Seminar
Infective endocarditis
Mingfang Li, Joon Bum Kim, B K S Sastry, Minglong Chen
First described more than 350 years ago, infective endocarditis represents a global health concern characterised by
infections affecting the native or prosthetic heart valves, the mural endocardium, a septal defect, or an indwelling
cardiac device. Over recent decades, shifts in causation and epidemiology have been observed. Echocardiography
remains pivotal in the diagnosis of infective endocarditis, with alternative imaging modalities gaining significance.
Multidisciplinary management requiring expertise of cardiologists, cardiovascular surgeons, infectious disease
specialists, microbiologists, radiologists and neurologists, is imperative. Current recommendations for clinical
management often rely on observational studies, given the limited number of well conducted randomised controlled
trials studying infective endocarditis due to the rarity of the disease. In this Seminar, we provide a comprehensive
overview of optimal clinical practices in infective endocarditis, highlighting key aspects of pathophysiology, pathogens,
diagnosis, management, prevention, and multidisciplinary approaches, providing updates on recent research findings
and addressing remaining controversies in diagnostic accuracy, prevention strategies, and optimal treatment.
Introduction
Infective endocarditis is defined as a disease of the
endocardial surface of the heart, with infection primarily
involving the cardiac valves (native or prosthetic), the
mural endocardium, a septal defect, or an indwelling
cardiac device. This condition can present with a broad
spectrum of symptoms and signs. Infective endocarditis
was first described in 1674.1 Infective endocarditis
predominantly affects young adults, is subacute in nature
with streptococci and enterococci as the most common
pathogens, and is often linked to underlying cardiac
abnormalities, such as rheumatic heart disease or
congenital heart disease.2–4 However, in the late 1980s,
the landscape of infective endocarditis transformed
considerably mainly due to the increased availability of
prosthetic heart valves, intracardiac pacemakers, and
catheters. This shift made infective endocarditis more
acute, affecting older individuals with a broader range of
pathogens. In the era of intravascular devices, these
changes in infective endocarditis are intensified by
alterations in the gut and oral microbiome and widespread
inflammatory response triggered by valvular pathogens.
In addition, several other factors might also contribute to
the changing landscape of infective endocarditis,
including more efficient diagnostic methods, improved
treatment rates, and an overall increase in life expectancy.
Despite advancements in treatment, infective endocarditis
continues to be clinically challenging with an overall
mortality rate of 30%.5,6 In this context, we provide a
comprehensive overview of optimal clinical practices in
infective endocarditis, highlight key aspects of
pathophysiology, pathogens, diagnosis, management,
prevention, and multidisciplinary approaches, provide
updates on recent research findings, and address
remaining controversies in diagnostic accuracy,
prevention strategies, and optimal treatment.
Epidemiology
The epidemiology of infective endocarditis has
undergone considerable changes in the past few decades.
Globally, both the number of cases and associated deaths
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have sharply increased over the last 30 years, rising
from 478 000 in 1990 to 1 090 530 in 2019, and from
28 750 in 1990 to 66 320 in 2019.7 The annual incidence
between 1970 and 2000 was about 3·0–10·0 cases per
100 000 person-years and did not have a statistically
significant change.8,9 The incidence gradually increased
to 13·8 per 100 000 population in 2019.
Notably, men exhibit a higher incidence of infective
endocarditis compared with women, with men-towomen ratios ranging from 3:2 to 9:1 in various
studies.10 However, mortality-to-incidence ratios are
higher in women than men, suggesting worse outcomes
in female patients.11 The reason behind the sex
difference remains unknown and warrants further
investigation. Age is another crucial factor in infective
endocarditis epidemiology. The incidence rate was
higher in older people and increased over time.12,13 In
2019, patients aged 50 years and older accounted for
nearly 63% of incidence and 79% of mortality, a
statistically significant increase compared to 1990.7
Among the younger population, congenital heart
Lancet 2024; 404: 377–92
Division of Cardiology, the First
Affiliated Hospital of Nanjing
Medical University, Nanjing,
Jiangsu, China (M Li MD,
Prof M Chen MD); Department
of Thoracic and Cardiovascular
Surgery, Aortic Center, Asan
Medical Center, University of
Ulsan College of Medicine,
Seoul, South Korea
(J B Kim MD); Department of
Cardiology, Renova Century
Hospital, Hyderabad,
Telangana, India
(B K S Sastry MD)
Correspondence to:
Prof Minglong Chen,
Division of Cardiology,
the First Affiliated Hospital of
Nanjing Medical University,
Nanjing, Jiangsu 210029, China
chenminglong@njmu.edu.cn
Search strategy and selection criteria
We performed a literature search of the PubMed database
using the search terms: “infective endocarditis”,
“epidemiology”, “pathogenesis”, “manifestations”, “imaging”,
“diagnosis”, “treatment”, “surgery”, and “management”.
We primarily selected publications from the past decade.
Studies published before 2016, the year in which the previous
Seminar on infective endocarditis was published in
The Lancet, were considered for inclusion if they were widely
cited in the literature or in the current guidelines.
Additionally, we extended our search by reviewing the
reference lists cited in articles identified by this strategy and
guideline statements in the diagnosis and management of
infective endocarditis published by the European Society of
Cardiology and the American Heart Association. Articles
deemed relevant were also included. Only articles published
in English were included.
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Seminar
1) Normal endothelium
Resistent to pathogen
2) Bacterial adhesion
3) Inflammatory response
Risk factors
• Prosthetic valve
• Cardiac implantable
electronic devices
• Congenital heart disease
• Intravenous drug use
Bacteria
Monocytes
Platelets
4) Vegetation formation
Thrombogenesis
Cytokines
Infective endocarditis
Endothelium
Figure 1: The pathophysiology of infective endocarditis
Infective endocarditis begins with bacterial adhesion to tissues within the circulatory system, particularly the vascular endothelium, endocardium, and valvular apparatus.
Once bacteria adhere, an inflammatory response is initiated with the involvement of inflammatory cells and is mediated by the production of multiple cytokines
associated with integrins, tissue factors, and adhesion molecules. These cytokines in turn attract monocytes and platelets with the associated production of fibronectin,
which leads to thrombus formation. The aggregated thrombi provide a favourable environment for bacteria to survive, constituting a vicious cycle that further activates
the inflammatory cascade in an orchestrated manner against the host’s defences, eventually forming an infected vegetation. Figure created with BioRender.com.
