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Endocarditis
Epidemiology
An estimated 10,000 to 15,000 new cases of infective endocarditis
(IE) are diagnosed in the United States each year.
Men predominate in most case series, with male-to-female ratios
ranging from 2:1 to 9:1.
The importance of underlying heart disease in children with IE varies
with age: 50 to 70 percent of children less than 2 years old have no
obvious underlying cardiac disease , while most older children have
coexistent congenital heart disease.
A number of factors predispose to the development of infective
endocarditis. These include IVDA, prosthetic heart valves, and
structural heart disease.
Newer trends show endocarditis has increasingly become a disease
of the elderly. This trend is probably due to the decline in the
incidence and importance of rheumatic heart disease as a risk factor
for IE and the increasing proportion of elderly subjects in the
general population.
Also the proportion of cases that present with an indolent course and
the proportion due to streptococci has declined recently, while
simultaneous increases have occurred in the proportion of cases due
to Staphylococcus aureus, fungi, and gram negative bacilli.
The rising incidence of injection drug use (IVDA) has had an
impact on the overall incidence of endocarditis, as well as it’s
geographic distribution. Drug addiction as a cause of IE is most
prominent in patients less than 40 years old.
Intravenous Drug Abuse (IVDA)
In addition to the injection itself, specific drugs of abuse may also
be risk factors for the development of endocarditis which often
involves the right side of the heart. One large study found that those
who used cocaine were significantly more likely to have
endocarditis than those using other drugs. Ann Int Med 1987. 106:833.
The most significant risk factor for right-sided IE is IVDA;
however, left-sided disease may be more common in addicts.
The most common infecting organism is S. aureus, particularly in
right-sided infection with prevalence up to 82 percent. The
vegetations are usually > or =1 cm in diameter, and there is a
marked increase in mortality associated with vegetations greater
than 2 cm (33 versus 1.3 percent for smaller vegetations). Ann Int Med 1992.
117;560.
Prosthetic Heart Valve
Prosthetic valve endocarditis develops in 1 to 4 percent of valve
recipients during the first year following valve replacement, and in
approximately 0.5-1 percent per year thereafter.
The type of prosthetic valve (bio vs mech) does not have an impact
on the development of IE.
Structural Heart Disease
Approximately 3/4 of all patients with IE have a preexisting
structural cardiac abnormality at the time that endocarditis begins.
The risk of IE in patients with mitral valve prolapse and associated
regurgitation is estimated to be 5 to 8 times higher than that in the
normal population. However, MVP without MR is a more common
abnormality that is associated with only a small risk of endocarditis.
NEJM 1982. 307;776.
The most common predisposing congenital heart lesions are bicuspid
aortic valves, patent ductus arteriosus, ventricular septal defect,
coarctation of the aorta, and tetralogy of Fallot.
Prevalence of rheumatic valve disease is on the decline.
The risk of IE appears to be dependent upon the specific congenital
or acquired cardiac lesion. One study, for example, evaluated 2401
patients with congenital heart lesions who were followed
prospectively for 40,000 days. Circulation 1993. 87; 121
• The overall incidence of endocarditis was 135 cases/100,000
person years.
• The highest rates of endocarditis occurred in patients with aortic
stenosis (271)and ventricular septal defects (145 cases/100,000
person yrs).
•Among patients with AS, the higher the peak gradient, the higher
the risk of developing endocarditis.
• The risk of IE with AS was approximately twice as high as with
aortic regurgitation.
• The lowest rate of endocarditis occurred with pulmonic stenosis.
•The risk of IE also appears to be very low in adults with congenital
heart disease, inherently normal pulmonic and tricuspid valves, and
pulmonary or tricuspid regurgitation due to pulmonary hypertension.
Other Risk factors
A prior history of endocarditis is an important predisposing cause for
IE. Recurrent endocarditis occurred in 4.5 percent of one large cohort
of non-addicts who survived their initial episode. Ann Int Med 1992 117;567.
