Clinical manifestations and diagnosis of infective endocarditis

INTRODUCTION In the modern era, infective endocarditis (IE) presents most

frequently as acute rather than chronic disease. The diagnosis is usually based
upon a combination of factors, including a careful history and physical
examination, blood cultures and other selected laboratory studies,
echocardiography, and chest radiography
The clinical manifestations and diagnosis of IE will be reviewed here. Treatment
of IE is discussed separately. (See "Antimicrobial therapy of native valve
endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".)
HISTORY AND PHYSICAL EXAMINATION Infective endocarditis (IE) usually
presents acutely [1]. A careful clinical history should be performed, including
surgical and medical procedures and recent bacterial infection. Special
attention should be given to preexisting cardiac lesion(s) and clues pointing
toward a recent source of bacteremia, such as indwelling prosthetic devices
(including intravascular catheters, orthopedic hardware, and cardiac devices)
or intravenous drug use.
The physical examination should include a careful cardiac examination for signs
of new regurgitant murmurs or heart failure. (See "Auscultation of cardiac
murmurs".)
A vigorous search should be undertaken for the clinical stigmata of
endocarditis, including evidence of small and large emboli with special
attention to the fundi, conjunctivae, skin, and digits. Peripheral cutaneous or
mucocutaneous lesions of IE include petechiae, splinter hemorrhages, Janeway
lesions, Osler's nodes, and Roth spots.
Petechiae and splinter hemorrhages are nonspecific for IE. Petechiae are the
most common skin manifestation (picture 1). They may be present on the skin
(usually on the extremities) or on mucous membranes such as the palate.
Lesions on the conjunctivae usually present as hemorrhages best seen with
eversion of the upper or lower eyelids. Splinter hemorrhages are also
nonspecific for IE; they are nonblanching, linear, reddish-brown lesions found
under the nail bed (picture 2).
Janeway lesions, Osler's nodes, and Roth spots are more specific findings of IE;
they occur most frequently in the setting of protracted bacteremia and
therefore are relatively uncommon in the modern era. Janeway lesions are
macular, nonpainful, erythematous lesions on the palms and soles (picture 3).
Osler's nodes are painful, violaceous nodules found in the pulp of fingers and
toes and are seen more often in subacute than acute cases of IE (picture 4).
Roth spots are exudative, edematous hemorrhagic lesions of the retina.
A neurologic evaluation should be undertaken for evidence of focal neurologic
impairment; it is also important as a baseline examination, should neurologic
deficits develop later. (See "Complications and outcome of infective
endocarditis", section on 'Neurologic complications'.)

Patients with IE may have involvement of other organs due to metastatic

infection (eg, vertebral osteomyelitis), embolic events (eg, focal neurologic
deficits, renal infarct, splenic infarct), or a systemic immune reaction (eg,
glomerulonephritis). In right-sided endocarditis, septic pulmonary emboli may
be seen (image 1). (See "Complications and outcome of infective endocarditis"
and "Renal disease in the setting of infective endocarditis or an infected
ventriculoatrial shunt".)
DIAGNOSIS The diagnosis of infective endocarditis (IE) is usually based upon
a combination of factors, including a careful history and physical examination,
blood cultures and other selected laboratory studies, echocardiography,
electrocardiography (ECG), and chest radiography.
The modified Duke criteria are the accepted criteria for diagnosis of IE; these
are summarized in the Tables (table 1 and table 2) (calculator 1). (See
"Infective endocarditis: Historical and Duke criteria", section on 'Duke criteria'.)
The diagnosis of IE is generally straightforward in the setting of positive blood
cultures for a pathogen likely to cause endocarditis, together with evidence of
endocardial involvement. However, it can be difficult to distinguish between IE
and an alternate source of infection in a bacteremic patient with underlying
heart disease.
In addition, some patients with IE do not have positive blood cultures (ie,
culture-negative endocarditis), and up to 25 percent of patients have no
identifiable cardiac lesion at initial presentation. The presence of atypical
features may result in a delayed diagnosis.
Laboratory studies
Blood cultures
Culture collection Blood cultures should be obtained prior to initiation of
antibiotic therapy. At least three sets of blood cultures should be obtained; in
patients who have received recent antimicrobial therapy, additional blood
cultures may be useful. If the tempo of illness is subacute and the patient is not
critically ill, it is reasonable to delay initiation of antimicrobial therapy while
awaiting the results of blood cultures and other diagnostic tests. In the setting
of acute illness, three sets of blood cultures should be obtained over a one-hour
period prior to initiation of empiric antimicrobial therapy. (See "Blood cultures
for the detection of bacteremia".)
The diagnostic yield of more than three sets of blood cultures is minimal in the
absence of recent antimicrobial therapy. In one series including 206 cases of
endocarditis, the initial blood culture in patients with streptococcal endocarditis
was positive in 96 percent of cases, and one of the first two blood cultures was
positive in 98 percent [2]. In patients with IE caused by organisms other than
streptococcus, the first blood culture was positive in 82 percent of cases and
one of the first two cultures was positive in 100 percent of cases [2].

A minimum of 10 mL (and preferably 20 mL) of blood should be obtained from

adults and 0.5 to 5 mL from infants and children. In one study, blood cultures
inoculated with at least 5 mL of blood had a significantly higher detection rate
for bacteremia than bottles inoculated with less than 5 mL of blood (92 versus
69 percent) [3]. The estimated yield of blood cultures in bacteremic adults
increased approximately 3 percent per mL of blood cultured.
Each set of cultures should be obtained from separate venipuncture sites, and,
ideally, blood cultures should not be obtained from a vascular catheter. Blood
cultures may be collected at any time; they do not need to be obtained at the
time of fever or chills since patients with IE typically have continuous
bacteremia [4].
Interpreting culture results The Duke criteria for the diagnosis of endocarditis
define the following organisms as "typical causes" of IE (table 1 and table 2)
[5]:
Staphylococcus aureus
Viridans streptococci and Streptococcus bovis
Enterococci
HACEK group organisms
The risk of endocarditis in patients with S. aureus bacteremia (regardless of
source or residence at the time of onset) is particularly high. As a result, all
patients with S. aureus recovered from the blood should be clinically evaluated
for IE. (See "Clinical approach to Staphylococcus aureus bacteremia in adults".)
The likelihood of endocarditis is variable depending on bacteria species. As
examples:
Bacteremia due to Streptococcus sanguis is more often indicative of
endocarditis than bacteremia due to Streptococcus milleri (also known as S.
anginosus).
Bacteremia due to group A or C streptococci is seldom associated with IE,
whereas group G streptococcal infection is more frequently associated with
endocarditis [6]. (See "Group C and group G streptococcal infection".)
Bacteremia due to Enterococcus faecalis has been more frequently
associated with IE than bacteremia due to other enterococcal species [7].
The microbiology of IE is discussed further separately. (See "Epidemiology, risk
factors and microbiology of infective endocarditis", section on 'Microbiology'.)
False-positive culture results occasionally occur despite careful techniques for
collection and processing. Organisms for which it can be difficult to distinguish
between pathogenicity and contamination include Propionibacterium acnes,
Corynebacterium species, Bacillus species, and coagulase-negative
staphylococci. In general, the likelihood of pathogenicity is increased if the
organism is observed in multiple blood cultures obtained by independent
venipunctures. Recovery of these organisms from a single blood culture or a
minority of blood culture bottles likely reflects a false-positive result. (See
"Blood cultures for the detection of bacteremia", section on 'Contamination'.)

The definition of persistent bacteremia depends on the likelihood of the

organism to cause endocarditis [5]. For organisms likely to cause endocarditis
(such as S. aureus or viridans streptococci), two positive blood cultures
collected more than 12 hours apart may be presumed to represent true
bacteremia. For organisms that are more commonly skin contaminants, three
or a majority of four or more positive blood cultures (with the first and last
samples collected at least one hour apart) may be presumed to represent true
bacteremia.
Culture-negative endocarditis Culture-negative endocarditis should be
considered in patients with negative blood cultures and persistent fever with
one or more clinical findings consistent with infective endocarditis (eg, stroke
or other manifestations of emboli). Culture-negative IE should also be
considered in patients with vegetation on echocardiogram and no clear
microbiologic diagnosis. Issues related to culture-negative IE are discussed
separately. (See "Epidemiology, microbiology, and diagnosis of culture-negative
endocarditis".)
Other laboratory tests The utility of other laboratory tests in the diagnosis of
endocarditis is limited. The following findings may be observed among patients
with IE but are relatively nonspecific:
An elevated erythrocyte sedimentation rate and/or elevated C-reactive
protein
A normochromic normocytic anemia
The white blood cell count may be normal or elevated in patients with
subacute presentations of endocarditis; however, most patients with
staphylococcal endocarditis have leukocytosis, and some may have
thrombocytopenia.
Hyperglobulinemia, cryoglobulinemia, circulating immune complexes,
hypocomplementemia, elevated rheumatoid factor titers, and false-positive
serologic tests for syphilis occur in some patients.
An elevated rheumatoid factor titer in patients without a known prior
rheumatologic disorder is a minor criteria in the Duke diagnostic scheme (table
2) [5]. (See "Origin and utility of measurement of rheumatoid factors".)
Most patients with endocarditis have an abnormal urinalysis, as manifested by
microscopic or gross hematuria, proteinuria, and/or pyuria. Each of these
findings lacks specificity. However, the presence of red blood cell casts on
urinalysis is generally indicative of glomerulonephritis (often in association with
hypocomplementemia) and is a minor diagnostic criterion for IE (table 2) [5].
(See "Renal disease in the setting of infective endocarditis or an infected
ventriculoatrial shunt".)
Some causes of culture-negative IE may be identified via serology; these
include Coxiella burnetii, Bartonella spp, Chlamydia spp, Legionella spp, and
Brucella [8]. (See "Epidemiology, microbiology, and diagnosis of culturenegative endocarditis", section on 'Diagnosis'.)