A
B
NCC
RCC
AL
Pathophysiology
AS
PL
LCC
RA
IVC
Figure 2: Vegetations in infective endocarditis
(A) Vegetations (green arrow) associated with native mitral valve. (B) Vegetations (green arrow) associated with
native aortic valve. AL=anterior leaflet of the mitral valve. AS=atrial septum. IVC=inferior vena cava. LCC=left
coronary sinus of the aortic valve. NCC=non-coronary sinus of the aortic valve. PL=posterior leaflet of the mitral
valve. RA=right atrium. RCC=right coronary sinus of the aortic valve.
disease remains the primary risk factor for infective
endocarditis, while intravenous drug use has become a
concerning issue. Among people aged 15–34 years,
there was a marked four-fold increase in the number of
hospital admissions for intravenous drug use-associated
infective endocarditis from 2005 to 2016, and a nearly
doubled proportion of admissions from 6·9% to 12·1%.14
Socioeconomic disparities also contribute to variations
in infective endocarditis incidence. Patients from lowincome and middle-income countries exhibited more
frequent complications, such as congestive heart failure
and persistent fever, and had a higher mortality rate
(23·7% vs 15·0%) compared with those from highincome countries, which could be attributed to delayed
diagnosis and lower use of surgery.15 Rheumatic heart
378
disease, with a prevalence of 52·0% (95% CI 42·4–61·5),
remains the major underlying cause of infective
endocarditis in low-income countries, accounting for
almost half of the cases.16,17 However, in high-income
countries, due to improvements in medical care and
living conditions, degenerative valve disease and
congenital heart disease have gradually replaced
rheumatic heart disease as the main cause of infective
endocarditis.11,18,19
Bacterial adhesion to tissues within the circulatory system
constitutes the initiating pathophysiological process of
infective endocarditis. However, lining tissues in the
circulatory system, such as the vascular endothelium,
endocardium, and valvular apparatus, are not subject to
such a process under normal physiological status
(figure 1).20 Aggravating conditions include previous
infective endocarditis, the presence of prosthetic heart
valves, residual intra-cardiac shunts, cyanotic congenital
heart defects, and ventricular assist devices. Of note,
intravenous drug use, which is an increasing global
occurrence, is associated with a markedly increased risk of
infective endocarditis by repetitive introduction of
contaminated particles into the circulatory system with a
high recurrence rate.21 Once the initial nidus is established,
an inflammatory response is initiated with the
involvement of inflammatory cells and mediated by the
production of multiple cytokines associated with integrins,
tissue factors, and adhesion molecules.22–24 These cytokines
in turn attract monocytes and platelets with the associated
production of fibronectin, which leads to thrombus
formation.23,24 The aggregated thrombi provide a favourable
environment for bacteria to reside, constituting a vicious
cycle that further activates the inflammatory cascade in an
orchestrated manner against the host’s defences,
eventually forming infected vegetation (figure 2).
Biofilm formation plays a crucial role in the
pathogenesis of infective endocarditis, particularly in
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Seminar
cases involving prosthetic material. A biofilm can
insulate the organisms from antibiotics in the blood­
stream and make microbiological cure impossible
without surgical intervention to interrupt the biofilm and
access the sequestered organisms.25
Pathogens
Staphylococcus, streptococcus, and enterococcus are the
top three most prevalent microorganisms, accounting for
about 80% of infective endocarditis cases.12,13,15,26–28 The
majority of cocci were Staphylococcus aureus, followed by
viridans group streptococci. Gram-negative bacilli are
also potential microorganisms, but these cases are rare.
Fungus-associated infective endocarditis, mostly caused
by Candida, can present in those who are under
immunosuppression, accounting for 1–2% of cases.28
Furthermore, there are also some infective endocarditis
cases involving multiple microorganisms.13,26 The
proportion of infective endocarditis cases caused by
resistant organisms has increased in recent years, which
poses challenges for the treatment of this disease.29
Positive blood cultures varied in different studies ranging
from 45·4 to 79·0%.12,13,15,26–28 Compared with individuals
without positive blood cultures, patients with S aureus or
enterococcus infections were at the highest risk of 1-year
mortality.12
Diagnosis
The diagnostic standard for infective endocarditis is
pathological confirmation, but this is rarely available
during the initial therapeutic decision. In most cases,
diagnosis relies on clinical findings, microbiological
data, and imaging results.
Clinical features
In general, one should consider the possibility of infective
endocarditis in any patient with sepsis of unknown origin
or fever accompanied by risk factors. Initial clinical
assessment of patients with suspicious symptoms
involves evaluating risk factors and exploring supportive
medical history and examination findings. Core cardiac
risk factors include previous infective endocarditis,
prosthetic heart valves, valvular heart disease, transvenous
cardiac implantable electronic devices (CIEDs) or
ventricular assist devices, congenital heart disease, and
hypertrophic cardiomyopathy. Of note, in low-income
countries (especially in Africa), rheumatic heart disease
remains the most prevalent risk factor for infective
endocarditis in adults.16 Non-cardiac risk factors include
older age, male sex, central venous or arterial catheter,
intravenous drug use, immunosuppression, recent dental
or surgical procedures, poor dental hygiene, recent
hospitalisation, and haemodialysis. Furthermore,
physical examinations can reveal various clinical signs,
such as fever, heart murmurs, petechiae, Osler nodes,
Janeway lesions, and splenomegaly. However, the
diagnosis of infective endocarditis should not be excluded
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based on clinical examination alone due to the overall low
sensitivity and specificity of clinical signs.
According to the European Society of CardiologyEURObservational Research Programme (ESC-EORP)
EURO-ENDO (European infective endocarditis) registry,
the most predominant clinical symptoms in 3116 patients
were fever in 2421 (77·7%) cases and congestive heart
failure in 848 (27·2%) cases. Cardiac murmurs, identified
as the most frequent sign, were reported in 2010
(64·5%) of these cases. Other symptoms and signs were
less common: septic shock in 209 (6·7%) cases,
cardiogenic shock in 72 (2·3%), syncope in 81 (2·7%),
Janeway lesions in 109 (3·5%), Osler’s nodes in
59 (1·9%), and Roth’s spots in 44 (1·4%) cases.30
Symptomatic embolic complications were present on
hospital admission in 788 (25·3%) of 3116 cases,
including cerebral in 352 (11·3%) cases, splenic in
177 (5·7%), pulmonary in 199 (6·4%), renal in 78 (2·5%),
hepatic in 16 (0·5%), and in 93 (3·0%) cases for other
peripheral embolic events. Conduction abnormalities
were detected on admission in 358 (11·5%) of 3116 total
cases and included first-degree atrioventricular block in
252 (8·1%) and third-degree atrioventricular block in
87 (2·8%) of total cases. Another frequent complication
was paravalvular abscess seen in 367 (11·8%) of total
cases.30
Infective endocarditis is associated with a wide range of
complications (figure 3). Routine laboratory investigation
often yields non-specific results, reflecting the complex
Cerebrum
• Ischaemic stroke
• Abscess
• Intracranial haemorrhage
• Intracerebral abscess
• Meningitis
• Infective intracranial aneurysms
Eye
• Roth spots
Heart
• Congestive heart failure
• Valvular dysfunctions
• Arrhythmias
• Myocardial abscesses
• Myocardial infarction
Kidney
• Acute kidney injury
• Glomerulonephritis
• Infarction
Musculoskeletal
complications
• Myalgias
• Arthralgias
• Osteomyelitis
Skin
• Janway lesions
• Osler nodes
Embolic complications
• Spleen
• Lung
• Kidney
• Liver
• Splinter haemorrhages
Other symptoms
• Fever
• Hepatosplenomegaly
• Metastatic infection
Figure 3: The complications of infective endocarditis
Infective endocarditis is associated with a wide range of complications, including cardiac complications (eg, heart
failure, valve perforation, valvular incompetence, periannular and myocardial abscesses, arrhythmias, or
myocardial infarction), neurologic complications (eg, ischaemic stroke, intracranial haemorrhage, intracerebral
abscess, meningitis, or infective intracranial aneurysms), systemic embolisation (involving the spleen, the kidney,
the liver, peripheral arteries, or the iliac or mesenteric arteries), renal complications (eg, acute kidney injury due to
immune-mediated glomerulonephritis or focal infarction secondary to emboli), musculoskeletal complications
(eg, myalgias, arthralgias, or osteomyelitis), pulmonary complications (right-sided vegetation leading to
pulmonary embolism, disseminated pulmonary abscesses, pneumonia, or empyema), metastatic infection
(including septic embolisation, metastatic abscesses, and mycotic aneurysm), and complications related to
medical or surgical therapy. Figure was created with BioRender.com.