A number of cases of IE have been reported in patients with HIV
infection with some valves have been infected with unusual
organisms such as Salmonella and Listeria. It has been suggested that
HIV infection is an independent risk factor for IE in injection drug
abusers but, this has not been confirmed in other reports.
Other less common predisposing factors for IE are pregnancy,
arteriovenous fistulas used for hemodialysis, central venous and
pulmonary artery catheters, peritoneovenous shunts for the control of
intractable ascites and ventriculoatrial shunts for the management of
hydrocephalus.
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.
IE has also been reported in patients undergoing liver, heart, and
heart-lung transplantation.
Pathogenesis
The endothelial lining of the heart and its valves is normally resistant
to infection with bacteria and fungi.
Although a few highly virulent organisms such as Staphylococcus
aureus are capable of infecting normal human heart valves, the
initial step in the establishment of a vegetation is injury to the
endocardium, followed by focal adherence of platelets and fibrin.
These injuries can probably occur naturally in bacteremic humans
with congenital or acquired cardiac lesions that induce continuous
endocardial trauma via regurgitant flow or high pressure jets of
blood through stenotic lesions.
The initially sterile platelet-fibrin nidus then becomes infected by
microorganisms circulating in the bloodstream, following
colonization then microbial growth results in the secondary
accumulation of more platelets and fibrin.
Microbial adherence is a crucial early event in the pathogenesis of
endocarditis. As an example, bacteria that are typically found in
patients with endocarditis, such as Staphylococcus aureus, viridans
streptococci, enterococci and P. aeruginosa, adhere more avidly to
excised canine heart valves in vitro than species which rarely cause
endocarditis (such as Escherichia coli).
Dextran in the cell wall of gram positive organisms is one factor.
Degree of intrinsic binding affinity to fibronectin is important in the
virulence of S. aureus species.
Components found in damaged endothelium and/or platelet-fibrin
aggregates that may mediate adherence include fibrinogen, laminin,
and type 4 collagen.
Animals treated with aspirin had reduction in the weight of valvular
vegetations, vegetation growth, density of bacteria in the kidneys and
in vegetations, and a decrease in embolic events compared to
controls.
This interference with platelet-fibrin aggregates suggests that
addition of low dose aspirin can reduce risk of embolization during
antibiotic treatment, or risk of IE recurrence.
A small clinical study of 9 pts suggested ASA to be protective.
J Int Med 1992; 231:543
However a more recent randomized trial showed despite promising
experimental data, there was no clinical benefit to ASA.
115 pts in Can&US were doubly blinded to receive ASA or placebo.
Followed for 4wks for primary outcome of clinical embolism,
secondary outcome of CT shown subclinical CVA, hemorrhage or
death.
No sig difference in embolization. (ASA 28% vs placebo 20%)
Non-sig trend for combined major&minor hemorrhage in ASA grp.
Total of 70% had CT head done, with significant lesions in 39.5%
ASA group vs 29.3% in placebo.
Total of 42% had TEE, which showed similar rate of vegetation
decrease or valvular regurgitation.
JACC 2003; 42:775
Physics of Vegetations
If nebulized Serratia marcescens, are injected into an air stream passing through an
agar-coated Venturi tube, the highest concentration of bacteria is found in the low
pressure area immediately distal to the narrowing. Circulation 1963. 27;18
Vegetations in patients with preexisting valvular lesions are usually located on the
atrial surface of incompetent atrioventricular valves, or the ventricular surfaces of
incompetent semilunar valves.
Patients with ventricular septal defects tend to develop vegetations on the orifice of
the defect, on the right ventricular side of the opening, and secondarily on the
tricuspid and pulmonic valves.
Vegetations may occasionally localize on the chordae tendineae of the anterior
leaflet of the mitral valve in patients with aortic insufficiency.
Patients with mitral regurgitation may develop vegetations (MacCallum's patch) on
the wall of the left atrium where the regurgitant jet strikes the atrial wall and results
in endocardial thickening.
