Infective Endocarditis

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 69, NO.
3, 2017
2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2016.10.066
THE PRESENT AND FUTURE
STATE-OF-THE-ART REVIEW
Challenges in Infective Endocarditis

Thomas J. Cahill, MBBS,a Larry M. Baddour, MD,b Gilbert Habib, MD,c,d Bruno Hoen, MD, PHD,e
Erwan Salaun, MD,d Gosta B. Pettersson, MD, PHD,f Hans Joachim Schfers, MD,g Bernard D. Prendergast, DMh
ABSTRACT
Infective endocarditis is dened by a focus of infection within the heart and is a feared disease across the eld of
cardiology. It is frequently acquired in the health care setting, and more than one-half of cases now occur in patients
without known heart disease. Despite optimal care, mortality approaches 30% at 1 year. The challenges posed by
infective endocarditis are signicant. It is heterogeneous in etiology, clinical manifestations, and course. Staphylococcus
aureus, which has become the predominant causative organism in the developed world, leads to an aggressive form
of the disease, often in vulnerable or elderly patient populations. There is a lack of research infrastructure and funding,
with few randomized controlled trials to guide practice. Longstanding controversies such as the timing of surgery or
the role of antibiotic prophylaxis have not been resolved. The present article reviews the challenges posed by
infective endocarditis and outlines current and future strategies to limit its impact. (J Am Coll Cardiol 2017;69:32544)
2017 by the American College of Cardiology Foundation.
I nfective endocarditis (IE) is a rare disease, but its

impact is signicant (1). It affects 3 to 10 per
100,000 per year in the population at large, and
epidemiological studies suggest that the incidence is
change in the risk factor prole,
mographic characteristics, and the microbiology of
IE. Prosthetic valve replacement,
venous catheters, immunosuppression, and intrave-
patient de-
hemodialysis,
rising (25). In the United States, there are 40,000 to nous (IV) drug use became the principal risk factors
50,000 new cases each year, with average hospital (8). The average patient was older and frailer, with
charges in excess of $120,000 per patient (3). Despite increasing comorbidities. Concurrently, staphylo-
trends toward earlier diagnosis and surgical interven- cocci overtook oral streptococci as the most frequent
tion, the 1-year mortality from IE has not improved in causative organism (9,10).
over 2 decades. In the 21st century, IE has continued to evolve
IE is an old problem in a new guise (6). In the pre- such that it is now health careacquired in >25% of
antibiotic and early antibiotic eras, it typically cases (9), while advances in cardiology have driven
affected young or middle-aged adults with underly- further changes in the patient demographics and
ing rheumatic heart disease or congenital heart dis- manifestations of the disease. Alongside the emer-
ease (CHD) (7). The development of antibiotics, the gence of cardiac implantable electronic devices
decline of rheumatic heart disease, and advances in (CIEDs), IE affecting complex devices has burgeoned
medicine through the 20th century heralded a (11). Similarly, transcatheter valve replacement is
From the aDepartment of Cardiology, Oxford University Hospitals, Oxford, United Kingdom; bDivision of Infectious Diseases,
Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota; cAix-Marseille Universite, URMITE, Marseille, France;
Listen to this manuscripts d
APHM, La Timone Hospital, Cardiology Department, Marseille, France; eUniversit des Antilles et de la Guyane, Facult de
audio summary by Mdecine Hyacinthe Bastaraud, Inserm, Service de Maladies Infectieuses et Tropicales, Dermatologie, Mdecine Interne, Centre
JACC Editor-in-Chief Hospitalier Universitaire de Pointe--Pitre/Abymes, Pointe--Pitre, France; fDepartment of Thoracic and Cardiovascular Surgery,
Dr. Valentin Fuster. The Cleveland Clinic Foundation, Cleveland, Ohio; gDepartment of Thoracic and Cardiovascular Surgery, Saarland University
Medical Center, Homburg/Saar, Germany; and the hDepartment of Cardiology, St. Thomas Hospital, London, United Kingdom. Dr.
Baddour has received royalty payments from UpToDate, Inc.; and Editor-in-Chief payments from Massachusetts Medical Society
(Journal Watch Infectious Diseases). The other authors have reported that they have no relationships relevant to the contents of
this paper to disclose.
Manuscript received August 28, 2016; revised manuscript received October 26, 2016, accepted October 30, 2016.
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326 Cahill et al. JACC VOL. 69, NO. 3, 2017
Challenges in Infective Endocarditis JANUARY 24, 2017:32544
ABBREVIATIONS revolutionizing the management of valvular vegetation (16). Many of the microorganisms associ-
AND ACRONYMS heart disease but may be associated with ated with IE (including staphylococci, streptococci,
18
higher rates of IE than surgically implanted and enterococci but also less common pathogens,
FDG-PET = 18
uorodeoxyglucose positron
prosthetic valves (1214). such as Candida species and Pseudomonas aeruginosa)
emission tomography The present review outlines the challenges produce biolms, which allow bacterial populations
ACC = American College of posed by contemporary IE in developed to embed within an extracellular polysaccharide
Cardiology countries, as well as the reasons why diag- slime-like matrix, with quorum sensing (chemical
AHA = American Heart nostic and treatment advances have failed to cell-to-cell communication) and synchronized gene
Association
have an impact on the disease. We highlight expression promoting assembly and maturation.
CDI = cardiac device infection recent data on the effect of changing anti- Once established, the biolm protects bacteria from
CHD = congenital heart disease biotic prophylaxis guidelines, as well as the host immune defenses, impedes antimicrobial ef-
CI = condence interval current status of molecular and imaging cacy, and hides resistant persister organisms (17).
CIED = cardiac implantable diagnostic strategies, and review policies for Biolm-forming capacity is now recognized as an
electronic device improving service delivery and surgical out- important determinant of virulence in the develop-
CoNS = coagulase-negative comes. Reecting the constant evolution of ment of staphylococcal device-related infections (18).
staphylococci
the disease, data on IE in 3 patient groups
CT = computed tomography ANTIBIOTIC PROPHYLAXIS. Preventive strategies
were also examined that encapsulate some
ESC = European Society of
have historically focused on bacteremia. In 1909,
of the key challenges: those with trans-
Cardiology Thomas Horder recognized that the mouth was a
catheter aortic valve replacement (TAVR)-
HR = hazard ratio major portal for bacterial entry, and, in 1935, strep-
endocarditis, those presenting with stroke,
IE = infective endocarditis tococcal bacteremia was detected after dental
and those with CIED infection. Finally, we
IV = intravenous
extraction (19,20). The rst trials of penicillin pro-
look ahead and emphasize the future need
phylaxis were conducted in the 1940s and showed
MRI = magnetic resonance for enhanced clinical care pathways, inter-
imaging that antibiotics reduced the incidence of bacteremia
disciplinary collaboration, and research,
NVE = native valve infective after dental extraction (21,22). Consequently, in 1955,
which will be required for effective disease
endocarditis the American Heart Association (AHA) published
prevention, diagnosis, and cure.
PVE = prosthetic valve guidelines recommending antibiotic prophylaxis for
infective endocarditis PREVENTION patients with rheumatic heart disease and CHD (23).
OPAT = outpatient parenteral Maintenance of good oral hygiene and antibiotic
antibiotic therapy
Prevention of IE is better than cure and re- prophylaxis for at-risk groups undergoing dental
OR = odds ratio
quires insight into the mechanisms of dis- extraction became the standard of care for 50 years.
RCT = randomized controlled ease, the patient populations at risk, and an Between 2007 and 2009, guidelines in the United
