Infective & Nonbacterial Endocarditis

Pathogenesis: how a vegetation forms

The nidus. Normal endothelium resists bacterial attachment. Turbulent flow from regurgitant jets and stenoses, or foreign material such as a prosthetic valve, injures the endocardium. Platelets and fibrin then deposit as a small sterile thrombus. A transient bacteremia from the teeth, skin, or GU or GI tract lets organisms adhere to this nidus and multiply. Layers of fibrin and platelets bury the bacteria, shielding them from neutrophils, and the vegetation sheds organisms continuously, so the bacteremia of endocarditis is sustained.

Virulence decides the valve. Low-virulence organisms such as viridans streptococci need a pre-damaged valve. Staphylococcus aureus can attach to and invade normal endothelium, so it causes acute endocarditis on previously healthy valves.

Acute versus subacute disease and the organisms

Acute endocarditis. S. aureus is the most common cause of infective endocarditis (IE) overall and of acute IE. Illness evolves over days with high fever and sepsis. Large, friable vegetations perforate leaflets and form perivalvular (ring) abscesses, and septic emboli seed metastatic abscesses. Mortality is high without prompt bactericidal therapy, and many patients need surgery.

Subacute endocarditis. Viridans streptococci (S. sanguinis, S. mutans, S. mitis) are α-hemolytic, optochin-resistant mouth flora, unlike the optochin-sensitive, bile-soluble S. pneumoniae. They enter the blood during dental work and infect valves already damaged by rheumatic disease, congenital lesions, or mitral valve prolapse with regurgitation. Dextran, a glucan they make from sucrose, binds the fibrin-platelet deposits. By contrast, protein A and TSST-1 are S. aureus factors, and M protein belongs to S. pyogenes. Weeks to months of low-grade fever, fatigue, and weight loss follow.

Enterococcus. Enterococcus faecalis causes subacute IE in older adults after urinary catheterization, cystoscopy, or GI procedures. It grows in 6.5% NaCl and on bile-esculin and is intrinsically resistant to cephalosporins. Treatment therefore pairs ampicillin with gentamicin or ceftriaxone for synergy.

Streptococcus gallolyticus. Formerly S. bovis biotype I, it is a nonenterococcal group D streptococcus that grows on bile-esculin but, unlike enterococci, not in 6.5% NaCl. Its bacteremia and endocarditis are strongly associated with colorectal adenoma and carcinoma, so every such patient needs a colonoscopy.

Prosthetic valves. Staphylococcus epidermidis (catalase-positive, coagulase-negative, novobiocin-sensitive) forms an extracellular polysaccharide biofilm on prosthetic valves, pacemaker leads, and catheters. With S. aureus, it dominates early prosthetic valve endocarditis. Prosthetic infection is best seen with TEE and frequently requires repeat valve surgery.

Culture-negative endocarditis. The commonest reason cultures stay sterile is antibiotics given before they were drawn. The fastidious causes are:

• HACEK gram-negative oral flora: Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella.
• Coxiella burnetii (Q fever), acquired from the birth products of farm animals and diagnosed by serology.
• Bartonella: B. quintana in homeless people with body lice, and B. henselae from cats.

Clinical findings and complications

Valves and emboli. The mitral valve is infected most often overall, followed by the aortic valve. The tricuspid valve dominates in injection drug use, usually with S. aureus (sometimes Pseudomonas or Candida). Its holosystolic murmur at the left lower sternal border grows louder with inspiration (Carvallo sign) as venous return to the right heart rises. Its septic pulmonary emboli produce multiple peripheral, often cavitating, lung nodules. Left-sided fragments travel systemically to the brain (stroke), spleen (infarct or abscess), kidneys (infarct with hematuria), gut, and limbs.

General findings. Fever occurs in about 90% of patients, and a new or changed regurgitant murmur is frequent. Subacute disease adds fatigue, weight loss, splenomegaly, clubbing, a normocytic anemia of inflammation, elevated ESR and CRP, and a positive rheumatoid factor. The peripheral stigmata are:

• Osler nodes: tender, raised violaceous nodules on the finger and toe pads from immune-complex vasculitis; they favor subacute disease.
• Janeway lesions: painless, flat, hemorrhagic macules on the palms and soles from septic microemboli with microabscesses; they favor acute disease.
• Roth spots: retinal hemorrhages with pale fibrin centers, also seen in leukemia and severe anemia.
• Splinter hemorrhages: linear red-brown streaks under the nails; nonspecific, since trauma causes many.
• Petechiae of the conjunctiva and palate.

