Basic description of Infective Endocarditis from a Clinical and Microbiological point of view with description on Pathogenesis, Clinical Manifestations, Clinical and Laboratory diagnosis.

1. Infective Endocarditis
Dr. SUPRAKASHDAS
Assist. Prof.

3. Introduction
 The term infective endocarditis (IE) denotes infection of the endocardial
surface of the heart and implies the physical presence of
microorganisms in the lesion.
 Although the heart valves are affected most commonly, the disease also
may occur within septal defects or on the mural endocardium.
 Infections of arteriovenous shunts and of arterioarterial shunts (patent
ductus arteriosus) and infections related to coarctation of the aorta are
included in the following discussion because the clinical manifestations are
similar.
 The term infective endocarditis, first used by Thayer and later
popularized by Lerner and Weinstein, is preferable to the former term
bacterial endocarditis, because nonbacterial pathogens, including fungi and
perhaps even viruses, may be responsible for the syndrome.

4. Introduction
 In the past, IE was classified as ACUTE OR SUBACUTE.
 This distinction was based on the usual progression of the untreated disease and is mainly
of historical interest.
The acute form follows a fulminant course, usually with
 High fever,
 Systemic toxicity, and leukocytosis;
 Death occurs in several days to less than 6 weeks.
It classically is associated with infection caused by
 Staphylococcus aureus,
 Streptococcus pyogenes,
 Streptococcus pneumoniae, or
 Neisseria gonorrhoeae.

5. Introduction
 The subacute form (death occurring in 6 weeks to 3 months) and the chronic form (death
occurring later than 3 months) usually are considered together.
 They commonly occur in the setting of prior valvular disease and are characterized by
A slow, indolent course
Low-grade fever,
Night sweats,
Weight loss, and
Vague systemic complaints.
 These two forms of IE classically are caused by the viridans streptococci.
 Although useful conceptually, this classification ignores the nonbacterial forms of IE and the
frequent overlap in manifestations of infection by specific organisms, such as the enterococci.
 The prototypic lesion of infective endocarditis, THE VEGETATION, is a mass of platelets,
fibrin, microcolonies of microorganisms, and scant inflammatory cells.

6. Introduction
 Infection most commonly involves heart valves (either native or prosthetic), but
 May also occur on the low-pressure side of the ventricular septum at the site of a
defect, on the mural endocardium where it is damaged by aberrant jets of blood or
foreign bodies, or
 On intracardiac devices themselves.
 The analogous process involving arteriovenous shunts, arterioarterial shunts (patent
ductus arteriosus), or a coarctation of the aorta is called infective endarteritis.
 In developed countries, the incidence of endocarditis ranges from 2.6 to 7.0 cases per
100,000 population per year and remained relatively stable from 1950 to 2000.
 10–30% of endocarditis cases involve prosthetic valves, greatest during the first 6 months
after valve replacement.
 Although many species of bacteria and fungi cause sporadic episodes of
endocarditis, only a few bacterial species cause the majority of cases.

7. Etiology
 The epidemiology of endocarditis, which has shifted in recent years, should guide diagnostic
testing.
 Today, staphylococci and streptococci combined cause 80% of cases.
 Staphylococcus aureus remains the dominant pathogen, associated with 25% to 30% of cases,
 Coagulase-negative staphylococci account for 11% of cases.
 Streptococci, primarily viridans group streptococci, cause 30% of cases, with Streptococcus
gallolyticus being involved in 20% to 50% of streptococcal cases.
 Enterococci, especially Enterococcus faecalis, account for 10% of cases.
 Gram-negative bacilli account for 5% of cases and include the HACEK group organisms
(Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella species) and, less
commonly Enterobacteriaceae and nonfermenting Gram-negative bacilli.
 Fungi are rare endocarditis causes, with Candida species being the most common.
 A number of uncultivable or challenging to cultivate organisms cause endocarditis, the most
common of which are Coxiella burnetii, Bartonella species, and Tropheryma whipplei.

8. Etiology
 Pathogens vary somewhat with the clinical types of endocarditis, in part because of different
portals of entry.
 The oral cavity, skin, and upper respiratory tract are the respective primary portals for the
Viridans streptococci,
Staphylococci, and
HACEK organisms (Haemophilus, Aggregatibacter (Actinobacillus), Cardiobacterium,
Eikenella, and Kingella) causing community-acquired native valve endocarditis.
 Health care–associated native valve endocarditis is the consequence of bacteremia arising
from
Intravascular catheter infections,
Nosocomial wound and
Urinary tract infections, and
Chronic invasive procedures such as hemodialysis.

