Infective endocarditis/ endocarditis

ENDOCARDITIS
SUNDARESAN_LAKSHMANAN
381810821
SEMINAR
PHARMACOTHERAPEUTICS-II

DEFINITION –
ENDOCARDITIS
Endocarditis is an
inflammation of the
endocardium ( the membrane
lining the chambers of heart
and covering the cups of the
heart valves)
It refers to an infection of
heart valves by various
microorganisms

INFECTIVE ENDOCARDITIS:
◦ IE is an infection of endothelial surface of the heart including the infections of
1. Large thoracic vessels
2. Intracardiac foreign bodies
◦ It is characterized by the presence of vegetation which is nidus for microbial invasion

CLASSIFICATION OF IE:
◦ IE is classified based on the
1. Etiologic organism
2. Anatomic site of infection
3. Pathogenic risk factor
 IE is mainly classified into two types. They are:
I. Native valve endocarditis (NVE)
II. Prosthetic valve endocarditis (PVE)

TYPES OF IE EXPALNATION:
NATIVE VALVE ENDOCARDITIS (NVE):
◦ It is an endovascular microbial infection of Native
Heart Valves ( i.e., leaflets of valves, endocardial
surfaces etc…,)
TYPES OF INFECTIONS IN NVE:
A. Local infections
B. Distal infections
Local infection:
◦ It includes valvular & perivalvular destruction
Distal infection:
◦ It is due to septal vegetation detachment with
embolization, metastatic infection & septicemia
PROSTHETIC VALVE ENDOCARDITIS (PVE):
◦ PVE is an endovascular microbial infections of
prosthetic heart valves
TYPES OF PVE:
 Early PVE
 Late PVE
EARLY PVE:
◦ Infections likely to have been acquired preoperatively & thus
being noscominal.
◦ It occurs within <12 months of valve implantation
LATE PVE:
◦ Community acquired & occurs ≥12 months after valve
implantation

TYPES OF NVE:
ACUTE NVE:
Fulminating form
Associated with
1. High fevers
2. Systemic toxicity
Caused by virulent organisms especially
staphylococcus aureus
 S. aureus frequently causes this syndrome
and if untreated , death may occurs with in
days to weeks.
◦ SUBACUTE NVE:
 Indolent form
Caused by less virulent organisms
Eg., streptococci
It usually occurs in pre-existing valvular heart
disease.

ETIOLOGY
• More commonly endocarditis is caused by bacteria and sometimes may be by fungi
et….,

BACTERIAL
• Staphylococus sp ( ≈
25% NVE)
1. Coagulase positive
staphylococcus
2. Coagulase negative
staphylococcus
• Streptococcus sp
• Enterococci
• Culture negative organisms

Coagulase positive
staphylococcus
• E.g…, S.aureus
• Commonly causes PVE & NVE in IVDA
& in patients with previously affected
cardiac valves
• S.aureus is the main causative
organism in healthcare associated IE &
IVDA
• IVDA often presents with right sided
cardiac involvement
• Non-IVDA usually presents with left
sided cardiac involvement and also
have
1. Skin infections
2. Soft tissue infections
with congenital
abnormalities

COAGULASE- NEGATIVE
STAPHYLOCOCCI
• Most common cause of PVE
& have been known tocause
NVE.
• Examples:
1. Methicillin resistant &
s.lungidunesis
2. Methicillin-susceptible
s.aureus (MSSA)
3. Methicillin-resistant
s.aureus (MRSA)
4. S. lungidunesis
5. S. epidermidis

METHICILLIN RESISTANT & S LUNGDUNESIS:
◦ Associated with very destructive valvular &
perivalvular lesions
METHICILLIN SUSCEPTIBLE S AUREUS (MSSA):
◦ May causes right sided endocarditis in IV drug users

Methicillin-resistant S aureus (MRSA):
• Occurs particularly in PVE,
• right-sided endocarditis in IV drug users and
• nosocomial endocarditis
• Causes aggressive endocarditis with increased risk of
• embolism,
• persistent bacteremia,
• stroke and
• death

Streptococcus sp
◦ viridans group of streptococci;
◦ S pneumoniae;
◦ S pyogenes;
◦ Lancefield group B, C, G streptococci;
◦ S gallolyticus (previously known as S bovis),
◦ S mitis,
◦ S mutans,
◦ S sanguis and
◦ Abiotrophia sp

Most common causes of NVE
•Group B streptococci:
• Most common beta-hemolytic streptococci and cause the most virulent IE among
streptococci which is characterized by a fulminant disease with large crumbling
vegetations with the frequency of embolization related to size
•Group G streptococci:
•Both native and prosthetic valves can be affected with left-sided involvement being more
common
•Viridans streptococci:
•Most common cause of NVE in patients with congenital heart disease or defects and in
patients who are not IV drug users
•S gallolyticus:
•Also causes bacterial endocarditis

ENTEROCOCCI:
◦ THIRD LEADING CAUSE OF IE
CULTURE NEGATIVE ORGANISMS:
• HACEK (Haemophilus parainfluenzae, aphrophilus,
and paraphrophilus; Aggregatibacter (formerly Actinobacillus) actin
omycetemcomitans; Cardiobacterium hominis, Eikenella
corrodens; and Kingella): Can cause NVE and PVE
• Bartonella henselae: Exposure to infected cats may predispose
patient to IE
• Brucella
• Chlamydia psittaci: Exposure to infected birds may predispose
patient to IE
• Coxiella burnetii: Exposure to infected sheep, cattle and wild
rabbits may predispose patient to IE
• Legionella: Characterized by a febrile course that extends up to
months with cardiac signs of newly developed murmurs and
extremely high anti-Legionella titers
• Mycobacterium
• Pseudomonas aeruginosa: Most commonly occurs in IVDAs and is
an important pathogen in early PVE
• Commonly involves the tricuspid valve and may present as subacute
infection with septic pulmonary emboli and right-sided heart failure