Cardiac studies
Echocardiography An echocardiogram should be performed in all patients
with a moderate or high suspicion of endocarditis (table 1 and table 2 and
algorithm 1) [9-11]. Among patients with a low clinical probability of
endocarditis, the diagnostic yield of transthoracic echocardiography (TTE) and
transesophageal echocardiography (TEE) is low and neither should be
performed [10]. (See "Infective endocarditis: Historical and Duke criteria" and
"Role of echocardiography in infective endocarditis".)
Echocardiography allows detection and characterization of vegetations on
valves or other sites (such as pacemaker wires), evaluation for valvular
dysfunction, assessment of hemodynamic severity, and detection of associated
abnormalities such as shunts or abscesses. It is also useful for follow-up
evaluation of patients with virulent organisms, severe hemodynamic instability,
persistent or recurrent bacteremia or fever, or other clinical deterioration.
In general, TTE is the first diagnostic test for patients with suspected IE.
Detection of a vegetation is a positive test (movie 1 and movie 2 and movie 3).
TTE has relatively low sensitivity (29 to 63 percent in different series), although
the specificity approaches 100 percent [12]. Thus, the absence of vegetation
does not preclude the diagnosis of IE, although the finding of normal valves
(both morphology and function) substantially reduces the probability of IE. In
one study, 96 percent of patients with normal valves and no vegetation on TTE
also had a negative TEE [13].
For patients with a normal TTE, it is reasonable to proceed to TEE in the
following circumstances:
A high clinical suspicion of IE (persistently positive blood cultures and/or
multiple minor criteria for endocarditis) (table 1 and table 2)
Bacteremia due to an organism known to be a common cause of IE such as S.
aureus or viridans streptococci
A technically limited TTE study
Patients with abnormal findings on TTE who may require further evaluation by
TEE include those with significant valvular regurgitation to determine need for
surgery, as well as those with one or more risk factors for perivalvular abscess
including new conduction delay on ECG, aortic valve endocarditis, and
persistent bacteremia or fever despite appropriate antimicrobial therapy.
It is reasonable to forgo TTE and proceed to TEE in the following circumstances:
Presence of prosthetic valve(s), particularly prosthetic aortic or mitral valve,
in which shadowing may make TTE visualization difficult
A prior valvular abnormality (including previous endocarditis)
Limited transthoracic windows (eg, due to obesity, chest wall deformity, or
mechanical ventilation)
Echocardiography should be performed as soon as possible after the diagnosis
of IE is suspected [9,14], even though TTE and TEE can be falsely negative if
vegetations are small (and, occasionally, if previously present vegetations have

embolized). High suspicion for IE in the setting of negative echocardiography

should prompt subsequent repeat study. The optimal timing for repeat studies
is uncertain; some favor repeat echocardiography after five to seven days in
patients with a high likelihood of endocarditis, when clinical findings suggestive
of IE are present in patients for whom initial studies were done during the first
few days of symptoms or when the initial study was technically suboptimal.
Echocardiography is warranted even for patients with an associated condition
that requires a protracted course of antimicrobial therapy (such as vertebral
osteomyelitis). Documenting the presence or absence of vegetation is
important for determination of subsequent follow-up.
Electrocardiogram A baseline electrocardiogram should be performed as part
of the initial evaluation of all patients with suspected endocarditis, even though
this test rarely demonstrates diagnostic findings. The presence of heart block
or conduction delay may provide an important clue to extension of infection to
the valve annulus and adjacent septum. In addition, the presence of findings
consistent with ischemia or infarction may suggest the presence of emboli to
the coronary circulation.
Thereafter, a weekly screening electrocardiogram may be useful (in the
absence of telemetry monitoring), particularly in the setting for patients with
vegetation(s) in close anatomic proximity to conductive tissue, which may
increase the risk of developing heart block.
Chest radiograph Chest radiography may demonstrate evidence of septic
pulmonary emboli or focal infiltrate, with or without cavitation. Rarely, valve
calcification may be seen that may suggest endocarditis in the setting of
suggestive history and physical findings.
Valve culture and histopathology Valve culture is useful if there are other
clinical signs and symptoms and/or echocardiographic findings that suggest the
presence of IE; routine culture of heart valves removed at the time of surgery
can lead to false-positive results. In one study including 1030 valves removed
at surgery, cultures were positive in 39 percent of patients that met Duke
criteria for IE and in 28 percent of patients without other criteria for IE [15].
Histologic demonstration of microorganisms, vegetations, or active endocarditis
in cardiac valve tissue obtained at surgery is included in the Duke criteria and
may be used to confirm the diagnosis of IE (table 1). The histologic features
that characterize endocarditis were defined in a retrospective pathologic
analysis of tissue adjoining mechanical cardiac valves in 90 patients who
underwent surgical removal of a mechanical valve for suspected IE (21
patients) or noninfectious dysfunction (69 patients) [16]. IE was characterized
by microorganisms, vegetations, and neutrophil-rich inflammatory infiltrates
with extensive neovascularization. In contrast, tissue adjoining valves from
noninfectious complications demonstrated extensive fibrosis and, when
present, inflammatory infiltrates that were mainly composed of macrophages
and lymphocytes.

Thus, when no microorganisms are detected and vegetations are lacking in

tissue adjacent to a mechanical valve, neutrophil-rich inflammation and
extensive neovascularization may allow differentiation between IE and
inflammatory noninfectious valve processes in patients with mechanical
cardiac valves who undergo surgery.
Other tests Radiographic imaging should be tailored to findings on history
and physical examination. Patients with back pain should be evaluated for
vertebral osteomyelitis and discitis with MRI. Computed tomography (CT) of the
torso should be pursued for patients with abdominal pain or costovertebral
angle tenderness to evaluate for presence of splenic infarct, renal infarct, psoas
abscess, or other intraabdominal sites of infection. Such imaging is also
appropriate for patients with documented endocarditis, even in the absence of
focal symptoms, to evaluate for subclinical sites of metastatic infection. An
initial imaging study performed early in the presentation of acute IE may be
negative, and worsening back pain should prompt repeat imaging, especially in
the setting of S. aureus infection.
The role of routine brain magnetic resonance imaging (MRI) is uncertain. In one
study including 53 patients, early use of cerebral MRI led to the reclassification
from possible to definite IE in one-third of cases [17]; further study is needed.
A bedside clinical score may be a useful tool for prediction of endocarditis in
some cases. In one study describing such a tool for prediction of endocarditis in
patients with enterococcal bacteremia (NOVA: number of positive blood
cultures [3/3 or the majority if more than 3], 5 points; unknown origin of
bacteremia, 4 points; prior heart valve disease, 2 points; auscultation of a heart
murmur, 1 point), a cutoff score <4 points suggested a very low risk for
enterococcal IE [18]. The NOVA score may be useful for avoiding unnecessary
TEE among patients with enterococcal bacteremia; further validation is
required.
DIFFERENTIAL DIAGNOSIS The differential diagnosis for endocarditis is broad.
Patients with bacteremia in the absence of evidence for valvular vegetation
should be evaluated for alternative causes of bacteremia including:
Skin and soft tissue infection Soft tissue infection should be suspected in
the setting of referable clinical symptoms. Severe infections may warrant
imaging and/or surgical exploration. (See "Cellulitis and erysipelas", section on
'Diagnosis' and "Necrotizing soft tissue infections".)
Cardiac device infection Cardiac device infection should be suspected in the
setting of an implanted device with overlying inflammation. Echocardiography
is warranted to evaluate for device-related endocarditis. (See "Infections
involving cardiac implantable electronic devices", section on 'Diagnosis'.)
Prosthetic joint infection Prosthetic joint infection should be suspected in the
setting of a prosthetic joint with local erythema or tenderness. Evaluation of
joint fluid or tissue is required to establish the diagnosis. (See "Clinical
manifestations and diagnosis of prosthetic joint infections", section on
'Diagnosis'.)