9. Etiology
 Prosthetic valve endocarditis arising within 2 months of valve surgery is generally the result of
intraoperative contamination of the prosthesis or a bacteremic postoperative complication.
 The nosocomial nature of these infections is reflected in their primary microbial causes:
Coagulase-negative staphylococci(CoNS),
S. aureus,
Facultative gram-negative bacilli,
Diphtheroids, and
Fungi.
 The portals of entry and organisms causing cases beginning >12 months after surgery are similar
to those in community acquired native valve endocarditis.
 Endocarditis occurring among injection drug users, especially when infection involves the
tricuspid valve, is commonly caused by S. aureus strains, many of which are methicillin-
resistant.

10. Etiology
 Left-sided valve infections in addicts have a more varied etiology and
involve abnormal valves, often ones damaged by prior episodes of
endocarditis.
A number of these cases are caused by
Pseudomonas aeruginosa and
Candida species, and sporadic cases are due to unusual organisms such as
Bacillus,
Lactobacillus, and
Corynebacterium species.
 Polymicrobial endocarditis is more common among injection drug users.

11. Etiology
 From 5 to 15% of patients with endocarditis have negative blood cultures; in one-
third to one-half of these cases, cultures are negative because of prior antibiotic
exposure.
 The remainder of these patients are infected by fastidious organisms, such as
Nutritionally variant organisms (Granulicatella and Abiotrophia species),
HACEK organisms, and
Bartonella species.
 Some fastidious organisms that cause endocarditis do so in characteristic
epidemiologic settings
Coxiella burnetii in Europe,
Brucella species in the Middle East).
Tropheryma whipplei

15. Pathogenesis
 Unless it is injured, the endothelium is resistant to infection by most bacteria and to thrombus
formation.
 Endothelial injury (e.g., at the site of impact of high velocity blood jets or on the low-pressure
side of a cardiac structural lesion) causes aberrant flow and
 Allows either direct infection by virulent organisms or the development of an uninfected platelet-
fibrin thrombus—a condition called nonbacterial thrombotic endocarditis (NBTE).
 The thrombus subsequently serves as a site of bacterial attachment during transient bacteremia.
 The cardiac conditions most commonly resulting in NBTE are
Mitral regurgitation,
Aortic stenosis,
Aortic regurgitation,
Ventricular septal defects, and
Complex congenital heart disease.

16. Pathogenesis
 These conditions result from rheumatic heart disease (particularly in the developing
world, where rheumatic fever remains prevalent), mitral valve prolapse, degenerative
heart disease, and congenital malformations.
 NBTE also arises as a result of a hypercoagulable state (marantic endocarditis).
 Organisms that cause endocarditis generally enter the bloodstream from mucosal surfaces,
the skin, or sites of focal infection.
 Except for more virulent bacteria (e.g., S. aureus) that can adhere directly to intact
endothelium or exposed subendothelial tissue, microorganisms in the blood adhere to sites
at NBTE.
 If resistant to the bactericidal activity of serum and the microbicidal peptides released
locally by platelets, the organisms proliferate and induce a procoagulant state at the site
by eliciting tissue factor from adherent monocytes or, in the case of S. aureus, from
monocytes and from intact endothelium.
 Fibrin deposition combines with platelet aggregation, stimulated by tissue factor and
independently by proliferating microorganisms, to generate an infected vegetation.

17. Pathogenesis
 The organisms that commonly cause endocarditis have surface adhesin molecules,
collectively called microbial surface components recognizing adhesin matrix
molecules (MSCRAMMs), that mediate adherence to NBTE sites or injured
endothelium.
Fibronectin-binding proteins
 Clumping factor (a fibrinogen- and fibrin-binding surface protein) on S. aureus, and
glucans or
 FimA (a member of the family of oral mucosal adhesins) on streptococci facilitate
adherence.
 In the absence of host defenses, organisms enmeshed in the growing platelet-fibrin
vegetation proliferate to form dense microcolonies.
 Organisms deep in vegetations are metabolically inactive (nongrowing) and relatively
resistant to killing by antimicrobial agents.
 Proliferating surface organisms are shed into the bloodstream continuously.