FUNGAL
◦ An increasing cause of PVE in IVDAs and
immunocompromised patients
• Candida: Most common cause of fungal endocarditis
• Aspergillus
• Nocardia

CLINICAL PRESENTATION
• HIGHLY VARIABLE;
• NON SPECIFIC

 Embolic event(s) of unknown origin
 Hematuria,
 glomerulonephritis & suspected renal infarction
 New valve lesion/regurgitant murmur
 Sepsis of unknown origin
 Fever
 Chills
 Weakness
 Dyspnea
 Cough
 Night sweats
 Weight loss
 Malaise
 Anorexia
 Fatigue
 Diaphoresis
 Nausea & vomiting
 Arthralgia
 Myalgai
 Moderate & remitting fever is the most common symptom

FEVER (+) PLUS
Positive blood culture (organism identified is typical for NVE/PVE)
Previous history of IE, valvular or congenital heart disease
Evidence of congestive heart failure (CHF) or pulmonary embolism
Focal or nonspecific neurological signs and symptoms
Cutaneous (Osler, Janeway) or ophthalmic (Roth) manifestations
Newly developed ventricular arrhythmias or conduction disturbances
Peripheral abscesses (renal, splenic, spine) of unknown origin
Predisposition and recent diagnostic/therapeutic interventions known to result in significant
bacteremia
Prosthetic material inside the heart
Pulmonic infiltrations that are multifocal/rapid changing (right IE)

RISK FACTORS
CARDIAC
HIGH INTERMEDIATE
NON CARDIAC

HIGH RISK FACTORS
Aortic regurgitation
Aortic stenosis
Coarctation of aorta
Cyanotic congenital heart disease
Mitral regurgitation
Mitral stenosis with regurgitation
Patent ductus arteriosus
Previous IE
Prosthetic heart valves
Surgically repaired intracardiac lesion with residual hemodynamic
abnormality
Ventricular septal defect

Intermediate Risk Factors
Asymmetrical septal hypertrophy
Bicuspid aortic valve disease
Calcific aortic sclerosis with minimal hemodynamic abnormality
Degenerative valve diseases in elderly patients
Mitral valve prolapse
Pulmonary stenosis
Pure mitral stenosis
Surgically repaired intracardiac lesion with minimal hemodynamic
abnormality <6 months after surgery
Tricuspid valve disease

Non-Cardiac Risk Factors Predisposing
Patient to IE
• Older age
• Nonbacterial thrombotic vegetation (NBTV): Microorganisms may adhere more easily in the presence of fresh,
platelet thrombi associated with leukemia, cirrhosis of the liver, carcinomas which may cause hypercoagulability
(marantic endocarditis), inflammatory bowel disease, systemic lupus erythematosus (SLE) and steroid medication
• Compromised host defense typical in steroid medication and possibly in chronic alcoholism
• IVDA risk of IE is 12-fold higher than non-IVDAs
• Compromised local non-immune defense mechanism
• Found in increased transmucosal permeability in mucous membrane lesions eg chronic inflammatory bowel
disease
• Reduced capillary clearance in arteriovenous fistulas of patients on chronic hemodialysis
• Increased risk or an increased frequency for bacteremia
• Patients with broken skin (eg DM, burns), on intensive care (eg lines, respirators), with polytrauma, with poor
dental status or on hemodialysis
• Previous exposure to endocarditis-causing microorganisms

Characteristics of Infective Endocarditis
(IE)
• IE often presents in an occult fashion.
Early diagnosis:
• Depends on a high index of clinical suspicion especially in patients with
Congenital heart disease,
Prosthetic valves or
Previous IE
Established diagnosis :
• By a positive blood culture (BC)
• Involvement of the endocardium detected during sepsis or systemic infection
• Though BC is negative , if the involvement of endocardium is detected during sepsis or
systemic infection IE may also be established

Classification
(MODIFIED DUKE CLINICAL CRITERIA FOR DIAGNOSIS OF IE)
MODIFIED
DUKE
CLINICAL
CRITERIA
DEFINITE IE
PATHOLOGIC
CRITERIA
CLINICAL CRITERIA
POSSIBLE IE REJECTED IE

Definite IE
Pathologic Criteria
• Microorganisms demonstrated by
culture or histologic exam of a
vegetation, a vegetation that has
embolized, or an intracardiac
abscess; or
• Pathological lesions: Vegetation or
intracardiac abscess is present
and confirmed by histology
showing active endocarditis
Clinical Criteria: Using specific
definitions found below
• 2 major criteria; or
• 1 major criterion + 3 minor criteria;
or
• 5 minor criteria

Possible IE
• 1 major criterion + 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 ≤4 days; or
• No pathological evidence of IE
at surgery or autopsy, after
antibiotic therapy for ≤4 days; or
• Does not meet the criteria for
possible IE, as above

Major Criteria
Positive blood culture for IE
• Typical microorganism consistent with IE from 2
separate BCs as noted below:
 Viridans streptococci, Streptococcus
gallolyticus (formerly known as S bovis), HACEK
group, or Staphylococcus aureus
 Community-acquired enterococci in the absence
of a primary focus; or
• Microorganisms consistent with IE from
persistently positive BCs defined as
 ≥2 positive cultures of blood samples drawn >12
hours apart; or
 All of 3 or a majority of ≥4 separate cultures of
blood (with first and last sample drawn ≥1 hour
apart)
• Single positive BC for Coxiella burnetii or
antiphase I IgG antibody titer ≥1:800
Evidence of endocardial involvement
• Positive echocardiogram for IE [transesophageal
echocardiogram (TEE) recommended in patients
with prosthetic valves and rated at least “possible
IE” by clinical criteria, or complicated IE
(paravalvular abscess); TTE as first test in other
patients] defined as:
 Oscillating intracardiac mass on valve or
supporting structures, in the path of
regurgitant jets, or on implanted material in
the absence of an alternative anatomic
explanation; or
 Abscess; or
 New partial dehiscence of prosthetic valve,
or
• New valvular regurgitation (worsening or
changing of preexisting murmur not sufficient)