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Seminar
pathophysiology involved in infective endocarditis.31
Biomarkers might have a role in initial risk assessment
and monitoring the response to antibiotic therapy. Future
studies are warranted to assess potential diagnostic
biomarkers, including N-terminal-pro-B-type natriuretic
peptide, cystatin C, lipopolysaccharide-binding protein,
troponins, aquaporin-9, S100 calcium-binding protein
A11, E-selectin, VCAM-1, and interleukin-6.32,33
Microbiology
Positive blood cultures remain the cornerstone of
diagnosis in infective endocarditis. Before administering
antibiotics, a standardised blood culture process that
involves obtaining at least three separate sets of blood
cultures at 30-min intervals is imperative.34,35 Blood
cultures can be collected at any time, irrespective of the
peaks of fever.36 Gram staining serves as the initial step for
presumed identification after positive blood cultures,
enabling clinicians to promptly initiate empirical
antibiotic treatment. Moreover, despite the considerable
advancements in rapid susceptibility testing, the minimal
inhibitory concentrations based on susceptibility testing
remain the gold standard for selecting appropriate
antibiotics.37
Blood culture-negative infectious endocarditis refers to
cases of infectious endocarditis where the pathogenic
microorganisms cannot be cultivated using the usual
blood culture methods and accounts for approximately
2·5–31·0% of all infectious endocarditis presentations.38,39
The primary cause of blood culture-negative infectious
endocarditis is the administration of antibiotics before
obtaining cultures, resulting in false-negative results.
Blood culture-negative infectious endocarditis can also
result from fungi or fastidious bacteria, especially
A
B
C
LA
MV
AV
AL
D
AL
AR
RV
E
RV
RA
MV AV
LV
PL
LV
LA
LV
RV
PL
LA
Aorta
RCC
AV
LA
LA
LA
Figure 4: Imaging results of infective endocarditis
(A) Three-dimensional transoesophageal echocardiogram (TOE) with MV vegetation (white arrow). (B) TOE with
MV vegetation (white arrow) and AV vegetation (white arrow) and colour doppler flow imaging with AV
regurgitation. (C) Four-chamber view of transthoracic echocardiography (TTE) with MV vegetation (white arrow).
(D) TTE with AV annular abscess (white arrows). (E) Cardiac computed tomography with MV vegetation (white
arrow) and AV vegetation (green arrow) in one single patient (left: aortic sinus view, and right: three-chamber
view). AL=anterior leaflet of the MV. AR=AV regurgitation. AV=aortic valve. LA=left atrium. LV=left ventricle.
MV=mitral valve. PL=posterior leaflet of the MV. RA=right atrium. RCC=right coronary sinus of the AV. RV=right
ventricle.
380
obligate intracellular bacteria (eg, Coxiella burnetiid,
Bartonella spp, and Brucella spp) that require specialised
culture media for isolation.40 The HACEK group of
organisms (Haemophilus, Aggregatibacter, Cardiobacterium,
Eikenella corrodens, and Kingella) are known as blood
culture-negative organisms that predominantly affect
individuals with heart disease or artificial valves.41 In cases
of C burnetiid and Bartonella spp, systematic serological
testing or PCR assays might be required to facilitate the
identification of causative bacteria.40,42 Culturing HACEK
organisms used to be difficult; however, when using
current automated blood culture systems, an incubation
period of 5 days is adequate for detecting the HACEK
group.43,44 Some other advanced technologies, such as
molecular analysis (16S ribosomal RNA for bacteria and
18S ribosomal RNA for fungi) and meta-genomic nextgeneration sequencing are becoming increasingly crucial
in diagnosing and managing blood culture-negative
infectious endocarditis.45,46
Imaging
Echocardiography is the primary diagnostic tool, with
additional modalities aiding when confirming the
diagnosis, assessing complications, and identifying the
source of bacteraemia. Transthoracic echocardiography is
commonly the initial imaging modality for suspected
infective endocarditis, with a high specificity (>90%) and
modest sensitivity (75%) in detecting vegetation.47
Transoesophageal echocardiography provides higher
sensitivity than transthoracic echocardiography for
diagnosing infective endocarditis;48 therefore, when there
is a strong suspicion of infective endocarditis, but the
transthoracic echocardiography results are negative or the
image quality is suboptimal, transoesophageal echo­
cardiog­raphy should be performed.36 In cases of suspected
prosthetic or intravascular device-related infective
endocarditis, transoesophageal echocardio­graphy should
be performed irrespective of high-quality transthoracic
echocardiography imaging.48 Moreover, transoesophageal
echocardiography could also be needed to screen for
specific complications (eg, perivalvular abscess) in patients
with known severe pathogens such as staphylococcus.49
Additionally, a repeat echocardio­
graphy should be
considered 5–7 days later to identify complications or if
clinical suspicion of infective endocarditis is high.50,51
Although not commonly used, three-dimensional
transoesophageal echocardiography can provide additional
information on vegetation size and morphology beyond
conventional transoesophageal echocardiography, leading
to a more accurate prediction of the embolism risk
associated with infectious endocarditis (figure 4A–D).52,53
When echocardiography is contraindicated or incon­
clusive in patients with suspected infective endocarditis,
cardiac computed tomography CT might be considered
as an alternative (figure 4E). Although inferior to
transoesophageal echocardiography in detecting
vegetations, cardiac CT surpasses transoesophageal
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Seminar
echocardiography in assessing paravalvular and
periprosthetic complications.54–56 The [¹⁸F]fluorodeoxy­
glucose ([¹⁸F]FDG)-PET-CT show an 86% sensitivity and
84% specificity for suspected prosthetic valve endocarditis
and can aid in differentiating alternative diagnoses.57–59
In comparison to CT, MRI has a higher sensitivity for
detecting cerebral lesions, making it a valuable tool for
both diagnosing and monitoring associated neurological
complications, such as ischaemic lesions and cerebral
microbleeds.60,61 CT angiography can also detect
complications such as mycotic arterial aneurysms,
including those affecting the CNS.62 Thrombolytic therapy
is not recommended in patients with infective endocarditis
and stroke, but thrombectomy can be considered in
specific cases of large vessel occlusion.63,64 Neurosurgical
treatment or endovascular therapy should be considered
in cases of large intracranial infective cerebral aneurysms,
ruptured aneurysms, or unruptured aneurysms that do
not respond to optimal antibiotic therapy.65
Moreover, whole-body and brain CT are valuable for
assessing systemic complications, assisting in the
identification of distant lesions and sources of bacteraemia.
In some instances, integrating multiple imaging
modalities is needed to improve accuracy of diagnosing
infective endocarditis.
