1. National Institutes of Health National Institute of Allergy and Infectious Diseases Infective Endocarditis

2. Talk Outline History Epidemiology Pathophysiology Risk factors Clinical presentation Causes How to diagnose Treatment Special groups

3. Alois Alzheimer

4. Alois Alzheimer 1906 identified an 'unusual disease of the cerebral cortex' which caused memory loss, disorientation, hallucinations and ultimately death and was associated with cerebral plaques and neurofibrillary tangles.

5. Alois Alzheimer 1906 identified an 'unusual disease of the cerebral cortex' which caused memory loss, disorientation, hallucinations and ultimately death and was associated with cerebral plaques and neurofibrillary tangles. Died in 1915 (age 51) from endocarditis.

6. Orville Gibson

7. Guitar manufacturer.

8. Orville Gibson Guitar manufacturer. Died in 1918 (age 62) from endocarditis.

9. Gustav Mahler

10. Gustav Mahler Composer. Mahler died on May 18, 1911, at age 50 from endocarditis. He never heard the Ninth Symphony performed. The Ninth tale By Kevin Berger / SALON

11. Why was infective endocarditis such a bad disease in the early 1900s?

12. Why was infective endocarditis such a bad disease in the early 1900s?  No antibiotics  No cardiac surgery

13. Is infective endocarditis still a problem now?

14. Is infective endocarditis still a problem now? YES ● AHA estimates there are 10,000-20,000 cases per year in the U.S. ● The incidence of disease (about 5 cases/100,000 pt years) has not changed in several decades!! ● Mortality is 20-30% at 1 year (for GNRs and fungi is 50%) Most common valves: Mitral valve (40%), Aortic valve (36%), then multivalvular. R sided <10% of all cases.

15. BUT, endocarditis is NOT the same disease it was a century ago. “Almost all aspects of the disease, including its natural history, predisposing factors, sequelae, and causative organisms, are virtually unrecognisable compared with Osler’s original descriptions from the 19 th century.” B.D. Prendergast Heart 2006;92;879-885.

16. Reasons IE remains a problem and why its clinical manifestations have changed  less rheumatic heart disease  more degenerative valve disease in the elderly  replacement valves  intravenous drug use  vascular instrumentation  resistant bacteria  earlier diagnosis  detection of previously unknown pathogens

17. Pathophysiology Damaged epithelium results in exposed stromal cells and extracellular matrix proteins. This triggers deposition of fibrin-platelet clots. Streptococci can bind to fibrin-platelet clots and Staphylococcus aureus can bind to beta-1 integrins expressed by inflamed endothelial cells. Heart 2006;92;879-885.

18. Pathophysiology Endothelial disruption also results in coagulation at site of defect. Bacteria bind to the clot. Cycle of monocyte activation and cytokine release contribute to a progressive inflammation and enlargement of the infected vegetation. Local extension and tissue damage may result in abscess formation. Ultimately septic emboli may disseminate to brain, spleen, and kidney. Heart 2006;92;879-885.

19. Pathophysiology Endothelial Damage Thrombus Bacterial Seeding Maturation of vegetation (deposition of fibrin, proliferation of bacteria)

20. Pathophysiology Endothelial Damage Thrombus Bacterial Seeding Maturation of vegetation (deposition of fibrin, proliferation of bacteria) Why is endocarditis so difficult to Rx?

21. Pathophysiology Endothelial Damage Thrombus Bacterial Seeding Maturation of vegetation (deposition of fibrin, proliferation of bacteria) Why is endocarditis so difficult to Rx? absence of vasculature makes delivery of Abx to bacteria within mature vegetation difficult

22. Risk factors for infective endocarditis?

23. Risk factors for infective endocarditis? ● underlying heart disease -degenerative aortic and mitral valve disease -rheumatic heart dz (less common) ● prosthetic valve or prior valve surgery ● previous infective endocarditis ● IVDU ● iatrogenic or nosocomial infection prior dental surgery?  risk likely overemphasized NOTE: in one recent study 47% of patients with infective endocarditis had no previous knowledge of an underlying cardiac disorder. JAMA 2002;288:75-81.

