Infective Endocarditis

Matthew Leibowitz, MDDavid 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 15-30 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 (109-1010 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 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

“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 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

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) 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

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