trial
effective preventive intervention. The dis- States and Europe were substantially revised to
SPECT = single-photon
ease develops in 3 stages. The initiating step restrict the use of antibiotic prophylaxis. There were
emission computed
tomography is bacteremia, with bacteria commonly several reasons for these revisions. First, in the era of
TAVR = transcatheter aortic entering the bloodstream via the mouth, evidence-based practice, there was (and remains) no
valve replacement gastrointestinal and urinary tracts, or the randomized controlled trial (RCT) of antibiotic pro-
TEE = transesophageal skin, through venous catheters or after an phylaxis for prevention of infective endocarditis in
echocardiography invasive medical or surgical procedure. The the context of dental extraction. Second, the efcacy
TTE = transthoracic second step is adhesion: whereas the normal of prophylaxis was questioned on the basis of an
echocardiography
endothelial lining of the heart is resistant to apparent failure rate of up to 50% (24). Third, the
bacterial adhesion, bacteria (particularly gram- importance of widespread antibiotic use as a contrib-
positive species) are able to adhere to abnormal or utor to emerging resistance was gaining recognition,
damaged endothelium via surface adhesins. These while the indications for prophylaxis had expanded
specialized proteins mediate attachment to extra- signicantly to encompass groups at moderate risk.
cellular host matrix proteins, a process which is Finally, the signicance of dental procedures as a
facilitated by brin and platelet microthrombi (15). cause of IE was questioned due to population studies
Gram-positive bacteria also lack an outer membrane that did not show dental intervention as a major risk
and have a thick surrounding peptidoglycan and are factor (25,26). In contrast, everyday bacteremia, due
therefore less sensitive to serum-induced killing. to tooth brushing, chewing, and inadequate dental
Bacterial adhesion gives rise to colonization, in hygiene, was recognized as a possible cause of IE. In a
which cycles of bacterial proliferation occur in addi- cohort awaiting dental extraction (i.e., with dental
tion to thrombosis, monocyte recruitment, and disease), tooth brushing alone was sufcient to cause
inammation, leading to formation of a mature bacteremia in 23% (27). The relative importance of rare
JACC VOL. 69, NO. 3, 2017 Cahill et al. 327
JANUARY 24, 2017:32544 Challenges in Infective Endocarditis
T A B L E 1 Time Trend Studies Addressing the Changing Population Incidence of IE After Guideline Change
First Author, Year (Ref. #) Study Location Population/Diagnoses Analyzed Incidence Change?
Bikdeli et al., 2013 (37) United States All diagnoses of IE from Medicare No evidence of an increase in adjusted rates of hospitalization or mortality after
Inpatient Standard Analytic Files 2007 guideline change.
Dayer et al., 2015 (5); England, United All diagnoses of IE from NHS Hospital In the 2015 analysis, there was an increase detected in the number of cases of IE
Thornhill et al., Kingdom Episode Statistics above the projected historical trend (by 0.11 case per 10 million people per
2011 (38) month). Statistical analysis identied June 2008 as the change point
(3 months after the NICE guideline change).
De Simone et al., 2015 Olmsted County, Diagnoses of VGS IE from the Rochester No evidence of an increase in VGS IE.
(35); DeSimone et al., Minnesota Epidemiology Project
2012 (34)
Duval et al., 2012 (33) France: Greater Paris, All diagnoses of IE and subgroups by No evidence of an increase in VGS IE.
Lorraine, and specic organisms
Rhne-Alpes
Mackie et al., 2016 (36) Canada Diagnoses of IE from Canadian Institute No signicant change in the rate of increase in IE cases after publication of
for Health Information Discharge guideline change. Reducing incidence of VGS IE over time. Change point
Abstract Database analysis did not identify guideline change as a signicant inection point.
Pant et al., 2015 (2) United States Diagnosis of IE using Nationwide Signicant increase in the rate of increase in streptococcal IE after 2007
Inpatient Sample (change in the slope before and after: 1.37; 95% CI: 0.692.05; p 0.002).
No change point analysis.
Keller et al., 2016 (156) Germany All patients hospitalized with acute or Yes. Continuous small increase in incidence of IE before guideline change
subacute IE between 2006 and 2010, with an accelerated increase in incidence following
guideline change, between 2011 and 2014.
Van den Brink et al., Netherlands All patients with IE identied from the Yes, signicant increase in IE above the projected historical trend, coinciding
2016 (157) national healthcare insurance with change in ESC guidelines in 2009 (rate ratio 1.327, 95% CI: 1.205
database 1.462; p<0.001). Increased proportion of streptococcal IE following
guideline change.
CI condence interval; IE infective endocarditis; NHS National Health Service (United Kingdom); NICE National Institute for Health & Care Excellence (United Kingdom); VGS viridans
group streptococci.
and high-magnitude bacteremia (e.g., caused by Epidemiology Project, DeSimone et al. (34,35)
dental extraction) compared with common, low-level analyzed the incidence of IE due to viridans group
bacteremia in the pathogenesis of IE remained streptococci before and after this change. No increased
poorly dened. Therefore, in the United States and incidence was identied and, conversely, there was
Europe, antibiotic prophylaxis was restricted to those a drop in incidence from 3.6 per 100,000 person-years
at highest risk (28,29). Meanwhile, in the United from 1999 to 2002 to 1.5 per 100,000 person-years from
Kingdom, antibiotic prophylaxis was abandoned 2011 to 2013. Similarly, 2 population studies from
entirely in a highly controversial decision by Canada and the United States found no evidence for a
the U.K. National Institute for Health and Care Excel- change point in the incidence of IE coinciding with the
lence (30,31). ACC/AHA guideline amendment (36,37).
In contrast, 2 nationwide epidemiological studies
EFFECTS OF CHANGING GUIDELINES ON THE from the United States and the United Kingdom have
INCIDENCE OF IE. Several studies have now exam- given cause for concern. Using the Nationwide Inpa-
ined the effect of restricting oral antibiotic prophy- tient Sample, Pant et al. (2) identied a statistically
laxis on the incidence of IE (Table 1). In France, where signicant increase in the incidence of IE caused by
antibiotic prophylaxis was limited to high-risk groups streptococci, although there was no signicant
as early as 2002, a survey approach was used to gather change in the (upward) trend in total hospitalizations
data on all cases of IE across several different regions or in staphylococcal endocarditis. This study included
(32,33). The incidence of IE in 3 survey years (1991, both nonviridans group streptococci and enterococci
1999, and 2008) was found to be stable at 35, 33, and in the incidence calculations, however, and did not
32 cases per million, suggesting no signicant change perform change point analysis to conrm that the
after restriction of oral antibiotic prophylaxis. change in rate coincided with the ACC/AHA guideline
Importantly, the number of cases caused by oral amendment. Furthermore, the investigators had no
streptococci was also stable. access to antibiotic prophylaxis prescribing data to
In 2007, the American College of Cardiology (ACC)/ conrm that this rate had declined.
AHA restricted antibiotic prophylaxis in the United In the United Kingdom, where national guidance
States to patients with prosthetic valves, CHD, and advised against use of antibiotic prophylaxis in March
previous IE, as well as cardiac transplant recipients 2008, early analyses signaled no rise in the incidence of
with valvulopathy (29). Using data from the Rochester IE (38). In 2015, however, Dayer et al. (5) published an
T A B L E 2 ACC/AHA and ESC Guidelines on Use of Antibiotic Prophylaxis for the Prevention of IE
Class, Level of Class, Level

