infective endocarditis clinical sign symptoms

1. Infective Endocarditis
Matthew Leibowitz, MD
David Geffen School of Medicine at UCLA
Division of Infectious Diseases

2. Epidemiology
• 10-20,000 cases per year in the US
• Male:Female ratio 1.7:1
• New trends
– Mean age was 30 in 1926, now > 50% of
patients are over 60
– Decline in incidence of rheumatic fever
– More prosthetic valves
– More nosocomial cases, injected drug use
– More staphylococcal infection

3. Epidemiology
• Mitral valve alone 28-45%
• Aortic valve alone 5-36% (bicuspid
valve in 20% of all native valve IE)
• Both mitral and aortic valves 0-36%
• Tricuspid valve 0-6%
• Pulmonic valve <1%
• Right and left sided 0-4%

4. Classification
• OLD
– Subacute Bacterial Endocarditis
• Death in 3-6 months
– Acute Bacterial Endocarditis
• Death in < 6 weeks
• NEW
– Native Valve Endocarditis
– Prosthetic Valve Endocarditis

5. Pathogenesis
• Alteration of the valvular endothelial
surface leading to deposition of
platelets and fibrin
• Bacteremia with seeding of non-
bacterial thrombotic vegetation (NBTE)
• Adherence and growth, further platelet
and fibrin deposition
• Extension to adjacent structures
– Papillary muscle, aortic valve ring abscess,
conduction system

6. Pathogenesis
• Low pressure side of structural lesion
– Atrial side of mitral valve (MR)
– Ventricular side of aortic valve (AR, AS with R)
– Congenital abnormality (MV prolapse, bicuspid AV)
– Scarring from rheumatic heart disease or sclerosis
as a consequence of aging
– Prosthetic valves
• Other turbulence, high-velocity jets
– Ventricular septal defect
– Stenotic valve
• Direct mechanical damage from catheters,
pacemaker leads

7. Pathogenesis
• Transient bacteremia
– Traumatization of mucosal surface
colonized with bacteria (oral, GI)
– Low grade, cleared in 15-30 minutes
– Susceptibility to complement-mediated
bacterial killing
• Leads to concept of prophylaxis

9. Microbiology
• Staphylococcus aureus (30-40%)
• Viridans group streptococci (18%)
• Enterococci (11%)
• Coagulase-negative staphylococci (11%)
• Streptococcus bovis (7%)
• Other streptococci (5%)
• Non-HACEK Gram negatives (2%)
• HACEK Organisms (2%)
• Fungi (2%)
• “Culture negative” (2-20%)

10. Characteristics of Causative Organisms
• Adherence factors critical for growth in the
vegetation
– Can adhere to damaged valves (Staph, Strep and
Enterococci have adhesins that mediate
attachment)
– Staph adhesin binds fibrinogen and fibronectin
– Bacteria trigger tissue-factor production from local
monocytes and induce platelet aggregation so the
organisms become enveloped in the vegetation
– Protection from immune clearance leads to large
numbers of bacteria (109
-1010
per g of tissue)

11. Risk Factors
• Structural heart disease
– Rheumatic, congenital, aging
– Prosthetic heart valves
• Injected drug use
• Invasive procedures (?)
• Indwelling vascular devices
• Other infection with bacteremia (e.g.
pneumonia, meningitis)
• History of infective endocarditis

12. Clinical Manifestations
• Symptoms
– Fever, sweats, chills
– Anorexia, malaise, weight loss
• Signs
– Anemia (normochromic, normocytic)
– Splenomegaly
– Microscopic hematuria, proteinuria
– New or changing heart murmur, CHF
– Embolic or immunologic dermatologic signs
– Hypergammaglobulinemia, elevated ESR, CRP,
RF

14. Cardiac Pathologic Changes
• Vegetations on valve closure lines
• Destruction and perforation of valve
leaflet
• Rupture of chordae tendinae,
intraventricular septum, papillary muscles
• Valve ring abscess
• Myocardial abscess
• Conduction abnormalities

