Infective

Endocarditis
[Link]
Introduction
• Infections involving heart valves(endocarditis) and those that involve
cardio-vascular devices including PPIs, ICDs, Ventricular assist devices
are associated with substantial morbidity and mortality.

• Infectious endocarditis has proclivity to cause complications both at

the cardiac valve site and at extra-cardiac locations.
Epidemiology
• In developing countries-Rheumatic fever is still endemic-Younger
adults with longstanding rheumatic heart disease- subacute clinical
course spanning several weeks that involve left-sided native valve
infection- VGS(Viridans Group streptococci)

• Developed countries-Acute illness – Staph aureus-with numerous

anatomic sites of metastatic foci of infection and worse outcomes.

• Injection Drug Use(IDU)- [Link]

Host factors & Pathogenesis
• Incidence is influenced by multiple host factors- that modify risk of
infection.

• Underlying anatomic(usually-valvular) cardiac conditions- resulting in

turbulent flow and endothelial cell disruption

• Aging- Myxomatous degeneration of mitral valve- with subsequent

prolapse and insufficiency.
• NBTE-Non Bacterial Thrombotic Endocarditis- underlying valvular or
nonvalvular cardiac structural abnormality that results in blood flow
turbulence, endothelial disruption, Platelet and fibrin deposition.

• NBTE-serves as a nidus for subsequent adhesion by bacteria/fungi in

blood stream.

• This accounts for majority of cases of IE- often related to left-sided

valvular stenosis or regurgitation.
• Predominance of gram positive cocci causing IE
• Infectivity studies have compared wild-type parent strains to
molecularly engineered strains using an experimental IE model- in
defining virulence factors among strains of staph,streptococci and
enterococci. (These factors- adhesins & largely responsible for initial
bacterial attachment to NBTE nidus /endothelial cells)
• Attachment to medical devices (prosthetic valves, CIED leads).
Microbiology
• Streptococcus- VGS(Viridans)- predominant
• Sub-acute presentation- symptoms of infection- weeks to few months
with low grade fever, night sweats, fatigue.
• These are found in mouth of humans-indolent infections
(sanguis,oralis, salivarius,mutans, intermedius,anginosus etc)
[Link]/milleri group- produce abscess &metastatic infection
foci both within heart and extra-cardiac locations).
• Predominant cause of native valve infection – VGS acquired in
community setting.(both in developing and developed nations)
• Beta-hemolytic streptococci- acute presentation of IE.(complications
are common and involve valve destruction and extra-cardiac sites.).
Prevalence is <10%.
• [Link]([Link])- GI tract- when recovered from blood
culture- examine for an underlying GI lesion including colon cancer. –
aging populations.
• [Link]- common cause of both native and prosthetic
valve endocarditis.
• Acute in onset & associated with systemic toxicity.(in cases of left-
sided heart infection, morbidity & mortality rates are high despite
appropriate therapy including surgery)
• Right sided heart infection- much higher cure rate than left-sided
• Rate of IE from [Link] is increasing because of increased exposure
to health care and I.v. drug abuse.(IDU)
• Drug resistance also common
• Coagulase-negative staph- frequently cause prosthetic valve infection.
• Sub-acute in presentation- [Link](most common in
coagulase negative) & lugdunensis (more virulent than other
coagulase negative)- also most common cause of contamined blood
cultures which will delay diagnosis.

• More drug resistant except lugdunensis which is usually penicillin

susceptible.
• Enterococcal species- among elderly persons
• Enterococcus faecalis- majority of cases and is associated with
genitourinary tract abnormalities.
• Recently these are associated with health care exposure and central
venous catheter use- present subacutely.

• MDR Enterococcal species- faecium- difficult to cure- includes VRE.

• HACEK- fastidious gram negative bacilli- colonise oropharynx and URT
Causing sub-acute IE-Community acquired. – Blood culture requires
several days of incubation.

Indolent clinical course- diagnosis often delayed with formation of

large vegetations on ECHO.- Embolism to brain & systemic sites occur
frequently.
Clinical presentation
• ICE-PCS(International collaboration on Endocarditis-Prospective
cohort study in 2781 patients)- Native valve IE predominant(72%)
followed by PVE(21%) & PPI/ICD IE(7%).