24. Clinical Presentation of IE -SYMPTOMS-

25. Clinical Presentation of IE -SYMPTOMS- -FEVER (90% of pts, but may be absent  esp in elderly) -Chills -Sweats -Poor appetite -Weight loss NOTE: emboli to brain, spleen, or lung occur in 30% of patients and are often the presenting symptom  Focal neurologic change if septic embolus to CNS OR if development of a mycotic aneurysm  Cough/SOB/chest pain if septic embolus to lungs  Abdominal pain if septic embolus to spleen

26. Clinical Presentation of IE -SIGNS-

27. Clinical Presentation of IE -SIGNS- -HEART MURMUR (85%) -Cutaneous manifestations of DIC -Focal neurologic deficits -Embolic phenomena  Roth spots  Janeway lesions  Osler’s nodes  distal infarcts of digits

28. Purpuric lesions on the arm of a woman with staphylococcal endocarditis.

29. Roth spots: “white-centered” hemorrhages. Likely are microinfarcts. In addition to endocarditis, occur in HTN, HIV, connective tissue disease, severe anemia, Behçet's disease, viremia, & hypercoagulable states.

30. Osler’s nodes -small hemorrhages with nodular quality on fingers, palms, and soles -very uncommon -likely septic emboli (could culture these) -no real difference between these and Janeway lesions (some say Osler’s nodes on digit tips and tender and Janeway lesions on palms/soles and non-tender) Note: Mahler, who had streptococcal endocarditis, developed septic abscesses all over his body. We just don’t see this anymore. Merk Medicus online

31. What about splinter hemorrhages?

32. What about splinter hemorrhages?  Splinter hemorrhages have been reported in up to 66% of all hospital admissions and in up to 56% of all healthy adults. (Sapira 1996)

33. splinter hemorrhages Merk Medicus online

34. Clinical Presentation of IE -LAB VALUES-

35. Clinical Presentation of IE -LAB VALUES- Nothing particularly helpful. -Elevated ESR or CRP -May have elevated WBC count as well as other changes in CBC. -May see changes c/w glomerulonephritis (due to immune complex deposition and/or septic emboli)

36. So, how is the prognosis for patients diagnosed with infective endocarditis?

37. So, how is the prognosis for patients diagnosed with infective endocarditis? Not good. ANNUAL MORTALITY FROM INFECTIVE ENDOCARDITIS APPROACHES 40%. Arch Intern Med 2002;162:90-4.

38. Clinical complications of IE HEARTOTHER heart failurevertebral osteomyelitis perivalvular abscessseptic arthritis pericarditismetastatic abscesses Ao valve dsxn BRAIN abscess meningitis encephalopathy hemorrhage KIDNEY infarct abscess glomerulonephritis

39. NNMC case from 8/07 (with thanks to Dr. Mark Johnson) 31yo M Symptoms for a few weeks, dental procedure 2 months prior Fevers HA Homonymous hemianopsia + MURMUR (and possible Osler’s node)

40. TTE  large MV anterior leaflet vegetation BlCx’s positive with Streptococcus mitis Brain MRI c/w L MCA septic embolism  Treated with PCN/gent and, developed heart failure from mitral regurgitation  Taken to OR

42. Had a mechanical valve placed. Placed on anticoagulation. Had a cerebral angiogram done which showed a 4mm right sided parietal “mycotic” (really, “infected” aneurysm). That vessel was then closed/filled with a glue by interventional neurology.

43. Morbidity in this 31 yo pt

44. Morbidity in this 31 yo pt 1.Stroke causing loss of vision 2.Infected brain aneurysm that required interventional embolization that may still have chance of bleeding. 3.In-hospital stay for >1 month with long course of Abx. 4.Had to undergo open heart surgery and now has a mechanical valve which  will probably need to be changed at some point  high risk for endocarditis 5.On life-long anticoagulation.

45. Because this is a highly morbid disease and because the clinical presentation is usually pretty non-focal (fever and chills), what is the best thing we can do on exam to help us think about the possibility of endocarditis?

46. Because this is a highly morbid disease and because the clinical presentation is usually pretty non-focal (fever and chills), what is the best thing we can do on exam to help us think about the possibility of endocarditis?  Do a careful examination for a heart murmur in all patients with fever.

49. Etiologic agents of IE

50. Etiologic agents of IE AgentCases (%) Streptococci70% Viridans streptococci35% Enterococci10% other streptococci20% Staphylococci20% coagulase +18% coagulase - 2% Aerobic GNRs 5% Fungi 2% Miscellaneous bacteria <5% Culture Negative <5-25%

51. Agents that make you think of endocarditis when they grow in the blood AgentEndocarditis/non-endocarditis Streptococcus mutans14:1 Streptococcus bovis 6:1 Streptococcus mitior 3:1 Streptococcus sanguis 3:1 Unclassified viridans strep 1.4:1 Adapted from PPID AND….when we diagnose which organism from a line infection?