15. S. Aureus mitral valve vegetation, anterior
leaflet

17. Pathologic Changes
• Kidney
– Immune complex glomerulonephritis
– Emboli with infarction, abscess
• Aortic mycotic aneurysms
• Cerebral embolism
– Infarction, abscess, mycotic aneurysms
– Purulent meningitis is rare

19. Pathologic Changes
• Splenic enlargement, infarction
• Septic or bland pulmonary embolism
• Skin
– Petechiae
– Osler nodes: diffuse infiltrate of neutrophils, and
monocytes in the dermal vessels with immune
complex deposition. Tender and erythematous
– Janeway lesions: septic emboli with bacteria,
neutrophils and SQ hemorrhage and necrosis.
Blanching and non-tender. Palms and soles

24. Case Definition
• 1977 Pelletier and Petersdorf criteria
• 1981 von Reyn criteria
• 1994 Duke criteria
• 2000 Modified Duke criteria

25. Modified Duke Criteria
• Major Criteria
–Positive blood cultures with typical
organisms
–Persistently positive blood cultures
–Evidence of Endocardial involvement
• Positive Echocardiogram
– Oscillating intracardiac mass
– Abscess
– Dehiscence of prosthetic valve
• New Valvular regurgitation

26. Modified Duke Criteria
• Minor Criteria
– Predisposition (valvular disease or IDU)
– Fever
– Vascular phenomena (Arterial emboli,
septic pulmonary infarcts, intracranial
hemorrhage, Osler, Janeway)
– Immunologic phenomena (GN, Osler, Roth
spots, Rheumatoid Factor)

27. Modified Duke Criteria
• Definite IE
– Pathologic criteria
– Clinical criteria
• 2 Major Criteria OR
• 1 Major and 3 minor Criteria OR
• 5 Minor Criteria
• Possible IE
• 1 Major and 1 Minor OR
• 3 Minor
• Rejected IE

28. Blood Cultures
• MULTIPLE BLOOD CULTURES
BEFORE EMPIRIC THERAPY
• If not critically ill
– 3 blood cultures over 12-24 hour period
– ? Delay therapy until diagnosis confirmed
• If critically ill
– 3 blood cultures over one hour
• No more than 2 from same venipuncture
• Relatively constant bacteremia

29. “Culture Negative” IE
• Less common with improved blood
culture methods
• Special media required
– Brucella, Mycoplasma, Chlamydia,
Histoplasma, Legionella, Bartonella
• Longer incubation may be required
– HACEK
• Coxiella burnetii (Q Fever), Trophyrema
whipplei will not grow in cell-free media

30. HACEK
• Haemophilus aphrophilus, H.
paraphrophilus, parainfluenzae
• Actinobacillus actinomycetemcomitans
• Cardiobacterium hominis
• Eikenella corrodens
• Kingella kingae

31. Other microbiologic methods
• PCR
– Coxiella burnetii
– Tropheryma whipplei
– Bartonella henselae
• Serology
– Coxiella burnetii
– Bartonella
– Brucella
– Legionella
– Chlamydophila psittaci

32. Echocardiography
• Transthoracic
– Relatively low sensitivity
– Good specificity
• Transesophageal
– Detection of valve ring abscess (87% vs.
28% sensitivity for TTE)
– Detection of prosthetic valve IE

33. When to go to TEE first?
• Limited thoracic windows = TTE low
sensitivity
• Prosthetic valves
• Prior valvular abnormality
• S. aureus bacteremia and suspected IE
• Bacteremia with organisms likely to
cause IE
= high prior probability of IE

34. Other tests
• Electrocardiogram
– Conduction delays
– Ischemia or infarction
• Chest X-ray
– Septic emboli in right-sided IE
– Valve calcification
– CHF

35. Treatment of IE
• Native vs. Prosthetic Valve
• Bactericidal therapy is necessary
• Eradication of bacteria in the vegetation
– May be metabolically inactive (stationary
phase)
– May need higher concentrations of
antimicrobial agents

36. Antimicrobial Therapy
• Most patients are afebrile in 3-5 days
• Long duration of therapy (4-6 weeks or
more)
• Combination therapy most important for
– Shorter course regimens
– Enterococcal endocarditis
– Prosthetic valve infections