Intravascular catheter infection Catheter-related infection should be

suspected when bacteremia occurs in the setting of a central venous catheter
with no other apparent source. The diagnosis is established based on
evaluation of samples drawn from the catheter and a peripheral vein. (See
"Diagnosis of intravascular catheter-related infections", section on 'Diagnosis'.)
Osteomyelitis Osteomyelitis should be suspected in the setting of focal pain
at an involved site. Evaluation with radiographic imaging is warranted; the
involved pathogen may be established by bone biopsy. (See "Overview of
osteomyelitis in adults", section on 'Diagnosis'.)
Antiphospholipid syndrome Antiphospholipid syndrome should be suspected
in the setting of culture negative endocarditis. It is characterized by venous or
arterial thromboses; disease features include transient ischemic attack and
pulmonary embolism. The diagnosis is established via the presence of at least
one type of antiphospholipid antibody in the setting of clinical thrombosis. (See
"Diagnosis of the antiphospholipid syndrome".)
Meningitis Meningitis should be suspected in the setting of headache and/or
altered mental status. Evaluation with head imaging and lumbar puncture is
warranted. (See "Clinical features and diagnosis of acute bacterial meningitis in
adults".)
Pneumonia Pneumonia should be suspected in the setting of dyspnea
and/or hypoxia. Evaluation with chest radiography and sputum culture is
warranted. (See "Diagnostic approach to community-acquired pneumonia in
adults" and "Epidemiology, pathogenesis, microbiology, and diagnosis of
hospital-acquired, ventilator-associated, and healthcare-associated pneumonia
in adults".)
These entities may also coexist with IE.
Patients with cardiac vegetation in the absence of positive blood cultures may
have culture-negative endocarditis (discussed above) or sterile vegetations
(marantic endocarditis) due to lupus or hypercoagulable states, such as
antiphospholipid syndrome. These entities should be suspected in the setting of
known lupus or hypercoagulability together with valvular lesion on
echocardiogram. (See "Non-coronary cardiac manifestations of systemic lupus
erythematosus in adults", section on 'Valvular disease' and "Non-coronary
cardiac manifestations of systemic lupus erythematosus in adults", section on
'Antiphospholipid antibodies and valvular disease'.)
Other entities that can present with fever and systemic symptoms include
vasculitis, temporal arteritis, and connective tissue disease. These are
discussed further separately. (See "Classification of and approach to the
vasculitides in adults" and "Diagnosis of giant cell (temporal) arteritis" and
"Definition and diagnosis of mixed connective tissue disease".)

Antimicrobial therapy of native valve endocarditis

Author
Daniel J Sexton, MD

Section Editor
Stephen B Calderwood, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures: Daniel J Sexton, MD Grant/Research/Clinical Trail Support: Cubist
[C. difficile infection (Fidaxomycin)]. Consultant/Advisory Boards: Johnson &
Johnson [Pelvic mesh-related infection]; Sterilis [Medical waste disposal
systems]; Magnolia Medical Technologies [Intravenous devices]. Other Financial
Interest: National Football League [Infection control program]. Equity
Ownership/Stock Options: Magnolia Medical Technologies [Intravenous
devices]. Stephen B Calderwood, MD Patent Holder: Vaccine Technologies Inc.
[Vaccines (Cholera vaccines)]. Equity Ownership/Stock Options: Pulmatrix
[Inhaled antimicrobials]; PharmAthene [Anthrax (Anti-protective antigen
monoclonal antibody)]. Elinor L Baron, MD, DTMH Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial
group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to
support the content. Appropriately referenced content is required of all authors
and must conform to UpToDate standards of evidence. Conflict of interest policy
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Apr 2015. | This topic last updated: Sep 16,
2014.
INTRODUCTION Issues related to the antimicrobial therapy of native valve
infective endocarditis (IE) will be reviewed here. The pathogenesis of
vegetation formation, complications, and indications for surgery are discussed
separately. (See "Pathogenesis of vegetation formation in infective
endocarditis" and "Complications and outcome of infective endocarditis" and
"Surgery for native valve endocarditis".)

GENERAL CONSIDERATIONS Bactericidal agents are necessary for effective

treatment of endocarditis. Therefore, antimicrobial therapy should be dosed to
optimize sustained bactericidal serum concentrations throughout as much of
the dosing interval as possible. In vitro determination of the minimum
inhibitory concentration (MIC) should be performed routinely.

Empiric therapy In general, therapy for infective endocarditis (IE) should be

targeted to the organism isolated from blood cultures; cultures are positive in
over 90 percent of patients with IE. For patients with suspected IE who present
without acute symptoms, empiric therapy is not always necessary, and therapy
can await blood culture results. Results of blood cultures are usually available
within one to three days, and an accurate diagnosis is a critical first step in
designing a management strategy. (See "Clinical manifestations and diagnosis
of infective endocarditis".)

For acutely ill patients with signs and symptoms strongly suggestive of IE,
empiric therapy may be necessary. Such empiric therapy should be
administered ONLY after at least two (preferably three) sets of blood cultures
have been obtained from separate venipunctures and ideally spaced over 30 to
60 minutes.

The choice of empiric therapy should take into consideration the most likely
pathogens. In general, empiric therapy should cover staphylococci (methicillin
susceptible and resistant), streptococci, and enterococci. Vancomycin (15 to 20
mg/kg/dose every 8 to 12 hours, not to exceed 2 g per dose) is an appropriate
choice for initial therapy in most patients.

Early consultation with a cardiac surgeon should be obtained for all cases in
which complications are observed or expected (such as in infections involving
prosthetic valves, or complicated by moderate to severe heart failure). In
addition, consultation by specialists in infectious diseases or cardiology may be
useful.

Clinical response to initial therapy Most patients with IE become afebrile

three to five days after treatment is begun with an appropriate antibiotic.
Patients with Staphylococcus aureus endocarditis may respond somewhat more
slowly, remaining febrile for five to seven days after initiation of therapy.
Patients with right-sided endocarditis and septic pulmonary emboli may remain
febrile for an even longer duration of time.

The initial microbiologic response to therapy should be assessed by obtaining

repeat blood cultures 48 to 72 hours after antibiotics are begun. Thereafter,

careful serial examinations should be performed to search for signs of heart

failure, emboli, or other complications.

Duration of therapy The duration of therapy depends on the pathogen and

site of valvular infection; it must be sufficient to eradicate microorganisms
growing within the valvular vegetations. Most patients are treated parenterally
with regimens given for up to six weeks. In general, six weeks of treatment is
appropriate for patients with virulent or relatively resistant pathogens,
secondary cardiac or extracardiac complications, and in the setting of
prolonged infection prior to diagnosis. Shorter therapeutic regimens may be
effective in selected patients with right-sided endocarditis and with
endocarditis due to highly susceptible viridans streptococci treated with
synergistic antimicrobials.

In one study including 74 patients with viridans streptococcal endocarditis,

none of 66 patients who survived a four-week course of penicillin G relapsed,
and no patient treated with this regimen died of active infection [1]. Similarly,
four to six weeks of bactericidal therapy with a single drug was shown to be
highly effective as treatment for endocarditis due to other streptococcal
species and for staphylococci. Prolonged therapy was presumed to be
necessary because bacterial concentrations within vegetations are as high as
109 to 1011 colony-forming units (CFUs)/gram of tissue and because organisms
deep within vegetations are not accessible to phagocytic cells and often are in
a state of reduced metabolic activity [2]. (See "Pathogenesis of vegetation
formation in infective endocarditis".)

Completion of therapy Patients may complete intravenous therapy as

outpatients once hemodynamically stable. They must be compliant and
capable of managing the technical aspects of intravenous therapy [3]. Such
patients require careful and regular monitoring and must have ready access to
full medical care should complications occur [3,4].

Reports on the use of oral therapy in patients with IE are limited to relatively
small numbers of patients with a history of drug abuse who have right-sided IE
due to S. aureus. (See "Infective endocarditis in injection drug users", section
on 'Antibiotic therapy'.)

VIRIDANS STREPTOCOCCI AND STREPTOCOCCUS BOVIS The various species

of streptococci that make up the viridans group and Streptococcus bovis
(renamed S. gallolyticus and S. infantarius) account for approximately 40 to 60
percent of native valve endocarditis in community practice. Members of the
viridans group include S. mitis, S. mutans, S. oralis, S. sanguinis, S. sobrinus,
and the S. milleri group (S. anginosus, S. constellatus, and S. intermedius). (See
"Clinical manifestations, diagnosis, and treatment of infections due to group D
streptococci (Streptococcus bovis/Streptococcus equinus complex)" and
"Microbiology, pathogenesis, and epidemiology of infections due to group D
streptococci (Streptococcus bovis/Streptococcus equinus complex)", section on
'Microbiology'.)

Most viridans group streptococci are highly penicillin susceptible, defined as a

minimum inhibitory concentration (MIC) 0.12 mcg/mL. Occasional strains
have "intermediate" susceptibility to penicillin (MIC >0.12 mcg/mL and 0.5
mcg/mL), and rare strains are considered to be fully resistant with a penicillin
MIC >0.5 mcg/mL [5].

Endocarditis due to viridans group streptococci and S. bovis organisms can

usually be microbiologically cured if one of four different regimens is used
(table 1 and table 2):

For treatment of penicillin-susceptible strains (MIC 0.12 mcg/mL), the

American Heart Association (AHA), British Society for Antimicrobial
Chemotherapy (BSAC), and European Society for Cardiology (ESC) all
recommend a regimen consisting of aqueous crystalline penicillin G at a dose
of 12 to 24 million units daily (either continuously or in four to six equally
divided doses) for four weeks in patients with endocarditis due to highly
penicillin-susceptible streptococci (table 1) [3,6,7]. Penicillin, or an equally
effective regimen consisting of ceftriaxone given intravenously or
intramuscularly as a 2 g daily dose for four weeks, remain the preferred
treatments for older adult patients or in other patients in whom aminoglycoside
therapy is considered risky or contraindicated.
Selected patients with native valve endocarditis due to penicillin-susceptible
strains who do not have evidence of intracardiac or extracardiac complications,
or preexisting renal or otic disease, may be treated with shorter courses of
combination therapy (table 1). The AHA guidelines recommend a regimen that
includes gentamicin plus either aqueous crystalline penicillin G or ceftriaxone
for two weeks [3]. The BSAC guidelines recommend a regimen of gentamicin

plus penicillin or ceftriaxone for two weeks [7], while the ESC guidelines
recommend monotherapy with penicillin G for two weeks [6]. Gentamicin, if
used, should be given either as a single dose of 3 mg/kg per day or in two to
three equally divided doses adjusted to give a peak serum level of 3 to 4
mcg/mL. We prefer to administer the gentamicin in two to three equally divided
doses for hospitalized patients when serum concentrations can be followed and
as a single daily dose in outpatients.
Gentamicin is more commonly used in clinical practice than streptomycin due
to the wider availability of gentamicin serum levels and because dosing
regimens for gentamicin are more familiar to most clinicians. When
streptomycin is used to treat endocarditis, the suggested dose in patients with
normal renal function is 15 mg/kg per day intramuscularly (IM) or intravenously
(IV) divided equally into two doses a day for two weeks. Dose intervals need to
be prolonged in patients with renal insufficiency.