52. Agents that make you think of endocarditis when they grow in the blood AgentEndocarditis/non-endocarditis Streptococcus mutans14:1 Streptococcus bovis I 6:1 Streptococcus mitior 3:1 Streptococcus sanguis 3:1 Unclassified viridans strep 1.4:1 Adapted from PPID AND….Staphylococcus aureus in the setting of a line infection S. aureus line infection carries a 22% likelihood of endocarditis.

53. How to diagnose endocarditis

54. How to diagnose endocarditis BLOOD CULTURES!!!! Three sets of PERIPHERALLY drawn blood cultures drawn one hour apart before the introduction of antibiotics. How much to draw?

57. How to diagnose endocarditis If antibiotics were started before adequate blood cultures were drawn, what can be done to make a microbiologic dx?

58. How to diagnose endocarditis If antibiotics were started before adequate blood cultures were drawn, what can be done to make a microbiologic dx? Strongly consider stopping antibiotics for 24-48 hours and then obtaining blood cultures.

59. How else to diagnose endocarditis

60. How else to diagnose endocarditis ECHOCARDIOGRAPHY Classic finding is of an oscillating intracardiac mass on a valve or in the path of a regurgitant jet. Other possible findings: abscess, dehiscence of a prosthetic valve, aneurysm, fistula, leaflet perforation.

61. What kind of ECHO?

62. What kind of ECHO? TEE  93% sensitive TTE  46% sensitive Both are very specific.

64. Diagnostic value of harmonic transthoracic echocardiography in native valve infective endocarditis: comparison with transesophageal echocardiography Davinder S Jassal, 1,2 Amin Aminbakhsh, 1 Tielan Fang, 2 Nasir Shaikh, 1 John M Embil, 3 Gordon S Mackenzie, 4 and James W Tam 1 2007 The sensitivity for the detection of vegetations by hTTE was 84%

65. Modified Duke criteria Definite infective endocarditis -Pathological criteria positive -Two major criteria -One major and three minor -Five minor criteria Major Criteria -2 + BlCxs with typical endocarditis organisms -2 +BlCxs taken >12hrs apart for other bacteria -Single + BlCx or positive serology for Coxiella -Positive echo showing moving structures, abscess, new regurgitation, other Minor Criteria -Prior heart dz -Fever -Immunological phenomena (GN, Osler’s nodes, Roth spots) -Increased CRP or ESR -Vascular phenomena (emboli, petechiae, purpura, splinters) -Microbiological data not fitting major criteria (Viridans strep, S. bovis, HACEK, S. aureus, enterococcus)

66. Treatment of Infective Endocarditis is multidisciplinary (primary team, surgical team, micro dept) ABX (typically 6 weeks from time of negative cultures) + possible surgery

67. What antibiotics to give? http://www.idsociety.org/pg/toc.htm

68. Indications for surgery

69. Some indications for surgery ≥1 embolic events during 1 st two weeks of Abx Increasing vegetation size or + BlCxs despite Abx Heart failure unresponsive to medications Valve perforation/rupture, dehiscence New heart block Large abscess Organism known to be difficult to Rx with Abx alone About 40% of all patients with endocarditis go to surgery (Candida, Pseudomonas)

70. What if the blood cultures are negative? (this occurs about 15% of the time) Reasons this occurs:

71. What if the blood cultures are negative? (this occurs about 15% of the time) Reasons this occurs: 1.slow-growing bacteria (ex Coxiella and Bartonella species) 2.Nonbacterial organisms (eg fungi) 3.Antibiotic administration preceding blood cultures

72. Culture negative endocarditis CAUSES Nutritionally-variant streptococci Fastidious GNR of HACEK group Haemophilus parainfluenza, aphrophilus, paraphrophilus, influenza Aggregatibacter actinomycetemcomitans Cardiobacterium hominis Eikenella corrodens Kingella kingae and denitrificans Brucella species Coxiella burnetii Bartonella species Chlamydia species Legionella species Mycoplasma species Tropheryma whipplei Fungi (Candida, Histoplasma, and Aspergillus)

73. Culture negative endocarditis CAUSES Nutritionally-variant streptococci Fastidious GNR of HACEK group Haemophilus parainfluenza, aphrophilus, paraphrophilus, influenza Actinobacillus actinomycetemcomitans Cardiobacterium hominis Eikenella corrodens Kingella kingae and denitrificans Brucella species Coxiella burnetii Bartonella species Chlamydia species Legionella species Mycoplasma species Tropheryma whipplei Fungi (Candida, Histoplasma, and Aspergillus)

