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

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

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%

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

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

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

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

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%)

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 ( per g of tissue)

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

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

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

S. Aureus mitral valve vegetation, anterior leaflet

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

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

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

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

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)

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

Blood Cultures MULTIPLE BLOOD CULTURES BEFORE EMPIRIC THERAPY If not critically ill –3 blood cultures over 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

“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

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

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

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

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

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

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

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

Native Valve IE Viridans Streptococci and S. bovis –Aqueous Penicillin G 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

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

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 ?

Native Valve IE S. aureus –Penicillinase-resistant semi-synthetic penicillin (oxacillin or nafcillin) 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

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

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

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

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

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

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

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

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

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

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