Infective endocarditis, an infection of the endocardium that usually involves the valves and adjacent structures, is caused by a wide variety of bacteria and fungi. The disease is a favorite of infectious disease clinicians, but may not be recognized by a busy general internist who is unlikely to encounter more than several cases a year.

This chapter reviews the epidemiology, pathogenesis, clinical findings, diagnosis, treatment, complications, and outcomes of the disease. In addition, current information on preventive therapy or prophylaxis is provided.

The incidence of infective endocarditis in a general population has been estimated between 2-6 cases per 100,000 patient years,¹ but it is clearly higher in patients with underlying valvular heart disease, and those with intravenous drug abuse (IVDA). Furthermore, invasive procedures performed in our technically robust health care system may cause bloodstream infections and result in endocarditis.

While historically, rheumatic valvulitis was considered a frequent pre-disposing factor for endocarditis, times have changed (Table 1).² Mitral valve prolapse, aortic sclerosis, and bicuspid aortic valvular heart disease are more frequent causes now. In addition, prosthetic valvular heart disease accounts for about 1/3 of all cases of endocarditis, and occurs in 1% to 3% of patients after valvular heart surgery.

Late-onset prosthetic valve endocarditis (infection at least one year after surgery) is more frequent now because patients with prosthetic heart valves are surviving longer. Fortunately, these cases are caused by the same organisms as native valve endocarditis (NVE), and are usually easier to treat.

Pacemaker-endocarditis, another complication of advancing technology, is caused by micro-organisms that usually migrate across a broken skin barrier from an eroding battery pack or generator pocket wound. Early cases are frequently due to Staphylococcus aureus, and late cases to Staphylococcus epidermidis. After time, intravascular pacemaker leads incapsulate deeply in the right ventricle, making explantation tedious and difficult.

A recent study demonstrated a high frequency of Staphylococcus aureus endocarditis secondary to preventable sources.³ Of fifty-nine cases reported from Duke University, 23 were caused by infected intravascular catheters and 14 from surgical wounds (Table 2). Approximately 25% of vascular catheter-associated bacteremias caused by Staphylococcus aureus may result in endocarditis.

A significant risk factor for endocarditis is intravenous drug abuse (IVDA). Patients who use injection drugs tend to be younger, and may be co-infected with human immuno-deficiency virus (HIV). Cases of IVDA-associated endocarditis usually respond quickly to antibiotic therapy, but recurrence is common.

Streptococci, especially viridans streptococci, are responsible for the largest percentage of cases (Table 3).⁴ Certain viridans streptococci, like Streptococcus mitis, may be nutritionally-variant and require active vitamin B₆ and thio-compounds for growth. Such variants account for 10% of cases, and tend to be less susceptible to penicillin. Enterococcus species are responsible for up to 10% of cases; some strains may be not only resistant to penicillin, but also to vancomycin.

Occasional cases due to Beta-hemolytic streptococci are reported; they often present with major embolic events. Rarely, Streptococcus pneumoniae may cause endocarditis. Such a case might present with the Osler triad of pneumonia, meningitis, and endocarditis. Often associated with alcohol abuse, mortality is extremely high.

Staphylococcus aureus in addition to causing endocarditis, may result in a severe sepsis syndrome with a fulminating coagulopathy. Metastic foci of infection spread to the brain, lungs, liver, and kidneys. These sequelae result in a very high mortality rate. The organism is also a cause of early-onset PVE, but not as common as Staphylococcus epidermidis (Table 4).⁵ This form of endocarditis, (occurring within one year, and usually within 60 days of surgery), used to result from intraoperative contamination by skin bacteria. Now, infections from vascular catheters and surgical wounds are more frequent sources of infection. Staphylococcus epidermidis, the usual cause of early-onset PVE, is almost always resistant to methicillin or oxacillin. Endocarditis due to Staphylococcus lugdunensis has been reported.⁶ This organism is coagulase-negative, but can be confused with Staphylococcus aureus in the laboratory. Despite being susceptible to penicillin, the organism is highly virulent, and death is almost certain unless infected valves are removed.

The HACEK group of fastidious gram-negative bacteria can cause endocarditis. HACEK is an all-inclusive term for endocarditis due to Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella species of bacteria. Clinically, these cases are characterized by a subacute or chronic course, and often present with embolic lesions from large vegetations.

Most cases of fungal endocarditis occur in patients who are receiving prolonged antibiotics or parenteral nutrition through central vascular catheters. Such patients may also be immunocompromised. The most common species is Candida albicans, followed by Candida parapsilosis. Endocarditis due to Histoplasma capsulatum or Aspergillus species is rare.