ACC/AHA Evidence ESC of Evidence
Dental procedures that 1. Patients with prosthetic IIa, B 1. Patients with any prosthetic IIa, C
involve cardiac valves valve, including a transcatheter valve,
manipulation of 2. Patients with previous IE or those in whom any prosthetic
gingival tissue, 3. Cardiac transplant recipients material was used for cardiac valve repair
manipulation of the with valve regurgitation due to a 2. Patients with previous IE
periapical structurally abnormal valve 3. Patients with CHD, including
region of teeth, or 4. Patients with CHD, including a. Any type of cyanotic CHD
perforation a. Unrepaired cyanotic b. Any type of CHD repaired with
of the oral mucosa* CHD, including palliative a prosthetic material, whether
shunts and conduits; placed surgically or by using percutaneous
b. Completely repaired CHD techniques, up to 6 months after the procedure,
repaired with prosthetic or lifelong if residual shunt or
material or device, whether placed valvular regurgitation remains
by surgery or catheter interven-
tion, during the rst 6 months after
the procedure; or
c. Repaired CHD with residual
defects at the site or adjacent to
the site of a prosthetic
patch or prosthetic device
Vaginal delivery 1. Patients with prosthetic cardiac IIa, C Not recommended. During delivery the indication for III, C
valve or prosthetic material used prophylaxis has been controversial and, given the lack
for cardiac valve repair of convincing evidence that infective endocarditis is related
2. Patients with unrepaired and to either vaginal or caesarean delivery, antibiotic
palliated cyanotic CHD, including prophylaxis is not recommended (145).
surgically constructed palliative
shunts and conduits
*ACC/AHA guidelines on valvular heart disease 2014 and ESC guidelines on infective endocarditis 2015. ACC/AHA management of adults with congenital heart disease 2008 (146); and ESC
management of cardiovascular diseases in pregnancy 2011 (145). Infective endocarditis prophylaxis at the time of vaginal delivery is controversial and not included as an indication in the ACC/
AHA guidelines on valvular heart disease 2014 or the main ESC 2015 guidelines.
CHD congenital heart disease; IE infective endocarditis.
extended analysis looking at National Health Service The current pragmatic approach (endorsed by the
hospital discharge diagnoses up to 2013. Antibiotic ACC/AHA and the European Society of Cardiology
prophylaxis dropped from 10,900 prescriptions per [ESC]) (Table 2) is to limit prophylaxis to individuals at
month to 2,236 prescriptions per month after intro- highest risk on the basis of the underlying cardiac
duction of the U.K. National Institute for Health and condition. In our view, this approach correctly bal-
Care Excellence guidelines. In parallel, there was a ances the risks and benets of individual and popu-
signicant rise (above the projected trend) in the lation antibiotic use. Importantly, this classication
number of IE cases, by 0.11 case per 10 million persons omits patients who have noncardiac risk factors (e.g.,
(or an additional 35 cases in England) per month. Sta- those who are immunocompromised) and who may be
tistical analysis identied June 2008 (3 months after at increased risk of both IE and poor outcome if the
implementation of the new guidelines for the use of disease develops. There are few data to guide specic
antibiotic prophylaxis) as the point of change, but it practice in these groups, and a tailored approach for
was not possible to conrm that these cases were due individual patients remains appropriate, according to
to oral streptococci because microbiological data were clinical circumstances (39,40).
unavailable.
These data are observational and cannot establish a PREVENTION OF HEALTH CAREASSOCIATED IE.
causal link between restriction of antibiotic prophy- Health careassociated IE accounts for an increasing
laxis and incidence of IE. They are subject to con- proportion of cases and requires specic strategies for
founding, for example, by increasing numbers of prevention. The affected patient demographic is
device implants, although this factor has been older, and most have either degenerative valve dis-
adjusted for in some studies. Despite the longstanding ease or no intrinsic cardiac risk factors. Instead, the
controversy and difculty with observational data, a most frequent risk factors are hemodialysis, cancer,
randomized trial is highly unlikely due to cost, logis- diabetes mellitus, and the presence of a CIED (9,41).
tics, and ethical debate as to whether true equipoise Staphylococcus aureus is the causative organism in
exists to allow conduct of a placebo-controlled trial. approximately one-third of cases, and the overall
proportion of IE due to S aureus in the United States DIAGNOSIS