Patients with prior histories of penicillin allergy can usually be treated with
ceftriaxone, if their prior history of penicillin allergy consists of rash without
other signs of immediate-type hypersensitivity. Patients with histories of
immediate-type hypersensitivity may either be treated with vancomycin (15 to
20 mg/kg/dose every 8 to 12 hours, not to exceed 2 g per dose) for four weeks
or desensitized to penicillin and treated with a standard regimen. In patients
with streptococcal endocarditis and a history of significant penicillin allergy,
some favor treatment with a combination of gentamicin with either vancomycin
or teicoplanin [7].

We believe that penicillin is preferable to vancomycin; we are unaware of

controlled treatment trials comparing the efficacy of vancomycin to penicillin in
cases of suspected drug hypersensitivity. Thus, when expertise is available to
safely supervise desensitization protocols, we advise desensitization to
penicillin rather than substitution of vancomycin. Following desensitization, the
tolerance persists only as long as the patient continues to receive the drug.
Once antibiotic therapy is stopped for a period of more than 24 hours, repeat
desensitization is required if the particular drug is to be used again. (See
"Allergy to penicillins".)

For treatment of endocarditis due to "intermediate" susceptibility viridans

streptococci (MIC >0.12 and 0.5 mcg/mL), the AHA guidelines recommend
aqueous penicillin G (24 million units daily either continuously or in four to six
equally divided doses) or ceftriaxone (2 g IV or IM once daily) for a total of four

weeks [3]. Gentamicin should be added to this regimen for the first two weeks
(dosed as above). As for other patients with streptococcal endocarditis who
have had an immediate-type hypersensitivity reaction to beta-lactams,
vancomycin is an acceptable alternative to penicillin (table 2) [3].
The 2012 BSAC guidelines recommend that streptococcal endocarditis
associated with strains with penicillin MICs >0.12 and 0.5 mg/L be treated
with benzylpenicillin for four to six weeks combined with an aminoglycoside for
the first two weeks of treatment [7]. Regimens used to treat enterococcal
endocarditis are recommended for streptococcal endocarditis due to strains
with MIC >0.5 mg/L. Both the ESC and the BSAC guidelines recommend that
vancomycin be used for the treatment of streptococcal endocarditis due to
strains with MICs >4 mg/L, although they acknowledge that there are no
controlled trials to support these consensus opinions.

Endocarditis due to strains of viridans streptococci and streptococcal-like

organisms (eg, Abiotrophia defectiva, Granulicatella spp, and Gemella spp) that
have penicillin MICs >1 mcg/mL and are considered fully resistant to penicillin
should be treated with regimens used to treat enterococcal endocarditis, as
recommended by the AHA (table 3) [3,7-9]. A review of 29 patients with
endocarditis due to penicillin-resistant viridans streptococci seen over a 39year period concluded that current treatment guidelines should be successful
in most patients. (See 'Enterococci' below.)
OTHER STREPTOCOCCAL SPECIES Other streptococcal species (eg, groups A,
B, C, G, and Streptococcus pneumoniae) are occasional causes of endocarditis
[10,11]. Therapy should always be based on the results of susceptibility
testing. Since most of these organisms are highly sensitive to penicillin,
regimens used to treat endocarditis due to viridans streptococci are typically
effective.

Many strains of groups B, C, and G streptococci are more resistant to penicillin

than S. pyogenes. For this reason, some experts recommend adding
gentamicin to a penicillin or cephalosporin for the first two weeks of a four to
six week course of therapy [11].

Pneumococcus Pneumococcal endocarditis typically follows pneumonia in

alcoholic patients and may be complicated by concurrent meningitis [10].
However, increasing numbers of isolates of S. pneumoniae have become
relatively or highly resistant to penicillin. These organisms may be

simultaneously resistant to other beta-lactams and other antimicrobial agents.

Therapy in these cases usually requires the input of an infectious disease
specialist or a microbiologist.

Penicillin G (24 million units per day either continuously or in four to six equally
divided doses) remains the therapy of choice for patients with endocarditis due
to penicillin-susceptible strains of S. pneumoniae and S. pyogenes [3]. The
2012 British Society for Antimicrobial Chemotherapy (BSAC) guidelines
recommend that the therapy of pneumococcal endocarditis be guided by the
same susceptibility breakpoints used to determine the therapy of endocarditis
due to other streptococcal species [7]. (See 'Viridans streptococci and
Streptococcus bovis' above.)

A few strains of S. pneumoniae only respond to vancomycin therapy. (See

"Resistance of Streptococcus pneumoniae to beta-lactam antibiotics".)

Pneumococcal endocarditis is usually fulminant and causes severe valve

damage and embolic complications. The potential complications of
pneumococcal endocarditis are illustrated by a case series from France [12].
Transesophageal echocardiography (TEE) was performed in 28 of 30 patients
with pneumococcal endocarditis; valvular vegetations, valve perforation, ring
abscess, and other complications were detected in 97, 20, 13, and 20 percent,
respectively. Early valve replacement may be necessary in patients with
pneumococcal endocarditis to prevent complications. (See "Surgery for native
valve endocarditis".)

ENTEROCOCCI Enterococci have a narrower spectrum of susceptibility than

streptococcal species. In particular, members of the genus Enterococcus are all
resistant to, at the least, low concentrations of penicillin. They are also
relatively resistant to expanded spectrum penicillins, resistant to
cephalosporins, and typically resistant to aminoglycosides at concentrations
achieved after standard dosing regimens. However, many strains of
enterococci are killed both in vitro and in vivo if penicillin, ampicillin, or
vancomycin is given in synergistic combination with an aminoglycoside such as
gentamicin.

There are also a number of additional trends in the resistance pattern of

enterococci. (See "Mechanisms of antibiotic resistance in enterococci".)

Rare strains of Enterococcus faecalis have acquired genetic material that

allows them to produce beta-lactamase [13,14].
Other strains have acquired high-level resistance to streptomycin and/or
gentamicin. The latter is accompanied by high-level resistance to synergy with
tobramycin, netilmicin, and amikacin.
High-level resistance to penicillin and ampicillin (minimum inhibitory
concentration [MIC] 128 mcg/mL) that is not mediated by penicillinase has
increased in some enterococci, primarily strains of Enterococcus faecium.
Increasing numbers of enterococci have acquired high-level resistance to
vancomycin as well as ampicillin. Some, but not all, of these highly resistant
strains are also resistant to the glycopeptide antibiotic teicoplanin.
These patterns of resistance have a direct impact on the guidelines for
treatment of enterococcal endocarditis (table 3 and table 4 and table 5).

Susceptible strains The majority of cases of enterococcal endocarditis are

caused by strains of E. faecalis [15]. The American Heart Association (AHA) and
British Society for Antimicrobial Chemotherapy (BSAC) recommend that
therapy for E. faecalis with typical low-level penicillin resistance consist of a
combination of intravenous aqueous penicillin G or ampicillin plus gentamicin
(table 3) [3,7]. In addition, the BSAC recommends either a combination of
vancomycin and gentamicin and teicoplanin as alternatives to penicillin or
ampicillin in the penicillin-allergic patient if the isolate is susceptible (MIC 4
mcg/L) [7]. The European Society for Cardiology (ESC) recommends
combination therapy with either penicillin G plus gentamicin for four weeks or
vancomycin plus gentamicin for six weeks (table 3) [16].

Although ampicillin is about one dilution more potent than penicillin in vitro,
there is no evidence that this is necessary or beneficial for synergism in most
instances. Because of the possibility of increased allergic reactions to
ampicillin, some experts prefer penicillin rather than ampicillin for synergistic
therapy. Gentamicin therapy is usually given at doses of 1 mg/kg every eight
hours to achieve peak serum levels of approximately 3 to 4 mcg/mL and trough
serum concentrations <1 mcg/mL. Tobramycin and amikacin are usually
avoided.

Data from a nonrandomized study suggest that two weeks of gentamicin (in
combination with an appropriate cell wall active agent for four to six weeks)
may be adequate for treatment of patients with infective endocarditis (IE) due
to E. faecalis with duration of symptoms <3 months and in the absence of highlevel aminoglycoside resistance [17]; longer duration of gentamicin treatment
has been associated with increased likelihood for decline in renal function. We
remain in agreement with guideline recommendations that IE due to
enterococcus should be treated with synergistic therapy of a cell wall active
agent and an aminoglycoside for the full course of four to six weeks, but this
nonrandomized study suggests that, in patients who develop aminoglycoside
toxicity, the aminoglycoside may be stopped after two weeks (with
continuation of the cell wall active agent).

In one study, patients with symptoms of endocarditis for less than three
months were usually treated successfully with four weeks of therapy [18]. By
contrast, six weeks of therapy is preferred in patients with symptoms of more
than three months duration prior to the initiation of treatment, with a relapsed
infection, or with prosthetic valve infection.