• IE manifests with definite vegetations in Mitral valve(41%) followed by

Aortic valve.

• Tricuspid and Pulmonary valves much less frequently involved.

Pre-existing valvular regurgitant lesions are much more
prone to infection than stenotic lesions.

Incidence- directly related to impact of pressure on closed

valve with shear stress disruption of valvular endothelium
in the vicinity of egressing regurgitant jet.
• Venturi-effect- circulating organisms are deposited within high
velocity lowered-pressure eddy zones of regurgitant orifice of
receiving chamber- typical localization of vegetations on upstream of
infected valve.

• Mitral regurgitation associated with degenerative MVP, particularly

with advanced myxomatous leaflet thickening – far more common
than Rheumatic mitral valve disease.
• Functional MR associated with LV remodelling causing malcoaptation
of intrinsically normal mitral leaflets in low pressure, low cardiac
output state- uncommon to see IE

• 2nd most common native valve lesion predisposing to IE – Aortic

regurgitation.
• BAV is relatively common in case series of confirmed aotic valve IE.-
high incidence of periannular complications- strong independent
predictor of perivalvular extension of infection.
• CHD like unrepaired VSDs- most frequent followed by ventricular
outflow tract obstructions. (TOF)
• Any highly turbulent shunt lesion- presence of prosthetic material for
palliative shunts, conduits, shunt closures- particularly if residual
shunt is present after intervention.
• ASDs less prone
• Presence of chronic IV access, IV drug abuse, indwelling endocavitary
devices.
• Diabetes mellitus, underlying malignancy, renal failure requiring
hemodialysis and chronic immunosuppressive therapy.