Clinical Sequelae
Vegetations often prevent proper valvular leaflet or cusp coaptation, thereby
causing valvular incompetence.
Congestive heart failure may result from worsening valvular incompetence or
leaflet perforation secondary to vegetation growth.
Patients with mitral or tricuspid valve vegetations may develop chordal rupture.
Infection may also extend into surrounding structures such as the valve ring, the
adjacent myocardium, the cardiac conduction system, or the mitral-aortic
intravalvular fibrosa.
Rarely, cavitation of periaortic abscesses occurs into the adjacent aortic wall,
resulting in the formation of a diverticulum or aneurysm.
Even more rarely, such aneurysms perforate into surrounding structures, resulting
in aortic-atrial or aortic-pericardial fistulae.
Etiology (Native Valve)
Although any bacteria can cause IE, Streptococci, Enterococci and
Staphylococci account for the majority of the cases.
Streptococci
Streptococci account for about 55% of non-IVDA cases.
Viridans streptococci account for ~75% of these cases.
Most common of the group are Streptococcus mutans, S.
mitis, S. Milleri.
S. Bovis account for ~20%.
Other Streptococci are ~5%.
Viridans strep are normal pharynx inhabitants and are generally very
susceptible to PCN.
80% of S. Bovis cases occurs in elderly (>60yrs). More than a third
have a malignant or pre-malignant colonic lesion.
Enterococci
Cause about 6% of native valve endocarditis and are normal flora of
GI tract, anterior urethra and occasionally the mouth.
They are relatively resistant to PCN-G and require the addition of
an aminoglycoside to achieve bactericidal effect.
More common among males who develop infection around 60 yrs of
age.
Many have history of GU tract manipulation, trauma or disease.
Cystoscopy, Foley catheter, prostatectomy.
Caesarian section, abortion, pregnancy.
Staphylococci
Staph cause about 30% of native valve IE cases, with S. aureus
being 5 to 10 times more frequent than S. epidermidis.
S. Aureus can rapidly attack normal or damaged valves.
It has a fulminant course with death from bacteremia within
days, or from heart failure within weeks.
Abscesses are common at multiple sites.
S. Epidermidis usually infects prosthetic valves.
HACEK organisms
Haemophilus
Actinobacillus
Cardiobacterium
Eikenella
Kingella
They are part of the oropharyngeal flora and produce large
vegetations with a subacute presentation.
They are difficult to isolate from blood and grow slowly in blood
culture media. Incubation for 7 to 14 days may be required to detect
their growth. This delayed growth makes standard antibiotic
susceptibility testing difficult.
Other Bacteria
Almost any bacteria can be an occasional cause of acute or subacute
endocarditis.
Streptococcus pneumoniae
Neisseria gonorrhoeae
Enteric gram –ve bacilli
Pseudomonas
Salmonella
Streptobacillus
Serratia marcescens
Bacteroides
Brucella
Mycobacterium
Neisseria meningitidis
Listeria
Legionella
Corynebacterium
Fungi
Rarely cause native valve IE. Subacute course with large
vegetations and large emboli.
Candida and Aspergillus species can occur in persons with
intravascular catheters who are frequently on glucocorticoids, broad
spectrum Abx, cytotoxic drugs.
Grave prognosis due to the relatively poor activity of antifungal;
agents.
Other Organisms
Rare causes can include Spirochetes, Rickettsiae (Coxiella burnetti),
Chlamydiae (C. pneumoniae, C. trachomatis, C. psittaci).
Etiology (IVDA)
Frequently occurs in young males with the skin being the most common source of
organisms. Contamination of drugs is less common.
More than 50% is by S. aureus.
~20% by Streptococci and Enterococci.
~6% Fungi, mainly candida.
~6% gram –ve bacilli, usually Pseudomonas species.
Onset is usually acute, with only 20% of addicts having previously damaged
valves.
Half the cases are involving the tricuspid valve. Aorta is involved in 25% of cases.
