Infective Endocarditis

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