The AHA recommends four to six weeks of treatment based upon the length of
time the patient reports symptoms at presentation (table 3) [3]. The BSAC
recommends at least four weeks of treatment [7], while the ESC recommends
only four weeks of treatment [16].

Patients with a history of penicillin allergy should be treated with a combination

of vancomycin (15 to 20 mg/kg/dose every 8 to 12 hours, not to exceed 2 g per
dose) and gentamicin (3 mg/kg per day) for six weeks or considered for
desensitization. As stated previously, we believe that penicillin is preferable to
vancomycin. Thus, when expertise is available to safely supervise
desensitization protocols and when the nature of the penicillin allergy is
doubtful or otherwise inconclusive, we advise desensitization to penicillin
rather than substitution of vancomycin. (See "Allergy to penicillins".)

If treatment with vancomycin is elected, the AHA and ESC recommend a

duration of therapy of six weeks rather than four weeks because vancomycin
has decreased activity against enterococci as compared with penicillin (table 3)
[3,16]. The BSAC recommends at least four weeks of treatment [7].

Gentamicin-resistant strains Enterococcal endocarditis caused by strains that

are susceptible to penicillin, vancomycin, and streptomycin but resistant to
gentamicin can be treated with one of two combinations. The preferred
treatment regimen is ampicillin or penicillin plus streptomycin (15 mg/kg per
day in two equally divided doses). In the penicillin-allergic patient, the
alternative treatment is vancomycin (15 to 20 mg/kg/dose every 8 to 12 hours,
not to exceed 2 g per dose) plus streptomycin [3]. Patients who have
enterococcal endocarditis due to ampicillin-susceptible (MIC of 4 mg/L or less)
and high-level gentamicin and streptomycin-resistant (MIC >128 mg/L)
enterococci may be treated with ampicillin monotherapy [7].

High-level penicillin resistance The AHA recommends that enterococcal

endocarditis due to strains with intrinsic high-level penicillin resistance (MIC
>16 mcg/mL) be treated with a combination of gentamicin plus either
ampicillin-sulbactam (12 g per day in four equally divided doses) (if the
resistance is beta-lactamase mediated) or vancomycin (15 to 20 mg/kg/dose
every 8 to 12 hours, not to exceed 2 g per dose) for six weeks (table 4) [3]. The
BSAC recommends the combination of gentamicin plus either vancomycin (1 g
every 12 hours) or teicoplanin (10 mg/kg once daily, if MIC 4 mcg/L) for at
least four weeks [7]. The ESC recommends vancomycin plus gentamicin for six
weeks [16].

Unfortunately, most beta-lactamase-producing E. faecalis strains have also

been highly resistant to streptomycin and gentamicin.

High-level aminoglycoside or vancomycin resistance E. faecium is the

enterococcal strain most likely to manifest vancomycin resistance, but this
strain is an uncommon cause of endocarditis. Therefore, literature on the
treatment of patients with endocarditis due to vancomycin-resistant
enterococci is limited to isolated case reports and extrapolation from in vitro
susceptibility studies and animal models of endocarditis. Management of
endocarditis due to enterococci with high-level aminoglycoside and/or
vancomycin resistance may require individualized consideration by the
microbiology laboratory as well as infectious disease consultation.

Results of in vitro susceptibility studies using various combinations of

daptomycin and gentamicin have demonstrated conflicting results for both

vancomycin-resistant enterococci and methicillin-resistant S. aureus (MRSA).

Some studies have shown modest additive effects [19,20]; other studies
showed synergy with some but not all strains of MRSA [21]. In view of these
findings and the added risk of toxicity to gentamicin therapy, we do not favor
using daptomycin and gentamicin in combination unless in vitro studies
support addition of gentamicin and other less toxic regimens have failed.

Some strains of enterococci that are streptomycin resistant lack high-level

resistance (HLR) to gentamicin and vice versa. However, HLR to gentamicin is
conferred by a bifunctional enzyme that also confers high-level resistance to
and/or resistance to synergism with tobramycin, netilmicin, and amikacin.
When endocarditis is due to enterococci that are highly resistant to both
streptomycin and gentamicin, the addition of an aminoglycoside is not
beneficial. (See "Treatment of enterococcal infections".)

Success and failure of therapy for endocarditis due to resistant organisms has
been described [22-24]. In a retrospective review of 12 cases of native valve
vancomycin-resistant enterococcal endocarditis, all patients had significant
comorbidities [22]. Three of the 12 patients died. Four patients were
successfully treated with six to nine weeks of linezolid (two received linezolid
alone, one each received an additional antibiotic, either alatrofloxacin or
chloramphenicol).

Optimal therapy for such patients has not been defined, but a number of
possible regimens were mentioned in the major society guidelines (table 5).
Subsequent to publication of the guidelines, a six-week regimen of ampicillin (2
g IV every four hours) plus ceftriaxone (2 g IV every 12 hours) has been
evaluated in patients with E. faecalis endocarditis [25,26] based upon
demonstrated efficacy in experimental endocarditis due to E. faecalis strains
that were highly resistant to aminoglycosides [27]. Among 246 patients in an
observational, nonrandomized multicenter study, 159 were treated with
ampicillin and ceftriaxone (AC) and 87 were treated with ampicillin and
gentamicin (AG) [26]. AC appeared to be as effective as AG; there were no
differences in mortality (during treatment or at three-month follow-up),
treatment failure, or relapse. Interruption of treatment due to adverse events
occurred more frequently among patients treated with AG, mainly due to renal
failure.

In patients who do not respond to antimicrobial therapy, surgical resection of

the involved valve may be necessary for cure. (See "Surgery for native valve
endocarditis".)

STAPHYLOCOCCAL ENDOCARDITIS The success of therapy for staphylococcal

endocarditis is dependent upon numerous factors, including involvement of
right- versus left-sided valvular structures, whether the staphylococcus is
coagulase negative or positive, the susceptibility of the staphylococcal isolate,
and whether the infection occurs on a native or a prosthetic valve.

Rare, occasional strains of S. aureus are found to be penicillin susceptible; the

strain should be tested to confirm the minimum inhibitory concentration (MIC)
is 0.1 mcg/mL and that the strain does not produce beta-lactamase in vitro. If
penicillin susceptibility is documented, penicillin (24 million units/day in four to
six divided doses) can be substituted for nafcillin or another semisynthetic
penicillin in the regimens discussed below.

Methicillin susceptible Native valve endocarditis due to methicillinsusceptible S. aureus is best treated with a semisynthetic penicillin, such as
nafcillin or oxacillin (12 g per day intravenously in four to six equally divided
doses) or flucloxacillin (2 g every four to six hours) (table 6).

Low-dose aminoglycosides should NOT be combined routinely with

antistaphylococcal penicillins or vancomycin for treatment of left-sided native
valve S. aureus endocarditis. Although in vitro and experimental models of
endocarditis have demonstrated that combination therapy facilitates more
rapid killing of methicillin-susceptible S. aureus than monotherapy, the
evidence for clinically significant benefit is minimal. This was illustrated by a
randomized trial of 48 patients with methicillin-susceptible S. aureus (MSSA)
native valve endocarditis; patients who received nafcillin plus gentamicin for
the first two weeks of therapy had more rapid clearing of bacteremia than
those who received nafcillin alone [28]. However, cure rates were comparable
and combination nafcillin and gentamicin therapy was associated with a higher
incidence of renal dysfunction.

Subsequently, a randomized trial including 236 patients with S. aureus

bacteremia and endocarditis demonstrated that daptomycin monotherapy is

not inferior to low-dose gentamicin plus an antistaphylococcal penicillin or

vancomycin, although those in the standard therapy arm experienced
significantly more renal impairment than those in the daptomycin arm [29]. An
investigation of the safety data from the trial noted significantly greater
reduction in creatinine clearance among those who received initial low-dose
gentamicin than those who did not (22 versus 8 percent, respectively) [30].

Therefore, initial low-dose aminoglycoside should NOT be combined routinely

with antistaphylococcal penicillins or vancomycin for treatment of S. aureus
endocarditis. The limited benefit must be weighed against evidence for
potential harm, particularly in older adults and in those with diabetes and mild
baseline renal dysfunction. (See "Clinical approach to Staphylococcus aureus
bacteremia in adults".)

In adults, six weeks of therapy is recommended for complicated right-sided

infective endocarditis (IE) and for all left-sided IE; complicated IE is defined as
metastatic infections or when the course is otherwise complicated by
secondary cardiac problems (eg, heart failure). In patients with uncomplicated
right-sided IE, the duration of therapy is two weeks if synergistic therapy can
be given. (See 'Uncomplicated right sided' below.)

In children, six weeks of therapy is recommended regardless of the site of

infection or absence of complications because of insufficient clinical experience
to support a duration of therapy of two weeks for uncomplicated right-sided IE
[31].

Penicillin allergy Patients with native valve endocarditis due to S. aureus who
have a history of penicillin allergy can be treated with a first-generation
cephalosporin, such as cefazolin (2 g intravenously every eight hours), if there
is no prior history of penicillin reaction that is typical of an immediate-type
allergy. Some experts caution against substituting cefazolin for nafcillin in the
treatment of staphylococcal endocarditis [32]. However, to our knowledge, the
only study purporting to show that cefazolin was inferior to nafcillin in
staphylococcal endocarditis was based on anecdotal observations of two
patients with S. aureus endocarditis who either relapsed after treatment or who
failed therapy [33]. The American Heart Association (AHA) recommends
cefazolin as an alternative in patients with penicillin allergy that is not
anaphylactoid type [3]; however, the British Society for Antimicrobial

Chemotherapy (BSAC) and the European Society for Cardiology (ESC)

recommend vancomycin therapy for all patients with penicillin allergy
regardless of type [7,16]. In addition, the BSAC 2012 guidelines recommend
adding rifampin (300 to 600 mg orally every 12 hours) to vancomycin when
treating methicillin-susceptible native valve endocarditis in patients with
penicillin allergy [7].

