Infective Endocarditis

1. Infective Endocarditis MMID Gary Wang, MD PhD Division of Infectious Diseases University of Florida November 8, 2011

2. Outline Epidemiology Pathogenesis & Antibiotic prophylaxis Clinical Manifestations Diagnosis (TEE & Modified Duke Criteria) Complications Treatment (emphasis on early surgery)

3. Case At midnight on July 2, your first night on call as an intern, you’ve just admitted 5 patients and are cross-covering for your co-intern. You got a call from the micro lab. One of the patients your colleague admitted earlier that day, one set of the blood cultures is positive, growing gram positive cocci. The patient is a 40 y.o. female with a history of asthma. One day PTA, she was seen in the ER with several days of low grade fevers, and the initial work up was unrevealing. Blood cultures were drawn and she was sent home. She came back with persistent low grade fevers, and now has pleuritic chest pain and some shortness of breath.

4. What would you do at this time? 1. This is bacterial endocarditis; I’d start her on vancomycin STAT 2. draw one more set of blood cultures to be sure, and start her on vancomycin 3. draw 2 more sets of blood cultures, and start her on vancomycin 4. could be a contaminant; I’d draw 2 more sets of blood cultures and hold off on abx 5. it’s probably a contaminant (coag negative staph); hold off on abx, order tylenol STAT, and go back to bed

5. Infective Endocarditis (IE):definition Infection of the endocardial surface of the heart 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

6. Acute vs. subacute IE Based on the usual progression of the untreated disease and is mainly of historical interest Acute follows a fulminant course, usually with high fever, systemic toxicity, and leukocytosis death occurs in several days to less than 6 weeks Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, or Neisseria gonorrhoeae Subacute death occurring in 6 weeks to 3 months (and the chronic form: death occurring later than 3 months) commonly occur in the setting of prior valvular disease a slow, indolent course with low-grade fever, night sweats, weight loss, and vague systemic complaints classically are caused by the viridans streptococci

7. Outline Epidemiology Pathogenesis Clinical Manifestations Diagnosis (TEE & Modified Duke Criteria) Complications Treatment (emphasis on early surgery)

8. Which group has the highest incidence of endocarditis? Children ages 1-10 y Women age 20-50 Men age 20-50 Women over age 50 Men over age 50

9. Epidemiology IE is relatively uncommon AHA: annual incidence in US is 10,000-20,000 new cases >50% of case over age 50 Male : Female 1.7:1 (1:1 – 3:1 in 18 large series) Aortic valve and Mitral valve most common (age dependent) Tricuspid rarer (iv drug abusers)  Pulmonary valve exceedingly rare

10. Epidemiology Almost any type of structural heart disease may predispose to IE, especially if the defect results in turbulence of blood flow Rheumatic heart disease Congenital heart disease patent ductus arteriosus, ventricular septal defect, coarctation of the aorta, bicuspid aortic valve, tetralogy of Fallot, and, rarely, pulmonic stenosis degenerative cardiac lesions e.g., calcified mitral annulus, calcific nodular lesions secondary to arteriosclerotic cardiovascular disease, post–myocardial infarction thrombus Prosthetic valves Intravascular infections involving cardiac devices e.g., permanent cardiac pacemakers, defibrillators

11. Outline Epidemiology Pathogenesis Clinical Manifestations Diagnosis (TEE & Modified Duke Criteria) Complications Treatment (emphasis on early surgery)

12. Pathogenesis IE probably requires the simultaneous occurrence of several independent events Valve surface first must be altered to produce a suitable site for bacterial attachment and colonization These changes may be produced by various local and systemic stresses, including blood turbulence and the offending organism itself These alterations result in the deposition of platelets, fibronectin, fibrin, and other matrix ligands in the formation of so-called sterile vegetation—the lesions of nonbacterial thrombotic endocarditis (NBTE) Bacteria then must reach this site and adhere to and invade the involved tissue to produce colonization and persistence After colonization, the surface is covered rapidly with a protective sheath of fibrin and platelets to produce an environment conducive to further bacterial multiplication and vegetative growth