Minor Criteria
• Predisposition:
 Predisposing heart condition or IV drug
use
• Fever:
 Temperature ≥38˚C
• Vascular phenomena:
 Major arterial emboli,
septic pulmonary infarcts,
 mycotic aneurysm,
 intracranial hemorrhage,
 conjunctival hemorrhages and
Janeway lesions
• Immunologic phenomena:
 Glomerulonephritis,
 Osler’s nodes,
 Roth spots and
rheumatoid factor
• Microbiological evidence:
 Positive BC but does not meet a major
criterion as noted above or serological
evidence of active infection with
organism consistent with IE

Assessment
Clinical Presentation
Signs and Symptoms
Moderate and remitting fever is the most common symptom
Anorexia,
weight loss,
 malaise,
 night sweats,
Fatigue,
 diaphoresis,
 chills,
 nausea and vomiting,
 arthralgia,
myalgia

Physical Examination
Heart murmur consistent with valvular regurgitation
Petechiae on the skin, conjunctivae or oral mucosa
Osler’s nodes: Red, painful, indurated lesions, 2-15 mm in diameter seen on
the palms or soles and usually in the digital phalanges
Janeway lesions: Non-tender, erythematous macules that appear on the palms
or soles
“Blue toe syndrome”: Embolization of small vegetation fragments
Roth’s spots: Red, retinal hemorrhages with a pale center
Splenomegaly
Signs of congestive heart failure (CHF)

Laboratory Tests
Blood Culture (BC)
• Most important laboratory test
• At least 3 BCs should be taken as soon as possible at
30-minute intervals
 Delaying blood sampling to coincide with peaks of fever
is unnecessary
• It is recommended to postpone antimicrobial therapy
until BCs become positive (unless the patient is septic)
• If antimicrobial therapy has been started, wait for at
least 3 days after discontinuing short-term antibiotic
treatment before taking BC
 If patient has been on long-term antibiotic treatment,
positive BCs may not appear until after 6-7 days
without antibiotic
• Identification of causative organism should be up to
species level
Other Lab Tests
Complete blood count (CBC) with differential
Many patients have leukocytosis: 15,000-
25,000/microliter with a left shift
Anemia is common: Normocytic and normochromic
with low serum iron level and total iron binding
capacity (TIBC)
Serum electrolytes
Some patients may have elevated serum creatinine
• Urinalysis:
May reveal microscopic hematuria, pyuria, red blood
cell (RBC) casts, bacteriuria, proteinuria
• Erythrocyte sedimentation rate (ESR): Elevated in
most cases
• C-reactive protein level: Elevated
• Rheumatoid factor: Elevated in approximately half
of the presenting patients

Imaging
Echocardiogram
• Diagnostic test of choice in detecting vegetations in cardiac valves
Three Echocardiographic Findings Considered to be Major Criteria in the
Diagnosis of IE
• Mobile, echodense mass attached to the valvular or the mural endocardium especially if present
on the preferred locations, or attached to implanted prosthetic material with no alternative
anatomical explanation
• Demonstration of abscesses or fistulas
• A new dehiscence of a valvular prosthesis especially when occurring late after implantation

Transthoracic Echocardiography (TTE):
2-Dimensional Transthoracic
Echocardiography
(2-D Echo)
• Recommended initial diagnostic test for native valve endocarditis (NVE) and prosthetic
valve endocarditis (PVE)
• Vegetation appears as a discrete mobile echogenic mass attached to the valvular surface
downstream from a high- to low-pressure chamber
• Vegetations ≥2 mm may be visualized; the larger the size, the more likely a vegetation will
be detected
• TTE sensitivity in detecting vegetations in native and prosthetic valves is 50-90% and 40-
70%, respectively, with a specificity of 90%
• If the clinical suspicion of IE is low, the TTE is of good quality and the result is negative,
endocarditis is unlikely

Transesophageal Echocardiography
(TEE)
• Has superior resolution, thus carries a greater sensitivity of 90-100% and 86%
in detecting vegetations in native and prosthetic valves, respectively, as
compared with TTE
• If suspicion of IE is high (eg staphylococcal bacteremia), then TEE should be
performed in all negative TTE cases
• TEE should be performed in all suspected PVE cases, in cases of aortic
location, prior to cardiac surgery during active IE, and when intracardiac
device leads are present
• If TEE is negative but suspicion of IE remains, repeat TEE in 5-7 days, or
earlier if Staphylococcus aureus infection is suspected

Other Diagnostic Studies
◦ Electrocardiogram (ECG)
• May be taken upon admission in patients with
suspected acute IE
• Evidence of low septal abscesses with
involvement of the intraventricular conduction
system is detected on ECG
• Can be used to rule out conduction abnormalities
and to establish baseline
◦ Chest Radiograph
• May delineate the presence of CHF
• May show septic pulmonary emboli and infiltrates with
cavitation that are associated with right-sided IE
◦ Computed Tomography (CT) Scan
• Obtain in any patient with neurologic signs and
symptoms
• Cardiac CT may be used as an adjunctive diagnostic
test when the anatomy is not clear on echocardiography
• Multislice CT (MSCT) is useful in evaluating IE-
associated valvular abnormalities eg perivalvular extent
of abscess, pseudoaneurysm
• Magnetic Resonance Imaging (MRI)
More sensitive than CT and increases the rate of
detecting cerebral emboli lesions
• Nuclear Imaging
Single-photon emission computed tomography (SPECT)
and positron emission tomography (PET) are new
modalities which may be used as supplementary tests
in patients with IE and diagnostic difficulties

Differential Diagnosis
◦Alternative Diagnosis
• Diagnose and treat patient appropriately for other disease states
 atrial myxoma,
 systemic lupus erythematosus (SLE) with marantic endocarditis,
 acute rheumatic fever and
cardiac syndrome
• presenting with similar signs and symptom