• History of Invasive or dental procedure within 60 days of clinical

presentation with IE.
Symptoms
• Virulence of infecting organism and persistence of bacteremia.
• Extent of local tissue destruction of involved valve and hemodynamic
sequelae
• Peri-valvular extension of infection
• Septic embolization to any organ in the systemic circulation or to
lungs in case of right sided IE.
• Consequences of circulating immune complexes and systemic
immunopathologic factors.
• Fever is the most common symptom -95% patients
• Persistence of fever-progressive infection with perivalvular extension
such as abscess, septic embolization, extra-cardiac site of infection,
infected indwelling catheters or devices, inadequate antibiotic
treatment of resistant organism.
• Dyspnea- left sided valvular regurgitation.
• Early recognition of heart failure symptoms- greates impact on
prognosis- most frequent indication for surgical intervention
• Chest pain syndromes- septic pulmonary embolus&infarction
complicating Tricuspid IE.
Physical examination
• Definite murmur- atleast 80% of patients- left-sided IE.
• In large ICE-PCS study murmur was new in almost 50% of patients.
• Worsening of pre-existing murmur occurred in 20% cases.
• Murmurs are detected in less than half of patients with IE
complicating an ICD and infrequently in patients with right sided IE.
• Murmurs associated with acute IE complicated by extensive left-sided
valvular destruction with acute severe regurgitation may be
deceptively unimpressive-rapid equalization of pressures between
chambers- diminishes substrate for turbulent flow.
• Classic peripheral manifestations of IE- infrequently seen.
• Petechiae-most common(conjunctiva/oral mucosa)
• Jane way lesions-painless hemorrhagic macules-
soles/palms(peripheral septic emboli-staphylococcal IE)
• Osler nodes- Painful red nodular lesions in palms & soles-immune
complex deposition and focal vasculitis.
• Roth spots-retinal hemorrhages- immune complex.
• Both Osler noses and roth spots are also seen in SLE, Leukemia.
• Blood culture findings-
Typical micro-organisms consistent with IE from 2 separate blood cultures.
--Viridans streptococci, [Link], [Link], HACEK group
- Community-acquired enterococci, in the absence of primary focus.
or
Micro-organisms consistent with IE from persistently positive blood
culture findings defined as
-- >2 positive blood cultures drawn>12hr apart.
- 3 or most of >4 separate blood cultures(with first and last sample >1hr
apart)
 Single positive blood culture for Coxiella burnetti or anti-phase I IgG
titer> 1:800
• ECHO findings positive for IE(TEE recommended in patients with
prosthetic valves, complicated IE-paravalvular abscess; ) TTE as first
test in other patients
- Oscillating intracardiac mass on valve or supporting structures, in
the path of regurgitant jets, or on implanted material in the absence of
alternative anatomic explanation, or
Abscess or
New partial dehiscence of prosthetic valve
• ECG- new AV block (10-20%) or BBB (2-3%)
• Due to close proximity of AV node and proximal intra-ventricular
conduction system- to aortic valve and root- perivalvular extension of
infection from this location- most common cause of new AV block.
• In minority patients this may compromise proximal coronary artery
patency causing STEMI.
• Echo –cornerstone of diagnostic imaging in IE
• Sensitivity of current TTE imaging techniques for native valve IE as
high as 89% if high quality images are obtained.(specificity- 70-90%)
• Absence of regurgitant lesions of mitral/aortic valves- makes
endocarditic involvement less likely.
• Multi-plane two dimensional and three dimensional TEE can
characterize vegetations with a resolution size of 2-3mm with 90-
100% sensitivity and specificity>90%.
• PVE- lower incidence of vegetations and higher incidence of
periannular infection and complications-difficult to detect with TTE.
• Vegetations of IE- typically upstream, lower pressure side of
regurgitant valve-multiple and lobulated- motion independent of
valve structure.
• Hyper-refractile, discretely nodular echodensities-downstream- less
likely IE.
• Local valvular destruction- due to left-sided valvular regurgitant
lesions(HF may complicate the course of approx 30-40% of patients
with IE. – 3 times more common in native than in prosthetic.
• HF – frequently assoc with aortic valve followed by mitral valve.
• Peri-valvular extension – peri-annular or intra-myocardial abscess,
mycotic false aneurysm and fistula.
• Perivalvular extension- almost 30% in native valve and 55% in
prosthetic valve.
• Independent predictors of peri-valvular extension are PVE, aortic
valve involvement, staph infection(both coagulase negative and
[Link])
• Periannular abscess-more with native BAV IE than with tricuspid
aortic valve.
• Persistent fever, ongoing bacteremia despite appropriate antibiotic
therapy, chest pain, new heart murmur, recurrent embolism or HF-
possible presence of perivalvular extension.
• MAIF-Mitral-Aortic intervalvular fibrosa- fibrous zone of continuity
between non coronary cusp and insertion of anterior mitral leaflet.
• Least vascular structure and more susceptible to infection and
mycotic false aneurysm- due to IE in aortic valve.
• Potential complications of MAIF mycotic false aneurysms include
fistulous communications into left atrium or aorta, extension around
aortic root, compression of proximal left coronaries with resultant
ischemia, systemic embolization and rupture into pericardial space.
Approach to ECHO in IE
• Clinical risk assessment of patient with suspected IE- 1st step in
deciding which Echo modality to use.
• Patients with undifferentiated febrile illness, chronic unchanged
murmur, no physical exam findings suggestive of IE, no high risk
cardiac anatomy(prosthetic valves/complex CHD)- low risk with lower
pretest likelihood of IE.
• High initial patient risk characters with high pretest probability of IE-
significant new heart murmur, peripheral stigmata of IE, new HF,
[Link] bacteremia and high risk cardiac anatomy-prosthetic
valve/complex CHD.
• TTE-showing high risk findings – large >10mm diameter or highly
mobile vegetations, perivalvular extension of infection, new grade III
to IV valvular regurgitation or new LV dysfunction- Proceed with TEE
to characterize anatomic extent and complications.

• Patients at high risk- new onset HF, significant new murmur, clinical
stigmata of IE, prosthetic heart valves/devices, complex CHD, [Link]
bacteremia- initial imaging with TEE with supplemental TTE for
complete quantification of regurgitation, hemodynamics and LV
function.
Antimicrobial therapy principles

General principles :

• Successful treatment of IE –
- Microbial eradication by anti microbial drugs .
-Surgery removes infected material and drains abscesses.

• Combination of antimicrobial therapy > monotherapy

- Reduces duration of therapy (aminoglycosides synergize
with cell wall inhibitors –beta lactams and glycopeptides).
• Slow growing + dormant microbes - Phenotypic tolerance towards
most of anti microbials (except rifampin ).

• Vegetations +biofilms- need for prolonged therapy (6 weeks)- to fully

sterilize infected heart valves .