The 2023 Duke–International Society for
Cardiovascular Infectious Diseases criteria for
infective endocarditis
The Duke criteria for infective endocarditis were initially
proposed in 1994 and refined in 2000 as the modified
Duke criteria.66,67 In response to the evolving understanding
of infective endocarditis, the 2023 Duke–ISCVID (the
International Society for Cardiovascular Infectious
Diseases) criteria were proposed as the most recent update
to the modified Duke criteria.68
The Duke–ISCVID criteria mainly proposed the number
of new additions (appendix pp 3–6). First, new microbiology
diagnostics (enzyme immunoassay for Bartonella species,
PCR, amplicon and metagenomic sequencing, and in situ
hybridisation) and imaging ([¹⁸F]FDG-PET-CT, and
cardiac CT) were introduced. Second, intraoperative
inspection was included as a new major clinical criterion.
Third, the list of typical microorganisms causing infective
endocarditis was expanded, considering some pathogens
typical only in the presence of intracardiac prostheses.
Fourth, specific requirements for timing and separate
venepunctures for blood cultures were eliminated. Last,
additional predisposing conditions including transcatheter
valve implants, CIED, and previous infective endocarditis
criteria were clarified.68 An external validation study
showed that the 2023 Duke–ISCVID criteria were more
sensitive than the modified Duke criteria (84·2% vs 74·9%,
p<0·001) without significant loss of specificity.69 However,
these criteria should be used with caution as they serve as
a diagnostic guide rather than a substitute for clinical
judgement.70
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Initial empirical
therapy
Endocarditis
Treatment
Duration
··
Ampicillin, cloxacillin, ceftriaxone,
or vancomycin* plus gentamycin
Until the pathogen
is identified
Based on results of blood culture
Bacteria
Streptococci
NVE
Ceftriaxone plus gentamycin
4 weeks
Streptococci
PVE
Ceftriaxone + gentamycin
6 weeks
Staphylococci
NVE
Flucloxacillin or cefazolin or vancomycin based
on sensitivity†
4–6 weeks
Staphylococci
PVE
Flucloxacillin, vancomycin‡, or cefazolin plus
gentamycin and rifampicin
6 weeks
Enterococci
NVE
Ampicillin plus gentamycin, vancomycin plus
gentamycin, or ampicillin plus ceftriaxone
6 weeks
Enterococci
PVE
Ampicillin plus gentamycin, vancomycin plus
gentamycin, or ampicillin plus ceftriaxone
6 weeks
NVE or PVE
Should be based on epidemiological factors and
in consultation with infectious disease expert
Variable
Culture negative
NVE=native valve endocarditis. PVE=prosthetic valve endocarditis. *Vancomycin for patients who are sensitive to
penicillin. †In penicillin-sensitive patients with methicillin-sensitive organisms, use cefazolin or vancomycin.
‡Daptomycin and linezolid can be used when vancomycin is ineffective or cannot be used.
Table 1: Antibiotic choice and duration of therapy in the treatment of infective endocarditis
Management
Antibiotics: principles and methods
If patients have an acute presentation, intravenous
antibiotic therapy should be started immediately after
obtaining blood samples for culture. The choice of
antibiotics depends on factors, such as underlying
cardiac disease, presence of infected foreign body
implants, epidemiological factors, the local community’s
pattern of microbial sensitivity, and the patient’s
immunological status. Infectious diseases experts should
be involved from the beginning. For insidious clinical
presentation, one can wait for blood culture results
before initiating antibiotics and if needed, repeat blood
cultures. There are few randomised controlled trials
(RCTs) available to inform therapy decisions for
antibiotics, and recommendations rely primarily on
guidelines.36 Many recommendations stem from expert
consensus, small studies, retrospective studies, or
registries.71 The details of the antibiotic choice and the
duration of treatment are listed in table 1 (appendix p 7).
The choice of antibiotics, dose, and duration are
dependent upon the minimal inhibitory concentrations
in blood culture. Treatment decisions are based on
clinical features and serological tests.
Treatment of infective endocarditis can be divided into
two phases (appendix p 8).36 During the early critical phase,
surgical or other appropriate interventions are made while
the patient is receiving intravenous antibiotics. This phase
lasts until the patient becomes afebrile with sterile blood
cultures. After a week or 10 days of effective antibiotic
therapy, patients enter the continuation phase. Patients
with complex infections should continue treatment in
hospital to receive a complete course of parenteral
antibiotics. The POET (Partial Oral Treatment of
See Online for appendix
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Seminar
Endocarditis) trial has shown that oral antibiotic therapy
can be considered during the continuation phase in stable
patients who no longer require any surgery or have
embolic phenomena.72 If good compliance can be assured,
patients can be discharged home with full 4–6 weeks of
intravenous antibiotic therapy or selected oral drugs that
reach effective bactericidal blood levels. Close postdischarge monitoring and completion of the full course of
treatment is mandatory.
Surgery: principles and methods
Surgical indication and timing for patients with infective
endocarditis are mainly based on the 2023 ESC
guidelines.36 The data supporting most of the other
recommendations are derived from large non-randomised
studies, expert consensus, or small-scale studies. Surgical
indications for infective endocarditis can be best
summarised by the triad, which refers to: (1) heart failure,
(2) uncontrolled infection, and (3) embolic prevention
(appendix p 9).36 Manifestations of heart failure as
the surgical trigger include refractory pulmonary oedema,
cardiogenic shock, dyspnoeic symptoms, or echocardio­
graphic signs of poor haemodynamic tolerance caused by
severe dysfunctions of affected heart valves.
Representative clinical scenarios of uncontrolled infection
can be categorised into local structural complications and
more general situations that correspond to medical
treatment failure. Local structural failures include
abscesses,
pseudo­
aneurysms,
fistula,
prosthetic
dehiscence, and the development of a new atrioventricular conduction block. General situations refer to
infective endocarditis caused by fungi or organisms
resistant to multi-antimicrobial drugs and persistent or
progressive diseases despite adequate antibiotic therapy
for sufficient periods. For embolic prevention, vegetation
with a size of 10 mm or more has been suggested as the
definite surgical trigger (class I recommendation) in the
presence of embolic episodes; however, those without
clinical evidence of embolism have been given a lower
level of surgical recommendation (class IIB).36
These traditional surgical indications have recently
been challenged by a study from South Korea, the only
RCT on intervention in infective endocarditis.73 While
the presence of severe dysfunction or large vegetation
(≥10 mm) without relevant symptoms has not been
considered for urgent surgery in the traditional
approach, the trial enrolled asymptomatic patients with
infective endocarditis presenting with severe dysfunction
of affected valves accompanied by large vegetations.73
Although the rates of death did not differ between the
early surgery group and the conventional medical
treatment group, the difference stemmed from the fact
that the rate of embolic events was significantly in favour
of early surgery (0% vs 21%, p=0·005). The findings
advocate early surgery for infective endocarditis in the
presence of severe valvular dysfunction and large
vegetation even in asymptomatic individuals.
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Risks imbedded in surgical therapy are also an
important consideration for decision making.74 For
instance, a non-negligible proportion of patients who have
clear surgical indications might not be offered operations
based on perceived unacceptable surgical risks, with a
resultant worse prognosis.75,76 To aid the decision making
in this complex scenario of infective endocarditis, several
surgical risk scoring systems have been developed.77–81
However, since these scoring systems are based on
retrospective data, their performances are variable and
none of these are generalised in daily clinical practices,
which calls for the development of scoring systems from
prospective data entailing greater predictive capacity.