EMPIRIC PHARMACOLOGICAL
THERAPY
General Therapeutic Principles
• Counting days of duration of therapy should start on the first day on which blood cultures (BCs)
were negative in cases in which initial BCs were positive
• At least 2 sets of BCs should be obtained every 24-48 hours until bloodstream infection is cleared
• For patients with native valve endocarditis (NVE) who undergo valve resection with prosthetic
valve replacement, the post-op treatment should be the one recommended for NVE, not for
prosthetic valve endocarditis (PVE)
• If the resected tissue is culture positive, then the entire course of therapy is recommended
after valve resection
• If the resected tissue is culture negative, then treatment should be given less the number of
days of treatment administered for NVE before valve replacement

•If combination antimicrobial therapy is used, then the agents should be
administered close together to improve synergistic killing effect
•Antibiotic prophylaxis has been limited to patients undergoing an invasive dental
procedure in whom exists a history of infective endocarditis (IE), prosthetic valve,
a heart transplant with abnormal heart valve function, or congenital heart disease
with the following: Unrepaired cyanotic congenital heart disease, congenital heart
defect completely repaired with prosthetic material or device for the first 6 months
post procedure, or repaired congenital heart disease with residual defects
• Patients with prosthetic valves are at the highest risk of developing IE
• Recommended prophylaxis regimens include the standard Amoxicillin,
Ampicillin if unable to take PO medications, and Clindamycin [PO or
intravenous (IV)], Cefazolin or Cefalexin if with penicillin allergy
• Recommended prophylaxis regimen for genitourinary and gastrointestinal
procedures should include drugs against enterococci eg Ampicillin or
Vancomycin

Empiric
Therapy
• Initial empiric therapy for IE will depend on the following factors:
• Acute or subacute presentation
• Whether the infection involves native or prosthetic valves
• Duration following prosthetic surgery: Early versus late PVE
• Whether the patient has received previous antibiotic
treatment
• Community-acquired or healthcare-associated
• Presence of risk factors for fastidious organisms and for
multidrug resistant microorganism
• In uncomplicated cases, antibiotics may be postponed up to 48
hours until results of initial BCs are known
• Empiric antibiotic treatment should be initiated immediately after
3 BCs have been taken in cases complicated by:
• Sepsis, severe valvular dysfunction, conduction
disturbances or embolic events

Empiric
Therapy
(CONTINUATIO
N)
• Empiric therapy should include use of agents that are
effective against streptococci, staphylococci and
enterococci
• Subsequent changes in the antibiotic regimen should
be based on the results of culture and sensitivity
testing
• Empiric therapy for intravenous drug abusers (IVDA)
depends on the suspected microorganism, type of
drug and solvent used by the addict and infection
location
 Most common causative agents are staphylococci
followed by streptococci and enterococci and
initial treatment should cover these organisms
 In suspected right-sided IE empiric treatment
should include penicillinase-resistant penicillins,
Vancomycin or Daptomycin; empiric therapy

Empiric
Therapy
(CONTINUATIO
N)
Initial Empirical Treatment Regimens of IE in Acute Severely Ill Patients
Community-acquired native valves
endocarditis or late PVE (≥12 months
post surgery)
Ampicillin IV plus (Flu)cloxacillin IV (if
with suspected S
aureus infection) plus Gentamicin IV or
Vancomycin IV plus Gentamicin IV (for
patients with beta-lactam allergy)
Early PVE (<12 months post surgery) or
nosocomial and non-nosocomial
healthcare-associated endocarditis
Vancomycin IV plus Gentamicin
IV plus Rifampicin IV with or
without Cefepime
‐ Rifampicin should be started 3-5 days
after Vancomycin and Gentamicin
‐ Cefepime is given if local
epidemiology suggests for non-HACEK
Gram-negative bacilli infection
(eg Pseudomonas)

PATHOGEN-SPECIFIC PHARMACOLOGICAL
THERAPY
General Therapeutic Principles
• Counting days of duration of therapy should start on the first day on which BCs become negative in cases
in which initial BCs were positive
• At least 2 sets of BCs should be obtained every 24-48 hours until blood stream infection is cleared
• For patients with NVE who undergo valve resection with prosthetic valve replacement, the post-op
treatment should be the one recommended for NVE, not for PVE
• If the resected tissue is culture positive, then the entire course of therapy is recommended after valve
resection
• If the resected tissue is culture negative, then treatment should be given less the number of days of
treatment administered for NVE before valve replacement
• If combination antimicrobial therapy is used, then the agents should be administered close together to
improve synergistic killing effect
◦ The therapeutic goal is to produce bactericidal levels of drugs at the infected site for a maximum
period of time

Streptococca
l IE
Highly Penicillin-Susceptible Viridans Group Streptococci
and S gallolyticus (MIC ≤0.12 mg/L)
• Penicillin, Amoxicillin, Ampicillin or Ceftriaxone
• These agents when used alone for 4 weeks obtain high bacteriologic cure
rates (≥98%)
• 4 weeks of monotherapy has the advantage of avoiding the potential
ototoxic or nephrotoxic effects of Gentamicin
• Ceftriaxone has the advantage of once-daily dosing
• Ampicillin may be used as alternative when Penicillin is not available
• (Penicillin, Amoxicillin or Ceftriaxone) plus Gentamicin or Netilmicin for the first 2
weeks
• When given in selected patients, gives similar cure rates to 4 weeks of
monotherapy
• Once-daily dosing of Gentamicin may be used
• Vancomycin
• Reserved for patients who are unable to tolerate Penicillin or Ceftriaxone
• Teicoplanin
• Alternative drug that may be used once daily to treat streptococcal IE in
penicillin-allergic patients
• Inadequate doses can result in treatment failure
• Steady-state serum is achieved only after 1 week

Streptococc
al IE
Relatively Penicillin-Resistant Viridans Group Streptococci and S
gallolyticus (MIC >0.12 to ≤0.5 mg/L)
• (Penicillin, Amoxicillin or Ampicillin) for 4 weeks plus Gentamicin for 2
weeks should be given
• Once-daily dosing of Gentamicin may be used
• Ceftriaxone
• Alternative if isolate is Ceftriaxone-susceptible
• Vancomycin
• Reserved for patients who are unable to tolerate Penicillin, Amoxicillin or
Ampicillin
Highly Resistant Viridans Group Streptococci (MIC >0.5 mg/L)
• Should be treated with regimens recommended for enterococcal
endocarditis