13. Proposed scheme for the pathogenesis of IE

14. Nonbacterial Thrombotic Endocarditis (NBTE) Initial colonization occurs on the damaged endothelial surface of the valve In experimental animals, it is almost impossible to produce IE with IV injections of bacteria, unless the valvular surface first is perturbed Damage to the endocardium results in the deposition of platelets, and fibrin Causes of endocardial damage include:1. Rheumatic heart disease (age 10-35)2. Bicuspid Valve (age 50-60) (Most common)3. Calcific Aortic Stenosis (age 60-70)4. Mitral Valve Prolapse (murmur present)5. Marfan’s Syndrome No risk factor in 38% (J.Infect. 38:87-93, 1999)

15. Pathogenesis – hemodynamic factorsVenturi effect Pressure gradient required producing a high-velocity jet stream The high flow results in a Venturi effect (a low pressure area adjacent to the area of high flow) Bacteria to settle in this area of low pressure

16. Venturi effect bacteria and the fibrin-platelet thrombus are deposited on the sides of the low-pressure sink In AS, just beyond a narrowing or stenosis In patients with mitral insufficiency, bacteria and the fibrin-platelet thrombus are located on the atrial surface of the valve In patients with aortic insufficiency, they are located on the ventricular side In the case of a ventricular septal defect, the low-pressure sink is the right ventricle and the thrombus is found on the right side of the defect

17. Transient bacteremia Transient bacteremia occurs whenever a mucosal surface heavily colonized with bacteria is traumatized dental extractions and other dental procedures or with gastrointestinal, urologic, or gynecologic procedures The degree of bacteremia is proportional to the trauma produced by the procedure and to the number of organisms inhabiting the surface Organisms isolated reflect the resident microbial flora. The bacteremia usually is low grade (=10 colony-forming units [CFU]/mL) and transient; the bloodstream usually is sterile in less than 15 to 30 minutes.

18. All but one procedure results in significant bacteremia that can result in endocarditis? Dental extraction Rigid bronchoscopy Urethal dilatation Transurethral prostatectomy Skin biopsy

19. Transient Bacteremia

20. Bacterial adhesion to NBTE Ability of certain organisms to adhere to NBTE lesions is a crucial early step in the development of IE Accounts for the preponderance of certain organisms organisms commonly associated with IE (enterococci, viridans streptococci, S. aureus, S. epidermidis, P. aeruginosa) adhered more avidly to normal canine aortic leaflets in vitro than did organisms uncommon in IE (Klebsiella pneumoniae, E. coli) Adherence of oral streptococci to NBTE may depend on the production of a complex extracellular polysaccharide, dextran S. aureus: ability to destroy normal valves

21. Pathogenesis Host factors Nonbacterial thrombotic endocarditis (NBTE) Venturi effect Bacterial factors Bacterial adherence Transient bacteremia “Vegetation”

22. Vegetation The classic vegetation of IE usually is located along the line of closure of a valve leaflet on the atrial surface of atrioventricular valves or on the ventricular surface of semilunar valves Microscopically, the lesion consists primarily of fibrin, platelet aggregates, and bacterial masses Platelet fibrin complex provides a protective environment. Phagocytes incapable of entering, eliminating an important host defense Pathogenic bacteria often induce platelet aggregation Colony counts in vegetations 10 9-10 11 bacteria/g of tissue

26. Outline Epidemiology Pathogenesis Clinical Manifestations Diagnosis (TEE & Modified Duke Criteria) Complications Treatment (emphasis on early surgery)

27. Case (back to the patient) You decided that you want to get more hx She tells you that 2 week prior to admission, she had removed a splinter from her foot. Over the past week, she has low grade fevers, malaise, and generalized weakness, but no pulmonary/GI/GU Sx

28. What is the most common symptom associated with endocarditis? Shortness of breath Chest pain Fatigue Low grade fever Chills Anorexia

29. How long after the inciting bacteremia does it take for a patient to develop symptoms? < 2 days < 1 week < 2 weeks < 3 weeks One month