In adult patients, homografts can serve as an alternative
to mechanical or bioprosthetic valves in acute aortic valve
endocarditis due to their lower susceptibility to infections
and high degree of resistance to recurrent infection.82
However, the use of homografts also poses specific
considerations, such as availability, durability, and the
risk of homograft degeneration over time. Therefore,
further investigation into the indications, surgical
techniques, outcomes, and potential complications
associated with the use of homograft aortic valves in
prosthetic or complex aortic infection is warranted.
Among people with intravenous drug use-associated
infective endocarditis, early survival rates were
favourable, while the long-term prognosis was
compromised.14,83 Compared with non-drug users, they
had longer hospital stays and higher rates of readmission, largely due to approximately a third of
patients resuming drug injection upon re-admission. In
this specific population, surgical intervention does not
offer a long-term survival advantage.83–85 Consequently,
both addiction treatment (ie, detoxification, medicationassisted treatment, behavioural therapy, psychosocial
support, and relapse prevention) and infection prevention
play crucial roles in managing this population.
The management of major complications
Major complications of infective endocarditis often
involve valvular dysfunction, heart failure, embolisation,
and infectious complications. Management of these
major complications requires a multidisciplinary
approach involving cardiologists, infectious disease
specialists, cardiac surgeons, radiologists, neurologists,
and other health-care professionals. In addition, early
recognition, timely medical or surgical intervention, and
close monitoring are essential in mitigating the effects of
complications and improving the overall prognosis of
individuals affected by infective endocarditis.
Adjunctive medical therapy
RCTs that specifically addressed antithrombotic or
anticoagulant therapy in infective endocarditis-related
stroke prevention or treatment were scarce. Infective
endocarditis alone does not necessitate the use of these
medications, but bleeding complications or strokes
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might justify their interruption or discontinuation. It is
generally accepted to bridge with low molecular weight
heparin or unfractionated heparin rather than oral
anticoagulants in the initial stage of infective endocarditis,
particularly for patients requiring surgery. Antiplatelet
agents showed mixed results in infective endocarditis.86
Current guidelines advise against the routine initiation
of antiplatelet agents, while maintaining long-term use
in those with low bleeding risk is considered reasonable.
Discussion within the endocarditis team is warranted
when facing the challenge of antithrombotic or
anticoagulant therapy.
Long-term prognosis and ongoing care
Long-term survival rates for patients with infective
endocarditis approximate to 85–90% at year 1 and
70–80% at 5 years.87–91 The main risk factors for poor
prognosis include recurrence of infective endocarditis,
heart failure, older age, comorbidities, and double valve
infection.87,90–92 Studies reported various recurrence rates,
with a range between 2% and 9%.87,88,90,91,93–96 Post-discharge
monitoring for relapses and reinfections of infective
endocarditis is of great importance, and it is crucial to
differentiate between the two since reinfections are
associated with worse outcomes compared with
relapses.97 Conceptually, relapse refers to a repeat episode
of the infection by the same microorganism, which
usually indicates ineffective antibiotic treatment.90
Reinfection, caused by another microorganism, usually
occurs 6 months after the initial episode.97 Treatment for
relapse should include intravenous antibiotics for an
additional 4–6 weeks, and cardiac surgery should be
considered for a persistent focus of infection.87,91–93,96
During the discharge follow-up, it is essential to
educate patients on recurrence risks and prevention
strategies. Education should include at least one clinical
reassessment in the first year and annually thereafter.
Patients should be vigilant for new onset symptoms of
fever, chills, or other signs indicating recurrence and
should also be monitored for secondary heart failure,
although the need for late valve surgery is quite low.92
Additionally, recommendations for maintaining good
oral health and skin hygiene, including avoiding tattoos
and piercings, should be provided to minimise the risk
for infection.98
Prevention
The development of infective endocarditis requires the
aforementioned risk factors, bloodstream entry of
pathogens, and a competent host immune response. The
role of predisposing risk factors is highlighted by
Thornhill and colleagues who reported that annually
280 cases per 100 000 patients at moderate risk and
497 per 100 000 patients at high risk had an incident of
infective endocarditis based on their predisposing risk
factors, respectively.99 Entry portals for bacteria and fungi
vary, including skin, oral cavity, gastrointestinal, or
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genitourinary infections; direct inoculation in drug users;
unsafe vascular punctures; and health-care exposure.64,100–104
Prevention strategies for infective endocarditis should
address the underlying risk factors prevalent in all regions
of the world. Particularly, implementing primary and
secondary prevention measures for acute rheumatic fever
and rheumatic heart disease is crucial to alleviate the
burden of infective endocarditis in Africa, given that
rheumatic heart disease is the most important risk factor
for infective endocarditis across the continent. Primary
prevention measures for acute rheumatic fever and
rheumatic heart disease include promoting awareness,
administering antibiotic prophylaxis, and improving
access to health care. Secondary prevention involves longterm antibiotic treatment, regular medical follow-ups,
and health promotion to reduce complications.
Historically, antibiotic prophylaxis was widely
advocated before various medical and dental procedures
for individuals at increased risk of infective endocarditis,
encompassing both moderate-risk and high-risk
categories. However, in the mid-2000s, the American
Heart Association and ESC restricted antibiotic
prophylaxis use solely to individuals at high risk
undergoing invasive dental procedures, such as
manipulation of the gingival tissue or periapical region
around the teeth and perforation of the oral mucosa due
to concerns regarding the lack of evidence for the efficacy
of antibiotic prophylaxis, the risk of adverse drug
reactions to antibiotic prophylaxis antibiotics, and the
potential for antibiotic resistance.105,106
However, in the last decade there has been much new
evidence on the association between invasive dental
procedures and subsequent infective endocarditis, and the
efficacy, safety, and cost-effectiveness of antibiotic
prophylaxis in preventing infective endocarditis.107 Most
importantly, two large US studies using both casecrossover and cohort methodologies—one in patients
with employer-provided medical and dental insurance
coverage and the other in Medicaid patients—have both
shown the efficacy of antibiotic prophylaxis in reducing
the risk of infective endocarditis following invasive dental
procedures for patients at high risk, thereby supporting
the guideline recommendations.108,109 Notably, despite the
availability of only one of these two studies at the time, the
2023 ESC guidelines upgraded the classification of the
recommendation for antibiotic prophylaxis before invasive
dental procedures in patients at high risk from class IIa
(weight of evidence, opinion in favour of usefulness, and
efficacy) to class I (evidence or agreement on the treatment
or procedure being beneficial, useful, and effective).36
Furthermore, the level of evidence supporting this
recommendation was elevated from level C (consensus
opinion of experts, small studies, retrospective studies, or
registries) to level B (data derived from a single
randomised clinical trial or large non-randomised studies)
for individuals with a previous history of infective
endocarditis. Moreover, recent studies have elucidated the
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minimal risk of adverse drug reactions associated with
amoxicillin antibiotic prophylaxis and underscored the
cost-effectiveness of antibiotic prophylaxis in preventing
infective endocarditis.110,111 However, it is essential to
recognise that not all viridans group streptococci-infective
endocarditis cases stem from invasive dental procedures.
