Epidemiology, risk factors and microbiology of infective

endocarditis
The incidence of predisposing conditions (eg, rheumatic
heart disease and injection drug use) has varied over
time and among different areas.
EPIDEMIOLOGY — Sex and age have an impact on the
incidence of IE. Men predominate in most case
Endocarditis has increasingly become a disease of the
elderly.
Characteristics of patients with S. aureus IE vary by
region.
Compared with patients with IE due to other organisms,
patients with S. aureus IE were significantly more likely
to:

Die (20 versus 12 percent)

Experience an embolic event (60 versus 31
percent)
Have a CNS event (20 versus 13 percent)
Not undergo surgery (26 versus 39 percent)
Prognostic factors as independently associated with
mortality in patients with S. aureus IE:

Increasing age, periannular abscess, heart failure

and absence of surgical therapy.
Drug addiction as a cause of IE is most prominent in
patients less than 40 years old.

MICROBIOLOGY — A variety of microorganisms can

cause IE, but staphylococci and streptococci account for
the majority of cases.
Most patients had native valve IE (72 percent) and 23
percent were healthcare associated.
S. aureus — 31 percent
Viridans group streptococci — 17 percent
Enterococci — 11 percent
Coagulase-negative staphylococci — 11 percent
Streptococcus bovis — 7 percent
Other streptococci — 5 percent
Non-HACEK gram-negative bacteria — 2 percent
Fungi — 2 percent
HACEK — 2 percent
Native valve IE due to CA-MRSA in young patients
without known preexisting valvular heart disease is an
important emerging infection

RISK FACTORS — A number of factors predispose to

the development of IE. These include IDU, prosthetic
heart valves, and structural heart disease. Other factors
are pulmonary, cardiac, gastrointestinal, and
genitourinary procedures or surgery
Injection drug use —often involves the right side of the
heart.
left-sided disease may be more common in addicts
The most common infecting organism is S. aureus,
particularly in right-sided infection. The vegetation was
usually ≥1 cm in diameter, and there was a marked
increase in mortality associated with vegetations greater
than 2 cm.
Prosthetic heart valves —Prosthetic valve endocarditis
develops in 1 to 4 percent of valve recipients during the
first year following valve replacement, and in
approximately 1 percent per year thereafter
The type of prosthetic valve does not have an impact on
the development of IE.
Structural heart disease — Approximately three-fourths
of all patients with IE have a preexisting structural
cardiac abnormality at the time that endocarditis begin.
Degenerative valvular lesions such as mitral valve
prolapse have become relatively more important as a
predisposing cause for IE. The risk of IE in patients with
mitral valve prolapse and associated regurgitation is
estimated to be five to eight times higher than that in the
normal population
The most common predisposing congenital heart lesions
are BAV,PDA,VSD , COA, and TOF.

The risk of IE appears to be dependent upon the specific

congenital or acquired cardiac lesion.
History of infective endocarditis — A prior history of
endocarditis is an important predisposing cause for IE.
Recurrent endocarditis occurred in 4.5 percent
Nosocomial and healthcare-associated endocarditis —
Nosocomial endocarditis has been defined as a diagnosis
of IE made more than 72 hours after admission in
patients with no evidence of IE on admission, or IE
developing within 60 days of a prior hospital admission
during which there was risk for bacteremia
Nosocomial IE is usually a complication of bacteremia
induced by an invasive intravascular procedure or an
intravenous catheter-related infection . It accounts for up
to 20 percent of cases of IE in some areas .
Nosocomial IE may be more common in the elderly than
in other age groups because elderly patients are more
likely to be hospitalized and undergo invasive
bacteremia-prone procedures
Hemodialysis — Chronic hemodialysis patients are at
significant risk for IE. Predisposing factors in this
population include intravascular access, calcific valvular
disease, and immune impairment
HIV infection —Some valves have been infected with
unusual organisms such as Salmonella and Listeria .