Streptococc
al IE
• Streptococcus pneumoniae, Streptococcus pyogenes, groups B,
C, F and G beta-hemolytic streptococci
Penicillin-susceptible S pneumoniae (MIC ≤0.06 mg/L)
• Penicillin, Amoxicillin, Cefazolin or Ceftriaxone for 4 weeks for NVE and 6
weeks for PVE
• Vancomycin for 4 weeks for NVE and 6 weeks for PVE is reserved for beta-
lactam-allergic patients
• Penicillin-resistant S pneumoniae (MIC 0.125-≥4 mg/L)
• Without meningitis: High-dose penicillin or third generation cephalosporin or
Vancomycin
• With meningitis: High doses of Cefotaxime or Ceftriaxone alone or in
combination with Vancomycin and Rifampicin depending on the susceptibility
pattern
• S pyogenes IE
• Penicillin or Ceftriaxone for 4-6 weeks is the recommended regimen
• Vancomycin is reserved for patients with beta-lactam allergy
• IE caused by groups B, C or G streptococci
• Recommended regimen includes Penicillin, Amoxicillin or Ceftriaxone for 4-6
weeks plus Gentamicin for at least the first 2 weeks
• Produce abscesses and may require adjunctive surgery

Streptococca
l IE
Abiotrophia and Granulicatella [formerl
y nutritionally variant streptococci
(NVS)]
• Antimicrobial susceptibility is technically difficult
to determine because it is slow growing
• Recommended regimen includes Penicillin,
Ampicillin, Ceftriaxone or Vancomycin for 6
weeks plus an aminoglycoside (eg Gentamicin)
for at least the first 2 weeks

Enterococ
cal IE
• All enterococci causing IE should be tested for
antimicrobial susceptibility to determine
optimal therapy
• In vitro susceptibility to Penicillin or
Ampicillin and Vancomycin along with
high-level resistance to Gentamicin and
Streptomycin should be tested
• Successful treatment requires the synergistic
action of Penicillin, Ampicillin or Vancomycin
with either Gentamicin or Streptomycin
• Multi-daily dosing should be used for the
aminoglycosides

Enterococ
cal IE
Ampicillin or Penicillin + Aminoglycoside
• Treatment duration is 4-6 weeks
• For enterococcal strains susceptible to Penicillin:
• Bactericidal activity of Ampicillin is 2 times that of
Penicillin against E faecalis
• Penicillin may be preferred because higher serum
concentrations of Penicillin will compensate for the
difference and because it is important to avoid Ampicillin
rash during long-term treatment
Double Beta-Lactam Combination
Ampicillin plus Ceftriaxone for 6 weeks
• Alternative regimen for patients with enterococcal strains
susceptible to beta-lactams and with resistance to
aminoglycosides or pre-existing mild or severe renal failure

Enterococ
cal IE
Enterococci with High-level Resistance to Gentamicin
• These enterococci are usually resistant to all other aminoglycosides
except Streptomycin
• Combination therapy with Ampicillin and Ceftriaxone should also be
considered
Glycopeptides (Vancomycin, Teicoplanin) + Aminoglycoside
• Should be reserved for patients allergic to Penicillin or in Penicillin-
resistant strains
• Glycopeptides need to be combined with aminoglycosides since they are
not usually bactericidal against enterococci
Vancomycin-Resistant Strains and Strains Resistant to Both
Gentamicin and Streptomycin
• Consultation with microbiologist/infectious disease specialist is
recommended
• Treatment options include Linezolid or Daptomycin for >6 weeks

Staphylococc
al IE
• Appropriate antibiotic therapy should be started
promptly to improve overall prognosis
• S aureus in non-IVDA usually involves the left-
sided cardiac valves
• Tricuspid valve is usually involved in S aureus IE
in IVDA
• Factor in determining antibiotic treatment is
whether the organism is sensitive to Methicillin
NVE - Penicillin-Susceptible S aureus
• <10% of IE strains of S aureus are susceptible to
Penicillin
• Penicillin may be used for 4 weeks

Staphylococc
al IE
NVE - MSSA
• Antistaphylococcal Penicillin is the treatment of choice (eg Cloxacillin,
Flucloxacillin, Nafcillin, Oxacillin)
• Combination therapy with Gentamicin is not recommended because
of increased risk of Gentamicin resistance, lack of clear-cut efficacy
and increased risk of nephrotoxicity
• Cephalosporin (First Generation)
• Eg Cefazolin
• May be used for the treatment of MSSA endocarditis when patient
has non-anaphylactoid Penicillin allergy
• 6 weeks of therapy with antistaphylococcal Penicillin or cephalosporin
may be used for uncomplicated infection
• Complicated IE eg abscess formation or septic metastatic
complications should be treated for ≥6 weeks
• Vancomycin
• Reserved for patients allergic to beta-lactams; there are recent
reports of suboptimal outcomes with Vancomycin therapy for
serious S aureus infections
• Daptomycin
• Alternative to Vancomycin and reserved for patients allergic to beta-
lactams

Staphylococc
al IE
NVE - MRSA
• Vancomycin
• Treatment of choice in MRSA
• Treatment duration is 6 weeks
• Addition of Gentamicin or Rifampin to Vancomycin is not recommended
for native valve IE because of increased risk of toxicity and lower
survival rate
• Daptomycin
• Alternative to Vancomycin
• Treatment duration is 6 weeks
• Linezolid plus beta-lactams or (Co-trimoxazole plus Clindamycin)
with or without Rifampicin
• These agents may be an option in patients who are intolerant of
Vancomycin or have failed therapy
• Data on clinical efficacy is limited compared to other agents
• Co-trimoxazole is inferior to Vancomycin but is used as alternative drug
• Routine use of Rifampicin as adjunct therapy is not recommended
because of increased risk of adverse effects and lower survival rate