• Drug treatment of PVE - 6 weeks (NVE -2 to 6 weeks)

• In NVE- needing valve replacement by a prosthesis during antibiotic

therapy ,the postoperative antibiotic regimen should be
recommended for NVE not for PVE.
Empirical therapy
• Treatment of IE should be started promptly.3 sets of blood
cultures should be drawn at 30 min intervals before initiation
of antibiotics.
• Initial choice of empirical treatment depends on:

[Link] the patient has received previous antibiotic therapy.

[Link] infection affects a native valve or prosthesis (if so,

when surgery was performed early vs late PVE).

[Link] place of infection –(community,nosocomial ,or non –

nosocomial health care associated IE) and knowledge of local
epidemiology
 Proposed antibiotic regimens for initial empirical
treatment of infective endocarditis in acute severely ill
patients (before pathogen identification)

Community acquired native valves or late prosthetic valves (≥12

months post surgery) endocarditis :

Ampicillin – 12g/day i.v. in 4-6 doses

or
Cloxacillin or - 12g/day i.v. 4-6 doses
Oxacillin
With
Gentamicin – 3mg/kg/day i.v. or [Link] 1 dose
Vancomycin – 30-60 mg/kg/day i.v. in 2-3 doses
With
Gentamicin – 3mg/kg/day i.v. or i.m. in 1 dose

Early PVE(<12 months post surgery ) or nosocomial and

non – nosocomial health care associated endocarditis :

Vancomycin – 30 mg/kg/day i.v. in 2 doses

With
Gentamicin – 3 mg/kg/day i.v. or i.m. in 1 dose
With
Rifampin – 900- 1200 mg i.v. or orally in 2 or 3 divided doses
Oral Streptococci and
Streptococcus bovis

Strains penicillin susceptible(mic≤0.125mg/l)oral and digestive streptococci :

• Standard treatment(Monotherapy) : 4 weeks duration

Penicillin G --- 1 2 -18 million U/day i.v either in 4-6 doses or continuously
- 4 weeks
or
Amoxicillin --- 100 -200 mg/kg/day i.v in 4 - 6 doses – 4weeks
or
Ceftriaxone --- 2 g/day i.v or i.m in 1 dose – 4 weeks
Standard treatment(Combination therapy) :2-weeks duration

Penicillin G --- 12 -18 million U/day i.v either in 4-6 doses or continuous infusion –
2weeks
or
Amoxicillin --- 100 – 200 mg/kg/day i.v in 4-6 doses -2 weeks
or
ceftriaxone --- 2g/day i.v or i.m in 1 dose -2 weeks

Combined with

Gentamicin --- 3 mg/kg/day i.v or I.m in 1 dose

-2weeks
or
Netilmicin --- 4 – 5 mg/kg /day i.v in 1 dose
-2 weeks

In beta lactam allergic patients :

Vancomycin --- 30 mg/kg/day i.v in 2 doses

Strains relatively resistant to penicillin (mic 0.250-2mg/l)
Standard teatment :

Penicillin G --- 24 million U/day i.v. either in 4-6

Doses or continuously -4 weeks
or
Amoxicillin --- 200 mg/kg/day i.v. in 4-6 doses -4 weeks
or
ceftriaxone --- 2g/day i.v. or i.m in 1 dose-4 weeks

Combined with

Gentamycin --- 3 mg/kg/day i.v. or i.m. in 1 dose

-2 weeks
In beta lactam allergic patients :

Vancomycin --- 30 mg /kg /day [Link] 2 doses -4 weeks

with
Gentamycin ---3 mg/kg/day [Link] i.m in 1 dose -2 weeks
 Staphylococcus spp
Native valves
Methicillin –susceptible staphylococci:
(flu)cloxacillin or oxacillin – 12g/day i.v. in 4-6 doses - 4- 6 weeks

Alternative therapy
Cefazolin 6g/24hr iv in 3 equally divided doses.
 Penicilln allergic patients or methicillin- resistant
staphylococci

Vancomycin –30-60 mg/kg/day i.v in 2-3 doses for 4-6 weeks

Alternative therapy

Daptomycin –10 mg/kg/day i.v. once daily -4-6weeks

Prosthetic valves

Methicillin- susceptible staphylococci:

(Flu)cloxacillin or Oxacillin--12g/day i.v. in 4-6 doses - ≥6 weeks.

