Cardiovascular Infections and Related Conditions

A. Prevalence

Subacute bacterial endocarditis (SBE) affects 0.5:1000 to 1:1000 hospital patients, excluding those with postoperative endocarditis.

B. Pathology and Pathogenesis

• 1.

  Two factors are important in the pathogenesis of IE: (a) structural abnormalities of the heart or great arteries with a significant pressure gradient or turbulence, with resulting endothelial damage and platelet-fibrin thrombus formation; and (b) bacteremia, even if transient, with adherence of the organisms and eventual invasion of the underlying tissue.

• 2.

  Those with a prosthetic heart valve or prosthetic material in the heart are at particularly high risk for IE because these promote deposition of sterile thrombus.

• 3.

  Almost all patients who develop IE have a history of congenital or acquired heart disease. Drug addicts may develop endocarditis in the absence of known cardiac anomalies.

• 4.

  Dental procedures or chewing with diseased teeth or gums may be the most frequent cause of bacteremia.

C. Microbiology

• 1.

  In the past, Streptococcus viridans , enterococci, and Staphylococcus aureus were responsible for over 90% of cases of IE. In recent years, this frequency has decreased to 50% to 60%, with a concomitant increase in cases caused by fungus and HACEK organisms ( Haemophilus, Actinobacillus, Cardiobacterium, Eikenella , and Kingella ). HACEK organisms are particularly common in neonates and immunocompromised children.

• 2.

  α-Hemolytic streptococci ( S. viridans ) are the most common cause of IE following dental procedures or in those patients with carious teeth or periodontal disease.

• 3.

  Staphylococci ( S. aureus and coagulase-negative staphylococci) account for more cases than S. viridans in developed countries, usually health care–associated infections, such as postoperative endocarditis, indwelling vascular catheters, prosthetic material, prosthetic valve, among newborn infants, and intravenous drug abusers.

• 4.

  Enterococci are the organisms most often found after genitourinary or gastrointestinal surgery or instrumentation.

• 5.

  Fungal endocarditis (which has a poor prognosis) may occur in sick neonates, in patients receiving long-term antibiotic or steroid therapy, or after open heart surgery.

• 6.

  Culture-negative endocarditis. Diagnosis of this condition is made when a patient has clinical and/or echocardiographic evidence of endocarditis but persistently negative blood cultures. This occurs in about 5% to 7% of endocarditis in the United States. The most common cause of the condition is current or recent antibiotic therapy. It can be caused by a fastidious organism that grows poorly in vitro and rarely by fungus. At times, the diagnosis can be made only by removal of vegetation (during surgery).

D. Clinical Manifestations

• 1.

  Most patients are known to have an underlying heart disease. A history of toothache, recent dental procedure, or tonsillectomy is occasionally present. A history of recent cardiovascular procedures or surgeries may be present. The onset is usually insidious with prolonged low-grade fever of 38°C but fever may fluctuate up to 39.5°C.

• 2.

  Heart murmur is almost always present and splenomegaly is common (70%).

• 3.

  Skin manifestations (50%) may be present in the following forms:

  • a.

    Petechiae on the skin, mucous membranes, or conjunctivae are frequent.

  • b.

    Osler nodes (tender, pea-sized red nodes at the ends of the fingers or toes) are rare in children.

  • c.

    Janeway lesions (small, painless, hemorrhagic areas on the palms or soles) are rare.

  • d.

    Splinter hemorrhages (linear hemorrhagic streaks beneath the nails) also are rare.

• 4.

  Embolic or immunologic phenomena in other organs are present in about 50% of cases.

  • a.

    Pulmonary emboli or hematuria and renal failure may occur.

  • b.

    Seizures and hemiparesis (20%) may occur.

  • c.

    Roth spots (oval, retinal hemorrhages with pale centers located near the optic disc) occur in <5% of patients.

• 5.

  Laboratory studies.

  • a.

    Positive blood cultures are obtained in more than 90% of patients in the absence of previous antimicrobial therapy.

  • b.