18. Pathogenesis
 The pathophysiologic consequences and clinical manifestations of
endocarditis—other than constitutional symptoms, which probably
result from cytokine production—arise from
 Damage to intracardiac structures;
 Embolization of vegetation fragments,
 Leading to infection or infarction of remote tissues;
 Hematogenous infection of sites during bacteremia; and
 Tissue injury due to the deposition of circulating immune complexes
or immune responses to deposited bacterial antigens.

20. Schematic representation of the
sequence of events of a patient with IE
who has a severe evolution and finally
dies of multiple organ failure.

21. Clinical Manifestations
 The clinical syndrome of infective endocarditis is highly variable and spans a continuum
between acute and subacute presentations.
 The causative microorganism is primarily responsible for the temporal course of endocarditis.
 β-Hemolytic streptococci, S. aureus, and pneumococci typically result in an acute course,
although S. aureus occasionally causes subacute disease.
 Endocarditis caused by Staphylococcus lugdunensis (a coagulase-negative species) or by
enterococci may present Acutely.
 Subacute endocarditis is typically caused by viridans streptococci, enterococci, CoNS, and the
HACEK group.
 Endocarditis caused by Bartonella species and the agent of Q fever, C. burnetii, is exceptionally
indolent.
 In patients with subacute presentations, fever is typically low-grade and rarely exceeds 39.4 C
(103 F); in contrast,
 Temperatures of 39.4 –40 C (103 –104 F) are often noted in acute endocarditis.

22. Clinical Manifestations
Cardiac
Heart murmurs
Congestive heart failure
Abscess formation
Varying degree of heart block
Coronary artery emboli
Myocardial infraction

23. Clinical Manifestations
Non Cardiac
 Septic embolization mimicking some of these lesions (Subungual hemorrhage, Osler’s
nodes)
 Nonspecific inflammatory arthritis
 Back pain
 Embolic events—often with infarction—involving the extremities, spleen, kidneys,
bowel, or brain
 Embolic strokes
 Aseptic or purulent meningitis, intracranial hemorrhage, seizures, and encephalopathy.
 Microabscesses in brain and meninges occur commonly in S. aureus endocarditis
 Immune complex deposition on the glomerular basement membrane causes diffuse
hypocomplementemic glomerulonephritis and renal dysfunction

25. Septic
Emboli
Osler’s Node
Osler’s node on the anterior surface of the distal phalange of the
long finger. The purplish area was tender to palpation.

26. Osler’s node on the toe pad of the fourth toe. Note
the multiple petechiae on the foot.
Janeway’s Lesion
Janeway lesions occur
on the palms and soles
and are nontender and
usually hemorrhagic

27. Conjunctival petechiae in a patient with
bacterial endocarditis.
Roth spots

28. Clinical & Laboratory Diagnosis
 The diagnosis of infective endocarditis is established with certainty only when vegetations
obtained at cardiac surgery, at autopsy, or from an artery (an embolus are examined
histologically and microbiologically.
 Nevertheless, a highly sensitive and specific diagnostic schema— known as the Duke
criteria—has been developed on the basis of clinical, laboratory, and echocardiographic findings.
 Documentation of two major criteria, or, one major and three minor criteria, or of five minor
criteria allows a clinical diagnosis of definite endocarditis.
The diagnosis of endocarditis is rejected if
 An alternative diagnosis is established
 Symptoms resolve and do not recur with ≤4 days of antibiotic therapy
 Surgery or autopsy after ≤4 days of antimicrobial therapy yields no histologic evidence of
endocarditis.
 Illnesses not classified as definite endocarditis or rejected are considered cases of possible
infective endocarditis when either one major and one minor criterion or three minor criteria are
identified.

31. Echocardiography
Imaging with echocardiography allows
 Anatomic confirmation of infective endocarditis,
 Sizing of vegetations,
 Detection of intracardiac complications, and
 Assessment of cardiac function.
 Transthoracic echocardiography (TTE) is noninvasive and
exceptionally specific; however, it cannot image vegetations <2 mm in
diameter, and in 20% of patients it is technically inadequate because of
emphysema or body habitus.