Vancomycin is an acceptable alternative in the patient with immediate-type

penicillin allergy. However, vancomycin should not be used on the basis of
convenience related to pharmacokinetics in patients without a history of
penicillin allergy, since clinical experience and in vitro studies have suggested
that vancomycin is a less effective antistaphylococcal antibiotic than nafcillin or
oxacillin [3,34].

Clindamycin is not an acceptable alternative for staphylococcal endocarditis

because relapse is common [3].

Uncomplicated right sided Selected patients with native valve right-sided

endocarditis due to S. aureus with no evidence of renal failure, extrapulmonary
metastatic infections, or simultaneous left-sided valvular infection may be
successfully treated with two-week regimens utilizing the combination of
nafcillin and gentamicin [3,35]. Regimens that substitute vancomycin or
teicoplanin for nafcillin (eg, for penicillin allergic patients) are not considered to
be reliably effective if only two weeks of therapy are given [32]. Although one
randomized study showed that cloxacillin alone for two weeks was equivalent
to the combination of cloxacillin plus gentamicin in the treatment of right-sided
IE in injection drug users, we do not routinely advise short-course monotherapy
for such patients [36].

Short-course regimens utilizing combination therapy are also not suitable for
patients with simultaneous infection of the left-side heart valves, isolates that
demonstrate high-level gentamicin resistance (MIC >500 mcg/mL), metastatic
infections outside of the lungs, or in patients who fail to defervesce in a normal
time period.

Methicillin resistant Native valve endocarditis due to either methicillinresistant S. aureus (MRSA) or coagulase-negative staphylococci should be

treated with vancomycin for six weeks (table 6) [3,16,37]. However, there have
been a number of reports of vancomycin treatment failure in serious infections
due to MRSA even when isolates are proven to be susceptible using current
microbiological testing methods [38-40].

Some guidelines [7] recommend the addition of rifampin (300 to 600 mg orally
every 12 hours) to vancomycin in the treatment of native valve endocarditis
due to methicillin-resistant but vancomycin-susceptible S. aureus. However, the
evidence for this approach is not conclusive and the risk of rifampin-induced
drug interactions or hepatic toxicity should be weighed before utilizing such
therapy.

Gentamicin should NOT be combined with vancomycin for treatment of MRSA

native valve IE [37]. (See 'Methicillin susceptible' above.)

Daptomycin is an acceptable alternative to vancomycin [37,41]. In a

randomized trial of 246 patients with S. aureus bacteremia (SAB) with or
without endocarditis, daptomycin (6 mg/kg intravenously [IV] per day) was not
inferior to standard therapy for SAB or right-sided endocarditis [29].
Daptomycin resistance (MIC 2 mcg/mL) developed in six patients. Another
study demonstrated that clearance of bacteremia among 29 patients with
gram-positive left-sided IE treated with daptomycin was significantly faster
than among 149 patients treated with conventional therapy (p<0.01) [41].

Randomized controlled trials of the effectiveness of linezolid and quinupristindalfopristin in humans with IE have not yet been published. Both treatment
failures and successes with linezolid in humans with IE due to MRSA have been
reported by several authors, and experimental studies in animal models have
shown promising results [42-48].

Coagulase negative staphylococci Treatment regimens for coagulasenegative staphylococci are identical to those for coagulase-positive
staphylococci. Most strains of coagulase-negative staphylococci are methicillin
resistant. As a result, unless susceptibility to methicillin can be conclusively
demonstrated, coagulase-negative staphylococci causing prosthetic valve
endocarditis should be assumed to be methicillin resistant and treated

accordingly [3]. (See "Clinical manifestations of infection due to coagulasenegative staphylococci".)

HACEK ORGANISMS A number of fastidious gram-negative bacilli, collectively

grouped by the acronym "HACEK," account for 5 to 10 percent of all cases of
native valve endocarditis in individuals who do not use illicit intravenous drugs.
Organisms in this category include the following: Haemophilus aphrophilus
(subsequently called Aggregatibacter aphrophilus and Aggregatibacter
paraphrophilus); Actinobacillus actinomycetemcomitans (subsequently called
Aggregatibacter actinomycetemcomitans); Cardiobacterium hominis; Eikenella
corrodens; and Kingella kingae. If traditional (non-automated) blood culture
systems are used, longer incubation periods (>6 days) may be required to
detect their growth. This delayed growth made these organisms synonymous
with culture-negative endocarditis. Since the introduction of automated blood
culture systems, the HACEK organisms are easily isolated when incubated for
five days. (See "Epidemiology, microbiology, and diagnosis of culture-negative
endocarditis".)

Although most HACEK organisms were ampicillin sensitive in the past, this is no
longer true, as many species in this group have acquired the ability to produce
beta-lactamase. However, virtually all of these organisms, even strains that
produce beta-lactamase, are highly susceptible to third-generation
cephalosporins, such as ceftriaxone (2 g once daily, given intravenously or
intramuscularly).

The American Heart Association (AHA) recommends treatment with ceftriaxone,

ampicillin-sulbactam, or ciprofloxacin for four weeks (table 7) [3]. The British
Society for Antimicrobial Chemotherapy (BSAC), in contrast, recommends
combination therapy with either ampicillin (if susceptible) or ceftriaxone for
four weeks with gentamicin added for the initial two weeks of treatment (table
7) [7]. The European Society for Cardiology (ESC) recommends either
ceftriaxone alone or ampicillin plus gentamicin; both regimens are given for
three to four weeks (table 7) [16].

OTHER GRAM-NEGATIVE ORGANISMS Native valve endocarditis due to other

gram-negative bacilli, such as E. coli, Pseudomonas, or mucoid strains of
Klebsiella or Serratia, is extremely rare. The most common predisposing factor

is an implanted endovascular device, and most cases occur in the setting of

recent healthcare contact [49].

The choice of antimicrobial therapy is dependent on the antimicrobial

susceptibility of the causative organism. Third-generation cephalosporins, such
as ceftriaxone (2 g once daily intravenously [IV]), or a fluoroquinolone, such as
ciprofloxacin (400 mg every 12 hours IV), are acceptable regimens if the
organism is susceptible in vitro. Combination antimicrobial therapy with an
antipseudomonal penicillin and an aminoglycoside is an effective regimen for
patients with infections due to Pseudomonas [3].

CULTURE-NEGATIVE ENDOCARDITIS Blood culture-negative infective

endocarditis (IE) is defined as endocarditis without etiology following
inoculation of three blood samples in a standard blood culture system (eg,
negative cultures after seven days).

Cultures are negative in infective endocarditis for three major reasons:

Previous administration of antimicrobial agents

Inadequate microbiological techniques
Infection with highly fastidious bacteria or nonbacterial pathogens (eg, fungi)
The most common causative agents of blood culture-negative IE are fastidious
organisms (eg, zoonotic agents and fungi) and Streptococcus spp in patients
who have received previous antibiotic treatment. (See "Epidemiology,
microbiology, and diagnosis of culture-negative endocarditis".)

Coxiella burnetii and Bartonella spp are relatively commonly agents of culturenegative endocarditis, although the frequency varies in different geographic
locations. Treatment of these cases is discussed separately. (See "Q fever
endocarditis" and "Endocarditis caused by Bartonella".)

Empiric treatment of patients with culture-negative endocarditis should cover

both gram-positive and gram-negative organisms. The American Heart
Association (AHA) recommends treatment with either ampicillin-sulbactam plus

gentamicin OR vancomycin plus gentamicin plus ciprofloxacin for four to six

weeks (table 8) [3]. The British Cardiac Society (BCS) and the European Society
for Cardiology (ESC), in contrast, recommend combination therapy with
vancomycin for six (BCS) or four to six (ESC) weeks with gentamicin added for
the initial two weeks of treatment (table 8) [16,50]. When diagnostic tests (eg,
polymerase chain reaction or serology) identify the etiologic agent, therapy
should be directed to the specific microorganism. (See "Clinical manifestations
and diagnosis of infective endocarditis".)

Complications and outcome of infective endocarditis

Authors
Denis Spelman, MBBS, FRACP, FRCPA, MPH
Daniel J Sexton, MD
Section Editors
Stephen B Calderwood, MD
Gabriel S Aldea, MD
Scott E Kasner, MD
Deputy Editors
Elinor L Baron, MD, DTMH
Susan B Yeon, MD, JD, FACC
Disclosures: Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose.
Daniel J Sexton, MD Grant/Research/Clinical Trail Support: Cubist [C. difficile
infection (Fidaxomycin)]. Consultant/Advisory Boards: Johnson & Johnson [Pelvic
mesh-related infection]; Sterilis [Medical waste disposal systems]; Magnolia
Medical Technologies [Intravenous devices]. Other Financial Interest: National
Football League [Infection control program]. Equity Ownership/Stock Options:
Magnolia Medical Technologies [Intravenous devices]. Stephen B Calderwood,
MD Patent Holder: Vaccine Technologies Inc. [Vaccines (Cholera vaccines)].
Equity Ownership/Stock Options: Pulmatrix [Inhaled antimicrobials];
PharmAthene [Anthrax (Anti-protective antigen monoclonal antibody)]. Gabriel
S Aldea, MD Nothing to disclose. Scott E Kasner, MD Grant/Research/Clinical
Trial Support: WL Gore and Associates [PFO, stroke (HELEX, GSO devices)];
AstraZeneca [Stroke (Ticagrelor)]. Consultant/Advisory Boards: Medtronic
[Stroke, atrial fibrillation (CoreValve, REVEAL)]; Merck [Stroke]; Pfizer [Stroke];
Novartis [Stroke]; GSK [Stroke]; AbbVie [Stroke]; Daiichi Sankyo [Stroke];

Boehringer Ingelheim [Stroke]. Elinor L Baron, MD, DTMH Nothing to disclose.