rose from 24% to 32% between 1998 and 2009 (3).
S aureus is consistently an independent risk factor for Reaching a rapid and accurate diagnosis in cases of
in-hospital death (42). In keeping with the affected suspected IE is a central challenge of the disease.
patient population and underlying microbiology, the Delayed diagnosis and initiation of therapy lead to
in-hospital mortality for patients with health care complications and worse clinical outcomes (5658).
associated IE is signicantly higher than for Clinical presentation is notoriously diverse, ranging
community-acquired infection (31.1% vs. 20.3%; from acute sepsis to an indolent low-grade febrile
p < 0.01) (9). illness, a heart failure syndrome, or stroke. Further-
Reduction of health careacquired bacteremia is more, the modied Duke criteria, originally designed
thus a logical target. Longitudinal studies from for research purposes and advocated by AHA guide-
Denmark found that an increase in S aureus bacter- lines for evaluation of patients with suspected IE,
emia occurred from 3 to 20 per 100,000 person-years have a lower sensitivity for patients with prosthetic
between 1957 and 1990, mirroring increasing rates of valve endocarditis (PVE) or cardiac device infection
hospital admission and invasive medical procedures (CDI) (59,60). Up to 30% of patients with subse-
(although rates have now plateaued in the developed quently proven IE are labeled as possible due to
world) (43,44). In the United States, 10% to 20% of the equivocal or negative ndings on echocardiography
population are persistent carriers of S aureus (45). For or blood cultures (61,62). Denitive cardiac imaging
central lineassociated bloodstream infection, and microbiology are therefore of integral importance
practice-changing interventions to improve adher- in making the diagnosis and also inform risk strati-
ence to sterile practice (hand hygiene, barrier pre- cation, direct management, identify complications,
cautions, and antisepsis) have already signicantly and assist with monitoring therapy. Key advances
reduced rates of bacteremia (46,47). Bundled in- have been made in recent years in reaching a deni-
terventions to reduce catheter-related bloodstream tive diagnosis in patients who fall into the possible
infection in high-risk groups, such as those under- group according to the Duke criteria.
going hemodialysis, could translate into a major
impact on the incidence of IE (48,49). IMAGING. Echocardiography remains the cornerstone
Novel approaches to prevention of bacteremia and of imaging and is rapid, straightforward, and, in many
strategies to target adherence are urgently required cases, diagnostic (63). Transthoracic echocardiogra-
(50). Innovative material technologies, which prevent phy (TTE) is the recommended initial modality of
interaction of bacteria with prosthetic surfaces (so- choice for both native valve infective endocarditis
called low-fouling coats) or contain long-lasting (NVE) and PVE. For suspected NVE, TTE has a sensi-
bactericidal coatings, hold promise but have so far tivity of 50% to 90% and a specicity of 90%. For sus-
failed to translate into clinical practice. Indeed, pected PVE, the sensitivity of TTE is lower, at 40% to
enthusiasm for antibacterial coatings has been 70%, yet it provides value in assessment of ventricular
tempered by experience with the Silzone valve (St. size and function, hemodynamic severity of valve le-
Jude Medical, St. Paul, Minnesota), which had a silver- sions, and in the diagnosis of anterior prosthetic aortic
coated sewing ring, but had to be recalled within 3 valve abscesses, which may be difcult to visualize on
years of its release in 1997 due to an increased risk of transesophageal echocardiography (TEE). TEE is indi-
thrombosis and paravalvular leak (51,52). Further- cated when TTE is positive or nondiagnostic, when
more, this outcome was seen as a failure of regulatory complications are suspected, or when intracardiac
approval processes for modication of existing valves. device leads are present. For suspected NVE, TEE has a
A vaccine targeted at bacterial components has long sensitivity of 90% to 100% and a specicity of 90% for
been seen as attractive for patients at high risk of detection of vegetations, and it is superior to TTE for
bacteremia. However, 2 candidate S aureus vaccines detection of complications, such as perforations, ab-
failed to demonstrate efcacy in Phase III clinical scesses, and stulae. In PVE, a recent meta-analysis
studies, with 1 failing to reach an efcacy endpoint reported a pooled sensitivity of only 86% (95% con-
(prevention of S aureus bacteremia in patients under- dence interval [CI]: 77% to 92%) for TEE in making the
going hemodialysis) and another leading to increased diagnosis (64), and other imaging modalities are
mortality in patients undergoing median sternotomy emerging to help make or exclude the diagnosis in
who developed staphylococcal infection (53,54). More cases in which TEE is nondiagnostic. Even when ab-
positively, a new composite vaccine targeting 5 com- normalities are detected, it can be difcult to differ-
ponents of S aureus has recently been shown to be entiate nodules from small vegetations or distinguish
highly protective in mouse models (55). signs of infection from post-operative changes.
F I G U R E 1 Cardiac CT in IE
A 78-year-old man was admitted with infective endocarditis (IE) on an aortic bioprosthesis. Blood culture specimens were positive for Enterococcus faecalis. Initial
transthoracic echocardiography imaging demonstrated a suspected anterior and intercoronary pseudoaneurysm on parasternal long-axis (A) and short-axis (B) views
(arrows). On transesophageal echocardiography (C and D), a vegetation (C, red arrow) and pseudoaneurysm (D, white arrow) were visualized, although the insertion of
the vegetation was not apparent due to shadowing from the frame of the bioprosthesis. On cardiac computed tomography (CT) scanning, the vegetation was seen in
the left ventricular outow tract view (E, red arrow), which also demonstrated the insertion of the vegetation on the anterior leaet. The short-axis cardiac CT view
(F) conrmed the anterior pseudoaneurysm and 3-dimensional reconstruction (G) allowed delineation of the position of the pseudoaneurysm relative to the coronary
arteries. AO aorta; LA left atrium; LV left ventricle; RV right ventricle.
Cardiac computed tomography (CT) scanning is the 73% and a specicity of 80% (69). The addition of
18
key adjunctive modality for use when the anatomy is abnormal prosthetic valve FDG-PET signal as a
not clearly delineated according to echocardiography, diagnostic criterion increased the sensitivity of the
and it now has a Class II, Level of Evidence: B recom- modied Duke criteria from 70% to 95%, reducing the
mendation for use in IE in the 2014 ACC/AHA valvular number of patients with possible IE from 56% to 32%.
heart disease guidelines (Figure 1) (59). Cardiac CT is In a Spanish cohort of patients with suspected PVE or
18
equivalent (and possibly superior) to TEE for demon- CDI, FDG-PET/CT (angiography) demonstrated an
strating paravalvular anatomy and complications (e.g., overall sensitivity and specicity of 87% and 90%,
paravalvular abscesses or mycotic aneurysms) and is respectively, and increased the sensitivity of the
subject to fewer prosthetic valve artifacts than echo- modied Duke criteria from 51% to 91% (70). Use of
cardiography (6567). This approach may help with PET/CT imaging allowed reclassication of 90% of
planning surgical strategy, and concurrent CT angiog- cases (35 of 39) with possible IE and provided a
raphy allows exclusion of signicant coronary disease conclusive diagnosis in 95% of cases overall. For
in younger patients. Detection of paravalvular lesions leukocyte scintigraphy with SPECT/CT imaging, a
by using CT imaging is now a major diagnostic criterion sensitivity of 90% and a specicity of 100% have also
in the 2015 ESC guidelines on IE (68). been reported (71). When directly compared in a cohort
Combining CT imaging with metabolic imaging by with suspected PVE and inconclusive echocardiogra-
18
18-uorodeoxyglucose positron emission tomography phy ndings, FDG-PET/CT imaging had higher
18
( FDG-PET) or leukocyte scintigraphy (radiolabeled sensitivity than SPECT/CT imaging, but SPECT
leukocyte single-photon emission computed tomog- demonstrated higher specicity (72). The signicance
18
raphy [SPECT]) to show regions of metabolic activity or of abnormal FDG-PET/SPECT imaging has been
inammation, respectively, is a hugely promising recognized in the 2015 ESC guidelines; a positive signal
approach in patients who, according to the Duke at the site of a prosthetic valve (if implanted >3 months
criteria, have possible IE or suspected CDI (Figure 2). previously) is now regarded as a major diagnostic cri-
Several studies have now investigated the sensitivity terion for PVE.
and specicity of PET/CT or SPECT/CT imaging in this Routine cross-sectional imaging of the brain, chest,
setting. In a cohort of 72 patients with suspected PVE, spine, and viscera can be diagnostic and can change
18
FDG PET/CT imaging had an overall sensitivity of management. Imaging cohort studies suggest that
patients with IE have a high incidence of subclinical streptococci comprise approximately 20% of cases,
complications, such as embolism, hemorrhage, or other streptococci approximately 10%, and entero-
abscess. Routine cerebral magnetic resonance imag- cocci a further 10%. HACEK organisms (Haemophilus
ing (MRI) identies abnormalities in 80% of patients, species, Aggregatibacter species, Cardiobacterium
and, in 1 prospective study, upgraded 14 (26%) of 53 hominis, Eikenella corrodens, and Kingella species),
patients from possible to denite IE (73). zoonoses, and fungi collectively account for <5% of
In another series, CT cerebral angiography identied cases.
intracranial mycotic aneurysms in 32% of patients Approximately 10% to 20% of patients have nega-
with left-sided endocarditis, of whom 50% subse- tive blood culture ndings at presentation, leading to
quently underwent endovascular or neurosurgical diagnostic uncertainty. Negative results on blood
intervention (74). Similarly, MRI imaging of the cultures may occur due to previous antibiotic use,
abdomen identied abnormalities in the spleen, liver, infection with fastidious intracellular organisms or
or kidneys in 34% of patients (75). Evidence of em- fungi, or an alternative diagnosis. The incidence of
bolism by cross-sectional imaging is a novel minor blood culturenegative IE may drop with increasing
diagnostic criterion in the ESC 2015 guidelines. use of newer blood culture techniques, which allow
Multimodality assessment by cross-sectional direct identication of bacterial species by mass
18
imaging, cardiac CT, and FDG-PET or SPECT has the spectroscopy and are signicantly faster than stan-
potential to improve diagnosis and detection of com- dard culture methods (82).
plications in patients with suspected IE (Figure 2). We A rigorous diagnostic approach to patients with
18
see CT and FDG-PET/CT becoming widely used for blood culturenegative IE allows a causative organ-
diagnosis in the Duke possible subgroup of patients ism to be identied in two-thirds of patients (83). The
and for CDI (see later discussion). There are drawbacks, rst stage is serological testing for zoonotic agents,
however. Metabolic imaging cannot accurately specically Coxiella burnettii (causing Q fever), Bar-
discriminate between sterile inammation and infec- tonella quintana and Bartonella henselae, Brucella
tion, and it is therefore of limited use in the early post- species, Myocoplasma species, and Legionella species.
operative period. False-positive ndings for PET/CT If serological ndings are positive, blood polymerase
imaging have been reported after cardiac surgery due chain reaction targeting the causative bacteria should
to post-pericardiotomy syndrome and prosthetic valve be undertaken. If serological ndings are negative,
thrombosis; they have also been reported at the site of molecular testing of blood or excised valve material is
an aortic graft. Access to advanced imaging is often valuable, including broad polymerase chain reaction
limited, and there is a risk that logistical hurdles may for bacterial 16S ribosomal ribonucleic acid genes and
delay denitive surgical intervention. Finally, identi- targeted polymerase chain reaction for Tropheryma
fying which patient groups derive the most clinical whipplei, Bartonella species, and fungi. If microbio-
benet from advanced imaging (and through precisely logical investigation remains negative, consideration
which modalities) remains to be established. should be given to autoimmune disease, and testing
for antinuclear antibodies and rheumatoid factor
MICROBIOLOGY. Health careassociated organisms initiated. In a French cohort of 759 patients with
have increasingly dened the microbiology of blood culturenegative IE, 476 patients ultimately
contemporary IE. S aureus is now the most common had an identied etiologic agent, most commonly
causative organism and accounts for approximately zoonoses (229 Q fever, 86 Bartonella species). Twelve
30% of cases (9,10). S aureus endocarditis is charac- patients were diagnosed with T whipplei, 8 with
terized by aggressive disease with increased risk of fungi, and 70 with common bacteria; 19 (2.5%) were
embolism, stroke, persistent bacteremia, and death found to have noninfectious endocarditis caused by
(76). S aureus is also the most common cause of PVE, autoimmune disease or marantic endocarditis (83).
often requiring redo surgery, and is associated with
mortality rates approaching 50% in some centers MANAGEMENT
(77,78). Coagulase-negative staphylococci (CoNS) have
a rising incidence of approximately 10% and play a Management of patients with IE is both a clinical
major role in PVE occurring in the rst year after the and logistical challenge. Delivery of optimal care re-
initial procedure (79,80). Importantly, CoNS have quires an administrative infrastructure and the
emerged as a cause of NVE, as well as PVE (81). They involvement of multiple hospital specialists,
are often methicillin resistant and, in the case of including cardiologists, surgeons, infectious disease
Staphylococcus lugdunensis, associated with highly physicians, microbiologists, nephrologists, neurolo-
destructive valvular and perivalvular lesions. Oral gists, and radiologists. Optimizing service delivery
F I G U R E 2 Integrated Imaging Strategy in Patients With Suspected IE
A
Clinical evaluation
Definite IE TTE & TEE Rejected IE
Consider further Possible IE