32. Echocardiography
 TTE detects vegetations in only 65% of patients with definite clinical endocarditis.
 TTE is not adequate for evaluating prosthetic valves or detecting intracardiac
complications.
 TEE is safe and significantly more sensitive than TTE.
 It detects vegetations in >90% of patients with definite endocarditis.
 TEE is the optimal method for the diagnosis of
Prosthetic endocarditis or
 Detection of myocardial abscess,
Valve perforation, or
Intracardiac fistulae.
 A negative TEE when endocarditis is likely does not exclude the diagnosis, but
rather warrants repetition of the study in 7–10 days.

34. ROLE OF BLOOD CULTURES IN DIAGNOSIS OF
INFECTIVE ENDOCARDITIS
 Blood cultures are the standard test to determine the microbiologic etiology of infective
endocarditis.
 Routine blood cultures incubated on modern automated, continuous-monitoring blood culture
systems allow recovery of almost all easily cultivable agents of endocarditis.
 The American Heart Association and the European Society of Cardiology recommend at least
three sets of blood cultures collected from different veni-puncture sites, with at least 1 h
between the first and last draw.
 The British Society for Antimicrobial Chemotherapy (BSAC) recommends collection of two sets
of blood cultures within 1 h of each other in patients with suspected endocarditis and acute
sepsis and three sets of blood cultures spaced 6 h apart in cases of suspected subacute or
chronic endocarditis.
 Conventionally, three sets of blood cultures, with each set including one aerobic and one
anaerobic bottle, are collected.
 Alternatively, two sets may be collected, with two aerobic and one anaerobic bottle per set
(i.e., a total of six blood culture bottles)

35. ROLE OF BLOOD CULTURES IN DIAGNOSIS OF
INFECTIVE ENDOCARDITIS
 Standard blood culture incubation times of 5 days are adequate for recovery of almost
all cultivable causes of endocarditis, including Candida species and HACEK organisms.
 Current blood culture systems also contain sufficient supplements to support growth of
Abiotrophia and Granulicatella species (nutritionally variant streptococci).
 Brucella species detection in routine blood cultures is typically achieved within the
standard 5-day incubation period; notably, serologic testing may be helpful if
exposures are suggestive of Brucella endocarditis.
 Cutibacterium acnes (formerly P. acnes) deserves special consideration, however, as
some strains of this species may require prolonged blood culture incubation (e.g., 14
days).
 The Clinical and Laboratory Standards Institute (CLSI) guidelines recommend
terminal subculture to chocolate agar if blood cultures are negative at 5 days and
an endocarditis diagnosis is under consideration.

36. ROLE OF BLOOD CULTURES IN DIAGNOSIS OF
INFECTIVE ENDOCARDITIS
Non-candidal fungal causes of endocarditis (e.g., Histoplasma capsulatum,
Aspergillus species) are
 Rare,
 Require specialized testing (e.g., antigen detection, specialized fungal blood
cultures), and
 Should only be considered in patients with specific risks for these types of
endocarditis
Malignancy,
Injection drug use,
Prolonged health care exposure,
Presence of a prosthetic heart valve

37. DIAGNOSIS OF CULTURE-NEGATIVE
ENDOCARDITIS
 Blood cultures are negative in 2% to 40% of cases of endocarditis.
 The causes of so-called “culture-negative endocarditis” fall into two categories:
Negative blood cultures due to concomitant or antecedent antibacterial therapy or
The presence of an organism that does not grow in routine blood cultures, with the first
being more common.
 Antibacterial agents should not be started in patients with suspected endocarditis until after blood
cultures have been collected.
 For cases in which antibiotics have been administered prior to blood culture collection,
consideration may be given to stopping antibiotics if possible, with recollection of blood cultures
after an antibiotic-free period7 to 10 days off antimicrobial therapy has been recommended.
 In patients who have not received antibiotics, the most common etiologies of culture-negative
endocarditis are C. burnetii and Bartonella species, with the former accounting for 28% to 37%
and the latter accounting for 12% to 28% of cases.
 T. whipplei causes up to 6% of cases of culture-negative endocarditis

38. DIAGNOSIS OF CULTURE-NEGATIVE
ENDOCARDITIS
 C. acnes, a rare cause of endocarditis, may cause culture-negative
endocarditis due to the requirement for prolonged blood culture
incubation for growth of some strains.
 Mycoplasmal endocarditis, primarily caused by Mycoplasma hominis
and is usually diagnosed using molecular methods.
 Mycoplasma pneumoniae has been considered an important cause of
culture-negative endocarditis diagnosed primarily by serologic testing.