Many could arise from daily activities, such as tooth
brushing, flossing, and chewing food, particularly in
individuals with poor oral hygiene. A recent case–control
study has revealed that even individuals at moderate risk
with poor oral hygiene are at significantly increased risk of
developing infective endocarditis compared with those
with better oral hygiene.104 This highlights the importance
of promoting and maintaining optimal oral hygiene in
preventing infective endocarditis in populations at
moderate risk and high risk.
Furthermore, emerging evidence challenges the notion
that antibiotic prophylaxis was abandoned for some
invasive medical and surgical procedures by the guidelines
in the mid-2000s.105,106 Recent studies have suggested that
the abandonment of antibiotic prophylaxis for procedures,
such as permanent pacemaker and defibrillator implan­
tation, upper and lower gastrointestinal endoscopy, and
bronchoscopy might have been premature.102,103
Reconsidering antibiotic prophylaxis coverage for some
invasive procedures is recommended by the most recent
ESC guidelines and the American Heart Association’s
recent scientific advisory.36,112
Rational antibiotic selection should target viridans group
streptococci, particularly penicillin and cephalosporins,
due to their lower rates of Clostridioides difficile infection
compared with clindamycin.113 Amoxicillin, despite lacking
RCTs, seems to be the most widely used with the lowest
overall adverse drug reactions.114,115 If used, oral
administration and a single dose are preferred (single 2 g
in most countries and 3 g in the UK).
In addition, patients at high risk should follow general
prevention measures, including maintaining good
cutaneous hygiene, avoiding self-medication with
antibiotics, applying strict infection control for any at-risk
procedure, and reducing catheter-associated bacteraemia
by optimising central venous catheter care. Patients with
a fever of unknown origin should promptly report it to
their physicians for early infective endocarditis screening.
Special entities
Prosthetic valve infective endocarditis
With the increasing number of patients receiving
prosthetic heart valve implantation (who serve as the
denominator population for potential infectious
complications thereafter), prosthetic valve endocarditis,
which is one of the most challenging clinical scenarios of
infective endocarditis, has been an important clinical
issue in the current era.116 Large-scale observational
studies have shown a rapid increase in the incidence of
prosthetic valve endocarditis and a stable increase in
overall infective endocarditis. The incidence rate of
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prosthetic valve endocarditis is reportedly 0·3–1·2 per
100 person-years, accounting for 20–30% of all infective
endocarditis that has been even higher in most recent
years.6,27,30,117,118 In one of the largest observational studies
with 39 199 patients undergoing aortic valve replacement,
prosthetic valve endocarditis is more common with
biological than with mechanical prostheses, but the
absolute difference is as small as 2·2% versus 1·5% over
12 years, making it hard to detect in smaller studies or
perceivable in daily practices.119
Prosthetic valve endocarditis can be categorised
into two forms, occurring within 1 year (early form)
or after (late form) following prosthetic valve
replace­ment surgery. Statistically significant differences
have been noted between early and late prosthetic
valve endocarditis in terms of microbiological pro­
files.120 Early prosthetic valve endocarditis is closely
associated with perioperative infections with common
pathogens including S aureus, coagulase-negative
staphylococci, Gram-negative pathogens, and fungi.121
Mycobacterium chimaera residing in the heat-exchange
system of the cardiopulmonary bypass machine has also
been identified as an important pathogen for early
prosthetic valve endocarditis, presenting diagnostic
challenges due to its indolent presentation but high
mortality risk.122 Meanwhile, late prosthetic valve
endocarditis usually follows the pattern of infective
endocarditis in native valves, with viridans group
streptococci being the most frequent pathogens.121
Cardiac implantable electronic devices
With the rising number of CIEDs, the incidence of CIED
infection is increasing. A National Inpatient Sample
Database study showed that the incidence escalated from
1·45% in 2000 to 3·41% in 2012.123 The infection could
involve different parts of the device, including the
generator, device leads, and the native cardiac structure
alone or in combination. The mortality is higher for
patients with CIED endocarditis than for those with
generator pocket infection.124 Major risk factors for CIEDrelated infective endocarditis include haematoma
formation and revisions with the reopening of the
pocket.125,126
Clinical signs of leads or endocardium infection
include fever, chills, and embolic events with or without
the signs of generator pocket infection (pain, swelling,
tenderness, purulent discharge, etc). Transthoracic
echocardiography and transoesophageal echocardio­
graphy are both recommended in patients with
suspected CIED-related infective endocarditis.127–129
However, repeated transthoracic echocardio­
graphy or
transoesophageal echocardiography might be necessary,
as the initial absence of vegetation does not rule out
infective endocarditis. [¹⁸F]FDG-PET-CT has emerged as
a great tool for assessing CIED-related infective
endocarditis.57,130 The management of a definite CIED
infection involves early and complete system extraction
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and empirical antibiotic therapy targeting methicillinresistant S aureus and Gram-negative bacteria.130 System
extraction should be performed in centres with expertise
and without delay.131,132
During the decision-making process, factors such as
pacemaker dependency, patient frailty, lead dwell time,
and procedural risks including the possibility of lifethreatening tamponade, should be carefully considered.
Percutaneous extraction is preferred except when the
vegetation is larger than 20 mm or when valve surgery is
indicated.133
Congenital heart disease
The incidence rate of infective endocarditis in children
with congenital heart disease is low, with an estimated
rate of 0·041 per 100 person-years,134 but as the surgical
outcomes of children with congenital heart disease have
improved, more adults now live with congenital heart
disease than children in recent years. As a result, the
incidence rate of infective endocarditis in adults with
congenital heart disease is reported as around 0·13 per
100 person-years—higher than in children with con­
genital heart disease—and is around 30-fold higher than
in the general population.135 Congenital heart disease at
increased risk of infective endocarditis includes untreated
cyanotic congenital heart disease and status postprosthetic material placed in the circulatory system, such
as valved conduits or systemic to pulmonary shunts.99,135,136
The risk of infective endocarditis in the cyanotic
functional single ventricle group is known to be
particularly high, with a relative risk of six compared with
biventricular diseases.30 Transcatheter device-closure of
atrial or ventricular septal defects is also known to be
associated with a risk of infective endocarditis, but only
within 6 months after intervention.135
Left ventricular assist device-related infection
With the increasing number of patients on left ventricular
assist devices (LVADs) worldwide over the past two
decades, LVAD-associated infections have been on the
rise and are one of the leading causes of mortality in
patients with LVADs. Two major modes of infection are
defined as LVAD-specific and LVAD-related infections.
LVAD-specific infections refer to infections that are
unique to patients with LVADs and might involve the
pump, cannula, pump pocket, or driveline.137 Meanwhile,
LVAD-related infections encompass non-endovascular
infections, such as mediastinitis and the endovascular
infections including bloodstream infections and infective
endocarditis, all of which might also occur in patients
without LVADs. Even though LVAD-related infections
might not originate from LVADs per se, secondary
involvement of the device is possible and it is generally
difficult to make a confirmative diagnosis.