    Anemia and leukocytosis with a shift to the left are common.

  • c.

    The sedimentation rate is increased unless there is polycythemia.

  • d.

    Microscopic hematuria is found in 30% of patients.

• 6.

  Echocardiography. Although standard transthoracic echo (TTE) is sufficient in most cases, transesophageal echo (TEE) may be needed in obese or very muscular adolescents.

  • a.

    The following echo findings are included as major criteria in the modified Duke criteria: (1) oscillating intracardiac mass on valve or supporting structures, in the path of regurgitation jets or on implanted material; (2) abscesses; (3) new partial dehiscence of prosthetic valve; and (4) new valvular regurgitation.

  • b.

    The absence of vegetations on echo does not in itself rule out IE. False-negative diagnosis is possible if vegetations are small or have already embolized.

  • c.

    Conversely, a false-positive diagnosis is possible. An echogenic mass may represent a sterile thrombus, sterile prosthetic material, normal anatomic variation, an abnormal uninfected valve (previous scarring, severe myxomatous changes), or improper gain of the echo machine. Echo evidence of vegetation may persist for months or years after bacteriologic cure.

  • d.

    Certain echo features suggest a high-risk case or a need for surgery: (1) large vegetations (greatest risk when the vegetation is >10 mm), (2) severe valvular regurgitation, (3) abscess cavities, (4) pseudoaneurysm, (5) valvular perforation or dehiscence, or (6) decompensated heart failure.

E. Diagnosis

The diagnosis of infective endocarditis is challenging. The modified Duke criteria are used in the diagnosis. There are three categories of diagnostic possibilities using the modified Duke criteria: definite, possible, and rejected ( Box 12.1 ). Box 12.2 shows definitions of major and minor clinical criteria. It is imperative for readers to carefully read and understand the statements in these boxes ( Boxes 12.1 and Box 12.2 ).

• 1.

  A diagnosis of “ definite ” IE is made when (a) pathologic evidence and (b) fulfillment of certain clinical criteria (listed in Box 12.1 ) are present.

• 2.

  The category of “possible ” IE is made when (a) one major criterion and one minor criterion or (b) three minor criteria are present.

• 3.

  The category of “ rejected ” IE is made when one of the four statements in Box 12.1 is present.

F. Management

• 1.

  Blood cultures are indicated for all patients with fever of unexplained origin and a pathologic heart murmur, a history of heart disease, or previous endocarditis.

  • a.

    Usually three blood cultures are drawn over 24 hours, unless the patient is very ill. In 90% of cases, the causative agent is recovered from the first two cultures.

  • b.

    If there is no growth by the second day of incubation, two more cultures may be obtained. There is no value in obtaining more than five blood cultures over 2 days unless the patient received prior antibiotic therapy.

  • c.

    Aerobic incubation alone suffices because it is rare for IE to be due to anaerobic bacteria.

• 2.

  Initial empirical therapy is started with the following antibiotics while awaiting the results of blood cultures. Consultation from a local infectious disease specialist is strongly recommended.

  • a.

    The usual initial regimen is an antistaphylococcal semisynthetic penicillin (nafcillin, oxacillin, or methicillin) and an aminoglycoside (gentamicin). This combination covers against S. viridans, S. aureus , and gram-negative organisms.

  • b.

    If a methicillin-resistant S. aureus is suspected, vancomycin should be substituted for the semisynthetic penicillin.

  • c.

    Vancomycin can be used in place of penicillin or a semisynthetic penicillin in penicillin-allergic patients.

• 3.

  The final selection of antibiotics for native valve IE depends on the organism isolated and the results of an antibiotic sensitivity test.

  • a.

    Streptococcal infective endocarditis

  • (1)

    For highly sensitive S. viridans , IV penicillin (or ceftriaxone given once daily) for 4 weeks is sufficient. Alternatively, penicillin, ampicillin, or ceftriaxone combined with gentamicin for 2 weeks may be used.