Staphylococc
al IE
PVE - MSSA
• (Antistaphylococcal penicillin + Rifampicin) x ≥6 weeks, + Gentamicin
for the first 2 weeks of treatment
• S aureus IE in PVE patients has a high mortality rate and surgery should be
combined with combination antimicrobial therapy
• Though in vitro and clinical studies are lacking, it is accepted that this 3-drug
combination is used to treat MSSA in PVE
• Cefazolin may be substituted for those with non-anaphylactoid-type Penicillin
allergy
• Rifampicin is started after 3-5 days of therapy or after blood cultures are
negative to prevent resistance
PVE – MRSA
• Vancomycin + Rifampicin + Gentamicin
• Used for MRSA and coagulase-negative staphylococci
• If with resistance to Gentamicin, other aminoglycosides may be used eg
Amikacin
• Quinolone
• May be used in combination with Vancomycin and Rifampicin when the
causative microorganism is resistant to all aminoglycosides

IVDA
Right-Sided Uncomplicated MSSA in IVDA
• 2 weeks antistaphylococcal penicillin or Daptomycin
• Should be reserved for uncomplicated cases
• 4 weeks oral Ciprofloxacin + Rifampicin
• Can be used in uncomplicated cases when
compliance can be monitored
• Though oral Ciprofloxacin and Rifampicin
combination has been shown to be effective in IV
drug users, currently, oral treatment for IE is
recommended only when the following criteria are
strictly met:
• Only when the tricuspid valve is involved
• Organism involved is susceptible to oral agents
• Long-term IV treatment is impossible or difficult

IVDA
Left-Sided or Complicated MSSA in IVDA
• Patient should be treated with standard 4-6 weeks
treatment if:
• After >96 hours patient fails to show clinical or
microbiological response to antibiotic therapy,
congestive heart failure (CHF), vegetations >20
mm, acute respiratory failure, septic metastatic
foci outside the lungs, extra-cardiac
complications (eg renal failure) or IVDA with
severe immunosuppression with or without
acquired immunodeficiency syndrome (AIDS)
Organisms Other Than MSSA in IVDA
• Treat as in non-addict

HACEK
• HACEK group may not be identified in BCs for a week or
longer and empiric antibiotics may be necessary while
awaiting culture results
• Beta-lactamase-producing strains of HACEK are appearing
with increased frequency
• Difficult to perform antimicrobial susceptibility tests on
HACEK organisms; therefore, these should now be
considered Ampicillin resistant and Ampicillin should
not be used for treatment
• Ceftriaxone
• Single-agent use is justified by its excellent
pharmacokinetic profile
• Effective against both beta-lactamase-producing and
non-beta-lactamase-producing strains of the HACEK
group
• May be administered alone for 4 weeks in NVE and for
6 weeks in PVE
• Alternative: Another third or fourth generation
cephalosporin

HACEK
Ampicillin/sulbactam
• Alternative for patients not able to tolerate
Ceftriaxone or other third or fourth generation
cephalosporins
• Consultation with infectious disease specialist is
recommended before using in patients intolerant to
beta-lactams
Quinolone
• Eg Ciprofloxacin, Levofloxacin, Moxifloxacin
• In vitro activity against the HACEK group but limited
clinical use; therefore, consult with infectious
disease specialist before using in patients intolerant
to beta-lactam therapy
• Alternative for patients not able to tolerate
Ceftriaxone or other third or fourth generation

Other Bacterial
Causes of IE
• Treatment of these less common causes of IE is still
not adequately defined
• In patients with difficult-to-treat organisms (as
below) and those with intracardiac device or foreign
bodies, surgery combined with antibiotic therapy
may be considered
Bartonella sp
• Most cases of Bartonella sp IE have required
antibiotic therapy and valve-replacement surgery for
cure
Brucella sp
• Few patients have been cured with antimicrobial
agents alone; most require valve replacement in
combination with antibiotics

Other Bacterial
Causes of IE
Coxiella burnetii
• Clinical response only persists as long as antimicrobial
therapy continues; eradication is unlikely and reinfection
of prosthetic material occurs after surgical replacement
of infected valves
Pseudomonas aeruginosa
• Most cases occur in IVDA and right-sided pseudomonal
IE can usually be treated with antibiotic therapy with or
without surgery
• Valve replacement is usually considered mandatory in
left-sided pseudomonal IE since medical therapy is rarely
effective alone
Enterobacteriaceae sp
• Susceptibility of these organisms can be unpredictable;
therefore, treatment should be based on susceptibility
testing

Fungal
Causes of IE
◦ Aspergillus sp
Voriconazole IV for ≥6 weeks plus Amphotericin B or
echinocandin IV for ≥6 weeks after surgery and suppressive
long-term treatment with Voriconazole PO
• Candida
Lipid formulation of Amphotericin B IV or Amphotericin B
deoxycholate IV for ≥6 weeks with or without Flucytosine
PO for ≥6 weeks after surgery and suppressive long-term
treatment with Fluconazole or Voriconazole PO
• High-dose echinocandin (Anidulafungin, Caspofungin or
Micafungin) IV for ≥6 weeks after surgery and suppressive
long-term treatment with Fluconazole or Voriconazole PO
• Valve replacement is recommended
• Long-term suppression with Fluconazole is
recommended for patients who cannot undergo valve
replacement

Outpatient
Parenteral
Antimicrobial
Therapy
(OPAT) for IE
• Safe and effective method of completing
therapy in patients with IE once infection-
related complications are controlled
• Patients should have a minimum of 2
weeks IV therapy
• OPAT may be considered in patients who
are medically stable, without high-risk
cardiac features on echocardiogram, and
no heart failure, neurologic signs or renal
impairment

CHOICE OF THERAPHY
◦ Choice of theraphy depends on
1.Result of culture & sensitivity
2.Patients allergic profile
3.Patient status
4.Cardiovascular ( cv ) risk factor
◦ If possible, reserve teicoplanin & vancomycin for patients with severe penicillin
allergy