Other — Other predisposing factors for IE include:

Pregnancy
Peritoneovenous shunts for the control of intractable
ascites
Ventriculoatrial shunts for the management of
hydrocephalus
In addition, patients with ulcerative lesions of the colon
due to carcinoma or inflammatory bowel disease have a
poorly understood predilection to develop endocarditis
secondary to Streptococcus bovis
Diagnostic approach to infective endocarditis
Usually based upon a constellation of clinical findings
rather than a single definitive test result.
The diagnosis is usually obvious when a patient has the
characteristic findings of IE:
Numerous positive blood cultures in the presence of a
well recognized predisposing cardiac lesion
Evidence of endocardial involvement
DIAGNOSTIC CRITERIA — The diagnosis of IE is based
upon a careful history and physical examination, blood
culture and laboratory results, an electrocardiogram
(ECG), a chest radiograph, and an echocardiogram.

Several sets of criteria for IE have been described.

The most commonly accepted are the Duke criteria

Modified Duke criteria for diagnosis of infective
endocarditis
Definite IE
Pathologic criteria
Microorganism: demonstrated by culture or histology in
a vegetation, or in a vegetation that has embolized, or in
an intracardiac abscess OR
Pathologic lesions: vegetation or intracardiac abscess,
confirmed by histology showing active endocarditis
Clinical criteria
2 major criteria OR
1 major and 3 minor criteria OR
5 minor criteria
Possible IE
1 major criterion and 1 minor criterion OR 3 minor
criteria
Rejected IE
Firm alternate diagnosis for manifestations of
endocarditis OR
Resolution of manifestations of endocarditis, with
antibiotic therapy for four days or less OR
No pathologic evidence of infective endocarditis at
surgery or autopsy after antibiotic therapy for four days
or less
Does not meet criteria for possible infective endocarditis,
as above

Modified Duke criteria for diagnosis of infective

endocarditis
Major criteria
Positive blood cultures for IE
Typical microorganism for infective endocarditis from
two separate blood cultures
OR
Persistently positive blood culture, defined as recovery of
a microorganism consistent with IE from:
Blood cultures drawn more than 12 hours apart OR
All of three or a majority of four or more separate blood
cultures, with first and last drawn at least one hour apart
Single positive blood culture for Coxiella burnetii or
antiphase I IgG antibody titer >1:800

Evidence of endocardial involvement

Positive echocardiogram for IE
Definition of positive echocardiogram
Oscillating intracardiac mass, OR
Abscess OR
New partial dehiscence of prosthetic valve
New valvular regurgitation
Increase in or change in preexisting murmur not
sufficient
Minor criteria
Predisposition - predisposing heart condition or
intravenous drug use
Fever - 38.0°C (100.4°F)
Vascular phenomena - major arterial emboli, septic
pulmonary infarcts, mycotic aneurysm, intracranial
hemorrhage, conjunctival hemorrhages, Janeway lesions
Immunologic phenomena - glomerulonephritis, Osler's
nodes, Roth spots, rheumatoid factor
Microbiologic evidence - positive blood culture but not
meeting major criterion
Echocardiographic minor criteria eliminated

HISTORY —a history of prior cardiac lesions and historical

clues pointing toward a recent source of bacteremia,
such as indwelling intravascular catheters or intravenous
drug use.

With the rise in rates of IE due to S. aureus in the 21st

century, IE is more often presents as acute rather than
chronic disease
PHYSICAL EXAMINATION —careful cardiac examination
for signs of new regurgitant murmurs or heart failure.

A vigorous search should be undertaken for the classic

clinical stigmata of endocarditis, including evidence of
small and large emboli with special attention to the
fundi, conjunctivae, skin, and digits.
A neurologic evaluation may reveal evidence of focal
neurologic impairment
Associated peripheral cutaneous or mucocutaneous
lesions of IE include petechiae, splinter hemorrhages,
Janeway lesions, Osler's nodes, and Roth spots.
Petechiae are not specific for IE but are its most common
skin manifestation
Splinter hemorrhages, also nonspecific for endocarditis,
are nonblanching, linear reddish-brown lesions found

under the nail bed .

Janeway lesions, Osler's nodes, and Roth spots are more

specific (but still not diagnostic) for IE. They are also less
common, and Roth spots are rare.
Janeway lesions are macular, nonblanching, nonpainful,
erythematous lesions on the palms and soles.