  • (2)

    For penicillin-resistant streptococci, 4 weeks of penicillin, ampicillin, or ceftriaxone combined with gentamicin for the first 2 weeks is recommended.

  • b.

    Staphylococcal endocarditis

  • (1)

    For methicillin-susceptible staphylococci IE, one of the semisynthetic β-lactamase–resistant penicillins (nafcillin, oxacillin, or methicillin) for a minimum of 6 weeks (with or without gentamicin for the first 3 to 5 days) is used.

  • (2)

    For patients with methicillin-resistant IE, vancomycin for 6 weeks (with or without gentamicin for the first 3 to 5 days) is used.

  • c.

    Enterococcus -caused endocarditis usually requires a combination of IV penicillin or ampicillin together with gentamicin for 4 to 6 weeks. If patients are allergic to penicillin, vancomycin combined with gentamicin for 6 weeks is required.

  • d.

    For HACEK organisms, ceftriaxone or another third-generation cephalosporin alone or ampicillin plus gentamicin for 4 weeks is recommended. IE caused by other gram-negative bacteria (such as Escherichia coli , Pseudomonas aeruginosa , or Serratia marcescens ) is treated with piperacillin or ceftazidime together with gentamicin for a minimum of 6 weeks.

  • e.

    Fungal endocarditis is very difficult to treat. Amphotericin B, with or without flucytosine, is most often used, but surgical replacement of the infected valve (native or prosthetic) is usually required.

  • f.

    In culture-negative endocarditis, treatment is directed against staphylococci, streptococci, and the HACEK organisms using ceftriaxone and gentamicin. When staphylococcal IE is suspected, nafcillin should be added to the above therapy.

• 4.

  Patients with prosthetic valve endocarditis should be treated for 6 weeks based on the organism isolated and the results of the sensitivity test. Operative intervention may be necessary before the antibiotic therapy is completed if the clinical situation warrants (such as progressive CHF, significant malfunction of prosthetic valves, persistently positive blood cultures after 2 weeks’ therapy). Bacteriologic relapse after an appropriate course of therapy also calls for operative intervention.

G. Prognosis

The overall recovery rate is 80% to 85%; it is 90% or better for S. viridans and enterococci, and about 50% for Staphylococcus organisms. Fungal endocarditis is associated with a very poor outcome.

H. Prevention

Until 2007, antibiotic prophylaxis for IE was routinely recommended before dental procedures for almost all CHDs (with exception of ASD), rheumatic and other valvular diseases, hypertrophic cardiomyopathy, and all other conditions included in the current recommendation. In 2007, the American Heart Association (AHA) made a major change in the antibiotic prophylaxis against IE.

• 1.

  The following are the updated recommendations for antibiotic prophylaxis.

  • a.

    Antibiotic prophylaxis is recommended only for cardiac conditions listed in Box 12.3 , which was updated in 2017.

    Box 12.3

    2017 AHA/ACC Updated Recommendation on Cardiac Conditions for Which Prophylaxis with Dental Procedures is Recommended

    ^a The risk of IE is highest in the first 6 months after transplantation because of endothelial disruption, high-intensity immunosuppressive therapy, frequent central venous catheter access, and frequent endomyocardial biopsies. IE , infective endocarditis.Adapted from Nishimura RA, Otto CM, Bonow RO, et al: 217 AHA/ACC focused update of the 2014 AHA/ACC guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, Circulation 2017;135(25): e1159-e1195.

    Prophylaxis against IE is reasonable before dental procedures that involve manipulation of gingival tissue, manipulation of the peripheral region of teeth, or perforation of the oral mucosa in patients with the following:

    • 1.

      Prosthetic cardiac valves, including transcatheter-implanted prostheses and homografts.

    • 2.

      Prosthetic material used for cardiac valve repair, such as annuloplasty rings and chords.

    • 3.

      Previous IE.

    • 4.

      Unrepaired cyanotic congenital heart disease or repaired congenital heart disease, with residual shunts or valvular regurgitation at the site of or adjacent to the site of a prosthetic patch or prosthetic device.