Mitral valve is involved 20% of the time. Multiple valves less than 5%.
In TV endocarditis, murmurs are usually absent and pneumoniae from septic
emboli is frequently the presenting picture.
Etiology (Prosthetic Valve)
With the aging population, prosthetic valve endocarditis now accounts
for 10 to 20% of cases.
Intravascular sutures, pacemaker wires and Teflon-Silastic tubes are
all foci for infection.
Most patients are males over 60 and IE occurs in 1-2% in the first
year after surgery , and 0.5% a year thereafter.
AV prosthesis are more likely to be involved than MV, and infection
is usually at the suture line.
Early onset (within 60days) is usually as a result of valve
contamination or peri-operative bacteremia.
Almost half of early onset, and third of late onset endocarditis are
due to Staphylococci. S. epidermidis is more frequently involved
than S. aureus.
Streptococci are the most common cause (40%) of late onset
endocarditis, but are rare in early onset.
Clinical Manifestations
Symptoms generally start within two weeks of precipitating event.
With low pathogenicity organism (ie viridans)the onset is usually
slow with low fevers. With fulminant disease (ie S. aureus) the onset
is rapid with high fevers.
Fever is almost always present. Arthralgias, myalgias and low back
pain are common.
Cardiac murmurs are almost always present, except in acute early IE
and in IVDA with TV lesions.
Splenomegaly and petechia are usually found in disease of long
duration.
Petechiae are more common on conjunctiva, palate, buccal mucosa
and upper extremities.
Splinter hemorrhages are subungual, linear dark red streaks that may
appear in IE, but can also result from trauma.
Roth’s spots are oval retinal hemorrhages with a clear pale center. But
it can occur in connective tissue diseases and sever anemia.
Osler’s nodes are small tender nodules in the pads of fingers and toes.
Janeway’s lesions are small circular hemorrhagic lesions, that are
nodular and occur on palms and soles of feet.
Clubbing has been reported in patients with long standing disease.
Embolic episodes can occur during or after therapy. Large emboli are
generaly fungal.
Neurologic manifestations are more common in left sided disease,
and in S. aureus infection.
Heart failure can occur long after it’s cure. Causes include valvular
damage, myocarditis, abscess formation and coronary artery
embolization with infarction.
Conduction defects occur due to septal invasion.
Renal disease exists in most patients due to renal emboli, or immune
complex mediated glomerulonephritis.
Diagnostic Workup
At least three blood cultures should be obtained from separate sites
over a time period ranging from a few hours to one to two days
depending upon the severity of illness and urgency of the need for
treatment.
The additional diagnostic yield of more than three cultures is minimal
in patients who have not recently received antimicrobial therapy.
A TTE should initially be obtained in patients with native heart
valves, while those with prosthetic valves should undergo TEE.
Detection of a vegetation is a positive test. However, this procedure
has relatively low sensitivity in IE. Thus, a negative study does not
preclude the diagnosis
TTE should be followed by TEE, which has higher spatial
resolution, when there is an intermediate or high suspicion of IE and
valvular abnormalities were found on TTE.
In general the sensitivity of TTE in detecting vegetations is ~6580%. The addition of TEE increases the sensitivity to 95%.
In prosthetic valves TTE is has poor diagnostic value. However,
TEE carries a 90% sensitivity in this setting.
JACC 1991;18
A meticulous clinical examination should be performed looking for
clinical evidence of small and large emboli with special attention to
the fundi, conjunctivae, skin, and digits.
In addition, a careful cardiac examination may reveal signs of new
regurgitant murmurs and signs of congestive heart failure, and
neurologic evaluation may detect evidence of focal neurologic
impairment and can be used to document a baseline should such
abnormalities appear later.
Additional clues to the presence of IE, such as microscopic
hematuria, leukocytosis, and evidence of renal impairment should
be sought with laboratory testing.
All patients with suspected IE should have an electrocardiogram to
determine whether there is evidence of heart block or a conduction
delay and to establish a baseline should such a complication develop
later.