74. C. burnetii in 167 cases (48 percent) Bartonella spp in 99 cases (28 percent) Streptococci in 4 cases Tropheryma whipplei in 2 cases Abiotrophia elegans in 1 case Mycoplasma hominis in 1 case Legionella pneumophila in 1 case Escherichia coli in 1 case

75. Culture negative endocarditis WORK-UP First thing to do?

76. Culture negative endocarditis WORK-UP Step 1: Talk to the microbiology lab

77. Culture negative endocarditis WORK-UP Step 1: Talk to the microbiology lab  hold BlCxs for 3-4 weeks  lysis centrifugation culture tubes good for fungi and Bartonella  shell vial culture tubes good for Coxiella, Bartonella, T. whipplei, and Brucella  special medias  blind sub onto chocolate agar

78. Nutritionally-variant streptococci  blood culture Fastidious GNR of HACEK group  Long term blood CX Haemophilus parainfluenza, aphrophilus, paraphrophilus, influenza Actinobacillus actinomycetemcomitans Cardiobacterium hominis Eikenella corrodens Kingella kingae and denitrificans Brucella species  blood culture, serology; Cx, IH and PCR of tissue Coxiella burnetii  serology; Cx, IH and PCR of tissue Bartonella species  blood culture, serology; Cx, IH and PCR of tissue Chlamydia species  serology; Cx, IH and PCR of tissue Legionella species  blood culture, serology, UAg; Cx, IH, and PCR of tissue Mycoplasma species  serology; Cx, IH and PCR of tissue Tropheryma whipplei  IH and PCR of tissue Fungi (Candida, Histoplasma, and Aspergillus)  blood culture IH = immunohistology

79. Culture negative endocarditis Empiric therapy?

80. Culture negative endocarditis Empiric therapy?  Try to tailor therapy to the organisms for which the patient is most at risk

82. Reasons we REALLY want to know the organism Recommended regimens for Cx negative endocarditis Native valve amp/sulbactam + gentamicin OR vancomycin + gentamicin + ciprofloxacin Prosthetic valve vancomycin + gentamicin + cefepime + rifampin Suspected Bartonella Ceftriaxone + gentamicin + doxycyline  keep in mind, these don’t take into account our high rate of community acquired MRSA

83. At the end of antibiotic therapy, re-evaluate valve by echocardiography

84. IE –special groups What type of heart infection causes this image on CT?

85. IE –special groups IVDU Endocarditis risk 1-5% per year Infection often right sided (50% of time) Staphylococcus aureus is most common pathogen Prosthetic valves Endocarditis risk 0.1-2.3% PER YEAR NEED TEE to evaluate Staphylococci predominate early Late, infxs spectrum resembles that of naïve valves Complications common (esp Ao root abscess) Mortality >40%

86. IE – Prevention (2007 AHA guidelines) Recommendations revised b/c ● Endocarditis more likely from frequent exposure to random bacteremias from daily activities than from dental/GI/GU procedures. ● Prophylaxis likely protects an exceedingly small, if any, cases of endocarditis. TRANSIENT BACTEREMIA Tooth extraction: 10-100% Peridontal surgery 40-90% Teeth cleaning 40% Tooth brushing/flossing: 20-70% Wooden toothpicks: 20-40% Chewing food: up to 50% To reduce risk of bacteremia from dental procedures: MAINTAIN GOOD ORAL HEALTH

87. IE – Prevention (2007 AHA guidelines) Prophylaxis ONLY for high-risk patients 1) prosthetic heart valve 2) previous infective endocarditis 3) complex congenital heart disease 4) valvulopathy after heart transplant ONLY prior to dental procedures involving manipulation of gingival tissue or periapical region of teeth or perforation of oral mucosa NOT prior to GI or GU procedures JACC 2008 v52 (8) 676-85 Single dose 30-60min b/f oral amoxicillin 2 g cephalexin 2g clindamycin 600mg azithromycin 500mg iv ampicillin 2g cefazolin or ceftriaxone 1g clindamycin 600mg Also NOT for intubation, cardiac cath, pacer placement, TEE

88. Take home points a common, highly lethal infection signs: fever and murmur get TEE in pts that develop S. aureus line infections get ECHO and draw 3 sets of large volume blood cultures OFF abx in patients suspected of endocarditis talk with the microbiology lab and the surgeons

89. In the summer of 1896, the German conductor Bruno Walter visited Mahler in the Austrian alps and gazed up at the steep cliffs. The bold composer told his young acolyte not to bother looking at them. "I have already composed that all away," he said. He was referring to his Third Symphony, with its exhilarating peaks of cellos and basses, rushing river of trumpets and trombones.