    • 5.

      Cardiac transplant with valve regurgitation due to a structurally abnormal valve. ^a

  • b.

    Procedures for which antibiotic prophylaxis is recommended and those not recommended are listed in Box 12.4 .

    Box 12.4

    Procedures for which Endocarditis Prophylaxis is Recommended

    GI , gastrointestinal; GU , genitourinary.

    • 1.

      Dental procedures

      All dental procedures that involve manipulation of gingival tissue of the periapical region of teeth or perforation of the oral mucosa. Antibiotic choices and dosages for dental procedures are shown in Table 12.1 .

    • 2.

      Respiratory tract procedures

      • a.

        Prophylaxis is recommended for the procedures that involve incision or biopsy of the respiratory mucosa, such as tonsillectomy and adenoidectomy.

      • b.

        Prophylaxis is not recommended for bronchoscopy (unless it involves incision of the mucosa, such as for abscess or empyema).

    • 3.

      GI and GU procedures

      • a.

        No prophylaxis for diagnostic esophagogastroduodenoscopy or colonoscopy.

      • b.

        Prophylaxis is reasonable in patients with infected GI or GU tract (with amoxicillin or ampicillin to cover against enterococci).

    • 4.

      Skin, skin structure, or musculoskeletal tissue.

      • a.

        Prophylaxis is recommended for surgical procedures that involve infected skin, skin structure, or musculoskeletal tissue (with antibiotics against Staphylococcus and β-hemolytic Streptococcus , such as antistaphylococcal penicillin or a cephalosporin).

      • b.

        Vancomycin or clindamycin is administered if unable to tolerate β-lactam or if infection is caused by methicillin-resistant Staphylococcus .

  • c.

    Antibiotic choices and dosages for dental procedures are shown in Table 12.1 .

    Table 12.1

    Prophylactic Regimens for Dental Procedures

    		Single Dose 30-60 MIN Before Procedure
    Situation	Agent	Children	Adults
    Oral	Amoxicillin	50 mg/kg	2 g
    Unable to take oral medications	Ampicillin, or cefazolin or ceftriaxone	50 mg/kg (IM, IV)50 mg/kg (IM, IV)	2 g (IM, IV)1 g (IM, IV)
    Allergic to penicillin or ampicillin—oral	Cephalexin a,b or clindamycin, or azithromycin or clarithromycin	50 mg/kg 20 mg/kg 15 mg/kg 15 mg/kg	2 g 600 mg 500 mg 500 mg
    Allergic to penicillin or ampicillin and unable to take oral medication	Cefazolin, or ceftriaxone Clindamycin	50 mg/kg (IM, IV)20 mg/kg (IM, IV)	1 g (IM, IV)600 mg (IM, IV)

    IM, intramuscular; IV, intravenous

    a Or other first- or second-generation oral cephalosporin in equivalent adult or pediatric dosage.

    b Cephalosporins should not be used in an individual with a history of anaphylaxis, angioedema, or urticaria with penicillin or ampicillin.

• 2.

  Special situations.

  • a.

    For patients receiving rheumatic fever prophylaxis, use other antibiotics, such as clindamycin, azithromycin, or clarithromycin, rather than using a higher dose of the same antibiotic.

  • b.

    When the patient is already receiving a course of an antibiotic for other reasons (such as tonsillitis), delay a dental procedure, if possible, until at least 10 days after completion of the antibiotic therapy.

• 3.

  For patients who undergo cardiac surgery, the following applies:

  • a.

    A careful preoperative dental evaluation is recommended so that required dental treatment may be completed before cardiac surgery.

  • b.

    Prophylaxis at the time of surgery should be directed primarily against staphylococci and should be of short duration.

  • c.

    Prophylaxis should be initiated immediately before the operative procedure, repeated during prolonged procedures to maintain serum concentrations intraoperatively, and continued for no more than 48 hours postoperatively.

A. Prevalence

Myocarditis severe enough to be recognized clinically is rare, but the prevalence of mild and subclinical cases is probably much higher.