Susan B Yeon, MD, JD, FACC Nothing to disclose. Contributor disclosures are
reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through
requirements for references to be provided to support the content.
Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence. Conflict of interest policy
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Apr 2015. | This topic last updated: Apr 28,
2015.
INTRODUCTION Infective endocarditis (IE) is associated with a broad array of
complications. The likelihood of complication(s) depends on several factors
including the infecting pathogen, duration of illness prior to therapy, and
underlying comorbidities [1]. Complications can occur before, during, and after
completion of therapy.

It can be difficult to assess the true incidence of complications since case series
are frequently retrospective. In one review including 223 episodes of IE, 57
percent of patients had one complication, 26 percent had two, 8 percent had
three or more, and 6 percent had six or more complications [2].

Issues related to complications and outcome of IE will be reviewed here. Other

issues related to IE are discussed separately. (See related topics.)

COMPLICATIONS OF ENDOCARDITIS Complications of infective endocarditis

(IE) include cardiac, neurologic, renal, and musculoskeletal complications, as
well as complications related to systemic infection (including embolization,
metastatic infection, and mycotic aneurysm). More than one complication can
occur simultaneously.

Complications can also be considered based on pathogenesis (ie, embolic [such

as cerebral infarct], local spread of infection [such as heart valve destruction],
metastatic infection [such as vertebral osteomyelitis], and immune-mediated
damage [such as glomerulonephritis]).

IE due to Staphylococcus aureus is associated with complications more

frequently than other pathogens (stroke 21 versus 14 percent, systemic emboli
27 versus 18 percent, persistent bacteremia 17 versus 5 percent, and inhospital mortality 22 versus 14 percent) [3].

Cardiac complications Cardiac complications are the most common

complications in IE; they occur in up to half of patients [4].

Heart failure Heart failure is the most common cause of death due to IE in
the modern era. The correlation between heart failure and mortality depends
on several factors including the valve involved (aortic valve involvement is
more likely to cause heart failure than mitral valve involvement), the pathogen
involved (S. aureus infection increases the likelihood of heart failure), and
whether the patient undergoes surgery for valve repair or replacement. Heart
failure is the most common reason for cardiac surgery in patients with IE;
indications for surgery in patients with cardiac complications are discussed
further separately. (See "Surgery for native valve endocarditis".)

The usual cause of heart failure in patients with IE is valvular insufficiency

resulting from infection-induced valvular damage. Rarely, embolized fragments
of valvular vegetations or vegetation-induced stenosis of the coronary ostia can
cause acute myocardial infarction and subsequent heart failure [4].

Perivalvular abscess The reported incidence of perivalvular abscess among

patients with IE is 30 to 40 percent [5-7]. The aortic valve and its adjacent
annulus are more susceptible to abscess formation and associated
complications than the mitral valve and annulus [5-7]. This was illustrated in an
autopsy study including 95 patients with native valve endocarditis; annular
extension of infection was more common in patients with aortic valve
compared with mitral valve endocarditis (41 versus 6 percent) [5].

Perivalvular abscesses can extend into adjacent cardiac conduction tissues,

leading to heart block. Involvement of the conducting system is most common
in the setting of aortic valve infection, especially when there is involvement of
the valve ring between the right and non-coronary cusp; this anatomic site
overlies the intraventricular septum that contains the proximal ventricular

conduction system. Rarely, perivalvular infection can result in extrinsic

coronary compression and can cause acute coronary syndrome [8].

Perivalvular abscess is associated with increased risk of systemic embolization

and death. In one study including 73 patients with IE, the embolization rate was
approximately twice as high among patients with perivalvular abscess (64
versus 30 percent) [6]. Another study including 118 patients with IE noted
higher mortality among patients with perivalvular abscess (23 versus 14
percent) [7]. In addition, moderate or severe regurgitation is associated with
higher mortality rate than normal valvular function [9].

Perivalvular abscess should be suspected in the setting of conduction

abnormalities on electrocardiogram (ECG) and/or persistent bacteremia or
fever despite appropriate antimicrobial therapy [10]. Data are conflicting
regarding correlation between vegetation size and risk for perivalvular abscess.
Large vegetation size had been implicated as a risk factor for perivalvular
abscess in some series, although subsequent studies have shown no
correlation [6,11]. Patients with IE involving congenital bicuspid aortic valves
appear to be more prone to perivalvular complications than those with IE
involving tricuspid aortic valves [12]. Injection drug use may be another risk
factor for perivalvular abscess [6].

Transesophageal echocardiography (TEE) is more sensitive for detection of

myocardial abscess than transthoracic echocardiography (TTE). In one study
including 43 patients with perivalvular abscess documented at surgery or
autopsy, the sensitivity, specificity, and positive and negative predictive values
of TEE were 87, 95, 91, and 92 percent, respectively [7]. The sensitivity of TTE
was much lower (28 percent), although the specificity was 99 percent. While
TEE is more sensitive than TTE for detecting an abscess, even TEE may miss a
significant number of abscesses in some populations (eg, mitral annular
abscesses in patients with large mitral annular calcification). (See "Role of
echocardiography in infective endocarditis", section on 'Perivalvular abscess or
fistula'.)

Other cardiac complications Pericarditis (suppurative or nonsuppurative) can

cause chest pain or cardiac tamponade [13,14]. (See "Purulent pericarditis" and
"Clinical presentation and diagnostic evaluation of acute pericarditis".)

Intracardiac fistula (eg, aorta-atrial or aorta-ventricular) may develop due to

extension of infection from the valve to adjacent myocardium. Rarely, this can
lead to development of an aneurysm, aortic dissection, or myocardial
perforation [15,16]. In one study including 4681 episodes of IE, the incidence of
fistulous intracardiac complications was 1.6 percent [17].

Metastatic infection Forms of metastatic infection include embolization,

metastatic abscess, and mycotic aneurysm.

Septic embolization General issues related to embolization in patients with IE

will be reviewed here; issues related to embolization in patients with IE who
undergo surgery are discussed separately, as are issues related to thrombotic
therapy. (See "Surgery for native valve endocarditis", section on 'Embolization'
and "Surgery for prosthetic valve endocarditis" and "Antithrombotic therapy in
patients with infective endocarditis".)

Embolization with clinical sequelae has been described in 13 to 44 percent of

patients with IE; in most cases, embolization occurs prior to clinical
presentation but can occur after initiation of antimicrobial therapy [18-20].
Systemic embolization most commonly occurs in left-sided IE; pulmonic
embolization most commonly occurs in right-sided IE. Systemic embolization
can also occur in patients with right-sided IE and a patent foramen ovale [21].

Emboli can occlude or damage virtually any vessel in the systemic or

pulmonary arterial circulation. As a result, embolization can cause:

Stroke
Paralysis (due to embolic infarction of either the brain or spinal cord)
Blindness (due to embolism or due to endophthalmitis as a result of
bacteremic seeding)
Ischemia of the extremities
Splenic or renal infarction
Pulmonary embolism

Acute myocardial infarction

Endocarditis should be considered as a possible etiology in patients who
present with signs or symptoms of systemic arterial embolization. Most
patients with acute stroke do not have endocarditis, although the likelihood of
IE is increased in relatively young patients and in patients with both cerebral
and systemic arterial embolization [22,23].

Risk factors Risk factors for embolization include presence of left-sided

vegetation, large vegetation size, microbiology, presence of antiphospholipid
antibodies, age, diabetes, atrial fibrillation, and embolization prior to initiation
of antibiotics [24-31]:

Left-sided vegetation Embolization with clinical sequelae occurs more

frequently in patients with left-sided than right-sided vegetations [25], and
more frequently with mitral vegetations than aortic vegetations [26]. In one
review including 281 patients with suspected IE, the incidence of embolic
events was greater with mitral than aortic valve vegetations (25 versus 10
percent) [26]. The risk was highest among patients with a vegetation on the
anterior mitral leaflet (37 percent), suggesting that the mechanical effects of
broad and abrupt leaflet excursion may contribute to the risk of embolization
[25].
Large vegetation size One study including 384 patients with IE noted that
vegetation size >10 mm and severe mobility of the vegetation were predictors
of new embolic events, even after adjustment for pathogen type, and
vegetation size >15 mm was a predictor of one-year mortality (adjusted
relative risk 1.8, CI 1.10-2.82) [30]. In another study including 59 patients with
IE due to S. aureus, the risk of embolization was greater in patients who had
visible vegetations by both TTE and TEE compared with patients who had
vegetations visualized only by TEE [27]. Another study noted that absence of
valvular abnormalities on TTE may be associated with reduced incidence of
complications [28]. (See "Role of echocardiography in infective endocarditis",
section on 'Echocardiographic estimation of outcome'.)
Microbiology The likelihood of symptomatic embolization is increased in the
setting of IE due to fungal pathogens or S. aureus. In a review including 270
patients with fungal endocarditis, peripheral arterial embolization occurred in
45 percent of cases [32]. The most common sites were the cerebral circulation
(17 percent) and femoral artery (16 percent). Another study including 384
patients with IE noted that emboli were more frequently observed in the setting
of infection due to S. aureus and Streptococcus bovis infection [30].