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.

Roth spots are exudative, edematous hemorrhagic
lesions of the retina.
LABORATORY STUDIES

Blood cultures

Collection — Blood cultures should be obtained prior to

antibiotic therapy.
A minimum of three blood cultures should be obtained
over a time period based upon the severity of the
illness. not critically ill, it is reasonable and often
preferable to delay therapy for one to three days while
awaiting the results of blood cultures and other
diagnostic tests. However, if the patient is acutely ill,
three blood cultures should be obtained over a one hour
time span before beginning empiric therapy.
The initial blood culture in patients with streptococcal
endocarditis was positive in 96 percent and one of the
first two blood cultures was positive in 98 percent; in
patients with IE caused by bacteria other than
streptococci, the first blood culture was positive in 82
percent and one of the first two cultures was positive in
100 percent
Since many patients with bacterial endocarditis have low
grade bacteremia (eg, 1 to 10 CFU/mL of blood) , 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.
Each set of cultures should be obtained from separate
venipuncture sites. Blood cultures can be taken at any
time; they do not need to be obtained with the
appearance of chills or fever since patients with IE
typically have a continuous bacteremia.

Organism —viridans streptococci and Staphylococcus

aureus are more likely to cause endocarditis than are
gram-negative rods such as Escherichia coli and Proteus
spp.
Organisms as "typical causes" of IE
Staphylococcus aureus
Viridans streptococci and Streptococcus bovis
Enterococci
HACEK group organisms
Community acquisition of bacteremia was not a risk
factor for IE.

The probability of endocarditis varies by species of

bacteria. As examples:

S. sanguis bacteremia is more often indicative of

endocarditis than is bacteremia due to S. milleri
The risk of endocarditis in patients with S. aureus
bacteremia is particularly high.

Positive cultures —The definition of persistent

bacteremia varies with the likelihood that the organism is
a cause of endocarditis
For an organism likely to cause endocarditis (eg, S.
aureus, viridans streptococci), two positive samples
collected more than 12 hours apart
For an organism that is more commonly a skin
contaminant, three or a majority of four or more
separate blood cultures are positive and the first and last
samples are collected at least one hour apart

Other laboratory tests —antiphase I IgG titer >1:800 for

Coxiella burnetii [10].

The following findings may be identified among patients

with IE but are relatively nonspecific:

An elevated erythrocyte sedimentation rate and/or an

elevated level of C-reactive protein.
A normochromic normocytic anemia.
most patients with staphylococcal endocarditis have
leukocytosis and some may have thrombocytopenia.

An elevated rheumatoid factor titer in patients without a

known prior rheumatologic disorder is one of six minor
criteria in the Duke diagnostic scheme
Most patients with endocarditis have an abnormal
urinalysis, as manifested by microscopic or gross
hematuria, proteinuria, and/or pyuria.
CARDIAC STUDIES

Electrocardiogram
Chest radiograph
Echocardiography
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 IE (eg, stroke or
other manifestations of emboli). Culture-negative IE
should also be considered in patients with a vegetation
on echocardiogram with no clear microbiologic diagnosis.

TREATMENT — Standard antimicrobial therapy for

infective endocarditis is generally administered to
patients characterized as definite or probable by the
Duke criteria. Patients in whom the diagnosis is
"rejected" by these criteria are not usually treated with
prolonged antimicrobial therapy.

Historical and Duke criteria

CASE DEFINITIONS —Pelletier and Petersdorf criteria —

The classification scheme of Pelletier and Petersdorf
consisted of three case categories: definite, probable,
and possible.

Definite IE required histologic evidence of infected

endocardial vegetation(s) from examination of tissue
obtained from cardiac surgery, embolectomy, or
autopsy.
Probable IE required either uniformly positive blood
cultures with known underlying valvular heart disease
and evidence of emboli to the skin or viscera; or negative
blood cultures in individuals with fever (>38ºC), new
regurgitant valvular heart murmurs, and embolic
phenomena.
Possible IE required either uniformly positive blood
cultures with known underlying heart disease or embolic
phenomena; or negative blood cultures with fever,
known underlying valvular heart disease, and embolic
episodes.