with
Rifampin -- 900 -1200 mg i.v. or orally in 2 or 3 divided doses - ≥6 weeks
and Gentamycin – 3 mg/kg/day i.v or i.m in 1 or 2 doses 2 weeks
 Prosthetic valves
Penicillin- allergic patient and
MRSA
Vancomycin -- 30-60 mg/kg/day i.v. in 2-3 doses - ≥6 weeks
with
Rifampin -- 900 -1200 mg i.v. or orally in 2 or 3 divided doses - ≥6 week
and
Gentamycin – 3 mg/kg/day i.v or i.m in 1 or 2 doses -2 weeks
Enterococcus spp
- Enterococcus faecalis (90% cases)
- Enterococcus faecium (5%)

2 major problems –
• [Link] resistant to antibiotic induced killing,
eradication requires prolonged administration(up to 6
weeks) of synergistic bactericidal combinations of 2 cell wall
inhibitors or one cell wall inhibitor with aminoglycosides.
• [Link] to multiple drugs ,including
aminoglycosided(HLAR),beta lactams and vancomycin.
 Antibiotic treatment of infective endocarditis due to
Enterococcus spp.

Beta -lactam and gentamicin –susceptible strains

• Amoxicillin –200 mg/kg/day i.v. in 4-6 doses - 4-6 weeks

With
Gentamicin –3mg/kg/day i.v. or i.m in 1 dose - 2-6 weeks
6 weeks therapy recommended for patients with >3 months
symptoms or PVE

• Ampicillin – 200 mg/kg/day i.v. in 4-6 doses - 6 weeks

With
Ceftriaxone –4g/day i.v. or i.m. in 2 doses - 6 weeks
This combination is active against [Link] endocarditis and is not
active against [Link].
Beta lactam resistance – due to-
[Link] lactamase – ampicillin- sulbactam or
- amoxicillin-clavulanate.
ii. PBP5 alteration – vancomycin based regimens

Vancomycin – 30 mg/kg/day i.v. in 2 doses - 6 weeks

With
Gentamicin –3 mg/kg /day i.v. or i.m. in 1 dose - 6 weeks.

High level resistance to gentamycin(MIC>500mg/L)

-if susceptible to streptomycin replace with it by 15mg/kg/day in 2 equally divided doses .
Gram negative bacteria
HACEK – related species – HACEK gram negative bacilli are
fastidious [Link] slowly ,standard MIC tests may be
difficult to interpret .some are beta -lactamase producing ,so
ampicillin is no longer the first line option.
Standard treatment:
Ceftriaxone -- 2g/day for 4 weeks in NVE ,
And for 6 weeks in PVE
If they do not produce beta – lactamase
It is –Ampicillin –12g/day i.v. in 4-6 doses
Plus
Gentamicin – 3 mg/kg/day divided into 2-3 doses
for 4-6 weeks is an option
Non-HACEK species
Recommended treatment –
• Early surgery + long term (at least 6 weeks )
therapy with bactericidal combinations of beta lactams and
aminoglycosides
Blood culture –negative infective
endocarditis
 Main complications of left-sided valve
infective endocarditis and their
management
• Surgical treatment is required in approximately half of the patients with IE
because of severe complications .
• In some cases surgery needs to be performed on an Emergency (with in 24 hr) or
urgent (with in a few days ,<7 days ) irrespective of duration of antibiotic
treatment
• In other cases surgery can be postponed to allow 1 or 2 weeks of antibiotic
treatment under careful observation.
• 3 main indications for early surgery in IE are Heart failure ,uncontrolled infection
and prevention of embolic events.
Indications and timing of surgery in the
presence of HF in IE

• Aortic or mitral NVE or PVE with severe acute

regurgitation ,obstruction or fistula causing refractory
pulmonary oedema or cardiogenic shock .- Emergency
surgery.- within 24 hrs

• Aortic or mitral NVE or PVE with severe regurgitation or

obstruction causing symptoms of HF or echocardiographic
signs of poor haemodynaic tolerance.-Urgent surgery.- within 7
days
Uncontrolled infection
[Link] infection :
- Consists of fever and persisting positive cultures after 7-10
days of antibiotic treatment .
[Link] extension in IE:
- Most frequent cause of uncontrolled infection.
- Pervalvular complications include Abscess
formation ,pseudoaneurysms and fistulae.
- Perivalvular abscess ismore common in arotic IE andis
frequent in PVE.
- Perivalvular extension sould be suspected in cases with
persistent unexplained fever or new atrio ventricular blocks.
- So echocardiogram should be performed frequently.
 Indications and timing of surgery in
presence of uncontrolled infection in IE
• Locally uncontrolled infection (abscess,false
aneurysm,fistula,enlarging vegetations)-Urgent surgery.