Data from the International Society for Heart and Lung
Transplantation Registry for Mechanically Assisted
Circulatory Support covering 10 171 patients provided the
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most robust analyses on infections in LVAD patients
to date. This registry showed that the LVAD-specific
infection rate was 17·3%, which comprised infections in
the driveline (82·9%), the pocket (12·8%), and the pump
or cannula (4·3%).138 LVAD-related infections were a
smaller category constituting 4·9%: 47·5% bloodstream
infections and 47·5% mediastinitis. 1-year mortality rate
after initial infection was 13·6% for driveline, 34·0% for
pocket infections, and 41·5% for pump or cannula.138
Patients with LVAD-specific infections were found to
have shorter median survival than those with LVADrelated infections. 139
Complete removal of the LVAD either by device
exchange or by heart transplantation is optional, but with
high risk in the setting of LVAD-associated endocarditis.
For instance, in a recent meta-analysis on LVAD-associated
endocarditis that involved 16 articles with 26 patients, the
surgical mortality rate was as high as 28·6%, although it
was lower than 72·6% for antibiotic therapy alone
(p=0·07).140 Notably, within the surgical therapy group,
there was no significant difference in the mortality rates
between device exchange and heart transplantation
(20·0% vs 33·3%, p=0·23). These findings indicate that
further research is needed to optimise the therapeutic
options for infectious complications occurring in
LVADs.140
Transcatheter valve prosthetics and other intracardiac
devices
The risk of infective endocarditis is higher within the
first year following transcatheter aortic valve implantation
(TAVI). The incidence of infective endocarditis following
TAVI ranges from 0·3 to 1·9 per 100 person-years, which
is comparable with that observed in surgical aortic valve
replacement (SAVR).141–145 However, the mortality was
higher for patients with infective endocarditis following
TAVI than for those following SAVR,143,144 which might be
attributed to the older age and more comorbidities in
that population. As for the treatment, antimicrobial
therapy for infective endocarditis post-TAVI is similar to
that of prosthetic valve endocarditis. Approximately
19% of cases of infective endocarditis following TAVI
require cardiac surgery, whereas the rate is around
50% for infective endocarditis associated with SAVR.146
Cardiac surgeries in patients post-TAVI pose considerable
risks due to advanced age, increased comorbidities, and
the potential for complex surgical interventions because
of the self-expanding devices in the ascending aorta.
Cardiac surgery is considered first when combining any
complications, particularly severe prosthetic failure or
heart failure. Compared with antibiotics alone, cardiac
surgery was not associated with reduced all-cause inhospital or 1-year mortality in post-TAVI infective
endocarditis.146 Notably, the incidence of TAVI-associatedinfective endocarditis has decreased in recent years,
particularly due to improvements in procedures and
refinements of devices.147
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The incidence of transcatheter pulmonary valve
implantation varies from 1·6 to 4·0 per 100 personyears.148–155 Data on the incidence, outcomes, and treatment
of infective endocarditis are restricted in patients with
transcatheter mitral and tricuspid valve interventions,
septal defect closure devices, left atrial appendage closure
devices, vascular grafts, vena cava filters, and central
venous system ventriculoatrial shunts. These patients are
considered to have increased infective endocarditis risk in
the first 6 months after the procedure.36
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy is an unusual cause of
infective endocarditis, with an estimated incidence of
1·4 cases per 1000 person-years.156 Earlier reports suggested
that patients with left ventricular outflow tract obstruction
and left atrial dilatation are at high risk of endocarditis.
However, later studies did not confirm this.157 The microbial
spectrum, antibiotic choice, and outcomes of patients with
hypertrophic cardiomyopathy are similar to those of other
patients with streptococcal infections and could be more
common. At present, antibiotic prophylaxis is not
recommended. A strong argument is made by Dominguez
and colleagues that patients with hypertrophic
cardiomyopathy should receive antibiotic prophylaxis.158
Right-sided infective endocarditis
Right-sided endocarditis is seen in about 5–10% of
patients and its incidence has been increasing.159 Patients
with congenital heart disease, CIED, indwelling
intravenous catheters, chronic haemodialysis, intravenous
drug use, and who are immunocompromised are
predisposed.159 Pulmonary symptoms such as cough and
haemoptysis are common. The tricuspid valve is often
affected, with staphylococcus being the predominant
organism. The prognosis is better compared with leftsided endocarditis. Although 90% of the patients respond
to medical therapy, patients who are immuno­
compromised and those with fungal infections have a
poor prognosis. Surgery is considered when the patient
has persistent bacteraemia, right heart failure, respiratory
failure, or has vegetations larger than 20 mm.160 Tricuspid
valve repair is preferred over replacement.161
The endocarditis team
The complexity of infective endocarditis necessitates
diverse decision-making strategies and a multidisciplinary
approach. The endocarditis team could facilitate early
and accurate diagnosis of the primary disease and
complications, initiating timely antibiotic therapy,
determining the type and duration of antibiotics, and
recommending early surgery.162–165 Previous studies have
shown that the team-based approach reduced 1-year
mortality by 7·5% to 10·3% in mixed cohorts.164,166
The core members of the endocarditis team typically
include cardiologists, cardiovascular surgeons, infectious
disease specialists, and microbiologists.167,168 The specific
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makeup of the team should be tailored to meet the
clinical needs of the patients and the capabilities of the
health-care centre. In facilities without cardiovascular
surgeons (known as referring centres), it is crucial to
establish communication with fully equipped centres
(referred to as heart valve centres) to coordinate optimal
patient transfer timing for advanced diagnosis and
treatment. These teams should maintain frequent
communication and operate under standardised
regulations to ensure effective management of infective
endocarditis.167
Knowledge gaps
The number of well-conducted RCTs studying infective
endocarditis is restricted due to the rarity of the disease.
Current recommendations often rely on observational
studies. Considerable knowledge gaps need to be
addressed in the field of infective endocarditis. Key areas
lacking robust evidence extend across various aspects of
infective endocarditis, including but not restricted to
some areas (table 2).
Accuracy of diagnosis
There is no consensus on the most accurate diagnostic
schema for infective endocarditis. Continued efforts are
required to improve the accuracy of diagnostic testing
for culture-negative infective endocarditis and elusive
pathogens, such as Bartonella, C burnetiid, and fungi. The
methodology to assess the size of the vegetation needs to
be standardised. More research is needed to evaluate the
diagnostic performance of intracardiac echocardiography
in prosthetic-valve endocarditis and [¹⁸F]FDG-PET-CT in
native-valve endocarditis. The role of molecular rapid
diagnostic tests and [¹⁸F]FDG-PET-CT on outcomes in
infective endocarditis needs to be clarified.
Prevention strategies
Further research is necessary to better define which
patients would benefit from antibiotic prophylaxis and
which invasive procedure requires antibiotic prophylaxis
to prevent infective endocarditis. There is a need for
robust evidence on the efficacy of various antibiotic
prophylaxis regimens in preventing infective endo­
carditis. The effect of antibiotic prophylaxis on
antimicrobial resistance needs to be determined.