RECOMMENDED ANTIMICROBIAL THERAPY
Choice of therapy will depend on results of culture and sensitivity, patient's allergy profile, patient status and cardiovascular (CV) risk factors. If possible, reserve
Teicoplanin and Vancomycin for patients with severe Penicillin allergy.
Pathogen NVE PVE
Viridans group streptococci,
Streptococcus gallolyticus
Penicillin-susceptible
Ceftriaxone IV x 4 weeks Ceftriaxone IV x 6 weeks with or without
Gentamicin IV x 2 weeks
Penicillin or Amoxicillin or Ampicillin IV x 4 weeks
Penicillin or Amoxicillin or Ampicillin or Ceftriaxone
IV x 2 weeks plus
Penicillin or Amoxicillin or Ampicillin IV x 6
weeks with or without Gentamicin IV x 2 weeks
Vancomycin IV x 4 weeks Vancomycin IV x 6 weeks
Penicillin-relatively resistant
(Pen MIC >0.12 but ≤0.5 mg/L)
Ceftriaxone IV x 4 weeks plus
Gentamicin x 2 weeks
Ceftriaxone IV x 6 weeks plus
Gentamicin x 6 weeks
weeks plus
weeks plus
Vancomycin IV x 4 weeks Vancomycin IV x 6 wk

Penicillin-resistant (Pen MIC >0.5 mg/L)
Ampicillin/sulbactam or Amoxicillin/clavulanate IV x 6 weeks or plus Gentamicin
IV x 6 weeks
Ceftriaxone IV x 6 weeks plus Gentamicin IV x 6 weeks
Vancomycin IV x 6 weeks
Streptococcus pneumoniae
Penicillin-susceptible (MIC ≤0.06 mg/L)
Penicillin, Amoxicillin, Cefazolin or
Ceftriaxone IV x 4 weeks
Penicillin, Amoxicillin, Cefazolin or
Ceftriaxone IV x 6 weeks
Vancomycin x 4 weeks Vancomycin x 6 weeks
Penicillin-resistant without meningitis
(MIC 0.125-≥4 mg/L)
High doses of Penicillin or third
generation cephalosporins (eg
Cefotaxime or Ceftriaxone) x 4 weeks
High doses of Penicillin or third
generation cephalosporins (eg
Cefotaxime or Ceftriaxone) x 6
weeks with or without Gentamicin x
first 2 weeks

Penicillin-resistant with meningitis (MIC
0.125-≥4 mg/L)
Cefotaxime or Ceftriaxone x 4 weeks Cefotaxime or Ceftriaxone x 6 weeks
Cefotaxime or Ceftriaxone x 4
weeks plus Vancomycin plus Rifampicin (for
Cefotaxime-resistant)
Cefotaxime or Ceftriaxone x 6
weeks plus Vancomycin plus Rifampicin (for
Cefotaxime-resistant)
Streptococcus pyogenes Penicillin or Ceftriaxone IV x 4 weeks Penicillin or Ceftriaxone IV x 6 weeks
Group B, C or G streptococci Penicillin, Amoxicillin or Ceftriaxone IV x 4
weeks plus Gentamicin x ≥2 weeks
Penicillin, Amoxicillin or Ceftriaxone IV x 6
weeks plus Gentamicin x ≥2 weeks
Abiotrophia sp and Granulicatella sp
(nutritionally variant streptococci)
Ampicillin or Penicillin IV x 6 weeks plus Gentamicin IV x 2 weeks
Ceftriaxone IV x 6 weeks plus Gentamicin IV x 2 weeks
Vancomycin IV x 6 weeks

Enterococci strains susceptible to
Penicillin, Gentamicin
Penicillin or Amoxicillin or Ampicillin IV x 4-6 weeks plus Gentamicin IV x 4-6 weeks
(6 weeks in complicated cases)
Ampicillin IV x 6 weeks plus Ceftriaxone IV x 6 weeks
Vancomycin IV x 6 weeks plus Gentamicin IV x 6 weeks (for patients with Penicillin
allergy)
Enterococci strains susceptible to
Penicillin, Streptomycin and Vancomycin
but resistant to Gentamicin
Amoxicillin or Ampicillin or Penicillin IV x 4-6 weeks plus Streptomycin IV x 4-6
weeks
Ampicillin IV x 6 weeks plus Ceftriaxone IV x 6 weeks
Vancomycin IV x 6 weeks plus Streptomycin IV x 6 weeks (for patients with
Penicillin allergy)

Enterococci strains resistant to Penicillin
and susceptible to aminoglycoside and
Vancomycin
Beta-lactamase - producing strain:
Ampicillin/sulbactam IV x 6 weeks plus Gentamicin IV x 6 weeks or
Amoxicillin/clavulanate IV x 6 weeks plus Gentamicin IV x 6 weeks or
Vancomycin IV x 6 weeks plus Gentamicin IV x 6 weeks
Intrinsic Penicillin resistance:
Vancomycin IV x 6 weeks plus Gentamicin IV x 6 weeks
Enterococci strains resistant to Penicillin,
aminoglycoside and Vancomycin
Linezolid IV/PO x ≥8 weeks
Daptomycin IV with or without Ampicillin or Ceftaroline IV x ≥8 weeks
Quinupristin/dalfopristin x ≥8 weeks (for E faecium only)

Methicillin-resistant S aureus (MRSA)
(left- and right-sided)
First-line agent:
Vancomycin x 6 weeks
Vancomycin IV x ≥6 weeks plus
Rifampicin IV x ≥6 weeks plus
Daptomycin x 6 weeks
Vancomycin treatment
failure/intolerance may try the
following:
Linezolid or
Co-
trimoxazole plus Clindamycin with or wi
thout Rifampicin
Methicillin-susceptible S aureus (MSSA) Antistaphylococcal Penicillin IV x 6
weeks
Antistaphylococcal penicillin IV x ≥6
weeks
or
Cephalosporin (first generation) IV x ≥6
weeks
plus
Rifampicin IV x ≥6 weeks
plus
For Penicillin-allergic patients:
Cephalosporin (first generation) IV x 6
weeks