imaging for detection
of complications or
surgical planning
Further diagnostic imaging
1. Cardiac CT
2. 18F-FDG PET/CT or SPECT/CT*
1. Cardiac CT 3. CT/MR cross-sectional imaging
2. CT/MRI
4. Repeat TEE
Definitive diagnosis
* In patients with prosthetic valves or cardiac implantable electronic devices
(A) Integrated imaging strategy in patients with suspected infective endocarditis (IE). In the challenging subgroup of patients with possible IE after initial evaluation by
transthoracic echocardiography and transesophageal echocardiography (TEE), cardiac CT imaging, metabolic imaging, or cross-sectional imaging of the head and
viscera by CT scanning or magnetic resonance imaging (MRI) may help to reach an early denite diagnosis. Panels B to F: 18-Fluorodeoxyglucose positron emission
tomography (18FDG-PET/CT) imaging for diagnosis. A 54-year-old woman with a history of mitral valve replacement 5 years previously was admitted with features of
acute left ventricular failure. Transthoracic echocardiography on admission revealed severe intraprosthetic regurgitation. The TEE bicommissural (B and C) and
3-dimensional atrial (D) views revealed a leaet perforation (arrow) and severe regurgitation but no evidence of vegetation. Blood cultures on admission were
18
negative, although inammatory markers were raised. Antibiotics for suspected blood culture-negative IE were started, and FDG-PET/CT imaging conrmed the
diagnosis with focal signal uptake on the mitral bioprosthesis (E and F, red arrow). Panels G to K: Cross-sectional imaging by CT or MRI (or metabolic imaging) scans
18
may assist with detection of complications, such as abscess, mycotic aneurysm, infarct, or hemorrhage in patients with denite IE. FDG-PET/CT for detection of
complications of IE. A 65-year-old woman with a mitral bioprosthesis was diagnosed with Staphylococcus aureus IE. TEE revealed a mobile vegetation with leaet
prolapse and severe regurgitation (G and H). On 18FDG-PET/CT imaging, there was 18FDG signal from the mitral bioprosthesis (I and J, white arrow) and evidence of a
splenic abscess (I and K, red arrow). SPECT single-photon emission computed tomography; other abbreviations as in Figure 1.
Continued on the next page
F I G U R E 2 Continued
and early decision making have the potential to The importance of balancing efcacy of treatment
improve clinical outcomes, leading to calls for for- with the overall risk and toxicity of prolonged inpa-
mation of IE teams, modeled on the heart team tient therapy is increasingly recognized. Emerging
approach to coronary and heart valve disease (84). evidence supports short-course or stepped-down
Introduction of a formalized multidisciplinary team antibiotic treatment in selected groups. In patients
approach in Italy, dened by initial evaluation within with uncomplicated IE caused by oral streptococci
12 h, early surgery (within 48 h) if indicated, and and normal renal function, a combination of a peni-
weekly review, led to a reduction in in-hospital (28% cillin or ceftriaxone with an aminoglycoside for a total
vs. 13%; p 0.02) and 3-year (34% vs. 16%; p 0.0007) of 14 days is safe and effective (90). Similarly, a
mortality, despite patients being older and having 2-week course of penicillin monotherapy or
more comorbidities (85). Similarly, a French multidis- penicillin-aminoglycoside in combination is effective
ciplinary team approach to standardizing care, for uncomplicated methicillin-sensitive S aureus
including antibiotic protocols and indications for sur- right-sided IE (91).
gery, reduced 1-year mortality from 18.5% to 8.2% (86). There are increasing data to suggest that the use of
Centralized care concentrated in tertiary centers aminoglycosides may be causing harm without clear
with advanced diagnostic imaging, surgical expertise, clinical benet. In a 2006 RCT of daptomycin compared
and higher throughput clearly has a role in complex with conventional therapy (penicillin or vancomycin
cases and may also be universally benecial. There with initial gentamicin) for S aureus bacteremia or
are arguments against this model, however, such as right-sided endocarditis, daptomycin was shown to be
delays during transfer and loss of local expertise. noninferior. Importantly, renal dysfunction occurred
Reconguration toward a system of centralized IE in 11% of those treated with daptomycin compared
care (or a hub-and-spoke model, with central multi- with 26% of the conventional therapy arm (92,93).
disciplinary review) should therefore be instituted on Aminoglycosides have now been removed from the
the basis of evidence. The efcacy of centralized care ESC and AHA guidelines for the treatment of
to improve decision making, time to surgery, cure methicillin-sensitive S aureus or methicillin-resistant
rates, and short- and long-term outcomes could be S aureus NVE. Although aminoglycosides have histor-
readily tested in a before-and-after study. ically been widely used for enterococcal IE, the
increasing frequency of resistance (25% to 50% of iso-
ANTIBIOTIC THERAPY. Before the discovery of peni- lates in recent studies), along with the recognition of
cillin, IE was an untreatable disease (87,88). Effective potential harm, led the ESC 2015 guideline committee
microbial clearance requires bactericidal antibiotic to identify ampicillin and ceftriaxone (Class IB
regimens, usually in combination. Detailed empirical recommendation) as the treatment of choice for
and organism-specic antibiotic protocols are beyond aminoglycoside-resistant Enterococcus faecalis. This
the scope of the present review but are provided in recommendation is supported by large observational
the latest AHA and ESC guidelines (68,89). studies showing that ampicillin/ceftriaxone is as
effective as ampicillin/gentamicin, with reduced underlies the historical requirement for 4 to 6 weeks
levels of nephrotoxicity (94,95). of parenteral antibiotic therapy.
Further research is needed to determine whether Novel strategies are required to prevent and treat
additional patient groups may be suitable for short- IE caused by biolm-forming strains of multidrug-
ened courses of antibiotic therapy. For example, in resistant S aureus. These strategies may include the
patients who have undergone successful surgery and initial inhibition of bacterial adhesion to both living
have negative valve culture ndings suggesting suc- and inert surfaces (thus reducing further biolm
cessful microbial elimination (after initially positive development), disruption of biolm architecture, and
blood culture results), it may be safe to stop antibi- antipathogenic or signal interference approaches
otics after 2 weeks (96,97). However, current AHA involving inhibition of quorum sensing (18). Preven-
guidelines suggest that the remaining duration of tion of bacterial adhesion at the time of intracardiac
antibiotics be given (including administration before device insertion is key and may be achieved by using
surgery), but this suggestion is indicated on the basis implants coated with various adhesion inhibitors.
of Level C evidence (89). However, despite inhibiting biolm formation
Reduction of in-hospital stays may also be ach- in vitro, antibiotic-, silver ion, and silver nano-
ieved through an early switch to regimens of oral particlecoated implants have proved to be ineffec-
antibiotics with good bioavailability. In IV drug users, tive and poorly tolerated in humans. Disruption of
there are RCT data supporting the safety and efcacy biolm architecture may be a more promising
of oral ciprooxacin and rifampicin for uncompli- approach, and several compounds, including human
cated methicillin-sensitive S aureus NVE, although monoclonal antibodies such as TRL1068, are
increasing rates of uoroquinolone resistance limit currently being assessed. Treatment of established
applicability (98). The POET (Partial Oral Treatment biolm using a combination of TRL1068 with dapto-
of Endocarditis) trial is an ongoing Danish multi- mycin in an in vivo murine model (in which biolm
center study designed to address whether step-down was formed by infection with methicillin-resistant
to oral treatment is safe after the rst 10 days of IV S aureus) signicantly reduced the adherent bacte-
antibiotics in staphylococcal, streptococcal, or rial count compared with daptomycin alone (104).
enterococcal NVE. Four hundred patients will be SURGERY. Surgery is performed for the specic in-
randomized to receive 4 to 6 weeks of IV treatment, dications of progressive valve and tissue damage,
compared with step-down to oral therapy after a uncontrolled infection, and high risk of embolism. The
minimum of 10 days, with a primary endpoint of all- objectives are as follows: to remove infected tissue,
cause mortality, unplanned cardiac surgery, embo- foreign material, and hardware; clear and debride
lism, or relapse of positive blood culture ndings (99). paravalvular infection and cavities; restore cardiac
Early hospital discharge is frequently facilitated by integrity and valve function; and remove threatening
the use of outpatient parenteral antibiotic therapy sources of embolism. Although various surgical tech-
(OPAT). OPAT can be initiated in specic patients niques have been used (e.g., mitral valve repair, aortic
after completion of the rst 2 weeks of treatment, homograft implantation), a clear long-term advantage
after which the risk of complications is reduced. of one technique has yet to be proven. Regardless of
OPAT is contraindicated in patients with heart failure, approach, the long-term results are inferior to elective
complex infection, high risk of embolism, neurolog- valve surgery: 10-year survival ranges from 40% to
ical complications, or renal impairment (100102). 60% (105,106). It remains unclear whether this late
Facilitated readmission pathways, as well as close mortality relates to late prosthetic valve complica-
nursing and medical monitoring, are necessary. tions, extracardiac manifestations of the disease, or
The major challenges to successful antibiotic persistence of the biolm complex.
therapy are bacterial tolerance and antibiotic resis- Surgery is currently performed in 50% to 60% of
tance. Tolerance occurs when phenotypic variants of patients, and 6-month survival rates are >80%
bacteria persist despite antibiotic therapy, and they (107,108). The indications for surgery have been pre-
resume growth and infection once antibiotic con- dominantly derived from historical observational
centrations fall. There are multiple underlying studies that show benet in patients with valve
mechanisms, including the very high bacterial den- dysfunction causing heart failure, uncontrolled
sity and poor antibiotic penetration within vegeta- infection (dened as paravalvular extension, abscess,
tions, low bacterial metabolic activity, and or persistent bacteremia), or recurrent embolism. For
production of protective biolms on prosthetic ma- a specic patient, there is often debate, for example,
terial (103). The risk of tolerance, combined with in cases of mild heart failure or regarding the deni-
relatively slow bactericidal antibiotic effects, tion of persistent bacteremia (109). Current
T A B L E 3 Indications for Surgery in AHA and ESC Guidelines
Class, Level Class, Level

