnostic Algorithm

Abbreviations: IE – infective endocarditis, TTE – transthoracic echocardiography, TEE – transesophageal echocardiography, MRI – magnetic resonance imaging, CT – computed tomography, ¹⁸F-FDG – fluorodeoxyglucose [18F], PET/CT – positron emission tomography, SPECT/CT – single-photon emission computed tomography, CIED*** – cardiac implantable electronic device, PE – pulmonary embolism

Appendix B4. Laboratory Diagnostics Algorithm for IE

a – experienced microbiology laboratory, b – immunology laboratory

Abbreviations: IE – infective endocarditis, PCR – polymerase chain reaction.

Appendix B5. Algorithm and indications for echocardiographic examination in suspected infective endocarditis

Abbreviations: IE – infective endocarditis, TEE – transesophageal echocardiographic examination, TTE – transthoracic echocardiographic examination

Appendix B6. Therapeutic Strategies for Patients with IE and Neurological Complications

Appendix B7. Therapeutic strategies for CIED*** pocket infection or CIED-associated systemic infection

* See the text of recommendations; antibiotic therapy (ABT) is selected depending on the causative agent. ABT duration should be at least 4–6 weeks for IE (4 weeks for native valve IE, 6 weeks for prosthetic valve IE or IE caused by Staphylococcus spp.). If vegetations are present on CIED*** leads without endocardial vegetations, ABT is recommended for 4 weeks for Staphylococcus aureus and for 2 weeks for other pathogens.

** Usually on the contralateral side; subcutaneous CIED*** may be considered

Appendix B8. Rehabilitation

Proper selection of exercise intensity is a key issue in cardiac rehabilitation [486]. For safety reasons, individuals with CVD should be recommended a moderate or low intensity level [487] taking into account their functional status (Table B.8.1).

The recommendations by the World Health Organization for healthy adults (>18 years) and patients with stable chronic conditions should be considered as targets [487]:

1) moderate-intensity dynamic (rhythmic) physical activity aimed at cardiorespiratory fitness: regular (≥5 times a week), 150–300 minutes per week;

2) to achieve a training effect from dynamic exercise, the duration of a single session should be at least 10 minutes;

3) exercises that prevent muscle mass loss and aim at strengthening muscle strength involving major muscle groups, ≥2 days a week;

4) for individuals ≥65 years – exercises that promote flexibility, balance, reduce the risk of falls, and ensure the safety of other types of physical activity ≥3 days a week.

All training sessions are conducted at the aerobic level – at the level of aerobic energy supply for muscle work (Table 2).

The functional status of patients, criteria for low-to-moderate intensity exercise, and training regimens can be determined using Tables 1–3. In Table 2, exercise intensity is defined either in absolute terms (in METs) or in relative terms – as a percentage of the individual's respective test parameter. Moderate-intensity exercise corresponds to 55–69% of the patient's maximum HR, 40–59% of the HR reserve (maximum HR – resting HR), or peak oxygen uptake (VO₂peak); in absolute terms – 4–6 METs for middle-aged individuals (40–64 years), 3.2–4.7 METs for individuals aged 65–79 years, and 2.0–2.9 METs for those ≥80 years [488].

Table B8.1. Criteria for assessing patient functional status

Notes. 1 MET = 3.5 ml O2 per 1 kg of body weight per 1 minute. Threshold workload. MET – metabolic equivalent. VO2 max – maximum oxygen consumption, 6MWT – 6-minute walk test

Table B8.2. Criteria for ranking physical exercise intensity [489]

Table B8.3. Selection of training regimen depending on baseline exercise tolerance

If functional testing to determine physical training parameters is not feasible, exercise intensity can be set using indirect methods (listed below).

1) Calculation of target HR using formulas, such as the HR reserve formula. HR reserve = 220 – age – resting HR [490].

Target HR (for physical training) = HR reserve × TI + resting HR, where TI is training/exercise intensity (see Table 2).

Generalized formula for calculating target HR using the Karvonen method:

Target HR = (220 – age – resting HR) × TI + resting HR

For example, a 60-year-old patient with a resting HR of 65 bpm, who previously led a sedentary lifestyle and is just starting physical training after hospital discharge, may be recommended a minimum exercise intensity of 40% of the HR reserve (Table B6.2); their target HR, which should not be exceeded during exercise, will be 103 bpm: (220 – 60 – 65) × 0.40 + 65 = 103 (bpm).

2) Using data on the energy expenditure of various types of physical activity; relevant information can be obtained from the Compendium of Physical Activities [491], which is available online and can be downloaded as a pdf file. Thus, low-intensity activities include washing dishes, ironing, cooking, working while seated at a desk (reading, writing, computer work, drawing, board games), reading aloud, and slow walking; moderate-intensity activities include brisk walking, housework (sweeping and mopping floors, carpet cleaning, vacuuming, etc.), ballroom dancing, cycling at <20 km/h, cycle ergometer training with a resistance of 50-90 Watts, non-competitive sports (rollerblading, ice skating, skiing, swimming, table tennis, volleyball, badminton, fishing).

3) "Talk test" – the ability to maintain a conversation during exercise: low-intensity exercise does not impair the ability to converse or sing; moderate-intensity exercise causes mild shortness of breath, the ability to converse in short sentences is preserved, singing is impossible; during (high-)intensity exercise, conversation and singing are impossible, and the ability to utter individual words or phrases with pauses for breath is preserved.

4) Patient self-assessment of the intensity of effort applied to the exercise — descriptively (light, moderate, hard) or using, for example, the Borg scale (10-11 points – low-, 12-13 – moderate-, 14-16 – high-intensity).

Recommended indicators for total exercise volume are calculated for a 1-week period: 1000-1500 kcal/week, or 500-1000 MET-min/week, or 150-300 minutes of moderate-intensity dynamic exercise per week [487, 492].

TV (MET-min/week) = I (METs) × D (min), where

TV is total volume (dose of physical activity), I is exercise intensity in METs, D is duration (time) of activity.

Knowing the target dose of physical activity (500-1000 MET-min/week) and determining the individual exercise intensity (e.g., moderate-pace walking – approximately 4 METs), one can calculate the time required for a particular patient to achieve the target level of physical activity.

The individual "energy cost" of the planned physical activity, taking into account the patient's weight (advantageous when performing exercises in an upright position, such as walking), can be determined based on the fact that 1 MET is approximately equivalent to 1 kcal per 1 kg of weight per hour [492].

E (kcal) = I (METs) × W (kg) × D (h), where

E is energy expenditure of physical activity (kcal), I is exercise intensity (METs), W is person's weight (kg), D is duration of physical activity.

Appendix C. Patient Information

Not applicable

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.