Right-sided MSSA in uncomplicated IE in
IVDA
Antistaphylococcal penicillin IV x 2 weeks -
Daptomycin x 2 weeks
Ciprofloxacin PO x 4 weeks plus
Rifampicin PO x 4 weeks
Left-sided or complicated MSSA in IVDA Antistaphylococcal Penicillin IV x 4-6 weeks -
For Penicillin-allergic patients:
Cephalosporin (first generation) IV x 6 weeks
Glycopeptides (Vancomycin) IV x 4-6 weeks
HACEK organisms Ceftriaxone IV x 4 weeks Ceftriaxone IV x 6 weeks
Ampicillin/sulbactam IV x 6 weeks
Ciprofloxacin IV/PO x 6 weeks
Ampicillin/sulbactam IV x 4 weeks
Ciprofloxacin IV/PO x 4 weeks

Non-HACEK Gram-negative bacilli (Pseudomonas aeruginosa,
Enterobacteriaceae sp)
Treatment should be based on in vitro sensitivity studies
Combination therapy with beta-lactam (penicillins, cephalosporins, or carbapenems) plus aminoglycoside or
fluoroquinolone or Co-trimoxazole x 6 weeks
Culture-negative endocarditis caused by uncommon organisms including:
Bartonella sp
Brucella sp
C burnetii
Legionella sp
Mycoplasma sp
T whipplei
Doxycycline PO x 4 weeks plus Gentamicin IV x 2 weeks
Doxycycline PO plus Rifampicin PO x ≥3-6 months plus Streptomycin or Gentamicin IV x 2-3 weeks
Doxycycline PO plus Hydroxychloroquine PO x >18 months
Levofloxacin IV or PO x ≥6 weeks or Clarithromycin IV x 2 weeks then PO x 4 weeks, plus Rifampicin PO
Levofloxacin IV or PO x ≥6 weeks
Doxycycline PO plus Hydroxychloroquine PO x ≥18 months
Culture-negative endocarditis Acute symptoms of NVE:
Treat as in NVE for MSSA and should cover beta-
hemolytic streptococci and aerobic Gram-negative
bacilli
Vancomycin and Cefepime
Subacute symptoms of NVE:
Treatment should cover MSSA, viridans streptococci,
enterococci; HACEK may be considered
Ampicillin/sulbactam x 6 weeks
Early PVE (<12 months)
Treatment should cover staphylococci, enterococci
and aerobic Gram-negative bacilli:
Regimen should include Vancomycin, Rifampicin,
Gentamicin and Cefepime
Late PVE (≥12 months), Culture negative
Treatment should cover MSSA, viridans
streptococci, enterococci and HACEK organisms x 6
weeks:
Treatment regimen includes Vancomycin and
Ceftriaxone

TREATMENT
SURGICAL INTERVENTION

Principles of Surgical Treatment
• Combined medical and surgical therapy for infective endocarditis (IE) can decrease mortality among patients who have
congestive heart failure (CHF), perivalvular invasive disease, or uncontrolled infection despite maximal antimicrobial
therapy
• Objectives of surgical treatment: Removal of infected tissue, foreign material and hardware, debridement of
paravalvular infection and cavities, restoration of cardiac integrity and valve function, and removal of threatening
sources of embolism
• The decision to perform surgery and its timing is dependent upon the cardiac and systemic complications caused by the
infection, the microorganism’s virulence and the response to antimicrobial therapy
• The optimal time to perform surgery is before severe hemodynamic disability or spread of the infection to
perivalvular tissue occurs
• Early surgery (while the patient is still on antibiotic treatment) is considered in patients with IE to avoid
progression of heart failure (HF) and irreversible cardiac structural damage and to prevent embolism
• Valve surgery is recommended without delay in patients with IE and an indication for surgery, who had a
stroke but without evidence of intracranial hemorrhage or extensive neurological damage
• Valve surgery should be delayed for ≥4 weeks in patients with IE and an indication for surgery, who had a
major ischemic stroke when patient is hemodynamically stable
• CHF is the strongest indication for surgery in IE

Surgery should be considered in the
following:
• Native valve endocarditis (NVE) patients with acute aortic or mitral regurgitation and CHF
• Evidence of perivalvular extension
• Persistent infection after 5-7 days of adequate antimicrobial therapy
• Relapsing infection ie recurrence of bacteremia following a complete antibiotic course and subsequently negative blood
cultures (BCs) with no known source of infection
• Infection with microorganisms that have poor response to antibiotic therapy (eg
fungi, Brucella sp, Coxiella sp, Staphylococcus lugdunensis, Enterococcus sp with high-level resistance to Gentamicin,
Gram-negative organisms)
• Left-sided IE caused by S aureus, fungal, or highly resistant organisms
• NVE patients with mobile vegetation >10 mm before or during the first week of antibiotic therapy
• Recurrent emboli despite appropriate antibiotic therapy
• Obstructive or persistent vegetations
• Early prosthetic valve endocarditis (PVE)
• Hemodynamically significant prosthetic valve malfunction
• IE complicated by annular or aortic abscess, destructive penetrating lesion, or heart block

•Daily exam including temperature and periodic blood tests to monitor for signs of
infection
• Temperature should normalize within 5-10 days with uncomplicated infective
endocarditis (IE)
•Continue to monitor for cardiac murmurs, blood pressure (BP), signs of heart failure
(HF) and embolism in the central nervous system (CNS), lungs, spleen and skin
•Secondary infections in joint and spine may occur
•C-reactive protein (CRP) decreases rapidly during first or second week of therapy but
may stay slightly elevated for 4-6 weeks or longer
• Persistently high CRP typically means an inadequately controlled infection
•Normalization of white blood cells (WBC) should also occur within 1-2 weeks
• Persistently elevated WBC indicates active infection
•Monitor renal function
•Good oral and overall hygiene are recommended for risk reduction

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