AHA Guidelines 2015 (89) of Evidence ESC Guidelines 2015 (68) of Evidence Timing
Heart Early surgery* is indicated in patients with IE who present I, B Aortic or mitral NVE, or PVE with severe acute I, B Emergency
failure with valve dysfunction resulting in symptoms or regurgitation, obstruction, or stula causing
signs of HF refractory pulmonary edema or cardiogenic
shock
Early surgery* is indicated in patients with PVE with I, B Aortic or mitral NVE, or PVE with severe I, B Urgent
symptoms or signs of HF resulting from valve dehiscence, regurgitation or obstruction causing symptoms
intracardiac stula, or severe prosthetic valve dysfunction of HF, or echocardiographic signs of poor
hemodynamic tolerance
Uncontrolled Early surgery* is indicated in patients when IE is complicated I, B Locally uncontrolled infection (abscess, false I, B Urgent
infection by heart block, annular or aortic abscess, or destructive aneurysm, stula, enlarging vegetation)
penetrating lesions
Early surgery* is reasonable for patients with relapsing PVE IIa, C
Early surgery* should be considered, particularly in patients with I, B Infection caused by fungi or multiresistant I, C Urgent/elective
IE caused by fungi or highly resistant organisms (e.g., VRE, organisms
multidrug-resistant gram-negative bacilli)
Early surgery* is indicated for evidence of persistent infection I, B Persisting positive blood cultures despite IIa, B Urgent
(manifested by persistent bacteremia or fever lasting appropriate antibiotic therapy and adequate
>57 d, and provided that other sites of infection and control of septic metastatic foci
fever have been excluded) after the start of appropriate
PVE caused by staphylococci or non-HACEK IIa, C Urgent/elective
antimicrobial therapy
gram-negative bacteria
Prevention Early surgery* is reasonable in patients who present with IIa, B Aortic or mitral NVE, or PVE with persistent I, B Urgent
of recurrent emboli and persistent or enlarging vegetations vegetations >10 mm after $1 embolic episode
embolism despite appropriate antibiotic therapy despite appropriate antibiotic therapy
Early surgery* is reasonable in patients with severe valve IIa, B Aortic or mitral NVE with vegetations >10 mm, IIa, B Urgent
regurgitation and mobile vegetations >10 mm associated with severe valve stenosis or
regurgitation, and low operative risk
Early surgery* may be considered in patients with mobile IIb, C Aortic or mitral NVE, or PVE with isolated very IIa, B Urgent
vegetations >10 mm, particularly when involving the anterior large vegetations (>30 mm)
leaet of the mitral valve and associated with
Aortic or mitral NVE, or PVE with isolated large IIb, C Urgent
other relative indications for surgery
vegetations (>15 mm) and no other indication
for surgery
*Dened as during initial hospitalization and before completion of a full course of antibiotics. Dened as: emergency surgery performed within 24 h; urgent surgery within a few days;
elective surgery after at least 1 to 2 weeks of antibiotic therapy.
HACEK Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species; HF heart failure; NVE native valve infective endocarditis; PVE prosthetic
valve infective endocarditis; VRE vancomycin-resistant Enterococcus; other abbreviations as in Tables 1 and 2.
indications for surgery, as dened in the AHA and surgery; operations for active IE present high risk,
ESC guidelines, are shown in Table 3. with an overall in-hospital mortality of 20% (and
In real-world situations, a signicant number of higher still in many centers).
patients with a guideline indication for intervention Improved risk-scoring models for IE would help to
still do not undergo surgery (i.e., 24% [202 of 863] of clarify the decision-making process. Gaca et al. (110)
patients with left-sided IE and a guideline indication used the Society of Thoracic Surgeons database
for intervention in the ICE-PCS [International to derive an IE surgical risk score, identifying 13
Collaboration on EndocarditisProspective Cohort risk factors for mortality, including emergency
Study] registry) (108). Predictors of nonsurgical status, cardiogenic shock, hemodialysis, and active
treatment were liver disease (odds ratio [OR] for endocarditis. Other, smaller cohorts have incorpo-
surgery: 0.16; 95% CI: 0.04 to 0.64), stroke before rated more detailed parameters of infection, including
surgical decision (OR: 0.54; 95% CI: 0.32 to 0.90), and valve type and organism (111,112). The PALSUSE score
S aureus infection (OR: 0.50; 95% CI: 0.30 to 0.85). In includes age $70 years, substantial intracardiac
contrast, severe aortic regurgitation, abscess, and destruction, staphylococcal infection, urgent surgery,
embolization were associated with surgery. Reasons female sex, and EuroSCORE (European System for
for avoiding surgery in 181 patients included an Cardiac Operative Risk Evaluation) $10 as predictors of
anticipated poor prognosis regardless of treatment in-hospital mortality, with in-hospital mortality
(34%), hemodynamic instability (20%), death before ranging from 0% in patients with a score of 0, to 45% in
surgery (23%), stroke (23%), sepsis (21%), and surgeon patients with a score >3 (112).
declined to operate (26%). Ultimately, the perceived The optimal timing of surgical intervention is also
risk of the operation determines the threshold for contentious. Delaying surgery may allow a longer
T A B L E 4 Twenty Years of RCTs in IE, 1996 to 2016
Firs Author, Year (Ref. #) Research Question Patient Population Conclusions
Kang et al., 2012 (126) What is the role of early surgery (within Adult patients with left-sided NVE, Early surgery reduced the composite endpoint of
48 h of randomization) in NVE? severe valve disease and large in-hospital death and embolic events within 6 weeks
vegetations from 23% to 3% (driven by a reduction in embolism)
Fowler et al., 2006 (92) Comparison of daptomycin vs. Adults with S aureus bacteremia Daptomycin was noninferior for the primary endpoint of
vancomycin or anti-staphylococcal or IE. Patients with intravascular clinically successful treatment (dened as lack of
penicillin with low-dose gentamicin material not intended to be clinical failure, microbiological failure, death, failure to
for bacteremia or IE caused by removed within 4 d or high obtain blood culture specimen at follow-up, receipt of
Staphylococcus aureus likelihood of valve replacement potentially effective nonstudy antibiotics, or
surgery or death excluded premature discontinuation of the study medication).
Clinically signicant renal dysfunction occurred
in 11% of patients who received daptomycin and
in 26% of patients who received standard therapy
(p 0.004)
Chan et al., 2003 (147) Does aspirin reduce the incidence Adults with left-sided endocarditis Aspirin did not reduce the risk of embolic events and
of embolism in patients (NVE or PVE). Patients with caused a nonsignicant trend toward increased
with IE? expected surgical intervention incidence of bleeding
within 7 days excluded
Fortn et al., 2001 (148) Is a short course of glycopeptide Adult IVDUs with right-sided NVE Glycopeptide therapy is inferior to cloxacillin
(vancomycin or teicoplanin) and caused by MSSA
gentamicin as effective
as combination cloxacillin and
gentamicin for treatment of right-sided
NVE caused by methicillin-sensitive
S aureus?
Sexton et al., 1998 (149) Is ceftriaxone plus gentamicin (for 2 weeks) Adults with penicillin-sensitive NVE Equivalent clinical cure in both groups
superior to ceftriaxone alone (for 4
weeks) for IE due to penicillin-sensitive
streptococci?
Ribera et al., 1996 (91) Is cloxacillin alone as effective as cloxacillin Adult IVDUs with isolated tricuspid No signicant benet from addition of gentamicin to
plus gentamicin in a 2-week course for valve endocarditis caused by MSSA cloxacillin (92% cure in 2-week cloxacillin group, 8%
treatment of right-sided required prolonged treatment)
S aureus endocarditis in IVDUs?
Heldman et al., 1996 (98) Is oral ciprooxacin/rifampicin treatment of Adult IVDUs with right-sided Oral therapy is as effective as parenteral treatment and
right-sided staphylococcal endocarditis staphylococcal endocarditis associated with reduced drug toxicity
in IVDUs as effective as parenteral
therapy (oxacillin or vancomycin, plus
gentamicin for the rst 5 days)?
IVDU intravenous drug user; MSSA methicillin-sensitive Staphylococcus aureus; RCT randomized controlled trial; other abbreviations as in Tables 1 and 3.
duration of antibiotic therapy and hemodynamic ndings are of uncertain applicability in older pop-
stabilization but incurs the risk of disease progression ulations with multiple comorbidities and staphylo-
with valve destruction, abscess formation, heart coccal infection. Studies from the ICE-PCS registry,
block, embolic complications, and even death. which dene early surgery as that undertaken within
Indeed, for some outcomes (e.g., embolism) the po- the course of the initial hospitalization for IE, have
tential gains from surgery are reduced with time (56). shown conicting results. Although early surgery for
In 2012, the rst RCT of surgery for IE compared early NVE is associated with reduced mortality, this sce-
surgery (undertaken within 48 h of randomization) nario does not hold true for PVE after adjustment for
with conventional care in patients with NVE, severe confounding variables, including survivor bias (i.e.,
valve regurgitation, and large vegetations (126). The the increased likelihood of patients who survive to
South Korean study cohort was young (mean age 47 undergo surgery) (113115).
years), with little comorbidity and predominantly The emphasis on early surgery differs signi-
streptococcal infection. Early surgery was associated cantly between European and U.S. guidelines.
with a signicant reduction in the composite The ESC guidelines distinguish emergency surgery
endpoint of in-hospital death or embolism (entirely (performed within 24 h), urgent surgery (within a few
driven by a reduction in embolism). Furthermore, days), and elective surgery (after 1 to 2 weeks of
>90% of patients in the conventional care group antibiotic therapy), with surgery advised on an urgent
eventually required surgery, thereby validating pre- basis for the majority of cases (68). In contrast, the
sent indications for intervention. This study is a AHA guidelines dene early surgery as during initial
landmark achievement for research in IE and has hospitalization and before completion of a full course
encouraged a trend toward early surgery, but its of antibiotics. Our conclusion at this time is that
T A B L E 5 Studies of IE After TAVR
First Author, 1-Yr Incidence In-Hospital 1-Yr