39. SEROLOGIC TESTING
 For organisms that do not grow in routine bacterial cultures (e.g., C. burnetii) or are especially
fastidious (e.g., Bartonella species), serologic evaluation may aid in diagnosis.
 Generally, these pathogens cause subacute endocarditis resulting in elevated IgG titers.
 In chronic Q fever with endocarditis, anti-phase I IgG C. burnetii titers of 1:800 are
diagnostic.
 Although Bartonella endocarditis is often diagnosed by serologic testing but it may be
complicated by serologic cross-reactivity; most notably, Chlamydia/Chlamydophila serologic
assays demonstrate high level cross-reactivity with Bartonella species, possibly leading to
erroneous diagnoses of chlamydial endocarditis.
 Low-level cross-reactivity has also been demonstrated between Bartonella and Coxiella.
 Serologic testing for extremely rare causes of endocarditis (e.g., Legionella species,
Chlamydia/Chlamydophila species) is not recommended due to challenges with falsely
positive results.

40. Epidemiological clues for
defining the etiology of blood
culture-negative infective
endocarditis

41. Suspected IE
Negative
Serological
Analysis
Positive
Specific PCR
Negative
Blood PCR
Negative
ANA/
APLA/Malignancy
Positive
Blood Cultures
C. burnetti/Brucella spp./Bartonella spp. T.
whipplei/Mycoplasmaspp./Legionella spp.
Diagnostic workup in
blood culture-negative
endocarditis

44. EVALUATION OF EXCISED
CARDIAC VALVULAR TISSUE Histopathology
 Surgical intervention is performed in 25% to 53% of cases of endocarditis.
 If a microbial diagnosis has not been established at the time of surgery, excised
valvular tissue should be submitted for histopathological and microbiological
evaluation.
 Representative sections of the valvular material should be processed for
histopathology.
 On histologic examination of excised valve tissue, patterns and degrees of
inflammation will vary depending on the infecting organism.
 Endocarditis caused by highly virulent organisms, such as S. aureus, is often
associated with
Acute inflammation characterized by extensive neutrophilic infiltration as well as
Large colonies of microorganisms with associated areas of tissue destruction.

45. EVALUATION OF EXCISED
CARDIAC VALVULAR TISSUE Histopathology
 In cases of subacute endocarditis caused by less virulent organisms, such as
Viridans group streptococci, in addition to focal colonies and neutrophilic
inflammation, evidence of healing, including fibrin deposition and
mononuclear inflammatory cells, may be present.
 In cases of endocarditis caused by Bartonella species, C. burnetii, or T. whipplei,
valves primarily show chronic inflammation and may be grossly normal in
appearance.
 Mononuclear, rather than neutrophilic, infiltration predominates and macrophages
are most frequently observed.
 Abundant foamy macrophages are the primary finding in T. whipplei endocarditis.
 Histopathologically, Bartonella endocarditis typically shows marked fibrosis with
minimal vegetation formation, in addition to macrophage and lymphocytic
infiltration.

46. EVALUATION OF EXCISED
CARDIAC VALVULAR TISSUE Histopathology
The following stains are used to identify the causative organisms
(H&E)-stain
Grocott-Gomori methenamine silver (GMS).
Tissue Gram stain
Warthin-Starry
Ziehl-Neelson
Periodic acid-Schiff

47. Section of mitral valve from a case of streptococcal
endocarditis showing focal basophilic bacterial
colonies (arrow) at low magnification
Gram stain of streptococcal endocarditis demonstrating
Gram-positive cocci mixed with occasional Gram negative
staining organisms (arrows; 1,000 total magnification,
Twort’s Gram stain)

48. EVALUATION OF EXCISED
CARDIAC VALVULAR TISSUE Culture
 Current recommendations for the diagnosis of endocarditis also recommend
culture of valvular tissue, with culture results being used to direct the
duration of postoperative antimicrobial therapy.
 Gram stain of tissue processed in the microbiology laboratory may be more
sensitive than histopathological Gram stain of tissue sections.
 In cases of blood culture-positive endocarditis, results of valve cultures may cause
unnecessary confusion if valve cultures generate discrepant (i.e., falsely positive)
results.
 In cases of blood culture-negative endocarditis, valve tissue culture still suffers
from low sensitivity and specificity, although growth of an organism does allow
for antimicrobial susceptibility testing.
 When available tissue is insufficient for all tests of interest, culture should not be
prioritized over more sensitive assays, such as molecular testing.