30. Clinical Manifestations The interval between an event likely to produce high-grade bacteremia (e.g., dental extraction) and the onset of symptoms of IE is quite short “Incubation period” usually < 2 wks In contrast, the time from onset of symptoms to diagnosis in the subacute form of IE is quite long Time of onset of symptoms until diagnosis is 4-5 wks

31. Signs and symptoms Essentially any organ system may be involved Four processes contribute to the clinical picture: infectious process on the valve embolization to virtually any organ constant bacteremia, often with metastatic foci of infection circulating immune complexes and other immunopathologic factors As a result, the clinical presentation of patients with IE is highly variable, Differential diagnosis often is broad, and the diagnosis of IE may be delayed

39. Signs and symptoms of IE

40. Case You decided to review her admission lab values WBC 9.0 Hct 30 (MCV 90) Cr 1.2 ESR 95 Q: WBC count is normal, this is unusual for IE 1. True 2. False

41. Laboratory Findings in IE Normochromic, Normocytic anemia (90%) WBC usually normal, can be increased High ESR (90-100%) Positive Rheumatoid factor (50%) Hypergammaglobulinemia (20-30%)(false positive lyme or VDRL serology) Proteinuria (50-65%), hematuria (30-50%)

42. Outline Epidemiology Pathogenesis Clinical Manifestations Diagnosis (TEE & Modified Duke Criteria) Complications Treatment (emphasis on early surgery)

43. Modified Duke Criteria for Diagnosis of IE (Clin. Inf. Dis. 30:633, 2000) Definite Infective Endocarditis- 2 major- 1 major & 3 minor- 5 minor Possible Infective Endocarditis- 1 major & 1 minor - 3 minor Duke Criteria Established in 1994 by the Duke Endocarditis Society-- wikiDuke Criteria Established in 1994 by the Duke Endocarditis Society-- wiki

44. Major Criteria Positive blood cultures for IE Two separate + BCx with typical organisms including S. aureus associated with line sepsis, or Persistent + BCx from any organism (i.e. from BCx drawn > 12 hr apart), or All of three or most of four or more separate BCx positive, with first and last specimens drawn at least 1 hr apart Evidence of endocardial involvement Echocardiogram positive for IE (patients with Possible IE a TEE is recommended), or new valvular regurgitation

45. Minor Criteria Predisposition: predisposing heart condition or IVDU Fever > 38°C Vascular phenomenon arterial embolism, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, Janeway lesions Immunologic phenomenon glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor Echocardiogram: findings c/w IE but not meeting major criteria Microbiologic evidence: positive BCx but not meeting major criteria, or serologic evidence of active infection with organism consistent with IE

46. Etiologic Agent in IE Streptococci 60-80%  Viridans Streptococci 30-40%  Enterococci 5-18% Other Streptococci 15-25% Staphylococci 20-35% Coagulase + 10-27% Coagulase - 1-3% Gram Negative aeorobic 1.5-13% Fungi 2- 4% Culture Negative <5-24%

47. HACEK Fastidious organisms, slow growing Hold blood cultures x 4 wks,  Subculture on chocolate agar, 5%CO2 Haemophilus aphrophilus Actinobaccillus actinomycetemcomitans Cardiobacterium hominus Eikenella Kingella An Additional cause of Culture Neg Tropheryma whippelii

48. HACEK Fastidious organisms, slow growing Hold blood cultures x 4 wks,  Subculture on chocolate agar, 5%CO2 Haemophilus aphrophilus Actinobaccillus actinomycetemcomitans Cardiobacterium hominus Eikenella Kingella An Additional cause of Culture Neg Tropheryma whippelii

50. Case The next day right before rounds, you got another call from the micro lab. Both sets of initial BCx are growing gm pos cocci in clusters

51. What do you think the patient has? (i.e. what is your diagnosis?) 1. This is obviously S. aureus endocarditis 2. She has S. aureus bacteremia, and possibly has endocarditis 3. She has S. aureus bacteremia, but no evidence of endocarditis 4. Hmmm, let me look up the Duke criteria, and get back to you in an hour 5. I’ll call ID consult and they’ll tell us the diagnosis