• Infection caused by fungi or multiresistant organisms-Urgent

/elective surgery .

• Persisting positive blood cultures despite appropriate antibiotic

therapy and adequate control of septic metastatic foci.-Urgent
surgery .
Prevention of systemic embolism
Embolic events in IE :
• Related to the migration of cardiac vegetations .
• The brain and spleen are the most frequent sites of embolism
in leftsided [Link] embolism is frequent in native right-
sided and pacemaker lead IE.
• Stroke is the severe complication .Embolic events sometimes
can be totally silent especially affecting spleenic or cerebral
circulation.
Predicting the risk of embolism:
• Echocardiography plays a key role in predicting embolic events
• Size and mobility of vegetations are most potent independent
predictors of a new embolic event.
• Patients with vegetations >10 mm in length are at higher risk of
embolism ,and this risk is even higher in patients with larger
(>15mm) and mobile vegetations ,especially in staphylococcal
IE affecting the Mitral valve.
• Neurological complications was high in patients with very large
(>30mm length) vegetations.
• 6 factors –age ,diabetes,atrial fibrillation,previous
embolism ,vegetation length and [Link] infection were
asociated with increased embolic risk and to create an embolic
risk calculator.
• Risk of new embolism is highest during the first days following
initiation of antibiotic therapy and rapidly decreases thereafter
,paticularly beyond 2 weeks.
Indications and timing of surgery to prevent
embolism in IE
• Aortic or mitral NVE or PVE with persistent vegetations >10 mm
after one or more embolic episode despite appropriate
antibiotic therapy-Urgent surgery.

• Aortic or mitral NVE with vegetations >10mm ,associated with

severe valve stenosis or regurgitation ,and low operative risk.-
Urgent surgery.

• Aortic or mitral NVE or PVE with isolated very large vegetations

(>30mm)-Urgent surgery.

• Aortic or mitral NVE or PVE with isolated large vegetations

(>15mm) and no other indication for surgery-Urgent surgery.
 •Heart failure
•Uncontrolled infection
•Abscess HH
YES •High embolic risk NO

•Intracranial haemorrhage
•Coma YES
nb
•Severe comorbilities
•Stroke with severe damage

NO
•Conservative treatment
•Consider surgery And monitoring
Cardiac Conditions Associated With the Highest Risk
of Adverse Outcome From Endocarditis for Which Prophylaxis
With Dental Procedures Is Reasonable

-Prosthetic cardiac valve or prosthetic material used for cardiac valve

repair
• Previous IE

• Unrepaired cyanotic CHD, including palliative shunts and conduits

• Completely repaired congenital heart defect with prosthetic material
or device, whether placed by surgery or by catheter intervention,
during the first 6 months after the procedure
• Repaired CHD with residual defects at the site or adjacent to the site
of a prosthetic patch or prosthetic device (which inhibit
endothelialization)
• Cardiac transplantation recipients who develop cardiac valvulopathy.
Follow-up

• A first episode of IE should not be seen as an ending once

the patient has been discharged.
• Residual severe valve regurgitation may decompensate
left ventricular function or valve deterioration may
progress despite bacteriological cure ,usually presenting
with acute HF.
• Patient should be educated about signs and symptoms of
IE after discharge ,they should be aware thar recurrence
could occur in IE.
• The new onset of fever,chills or other signs of infection
mandate immediate evaluation ,including procurement of
blood cultures before empirical use of antibiotics.
• To monitor the development of secondary HF,an initial clinical
evaluation and baseline TTE should be performed at completion of
antimicrobial therapy and repeated serially ,particularly during 1st
year of followup.

• Regular clinical and echocardiographic follow-up should be

performed during the 1st year following completion of treatment.

• Good oral health maintenance ,preventive dentistry and advice

about skin hygiene,including tattoos and skin piercing are
mandatory.