49. Molecular techniques
 Molecular methods are increasingly utilized to aid in the diagnosis of culture-negative endocarditis
and have been applied to both blood and excised valve tissue.
Molecular methods used in endocarditis diagnosis include
 Organism-specific pcr and
 Broad-range bacterial pcr followed by sequencing.
 Currently, these techniques are not widely available in clinical microbiology laboratories, but
laboratory-developed tests (LDTs) performed in specialized reference laboratories and large
clinical laboratories are available.
LDTs using organism-specific primers have been developed for
 C. burnetii,
 Bartonella species,
 T. whipplei,
 C. acnes, M. hominis & others.

50. Molecular techniques
 Due to the relative abundance of bacterial DNA in valve tissue versus blood,
testing of cardiac valve tissue with organism-specific PCR assays is more
sensitive than testing blood or serum.
 Broad-range bacterial PCR, with amplification primers targeting the bacterial
16S rRNA gene, is a molecular method for detecting bacteria in general.
 Following amplification, bacterial identification is determined by sequencing
amplified DNA followed by comparison of the sequence to established databases.
 Although broad-range bacterial PCR has been applied to blood sources,
sensitivity is superior when performed on excised valve tissue.
 It is recommend testing valvular tissue by broad-range bacterial PCR when
histopathologic examination of excised tissue shows acute inflammation.
 Broad-range fungal PCR is technically possible but has low yield for endocarditis
diagnosis due to the rarity of fungi as causes of endocarditis.

51. Molecular techniques
 For diagnosis of culture-negative endocarditis, broad-range bacterial PCR
should not be performed in lieu of organism-specific PCR.
 Caution should be exercised in the interpretation of nucleic acid amplification test
results from removed valves after completion of antibiotic therapy.
 Long-term persistence of bacterial DNA has been reported in patients who have
completed a full course of antibiotic therapy, in some cases several years after
diagnosis of endocarditis.
Conversely, results can be falsely negative
 Due to the presence of PCR inhibitors,
 The presence of microbial nucleic acid below the limit of detection of the assay
being used, or
 Sampling error since microorganisms are often not homogenously distributed in
resected valves.

55. A PROPOSED MICROBIOLOGIC AND PATHOLOGICAL
DIAGNOSTIC ALGORITHM FOR ENDOCARDITIS
 This algorithm is intended for use in patients with clinical and/or
echocardiographic findings suggestive of infective endocarditis based on the
modified Duke criteria.
 Strong recommendations appear in boldface, with other diagnostic testing
considerations shown in standard typeface.
1 Details on blood culture collection are provided in the text.
2 C. burnetii anti-phase I IgG antibody titer of 1:800 is considered
positive.
3 The sensitivity of T. whipplei PCR from blood in endocarditis is
unknown; a negative result should not be used to rule out T. whipplei
endocarditis.
4 If surgery is not performed, consider testing for noninfectious etiologies.

56. A PROPOSED MICROBIOLOGIC AND PATHOLOGICAL
DIAGNOSTIC ALGORITHM FOR ENDOCARDITIS
5 Histologic evaluation is used to evaluate for infectious and noninfectious
etiologies and for correlation with microbiology test results.
6 Ideally, a representative sample of valvular tissue should be specifically
collected for molecular testing in a sterile fashion in the operating room.
7 If sufficient valvular tissue is available after sampling for
histopathological and molecular (microorganism-specific and broad-range)
testing, consider culture and microbiology Gram stain. Due to the low
sensitivity and specificity of culture, molecular testing should be prioritized
over culture.
8 PAS-D, periodic acid-Schiff with diastase. Macrophages infected with T.
whipplei will stain PAS positive following diastase digestion.
9 Examples include Mycoplasma hominis and Cutibacterium (formerly
Propionibacterium) acnes PCR.