These criteria were reasonably specific but lacked

sensitivity.
von Reyn criteria —definite, probable, possible, and
rejected .
pathological confirmation of vegetations or an abscess
was required to define a case as definite. Other criteria
for diagnosis included:

Persistent bacteremia
Evidence of active endocardial pathology (eg, the
presence of a new regurgitant murmur)
Predisposing valvular heart disease
The presence of vascular phenomena such as emboli or
splinter hemorrhages
DUKE CRITERIA —modified the von Reyn criteria to
include the role of echocardiography in diagnosis.

The Duke classification relies upon major and minor

criteria in a manner analogous to the Jones criteria for
acute rheumatic fever.
Cases can be classified as definite, possible, or rejected
using the Duke criteria. Two of these criteria are
pathological, and three are clinical.

Definite endocarditis —if any one of the following

pathological findings or combinations of clinical findings
are present:

Two major clinical criteria

One major and any three minor clinical criteria, or
Five minor clinical criteria.

Possible endocarditis — Possible endocarditis is defined

as the presence of one major and one or two minor
clinical criteria or the presence of three minor clinical
criteria.

Rejected endocarditis —
A firm alternate diagnosis is made
Resolution of clinical manifestations occurs after four
days of antibiotic therapy or less
No pathological evidence of infective endocarditis is
found at surgery or autopsy after antibiotic therapy for
four days or less
Clinical criteria for possible or definite infective
endocarditis not met
Major clinical criteria:

Persistently positive blood cultures for organisms that

are typical causes of endocarditis
Vegetations or other typical findings of endocarditis
present on echocardiography; these other typical
findings include new or partial dehiscence of a prosthetic
valve or an abscess in the tissues surrounding a heart
valve
Evidence of endocardial damage such as a new
regurgitant murmur
Serological or culture evidence of infection with Coxiella
burnetii
Minor clinical criteria:

Fever
The presence of a predisposing valvular
"Vascular phenomenon" such as emboli to organs or the
brain, hemorrhages in the mucous membranes around
the eyes.
"Immunologic phenomenon" such as glomerulonephritis,
or lesions such as Roth's spots (in the retina of the eyes)
or "Osler's nodes (nodules on the fingers or toes)
Positive blood cultures that do not meet the strict
definitions of a major criterion.

Other minor criteria (including hematuria and

splenomegaly)
Complications and outcome of infective endocarditis
Complications such as heart failure and stroke are
relatively common and feared outcomes of IE
The frequency of specific complications depends upon
variables such as the infecting pathogen, duration of
illness prior to therapy, and the type of treatment
facility
Complications and outcomes are related in part to
underlying comorbidities.
DEFINITIONS — Complications of IE can be broadly
categorized as:

Cardiac
Septic
Embolic
Neurologic
Musculoskeletal
Renal
Associated with medical treatment
BUT,patients with neurologic involvement can
simultaneously have embolic and septic processes.

Complications in terms of their pathogenesis, which

leads to different groupings:

Embolic (eg, cerebral infarct)

Local spread of infection (eg, heart valve
destruction)
Metastatic infection (eg, vertebral osteomyelitis)
Immune-mediated damage (eg, glomerulonephritis)

CARDIAC COMPLICATIONS — Cardiac complications are

the most common complications seen in IE, occurring in
one-third to one-half of patients in most recent case
series.
Heart failure — Heart failure (HF) remains the most
common cause of death due to IE
Causes: valvular insufficiency resulting from infection-
induced valvular damage. Rarely, embolism -can cause
acute myocardial infarction.

Perivalvular abscesses —about 30 to 40 percent.