52. Quantitation of Bacteremia in IE

53. Blood Cultures in IE Blood Cultures (15 min intervals) Yield 85-95% on 1st BC 95-100% on the 2nd Recommend 3 BC in the 1st 24 hrs. Low level bacteremia, 100 bacteria/mlDraw at least 10 ml/BC If HACEK group suspected hold 4 wks. Prior antibiotics within 2 wks lower sensitivity

54. What is your next step to confirm the diagnosis of endocarditis? 1. order EKG 2. draw more blood cultures 3. order TTE (transthoracic echo) 4. order TEE (transesophageal echo) 5. order both TTE and TEE 6. call infectious disease consult 7. call cardiology consult

55. Cardiac Echo in IE Transthoracic(TTE): sensitivity 65%If negative order a transesophageal echo Transesophageal(TEE): sensitivity 95-100%Can detect vegetations < 10 mmHelpful in assessing the need for surgeryDetects perivalvular extensionUse in the initial evaluation for suspected IE(if prior probability 4-60%) (useful in S. aureus line sepsis 2 vs 4 wk abx)

57. Outline Epidemiology Pathogenesis & Antibiotic prophylaxis Clinical Manifestations Diagnosis (TEE & Modified Duke Criteria) Complications Treatment (emphasis on early surgery)

58. Cardiac Complications of IE Congestive Heart Failure Myocardial abscess/pericarditis Conduction defects can progress to complete heart block (which valve most commonly is associated with this complication?) Myocardial Infarction

59. Other Complications of IE Emboli - CNS, Splenic, Lung (Rt sided IE) Immune-complex glomerulonephritis Mycotic aneurysms Occur at bifurcations  -Middle cerebral artery -Adominal aorta -Mesenteric arteries

62. Case Initial blood cultures identified as MSSA TTE showed a small vegetation on the tricuspid valve, there is no abscess She is currently on vancomycin, what would you do? Penicillin 20 million units per day x 6 weeks Oxacillin 10 gms per day x 4 weeks Doxycycline 100 mg iv twice per day x 4 weeks Penicillin 20 million units per day combined with gentamicin 80 mg 3 x per day x 2 weeks Chloramphenicol 400 mg four times per day x 4 weeks Ceftriaxone 1 gm per day x 6 weeks

63. Outline Epidemiology Pathogenesis & Antibiotic prophylaxis Clinical Manifestations Diagnosis (TEE & Modified Duke Criteria) Complications Treatment (emphasis on early surgery) IV antibiotics consider surgery evaluation

64. Antibiotic Treatment Prolonged parenteral therapy required Privileged environment of vegetation High number of organisms some dormant Avoid Bacteriostatic agents Serum bacteriocidal level of possible value (1:64 peak, 1:34 trough = 100% cure) Important to follow up blood cultures to document sterilization

65. Antibiotic Treatment (Continued) Penicillin susceptible Streptococci (MBC 0.1-1 ug/ml)PCN x 4 wks or PCN + gentamicin x 2 wk Enterococci (High risk of relapse, MBC to PCN high)PCN (ampicillin) and Gentamicin x 4-6 wks Staphylococcus aureus (coagulase +)Oxacillin or Nafcillin x 4-6 wks

67. Surgery for IE Threshold has loweredDelay to often results in a fatal outcome due to irreversible L. ventricular dysfunction Indications: (1) Refractory CHF, (2) more than one systemic embolus, (3) uncontrolled infection, (4) resistant organisms, (5) perivalvular/myocardial abscess Focal neurological deficit is not a contraindication for surgery

68. SummaryInfective Endocarditis Usually requires an NBTE except S. aureus Organisms that cause IE increased adherence Clinical symptoms usually nonspecific Always look for embolic lesions Duke criterion, importance of timed Blood Cultures, use of TEE Privileged environment of vegetation requires prolonged cidal antibiotics Low threshold for surgery