Optimal treatment
There are uncertainties regarding the efficacy of empirical
antibiotic regimens in treating known or suspected
infective endocarditis, the efficacy and safety of
recommended antimicrobial treatment regimens and
new combinations of antimicrobials, and the effectiveness
of combined antifungal therapy. Additionally, questions
remain about the optimal medical strategies for specific
pathogens, such as highly penicillin-resistant oral
streptococci, staphylococci, high level aminoglycosideresistant Enterococcus faecalis, and vancomycin-resistant
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Knowledge gaps that need strong evidence from further research
Proposed
study designs
Diagnosis
Diagnostic schema
Which diagnostic schema is the most accurate? What is the diagnostic accuracy of the different schema in diverse care settings?
A
Microbiology
What is the accuracy of diagnostic testing for Bartonella infective endocarditis?
A
Microbiology
What is the accuracy of diagnostic testing for Coxiella burnetii (Q fever) infective endocarditis?
A
Microbiology
What is the accuracy of diagnosis of culture-negative infective endocarditis using molecular rapid diagnostic tests, or the determination of bacterial
or fungal cell-free DNA in blood samples?
A
Microbiology
What is the role of molecular and biochemical indicators to establish the diagnosis in fungal endocarditis?
B
Microbiology
What is the effect of molecular rapid diagnostic tests on outcomes in infective endocarditis?
C
A
Imaging
What is the standard method to assess the size of the vegetations?
Imaging
What is the diagnostic performance of intracardiac echocardiography in prosthetic valve endocarditis?
A
Imaging
What is the role of scoring systems in the identification of patients who might require a transoesophageal echocardiogram in the diagnosis of
infective endocarditis?
B
Imaging
What is the role of repeat echocardiograms in patients with an initial negative study suspected of having infective endocarditis or in patients with
an established diagnosis of infective endocarditis?
B
Imaging
What is the role of [¹⁸F]FDG-PET-CT in native valve endocarditis?
B
Imaging
What is the ability of [¹⁸F]FDG-PET-CT to affect clinical outcomes of infective endocarditis?
C
Prevention
Antibiotic prophylaxis
Which patients can benefit from antibiotic prophylaxis to prevent infective endocarditis?
C
Antibiotic prophylaxis
Which invasive procedure requires antibiotic prophylaxis to prevent infective endocarditis?
C
Antibiotic prophylaxis
What is the efficacy of various antibiotic prophylaxis regimens in preventing infective endocarditis?
C
Antibiotic prophylaxis
What is the effect of antibiotic prophylaxis on antimicrobial resistance?
D or E
Treatment
Antimicrobial treatment What is the efficacy of different empirical antibiotic regimen therapies in treating known or suspected infective endocarditis?
C
Antimicrobial treatment What is the efficacy and safety of recommended antimicrobial treatment regimens and new combinations of antimicrobials?
C
Antimicrobial treatment What is the effective antibiotic treatment in patients with highly penicillin-resistant oral streptococci infective endocarditis?
C or E
Antimicrobial treatment What is the best medical strategy in staphylococcal infective endocarditis?
C or E
Antimicrobial treatment What are the effective antibiotic treatments for patients with high level aminoglycoside-resistant Enterococcus faecalis infective endocarditis and
hypersensitivity to β-lactams?
C or E
Antimicrobial treatment What are the effective treatments for vancomycin-resistant enterococcal infective endocarditis?
C or E
Antimicrobial treatment What is the efficacy of combined antifungal therapy?
C or E
Antimicrobial treatment Are dual regimens, as used in the POET study,72 required for effective treatment?
C
Antimicrobial treatment To what extent is intravenous lead-in therapy needed before transitioning to oral therapy?
C or E
Antimicrobial treatment What is the duration of antibiotic therapy for infective endocarditis?
C or E
Surgery
C
What is the indication and timing of surgical treatment in patients with infective endocarditis?
Surgery
What is the need and timing of coronary angiogram before endocarditis surgery?
C
Surgery
What is the timing and sequence of surgical interventions in patients with multiple septic sources?
C or E
C or E
Surgery
What is the efficacy and safety of vegetation extraction systems in right-sided infective endocarditis?
Anticoagulation
What is the appropriate anticoagulation regimen in patients with prosthetic valve endocarditis that is complicated by haemorrhagic stroke?
C or E
Management of other
main complications
What is the efficacy and safety of mechanical thrombectomy in infective endocarditis-related embolic strokes?
C or E
Management of other
main complications
What is the timing and safety of splenectomy for splenic abscess complicating infective endocarditis in relation to surgical valve treatment?
E
Long-term outcomes
Outcomes
What are the optimal timing, duration, methods, and components of rehabilitation?
C
Outcomes
What is the efficacy of rehabilitation?
C
Outcomes
What are the patient-reported outcomes during short-term and long-term follow-up?
B
[¹⁸F]FDG-PET-CT=[¹⁸F]fluorodeoxyglucose-PET-CT scan. A=multicentre prospective comparative studies. B=multicentre prospective observational studies. C=multicentre randomised controlled trials.
D=multicentre prospective interventional studies. E=large-scale prospective registries with analysis performed with artificial intelligence.
Table 2: Knowledge gaps in the field of infective endocarditis
enterococci. The necessity of the dual antibiotic regimens
used in the POET study need to be clarified. Further
research is required to establish the extent of intravenous
lead-in therapy before transitioning to oral therapy, the
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duration of antibiotic therapy, the indication and timing
for surgical intervention, and the need for and timing of a
coronary angiogram before endocarditis surgery. Other
areas needing clarification include the timing and
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sequence of interventions in patients with multiple septic
sources, the appropriate anticoagulation regimen in
patients with prosthetic valve endocarditis affected by
haemorrhagic stroke, the efficacy and safety of mechanical
thrombectomy in infective endocarditis-related embolic
strokes, and the timing and safety of splenectomy for
splenic abscess complicating infective endocarditis in
relation to surgical valve treatment.
Long-term outcomes and other considerations
The optimal timing, duration, methods, components,
and efficacy of rehabilitation need to be determined.
There are a paucity of data on the short-term and longterm patient-reported outcomes, including recurrence
rates, post-treatment sequelae, and the effect on quality of
life.
The use of artificial intelligence remains underexplored
in patient management, such as identifying patients at
high risk, predicting the appropriateness of surgical
intervention and surgical timing, or better characterising
vegetations to predict response to antibiotic therapy or
risk of complications. Further research is also needed in
post-discharge rehabilitation efficacy, patient-centred
care, shared decision making, and sex-specific
considerations. Management of specific situations, such
as transcatheter valve therapies, left atrial appendage
occlusion, CIED reimplantation following device removal
after CIED infection, CIED removal in patients with leftsided infective endocarditis, and right-sided infective
endocarditis demands rigorous study as well.
Conclusion
Infective endocarditis remains a formidable challenge,
emphasising the need for a multidisciplinary approach in
both management and research. Despite progress, crucial
questions persist demanding urgent RCTs to enhance
our understanding of infective endocarditis. Advances
in microbiological services, imaging technology, and
artificial intelligence-driven machine learning offer
promising avenues for improved patient outcomes. Only
with coordinated and sustained efforts can we effectively
confront the evolving nature of infective endocarditis and
strive for continued advancements in patient care and
outcomes.
Contributors
ML, JBK, BKSS, and MC jointly drafted and revised the manuscript.
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Declaration of interests
We declare no competing interests.
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Acknowledgments
The authors are grateful to Yanjuan Zhang, Le Geng, and Jun Wang for
assistance with images.
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