Year (Ref. #) No. of TAVR-IE Patients of TAVR-IE Microbiology Mortality Mortality
Aung et al., 2013 (150) 4 (cohort of 132) 3.0% Enterococci (75%), oral 0% 0%
streptococci (25%)
Amat-Santos et al., 53 (cohort of 7,944) 0.5% CoNS (24%), Staphylococcus aureus (21%), 47% 66%
2015 (12) enterococci (21%), oral
streptococci (5.7%)
Bosmans et al., 2 fatal cases (cohort of 0.61% Not reported Not reported 100%
2011 (151) 328)
Latib et al., 2014 (152) 29 (cohort of 2,572) 0.89%* Enterococci (21%), CoNS (17%), S aureus 45% Not reported
(14%), oral streptococci (3.4%)
Mangner et al., 2016 (13) 55 (cohort of 1,820) 2.25%* S aureus (38%), enterococci (31%), CoNS 64% 75%
(9.1%), oral streptococci (3.6%)
Olsen et al., 2015 (153) 18 (cohort of 509) 3.1% Enterococci (33%), S aureus (17%), oral 11% Not reported
streptococci (17%), CoNS (11%)
PARTNER A, 2011 (118) 3 (cohort of 344) 0.87%* Not reported Not reported 33%
PARTNER B, 2010 (117) 2 (cohort of 179) 1.12%* Not reported Not reported 100%
Puls et al., 2013 (154) 5 (cohort of 180) 2.78% Enterococcus (40%), oral streptococci (20%), 40% 40%
S aureus (20%), E. coli (20%)
Regueiro et al., 250 (cohort of 20,006) 1.1% per Enterococcus (25%), S aureus (24%), 36% 66.7% (2-yr
2016 (119) person-year CoNS (17%) mortality)
Thomas et al., 2011 (155) 99.0% free of IE at 1 yr 0.1% Not reported Not reported 3 deaths
(cohort of 1,038) reported
*Calculated/estimated.
CoNS coagulase-negative staphylococci; IE infective endocarditis; PARTNER Placement of Aortic Transcatheter Valve; TAVR transcatheter valve replacement.
there is no proven benet in delaying surgery once an high-risk features (but not classical surgical in-
indication for intervention has been established. dications) randomized to undergo surgery within 48 h
Whether this surgery is undertaken the same day or or receive conventional care, with mortality as the
within 48 h depends on the individual clinical cir- primary endpoint. Although logistically challenging,
cumstances and availability of appropriate surgical this study would be extremely valuable and may
expertise. Current series show that very low mortality herald a long-awaited shift from observational
can be achieved in centers of excellence with high- studies to RCT-level research.
level experience of the management of complex pa-
tients and concentrated expertise in cardiology, CONTEMPORARY MANAGEMENT CHALLENGES IN IE.
microbiology, and surgery (106,116). I E a f t e r T A V R . TAVR has transformed the outlook for
Resolving the controversy of early surgery requires patients with aortic stenosis who were previously
robust evidence to move the eld forward. RCT-level deemed inoperable or at high risk for surgery.
data are required to drive practice change, which is Although the technology looks set to expand to
harder to progress on the basis of observational data intermediate-risk populations over time, current
alone. In the last 20 years, only 7 RCTs involving TAVR patients are often frail, undergoing multiple
patients with IE have been published, the majority of health care interventions, and may therefore be at
which have focused on antibiotic therapy (Table 4). high risk of bacteremia and IE. The TAVR-
The rst stage is to carefully dene the priorities for endocarditis population represents a common
new RCTs that are reasonable and acceptable to the challenge to cardiologists and surgeons managing
medical community. Multicenter studies are chal- contemporary IE, namely, how should we manage
lenging, as experience and outcomes vary greatly PVE in patients who are elderly and at high risk of
between centers, whereas few have the volume to surgery but with expected poor outcome if managed
perform such studies in isolation. Furthermore, un- medically?
resolved issues, such as early surgery, may be left Small numbers of cases of TAVR-endocarditis were
behind as competing research priorities emerge. For reported in the seminal PARTNER (Placement of Aortic
example, should PVE be considered as a uniformly Transcatheter Valve) trials (117,118), and real-world
surgical disease? Should all patients with IE and se- cohorts are now starting to shed light on incidence
vere valve dysfunction have surgery, even if they are and outcomes (Table 5). Amat-Santos et al. (12)
not in heart failure? San Romn et al. (109) have described 53 patients with TAVR-endocarditis in a
proposed a trial of patients with left-sided IE and multicenter U.S. registry, representing an overall
incidence of 0.67% at a mean follow-up of 1.1 years. The risk or very high risk for surgery before undergoing
incidence of TAVR-endocarditis was 0.5% in the rst TAVR. Indeed, <20% of patients underwent either
year post-procedure, occurring at a median time point open-heart surgery or a transcatheter valve-in-valve
of 6 months. More than 70% of patients presented with procedure in the studies to date. Meanwhile, out-
fever, and 77% had an identiable vegetation on comes with antibiotic therapy alone are extremely
echocardiography. An antecedent procedure was poor, with in-hospital and 1-year mortality ranging
identied as the likely cause of bacteremia in approx- from 47% to 64% and 66% to 75%, respectively. These
imately one-half of patients, and antibiotic prophy- data underscore the importance of developing better
laxis had been used in 59% of cases. Infection was most preventive strategies in terms of valve design and
commonly due to staphylococci (CoNS 25%; S aureus prevention of bacteremia.
21%; and enterococci 21%). Although the self-
expanding CoreValve system (Medtronic, Minneap- STROKE AND IE. IE is complicated by stroke in 20%
olis, Minnesota) was an independent risk factor for IE to 40% of cases (120,121). In addition to causing var-
(hazard ratio [HR]: 3.1; 95% CI: 1.37 to 7.14), this nding iable neurological disability, stroke is an independent
requires validation in other series. adverse prognostic factor for survival (120,122). The
Mangner et al. (13) described 55 patients with TAVR- risk of stroke is highest at diagnosis and decreases
endocarditis from a single center in Germany, repre- rapidly after the initiation of antibiotic therapy
senting a cumulative incidence of 3.02% (1.82% per (incidence drops from 4.82 per 1,000 patient-days in
patient-year); 42% of the cases (23 of 55) were health the rst week of therapy to 1.71 per 1,000 patient-days
care acquired. On multivariate analysis, chronic in the second week) (56). Identied risk factors for
hemodialysis and peripheral arterial disease were embolism are vegetation size (>10 to 15 mm), mitral
signicant risk factors for the development of subse- valve involvement, vegetation mobility, and S aureus
quent TAVR-endocarditis (chronic hemodialysisHR: infection (123125).
8.37; 95% CI: 2.54 to 27.63; p < 0.001; peripheral arterial A key unresolved challenge in the contemporary
diseaseHR: 3.77; 95% CI: 1.88 to 7.58; p < 0.001). management of IE is the role of surgery in prevention
Infection was caused by S aureus in 38% of cases, of stroke/embolism and selection of patients for such
enterococci in 31%, CoNS in 9%, and streptococci in surgical intervention. The 2015 update to the AHA/ACC
9.1% of cases. In 7 patients, a valve other than the TAVR guidelines provided a Class IIa indication for surgery to
prosthesis was infected. prevent recurrent embolism in patients with $1 pre-
Most recently, 250 cases from the Infective Endo- vious emboli and ongoing high risk of further embo-
carditis after TAVR International Registry were re- lism (dened as persistent or enlarging vegetations)
ported from 47 centers worldwide (119). The overall (89). Similarly, the ESC guidelines provide a Class I
incidence was 1.1% per person-year, presenting at a recommendation for surgery to prevent recurrent
median time of 5.3 months post-procedure. On emboli in patients with a persisting vegetation >10 mm
multivariate analysis, predictive factors were younger in size (68). On the basis of RCT evidence, both
age (HR: 0.97 per year; 95% CI: 0.94 to 0.99), male sex guidelines indicate a Class IIa recommendation for
(HR: 1.69; 95% CI: 1.13 to 2.52), diabetes mellitus (HR: surgery in patients at risk of rst embolism (vegetation
1.52; 95% CI: 1.02 to 2.29), and moderate-to-severe >10 mm in size) when associated with severe valvular
aortic regurgitation (HR: 2.05; 95% CI: 1.28 to 3.28). regurgitation or stenosis (126). Surgery for prevention
Infective organisms were enterococci in 24.6% and S of embolism (in the absence of valve dysfunction) may
aureus in 23.3%. The in-hospital mortality rate was be considered in patients at highest risk
36%, and 2-year mortality was 67%. Additional patient- (e.g., vegetations >15 mm) but is rarely undertaken in
and device-related factors contributing to increased most institutions for this indication alone.
risk of endocarditis are likely to be identied and may The optimal timing of surgical intervention in pa-
also teach us more about the nature of endocarditis. tients who have already had a stroke is contentious,
The apparently high incidence may also be due to with a number of older studies suggesting poor out-
front-loaded risk in the early months after the pro- comes from early surgery (107). There is a risk of
cedure, and longer follow-up will be required to hemorrhagic transformation caused by anti-
compare outcomes with surgical valve replacement. coagulation therapy for cardiopulmonary bypass, and
Management of TAVR-endocarditis is highly chal- hypotension during surgery might theoretically
lenging. It remains to be shown whether trans- worsen cerebral ischemia. Observational studies have
catheter techniques can be used successfully in its typically been small and inadequately controlled for
management without removal of the infected confounding variables (120,121). In the largest study
implant. Many of these patients were considered high from the ICE-PCS collaboration, the outcome from
18
F I G U R E 3 Cardiac CT and FDG-PET/CT Imaging in the Diagnosis of CDI
Pacemaker lead IE in a young man with congenital atrioventricular block. On TEE, vegetations were seen on the pacemaker leads (A and B, white arrow). On CT imaging,
vegetations were seen on the pacemaker lead (C, white arrow) with an accompanying pulmonary embolism (D, red arrow). Conrmation of active pacemaker
endocarditis was provided by 18FDG-PET/CT imaging, with uptake seen on the pacemaker lead (E, white arrow) and within the pulmonary vascular tree (F, red arrow).
CDI cardiac device infection; RA right atrium; SVC superior vena cava; other abbreviations as in Figures 1 and 2.
58 patients with an ischemic stroke undergoing early complex devices) (129131). Patients with CDIs
surgery (<7 days) was compared with late surgery. have increased short- and long-term morbidity and
After risk adjustment, surgery was associated with a mortality, and the incremental cost of management
nonsignicant increase in the risk of in-hospital is estimated at more than $15,000 per patient
mortality (OR: 2.3; 95% CI: 0.94 to 5.65) (121). This (132,133).
nding has been interpreted by both the AHA and ESC CDI may involve the generator pocket, device
to suggest that surgery can be undertaken safely if leads, or endocardial (valve or nonvalve) surfaces (or
required, although stroke remains a common reason any combination of these locations). Pocket in-
for lack of surgical intervention in everyday practice fections are characterized by cellulitis, erythema,
(108). In contrast, transient ischemic attack or silent wound discharge, and pain, and there may be incip-
embolism should not delay surgery that is indicated ient or overt erosion of the skin overlying the pocket.
for other reasons (120). Conversely, patients with Infection involving CIED leads or the endocardial
cerebral hemorrhage or complex stroke (causing surface (CIED-IE) is characterized by systemic fea-
coma) have signicantly higher surgical mortality, tures (e.g., fevers, rigors), and frequently coexists
and surgery should be deferred for at least 4 weeks if with pocket infection. IE may originate from a pocket
indicated in these patients (125,127). The plan of ac- infection or occur by seeding of infection to the leads
tion for patients with minor bleeding or minor hem- via the bloodstream. Staphylococci (particularly
orrhagic conversion of an ischemic stroke remains CoNS) account for 60% to 80% of cases (134).
open to clinical judgment. Clinical scenarios are often Risk factors for CDIs may be patient-, procedure-, or
complex, and the risk and benet equation often device-related factors (135). Patient-specic risk fac-
challenges any rigid recommendation. tors include corticosteroid use, diabetes mellitus, end-
CARDIAC DEVICE INFECTION. CIEDs include per- stage kidney disease, previous device infection,
manent pacemakers, implantable cardioverter- chronic obstructive pulmonary disease, malignancy,
debrillators, and cardiac resynchronization therapy and heart failure. Procedural risk factors are the
devices. The number of CDIs in the United States has development of a post-operative hematoma (OR: 8.46;
increased out of proportion to the increase in im- 95% CI: 4.01 to 17.86), reintervention for lead
plantation rates (128). Overall, the incidence of CDI displacement, long procedure times, and implantation
after rst implantation is 1 to 10 per 1,000 device- of $2 leads. Need for a revision procedure is associated
years (approximately 1 per 1,000 device years for with a 2- to 5-fold higher risk of infection than the
pacemakers and 8 to 9 per 1,000 device-years for initial implantation. Use of antibiotic prophylaxis has
C E NT R AL IL L U STR AT IO N Infective Endocarditis: Preventive Strategies, Diagnosis, and Management
Preventive strategies Improving diagnosis Optimal management
Reduce hospital acquired High index of clinical Evaluation by an