Presence of antiphospholipid antibodies In one series including 91 patients

with IE, the presence of antiphospholipid antibodies was associated with an
increased risk of embolization (62 versus 23 percent); this may be due to
increased endothelial cell activation, generation of thrombin, and defective
fibrinolysis [29].
Effect of antibiotic therapy The risk of embolization declines after institution
of appropriate antimicrobial therapy, and serious embolic events weeks after
such therapy is instituted are rare [18,33,34]. In one study including 1437
patients with left-sided IE receiving appropriate therapy, the incidence of stroke
fell from 4.8 to 1.7 per 1000 patient days between the first and second week of
therapy [34]. These findings suggest that surgery may not be necessary for
prevention of embolic stroke in the early weeks following initiation of
appropriate therapy if there are no other surgical indications (such as a large
mobile vegetation or congestive heart failure due to valvular regurgitation).

Metastatic abscess Development of metastatic abscess occurs as a sequela

of septic embolization; this may occur in the spleen, kidneys, brain, and/or soft
tissues (such as the psoas muscle).

Patients with splenic abscess do not always have significant abdominal pain or
splenomegaly on physical examination; in some cases, the only clue(s) may be
persistent fever and/or recurrent bacteremia after completion of antimicrobial
therapy [35]. Splenic abscess frequently requires splenectomy for cure. In one
series including 27 patients with splenic abscesses, mortality among 17
patients who underwent splenectomy was 18 percent; mortality among 10
patients who did not undergo splenectomy was 100 percent [36]. (See
"Approach to the adult patient with splenomegaly and other splenic disorders",
section on 'Splenic abscess'.)

Solitary brain abscess(es) or discrete microabscess(es) can also occur; purulent

meningitis has been observed in some cases. The presence of meningitis due
to S. aureus should suggest the possibility of concomitant S. aureus
endocarditis. In one series including 33 patients with S. aureus meningitis, IE
was diagnosed in 21 percent of cases [37]. Abscess drainage is required to
control local infection and to prevent ongoing bacteremia. (See "Treatment and
prognosis of bacterial brain abscess".)

Mycotic aneurysm Mycotic aneurysm can develop in the cerebral or systemic

circulation in the setting of IE, usually at points of vessel bifurcation. Although
some authors use the term "mycotic" to describe infected aneurysm regardless
of etiology, we limit the use of this term to those aneurysms that develop when
material originating in the heart causes arterial wall infection and,
subsequently, dilation [38]. (See "Overview of infected (mycotic) arterial
aneurysm".)

Neurologic complications Manifestations of neurologic complications include:

Embolic stroke
Brain abscess or cerebritis
Purulent or aseptic meningitis
Acute encephalopathy
Meningoencephalitis
Cerebral hemorrhage (due to stroke or a ruptured mycotic aneurysm)
Seizures (secondary to abscess or embolic infarction)
Symptomatic cerebrovascular complications occur in up to 35 percent of
patients [20,21,39-44]. Silent cerebrovascular complications (including
ischemia and microhemorrhage) may occur in up to 80 percent of patients
[20,45-47].

Neurologic complications may be the presenting symptom in patients with IE,

and the possibility of IE should be considered in patients who present with
stroke, meningitis, or brain abscess. In one series including 68 patients with
stroke and IE, for example, two-thirds presented with stroke prior to diagnosis
of endocarditis [48]. Unexplained fever accompanying a stroke in a patient with
valvular disease can be an important clue for IE. (See "Clinical manifestations
and diagnosis of infective endocarditis".)

Among patients with IE, the incidence of cerebral emboli detected by magnetic
resonance imaging (MRI) is markedly higher than the incidence of emboli
detected based on clinical signs and symptoms [20,47,49]. In one study
including 65 patients with IE, clinical findings consistent with embolism were

observed in 20 percent of cases; among patients with no symptoms, emboli

were detected on MRI in 46 percent of cases [49]. In another study including 60
patients with IE, clinical signs and symptoms of cerebral embolism were
observed in 35 percent of cases; clinically silent emboli were detected on MRI
in an additional 30 percent of patients [20].

Patient outcomes after a neurologic complication of IE are variable. In one

study including 214 patients who underwent cardiac surgery for IE, 70 percent
of patients with a preoperative stroke had full neurologic recovery; outcomes
were worse in patients with stroke complicated by meningitis, abscess, or
intracerebral hemorrhage [43]. Patient mortality in another series including 68
patients with stroke and IE was 50 percent at one year [48]. One study of 91
patients with S. aureus IE and neurologic manifestations noted mortality of 74
percent [41].

Renal complications Renal complications of IE include renal infarction or

abscess following septic embolization, glomerulonephritis (due to deposition of
immunoglobulins and complement in the glomerular membrane), and druginduced acute interstitial nephritis. Acute renal failure, defined as a serum
creatinine of 2 mg/dL (177 mcmol/L), has been described in up to one-third of
patients [50]. Immune complex-mediated renal disease is uncommon in the
antibiotic era, especially in patients whose infection is detected and treated
early. Chronic renal failure due to immune-complex-mediated
glomerulonephritis was a common cause of death in patients with IE in the
preantibiotic era; in the modern era, it is rare. (See "Renal disease in the
setting of infective endocarditis or an infected ventriculoatrial shunt".)

Renal complications can also occur as a result of toxicity associated with

administration of therapeutic drugs; this is particularly important in the setting
of coadministration of vancomycin with aminoglycosides and among patients at
the extremes of age. (See 'Complications related to therapy' below.)

Musculoskeletal complications Musculoskeletal complications of IE include

vertebral osteomyelitis and septic arthritis. Back pain in patients with IE should
prompt consideration of vertebral osteomyelitis, particularly in the setting of S.
aureus infection [51]. (See "Vertebral osteomyelitis and discitis in adults".)

Clues to the presence of septic arthritis in the setting of IE include involvement

of multiple joints and involvement of the axial skeleton (eg, sacroiliac, pubic, or
manubriosternal joints). Acute septic arthritis involving one or more joints may
be the first clue to the presence of IE in a small percentage of patients,
particularly for cases in which an organism with known propensity to cause IE
(such as S. aureus, S. viridans, or non-group A beta-hemolytic streptococci)
grows from a joint aspirate.

Complications related to therapy Patients with infective endocarditis can

develop a number of the complications associated with prolonged parenteral
antimicrobial therapy or surgery:

Aminoglycoside-induced ototoxicity or nephrotoxicity, particularly in patients

who receive simultaneous treatment with vancomycin and aminoglycosides
(see "Pathogenesis and prevention of aminoglycoside nephrotoxicity and
ototoxicity")
Secondary bacteremia due to central vascular lines (see "Epidemiology,
pathogenesis, and microbiology of intravascular catheter infections")
Mediastinitis or early postoperative prosthetic valve endocarditis (see
"Postoperative mediastinitis after cardiac surgery")
Intravenous catheter-associated thrombosis (see "Catheter-related upper
extremity venous thrombosis")
Drug fever (see "Drug fever")
Allergic or idiosyncratic reactions to various antimicrobial agents. Some
agents (such as beta-lactams) that are generally tolerable for short courses
may not be associated with significant reactions (such as pyelonephritis and
acute interstitial nephritis) in the setting of long-term therapy.
Bleeding due to disturbances in coagulation caused by anticoagulants (eg, in
prosthetic valve endocarditis) (see "Antithrombotic therapy in patients with
infective endocarditis")
OUTCOME Among patients with infective endocarditis (IE), in-hospital
mortality rate is 18 to 23 percent; the six-month mortality rate is 22 to 27
percent [52-56]. The outcomes in patients with neurologic complications are
described above. (See 'Neurologic complications' above.)

Some data suggest that the following characteristics appear to confer

increased risk of mortality in patients with infective endocarditis:

Microbiology (for example, mortality is higher in the setting of S. aureus

infection than streptococcal infection) [53,55,57]
Heart failure [54,56]
Diabetes mellitus [53]
Embolization [53,57]
Perivalvular abscess [7,9,56]
Larger vegetation size [30,57]
Female gender [30]
Low serum albumin [52]
Persistent bacteremia [56]
Abnormal mental status [55]
Poor surgical candidacy [55]
The association between cardiac surgery, heart failure, and mortality risk is
uncertain. In one prospective report, neither cardiac surgery nor heart failure
was independently associated with in-hospital mortality [53]. However, among
patients with moderate to severe heart failure, other studies have noted an
association between cardiac surgery and lower mortality rate compared with
medical therapy alone. In one study including approximately 260 patients, the
presence of three risk factors (heart failure, periannular complications, and S.
aureus infection) during the first 72 hours of hospitalization was predictive of
need for urgent surgery or in-hospital mortality [58]. Subsequent prospective
validation of the model noted that one risk factor conferred approximately 60
percent risk of adverse outcome; three risk factors conferred nearly 100
percent risk of adverse outcome.

Issues related to the association between cardiac surgery and clinical outcome
are discussed further separately. (See "Surgery for native valve endocarditis",
section on 'Efficacy'.)