Injection drug use may be another risk factor for
perivalvular abscess
Perivalvular abscess should be suspected when fever
persists despite appropriate antimicrobial therapy and/or
when conduction abnormalities appear on the ECG.
Patients with perivalvular abscesses appear to have
higher rates of systemic embolization and fatal
outcomes.
Other extravalvular complications — Other rare
extravalvular cardiac complications of IE include:

Pericarditis, which may be suppurative or

nonsuppurative, can rarely cause pain or even cardiac
tamponade
Aortic valve dissection.
Descending thoracic aorta intraluminal infectious masses

EMBOLIZATION — Embolization remains a distressingly

common complication of IE and can occur even after
appropriate therapy is well underway.
Systemic emboli most commonly complicate left-sided IE
but rarely can occur in tricuspid valve endocarditis via a
patent foramen ovale
However, emboli to the lung with subsequent abscess
formation occur frequently in patients with tricuspid
endocarditis.

Emboli consisting of vegetation fragments can occlude

or damage virtually any blood vessel, large or small, in
the systemic or pulmonary arterial circulation. As a
result, emboli can produce:

Stroke
Blindness
Painful ischemic or frankly gangrenous extremities
Unusual pain syndromes (eg, due to splenic or renal
infarction)
Hypoxia (due to pulmonary emboli in right-sided
endocarditis)
Paralysis (due to embolic infarction of either the brain or
spinal cord)
Acute myocardial infarction
Endocarditis should be considered as a possible etiology
in virtually all patients who present with signs or
symptoms of systemic arterial embolization.
Symptomatic embolization appears to be more common
with IE due to fungal pathogens.
Effect of antibiotic therapy on embolic risk — The risk of
embolization tends to decline after the institution of
effective antimicrobial therapy, and serious embolic
events rarely occur several weeks after such therapy is
instituted
Predictors of embolization —vegetation size is generally
a risk factor for embolization.

more frequently observed in cases due to Streptococcus

bovis and S. aureus
Embolization occurs more frequently with left-sided than
right-sided vegetations
NEUROLOGIC COMPLICATIONS — Symptomatic
cerebrovascular complications occur in about 35 percent
of patients.
Silent cerebrovascular complications (including ischemia
and microhemorrhage) may occur in up to 80 percent of
patients.

Manifestations — The mechanism for and types of

neurologic complications are diverse and include:

Embolic stroke
Acute encephalopathy
Meningoencephalitis
Purulent or aseptic meningitis
Cerebral hemorrhage (due to stroke or a ruptured
mycotic aneurysm)
Brain abscess or cerebritis
Seizures (secondary to abscess or embolic infarction)
Thus, the possibility of IE should be considered in all
patients who present with strokes, meningitis, or a brain
abscess. Unexplained fever accompanying a stroke in a
patient with valvular disease is an important clue in some
patients.
MYCOTIC ANEURYSMS — Mycotic aneurysms can occur
in the cerebral or systemic circulation of patients with IE,
usually at points of vessel bifurcation.
RENAL DISEASE — Renal infarction , drug-induced acute
interstitial nephritis, glomerulonephritis and, rarely,
renal abscess can occur in patients with IE.
Acute renal failure, defined as a serum creatinine of 2
mg/dL or greater, has been reported in up to one-third of
patients.
METASTATIC ABSCESSES — Rarely, metastatic abscesses
develop in the kidneys, spleen, brain or soft tissues.
Persistent fever during or after treatment for IE and
occasionally recurrent bacteremia after cure of the
valvular infection may be the only clues to the presence
of this complication.
Abscess formation occurs as a sequela of septic
embolization. Some patients with IE and brain abscesses
also have purulent meningitis.
MUSCULOSKELETAL COMPLICATIONS — Vertebral
osteomyelitis is a well known but relatively rare
complication of IE. severe back pain in any patient with IE
should alert the clinician to this possibility.
Acute septic arthritis, involving one or more joints, may
be the first clue to the presence of IE in a small
percentage of patients.
COMPLICATIONS OF MEDICAL OR SURGICAL THERAPY
—Aminoglycoside-induced ototoxicity or nephrotoxicity
Secondary bacteremia due to central vascular lines
Mediastinitis or early postoperative prosthetic valve
endocarditis
Intravenous catheter-associated phlebitis
Drug fever
Allergic or idiosyncratic reactions to various antimicrobial
agents
Bleeding due to disturbances in coagulation caused by
anticoagulants

Miesso(MD)