Echo Samples
Duke Classification
In 1994 investigators from Duke University modified the von Reyn
criteria to include the role of echocardiography in diagnosis. They
also expanded the category of predisposing heart conditions to
include injection drug use.
This was later modified further to include the role of TEE as well as
the agent of Q fever (Coxiella brunetti).
The Duke classification relies upon major and minor criteria in a
manner similar to the Jones criteria for rheumatic fever.
Major Criteria
•Isolation of causative organism by two separate blood culture’s at
least 12hrs apart.
•Endocardial involvement evidence by echo. Oscillating mass,
prosthetic valve dehiscence, abscess, new regurgitation.
Minor criteria
•Predisposing lesion or IVDA
•Fever >38C
•Signs of embolization: Janeway lesion, Intracran hem.
•Immunologic phenomena: Glomerulonephritis, Oslers nodes,
Rheumatoid factor, Roths spots.
•Positive blood culture not meeting major criteria.
•Echo finding, but not meeting major criteria.
Modified Duke Criteria
Definite Infective Endocarditis
Pathologic criteria:
Microorganisms demonstrated by culture or histology in a
vegetation or embolus.
Clinical criteria:
2 major or
1 major + 3 minor or
5 minor
Possible endocarditis
Findings that are suggestive of IE but fall short of definite, but not rejected.
Rejected Infective Endocarditis
Alternate diagnosis explaining evidence of endocarditis
Resolution of syndrome with antibiotic therapy in 4 days or less.
No pathologic evidence at surgery with Abx therapy of four days or less.
Clin Inf Dis 2000;30
Treatment Regimens
In general the antibiotic regimen chosen is based on agent isolated.
The initial microbiologic response to therapy should be assessed by
obtaining repeat blood cultures 48 to 72 hours after antibiotics are
begun.
Most patients with IE generally become afebrile three to five days
after treatment is begun with an appropriate antibiotic. Patients with
Staphylococcal aureus endocarditis may respond somewhat more
slowly, remaining febrile for five to seven days after the institution of
therapy.
In general, oral regimens should not be used as initial therapy, but
may be used in highly selected cases. In right-sided endocarditis of
IVDA combination oral therapy with rifampin and ciprofloxacin was
as effective as parenteral therapy in patients in whom oral therapy
could be closely supervised. Am J Med 1996.101;68
Treatment regimen summary
Native valve
Strep Viridans or Strep Bovis -PCN sensitive
PCN-G or Ceftriaxone 4wks
If allergic, Vancomycin 4wks
Strep Viridans or Strep Bovis - PCN resistant
PCN 4wks+Gent 2wk
Vancomycin 4wks
Enterococcus
PCN/AMP + Gent 6wks
Vanco + Gent 6wks
Staph infection
Cefazolin 6wks +/- Gent 5days
Vanco 6wks
HACEK Organisms
Ceftriaxone 4wks
Prosthetic valve
Streptococcus-PCN sensistive
Ceftriaxone 6wks + Gent 2wks
Vanco 6wks
Streptococcus-PCN resistant Strep
Vanco 6wks
Enterococci
PCN or Amp 6wks + Gent 6wks
Vanco+Gent 6wks
Methicllin Susceptible Staph
Nafcillin 6wks + Gent 2wks + Rifampin 6wks
MRSA
Vanco 8wks + Gent 2wks + rifampin 8wks
HACEK
Ceftriaxone 6wks
Diptheroides
PCN +Gent 6wks
Vanco 6wks
Surgical Intervention
The outcome of surgery is better when the infection is partially
treated or healed. So, patients with severe valve dysfunction who
respond to antibiotic therapy and who manifest evidence of only
mild and nonprogressive heart failure should complete a full course
of antibiotics before surgery is undertaken to minimize morbidity
and mortality.
However, surgery should not be delayed to complete antimicrobial
therapy in patients with progressive heart failure or evidence of other
complications.
Two general classes of valves exist, bioprosthetic and mechanical.