Kidney. Prolonged bacteremia generates circulating immune complexes that deposit in glomeruli and fix complement (type III hypersensitivity). The result is a proliferative glomerulonephritis with hematuria, RBC casts, and low C3. Separately, emboli cause wedge-shaped renal infarcts with flank pain and hematuria.

Mycotic aneurysm. Septic emboli lodge in the lumen or vasa vasorum of an artery and weaken its wall. Cerebral mycotic aneurysms sit at distal branch points, often in middle cerebral territory; congenital berry aneurysms, by contrast, sit at proximal circle of Willis bifurcations. Rupture causes subarachnoid or intracerebral hemorrhage and may be the first sign of IE. "Mycotic" is historical: Osler thought the lesions resembled fungal growths, but most are bacterial.

Cardiac destruction. Leaflet perforation or chordal rupture produces acute regurgitation and heart failure, the leading cause of death in IE. A perivalvular (ring) abscess, most often from aortic valve infection, burrows into the septum near the AV node and His bundle.

New PR prolongation or AV block in a patient with endocarditis means a perivalvular abscess until proven otherwise.

Diagnosis: the Duke criteria

Major criteria. The first is a typical organism in at least two separate blood cultures, or persistently positive cultures; for Coxiella, one positive culture or a high phase I IgG titer is enough. The second is evidence of endocardial involvement: a vegetation, an abscess, or new valvular regurgitation.

Minor criteria. These are a predisposing heart lesion or injection drug use, and fever ≥38 °C. Vascular phenomena count (arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, Janeway lesions), as do immunologic phenomena (glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor). The last is microbiologic evidence that falls short of a major criterion.

Nonbacterial endocarditis

Nonbacterial thrombotic (marantic) endocarditis. Hypercoagulable, wasting states deposit small, bland, sterile fibrin-platelet vegetations along the closure lines of the mitral or aortic leaflets. The classic causes are mucin-secreting adenocarcinoma (pancreas, lung, stomach, colon), sepsis, and DIC. The vegetations cause no inflammation or valve destruction but embolize readily, so the typical presentation is an embolic stroke with sterile blood cultures. It often accompanies Trousseau syndrome (migratory superficial thrombophlebitis) in pancreatic cancer.

Libman-Sacks endocarditis. In SLE, especially with antiphospholipid antibodies, and in primary antiphospholipid syndrome, small sterile warty vegetations form on both the atrial and ventricular surfaces of the mitral (less often aortic) valve. Inflammation and fibrosis follow, usually causing mitral regurgitation and rarely stenosis, and the vegetations can embolize.

Treatment and prophylaxis

Treatment principles. Organisms buried in a vegetation are protected from host defenses, so cure needs prolonged (usually 4–6 weeks) high-dose IV bactericidal therapy. Empiric vancomycin-based therapy starts after cultures and is then narrowed:

• Methicillin-sensitive S. aureus: nafcillin, oxacillin, or cefazolin.
• MRSA: vancomycin or daptomycin.
• Viridans streptococci: penicillin G or ceftriaxone.
• Enterococci: ampicillin plus gentamicin or ceftriaxone.

Surgery is indicated for heart failure from valve destruction, uncontrolled infection such as an abscess or heart block, and recurrent emboli from large vegetations.

Prophylaxis. Prophylaxis is reserved for patients at highest risk of a bad outcome from IE. These are patients with a prosthetic valve or valve-repair material, prior IE, unrepaired cyanotic congenital heart disease, or congenital heart disease repaired with prosthetic material (for the first 6 months, or longer if a residual defect remains), plus cardiac transplant recipients with valvulopathy. It is given only for dental procedures that manipulate gingival or periapical tissue or perforate the oral mucosa: amoxicillin 2 g orally 30–60 minutes beforehand. With penicillin allergy, use azithromycin, clarithromycin, or doxycycline; clindamycin is no longer advised.

Mitral valve prolapse, a bicuspid aortic valve, hypertrophic cardiomyopathy, and routine GI or GU procedures do not warrant prophylaxis.