bacteremia suspicion in at-risk groups endocarditis team
Good oral hygiene

Patient education Early risk stratification
for at-risk groups
Antibiotic prophylaxis Early transfer to

Early echocardiography
for high risk groups center of expertise
Adjunctive imaging if
In future, antibacterial
echocardiography Tailored antibiotic therapy
coatings/materials
non-diagnostic
Rapid microbiology results Early surgery for

with antibacterial sensitivity selected patients
Monitoring for complications
Cahill, T.J. et al. J Am Coll Cardiol. 2017;69(3):32544.
been shown to protect against CDI in both RCTs and alone is associated with increased risk of recurrence
observational studies (136). and mortality (142,143). Percutaneous extraction is
Diagnosis of CIED-IE is made on the basis of echo- usually feasible but associated with a major compli-
cardiography and blood culture results, with TEE cation rate of 1.9% (144). Prolonged antibiotic therapy
having better sensitivity and specicity than TTE for is advised, and blood culture ndings should be
detection of lead vegetations (137). Importantly, ster- negative for at least 72 h before reimplantation if a
ile clots are seen in a high percentage of CIED patients new device is essential.
without infection, and these lesions are indistin-
guishable from infected vegetations (138). In cases in CONCLUSIONS
which echocardiography is negative or equivocal,
18
radiolabeled leukocyte scintigraphy or FDG-PET/CT The challenges of IE are diverse, but many are trac-
scans are highly valuable, and they may become the table (Central Illustration). Prevention is undoubtedly
denitive investigation on the basis of a number of better than cure. Translating advances in materials
studies demonstrating high sensitivity and specicity science into prosthetic devices with reduced sus-
for infection (Figure 3) (139141). However, there is ceptibility to bacterial adhesion would be revolu-
18
evidence that FDG-PET/CT imaging may yield a tionary. Understanding the relative importance of
false-negative result for CIED-IE (i.e., lead involve- dental procedures for patients with known cardiac
ment) if patients have received previous antibiotic risk factors would help direct use of antibiotic pro-
therapy. In 1 study, 9 of 13 patients had a false- phylaxis. The value of integrated diagnostic strate-
negative scan for CIED-IE (sensitivity 30.8%) (141). gies using multimodality imaging is emerging and
Further studies are required to assess the time course needs renement on the basis of real-world patient
18
over which the diagnostic value of FDG-PET/CT im- cohorts. Surgical treatment plays an increasing role,
aging is preserved. but the current wide variation in outcomes suggests
Strategies for the prevention and management of that management should be concentrated in larger
CDI are beyond the scope of the present review but valve centers of excellence. Further improving the
are covered in detail by recent guidelines (142). If quality and breadth of the evidence base through
CIED-IE is conrmed, complete removal of the new RCTs is essential. At the time of writing, only 6
infected system is indicated because medical therapy RCTs in IE are shown as currently recruiting. Trials
may be difcult to design but are eminently achiev- such as mortality. Now is the time to transform cur-
able and could be used to assess novel antibiotic rent challenges in IE into answers.
strategies, as well as indications for surgery and
optimal timing of surgery. The ESC and AHA, in REPRINT REQUESTS AND CORRESPONDENCE: Dr.
collaboration with the surgical societies, are well Bernard D. Prendergast, Department of Cardiology,
placed to host and coordinate such studies, which St. Thomas Hospital, Westminster Bridge Road,
will need to be multicenter and multinational in London SE1 7EH, United Kingdom. E-mail: bernard.
design and rely on noncomposite, hard endpoints, prendergast@gstt.nhs.uk.
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Infective Endocarditis

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Infective Endocarditis

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 69, NO.

2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2016.10.066

THE PRESENT AND FUTURE

Challenges in Infective Endocarditis

I nfective endocarditis (IE) is a rare disease, but its

Challenges in Infective Endocarditis JANUARY 24, 2017:32544

Challenges in Infective Endocarditis JANUARY 24, 2017:32544

Class, Level of Class, Level

proportion of IE due to S aureus in the United States DIAGNOSIS

Challenges in Infective Endocarditis JANUARY 24, 2017:32544

Challenges in Infective Endocarditis JANUARY 24, 2017:32544

F I G U R E 2 Integrated Imaging Strategy in Patients With Suspected IE

Definite IE TTE & TEE Rejected IE

Consider further Possible IE

* In patients with prosthetic valves or cardiac implantable electronic devices

Continued on the next page

Challenges in Infective Endocarditis JANUARY 24, 2017:32544

T A B L E 3 Indications for Surgery in AHA and ESC Guidelines

Class, Level Class, Level

Challenges in Infective Endocarditis JANUARY 24, 2017:32544

T A B L E 4 Twenty Years of RCTs in IE, 1996 to 2016

Firs Author, Year (Ref. #) Research Question Patient Population Conclusions

T A B L E 5 Studies of IE After TAVR

First Author, 1-Yr Incidence In-Hospital 1-Yr

Challenges in Infective Endocarditis JANUARY 24, 2017:32544

Challenges in Infective Endocarditis JANUARY 24, 2017:32544

C E NT R AL IL L U STR AT IO N Infective Endocarditis: Preventive Strategies, Diagnosis, and Management

Preventive strategies Improving diagnosis Optimal management

Reduce hospital acquired High index of clinical Evaluation by an

Good oral hygiene

Antibiotic prophylaxis Early transfer to

Rapid microbiology results Early surgery for

Monitoring for complications

Cahill, T.J. et al. J Am Coll Cardiol. 2017;69(3):32544.

Challenges in Infective Endocarditis JANUARY 24, 2017:32544

Challenges in Infective Endocarditis JANUARY 24, 2017:32544

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