Prosthetic Valves
Class I indication for native valve surgery
Acute AR or MR with heart failure
Acute AR with tachycardia or early closure or MV on echo
Fungal endocarditis
Aortic or annular abscess, or aortic aneurysm
Valve dysfunction or infection after 10 days of Abx therapy
Class II indication for native valve surgery
Recurrent emboli after >24hrs Abx therapy
Mobile vegetations >10mm
Recommendation for Bioprosthesis placement
Pt cannot take warfarin
>65yrs who do not need warfarin for another cause
Recommendation for mechanical valve placement
Expected long life span
Mechanical valve in another position
Pt with renal failure or hypercalcemia
Require warfarin for another cause
Non-bacterial Thrombotic
Endocarditis
Combination of endothelial injury and hypercoagulable state can
lead to platelet-thrombin deposition.
These deposits are found on the atrial side of MV & TV, and the
ventricular side of AV & PV; similar to location of infective
vegetations.
Most common associated syndrome with this condition is the antiphospholipid syndrome.
The atypical verroucous Libman-Sacks vegetations are usually
difficult to see on TTE.
They usually accumulate on the distal tip of the MV.
Metastatic tumours can also involve cardiac valves and produce
lesions similar to IE.
These marantic endocarditis lesions occur more frequently in
Hodgkin and adenocarcinoma of the lung, stomach and colon.
All non bacterial thrombotic lesion can become infected if exposed
to bacteremia.
Antibiotic Prophylaxis
Bacteria colonize and adhere to platelet-fibrin aggregates during
bacteremia.
Although many bacteria enter the blood stream, only those suited to
adhere to surfaces can become infective.
Certain predisposing valvular lesions are also required to increase
your risk of colonization.
This has led to identifying patients at risk during surgical
procedures and the use of prophylactic antibiotics.
Prophylaxis recommended
Dental procedures, including scaling and cleaning
Tonsillectomy & adenoidectomy
Surgery involving GI or upper respiratory mucosa
Esophageal varices sclerotherapy
ERCP
Cholecystectomy
Cystoscopy, urethral dilatation
GU surgery
Incision and drainage of infected tissue
Prophylaxis not recommended
Dental procedures not likely to produce bleeding, i.e. filling
above gum line, orthodontic adjustments.
Endotracheal intubation
TEE
Flexible bronchoscope +/- biopsy
Angiography +/- PTCA
Pacemaker implantation
GI Endoscopy +/- biopsy
C-section
In absence of infection: uncomplicated vaginal delivery,
therapeutic abortion, IUD, laparoscopy, circumcision.
High Risk Patients
Prosthetic valve
Prior IE
Cyanotic congenital heart disease
PDA
AR
AS
MR
MS + MR
VSD
Coarctation of Ao
Surgically constructed systemic-pulmonary shunts
Surgically corrected cardiac lesion with residual hemodynamic
abn or prosthesis.
Intermediate Risk Patients
MV prolapse or thickening with murmur
Pure MS
TV disease
PS
Asymmetrical septal hypertrophy
Bicuspid AV with minimal hemodynamic changes
Ao sclerosis with minimal hemodynamic changes
Surgically repaired intracardiac lesions, less than six mos postop,
with minimal hemodynamic changes.
Low Risk Patients
MV prolapse without murmur
Isolated secundum ASD
Implanted devices
CABG
Prior Kawasaki’s or Rheumatic disease without valvular
dysfunction
Antibiotic Prophylaxis Summary
GI/GU regimen
High risk Amp 2g & Gent 1.5mg/kg.
Mod risk Amox 2g or Amp.
PCN allergy = Substitute Vanco 1g
Oral/Esoph/Resp regimen
Amox PO or Amp IV
PCN allergy = Substitute Clinda 600mg PO/IV
Cefazolin 1g
Azith/Clarith PO 500mg
Abx should be given prior to procedure,
1hr for oral
1/2hr for parenteral
Questions?
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