37. Native Valve IE
• Viridans Streptococci and S. bovis
– Aqueous Penicillin G 12-20 million
units/day continuously or divided q4 or q6
for 4 weeks
– If intermediate susceptibility to penicillin,
aqueous penicillin G 24 million units or
ceftriaxone 2 g q24 PLUS aminoglycoside
for the first 2 weeks

38. Native Valve IE
• Aminoglycosides for synergy
– Low concentrations are adequate (1-3
mcg/ml)
– Gentamicin 3 mg/kg divided q12 or q8
– Little data for q24 dosing

39. Native Valve IE
• Enterococci, ampicillin sensitive
– High rates of failure
– β-lactams are bacteriostatic, must combine with
aminoglycoside for optimal therapy
– High-level gentamicin resistance occurs in 35%
• High-dose ampicillin for 8-12 weeks
• Enterococci, ampicillin resistant
– Vancomycin plus gentamicin
• Enterococci, vancomycin resistant
– Linezolid or daptomycin
– Penicillin + vancomycin + gentamicin ?

40. Native Valve IE
• S. aureus
– Penicillinase-resistant semi-synthetic
penicillin (oxacillin or nafcillin) 1.5-2 g IV q4
or cephalosporin (cefazolin 1-2 g IV q8) for
4-6 weeks
– Aminoglycoside synergistic but does not
affect survival, not recommended
– Short course in right-sided IE
• 2 weeks of semi-synthetic penicillin and
aminoglycoside

41. Native Valve IE
• Methicillin-resistant S. aureus
– Vancomycin is bacteriostatic
– Vancomycin plus aminoglycoside or
rifampin
– Daptomycin
– Linezolid

42. Native Valve IE
• HACEK
– Ceftriaxone 2 g IV q 24 x 4-6 weeks
• Fungal
– Amphotericin
– Fluconazole
– Caspofungin, little data
– Surgery usually necessary 1-2 weeks into
treatment

43. Native Valve IE
• Indications for surgery
– Refractory CHF
– More than one systemic embolic event
– Uncontrolled infection
– Physiologically significant valvular
dysfunction
– Ineffective antimicrobial therapy (e.g.
fungal)
– Local suppurative complications
– Mycotic aneurysm

44. Prosthetic Valve IE
• Staphylococci most common
– Coagulase negative staphylococci
• Enterococcus
• Nutritonally variant streptococci
• Fungi

45. Prosthetic Valve IE
• Risk is greatest in the first 3 months and
first year (early PV IE)
– Coagulase-negative staphylococci in early
endocarditis, S. aureus
– Late-onset more similar to native valve
disease in microbiology but more
coagulase-negative staphylococci. Valve is
endothelialized

46. Prosthetic Valve IE
• TEE should be used first
• Staphylococci
– Vancomycin or oxacillin plus rifampin for at
least six weeks, gentamicin for the first two
weeks (3 mg/kg q24)
– Rifampin started at least 2 days after 2
other agents to avoid resistance

49. Prophylaxis of IE
• Uncertainty and controversy
• No randomized trials
• Indirect evidence (uncontrolled clinical
series, case-control studies)
• Decision analysis

54. Clinical Case
• 43 yo man ESRD, Cadaveric Renal
Transplant 2004
• Recurrent UTIs, placement of
nephrostomy tube
• Fevers, chills, altered mental status,
sepsis syndrome
• Bradycardia to 35 and increased PR

55. Clinical Case
• Urine with MRSA, 4/4 blood cultures with MRSA
• Initial TTE: EF 35-45%, thickened AV with moderate
AS, thickened or calcified MV mild MR
– “Compared with last previous echo, 3/3/00, there is no
significant change. In the presence of valvular thickening,
cannot rule out endocarditis.
• Next day TEE
– thickened AV, mild to moderate AS, no AR. 2 vegetations
~1 cm on ventricular side
– Markedly thickened MV, large mobile vegetation >4cm on
atrial side anterior leaflet, possible second vegetation on
posterior leaflet, mild MR

56. Clinical case
• Renal allograft removed the following
day with abscess
• Replacement of AV and MV and
resection of left ventricular abscess
cavity two days later