Finally, unusual cases of endocarditis should be considered when standard microbiologic techniques fail to provide a diagnosis. Q-fever endocarditis due to Coxiella burnetii is an example. Patients may not have fever, but they frequently have underlying valvular heart disease and are on immuno-suppressive therapy. Vegetations are rarely detected on echocardiogram. Although routine blood cultures are negative, an alerted microbiology laboratory may recover the organism from buffy-coat cultures. Serologic studies are reasonably specific. Bartonella henselae may also cause endocarditis, and diagnosis here is also difficult. Infections are seen in the homeless and alcoholic population. Blood cultures are negative, but, again, serology may be helpful. Identification by polymerase chain reaction (PCR) on resected valve tissue has been reported, but this test is not readily available in most clinical laboratories.

While uncertain, it is thought that cardiac valves and other endocardial surfaces become infected after exposure to microemboli from bacteria or fungi circulating in the bloodstream. Dextran-producing bacteria, like Streptococcus mutans, have a virulence factor which promotes adherence to endovascular surfaces. Coagulase-negative staphylococci will produce a biofilm on prosthetic surfaces, which also promotes adherence. Beta-hemolytic streptococci and enteric gram-negative bacteria lack recognized adherence factors, and appear less likely to cause endocarditis. Endocardial surfaces previously damaged from valvular heart disease, endocarditis, surgery, and pacemaker wires provide a favorable environment for thrombus formation. Over time, micro-organisms proliferate in the thrombus resulting in a classic vegetation. Their release, into the circulation, usually on a continuous basis, produces a number of interesting and sometimes serious findings.

The illness often begins like a "flu-like" illness with a dry cough, body aches and fatigue, which follows a subacute or chronic course. Low grade fevers, night sweats and weight loss are cardinal manifestations (Table 5). Suprisingly, most patients, especially younger ones, continue on their way without seeking medical advice until fatigue or fevers become unbearable, or they suffer a major complication such as an embolic event or heart failure. Patients who have had heart surgery in the recent past usually seek medical advice earlier, because of their heightened awareness of post-operative complications.

A careful physical examination will usually disclose at least several interesting findings. Skin or mucosal lesions are seen in about 50% of cases (Figure 1).⁷ These include subconjunctival and soft palate petechiae, hemorrhages within the nail beds ("splinter hemorrahages"), painful subcutaneous nodules on the palms or soles ("Osler's nodes"), and generalized rashes. Patients may also present with painful embolic lesions to the hands or feet which can be visable.

Almost always, one hears a regurgitant heart murmur, usually in the mitral or aortic valve position. In patients with pre-existing murmurs, a new or changing murmur is noted in about 30% of cases. This may be a sign of valve dehiscence and require urgent surgical intervention. A widening pulse pressure and bradycardia are also ominous signs and require immediate attention.

Splenomegaly is reported in about 20% of cases, more likely in patients who have been ill for months rather than days or weeks.

In 1981, Von Reyn and associates,¹⁰ published an important article which used strict criteria for the diagnosis of endocarditis (Table 6). A positive valve culture or histology was the gold standard. Major criteria for probable endocarditis were either persistent bacteremia with a new regurgitant heart murmur or valvular heart disease with vasculitis; or negative or intermittent bacteremia with fever and a new regurgitant heart murmur with vasculitis. Further refinements in the diagnosis have occurred with ECHO cardiography. Transesophageal echocardiography is preferred to the transthoracic approach, because it provides superior imaging for detecting vegetations and abscesses.

Durak and Associates¹¹ at Duke University have subsequently added ECHO cardiography as a criteria for the diagnosis (Table 7). An echocardiogram clearly showing vegetations, abscesses, or valve dehiscence coupled with either a typical organism cultured from blood or persistant positive blood cultures is sufficient for the diagnosis.

Antimicrobial Selection:

The penicillins, often in combination with gentamicin, remain cornerstones for therapy of endocarditis when due to susceptible streptococci (Table 8).¹² For penicillin-allergic patients, vancomycin is substituted for penicillin. Intravenous ceftriaxone (Rocephin), given once daily for four weeks, also works, and even a two week course in combination with gentamicin has proven successful.¹³ However, short course therapy is not indicated for patients who have PVE, major embolic complications, or symptoms for longer than two months. Furthermore, in this study, 24% of patients required urgent valvular heart surgery within one to five weeks after beginning treatment. Therefore, careful follow-up is essential, especially for patients who leave the hospital to complete antibiotic therapy at home.¹⁴

For relatively penicillin-insensitive streptococci (minimal inhibitory concentration 0.1-0.5 µg/ml), penicillin dosage is increased and continued for four weeks (Table 9). Gentamicin is given for the first two weeks. Treatment of enterococcal endocarditis is longer; both penicillin and gentamicin are given for six weeks. For documented penicillin allergy, vancomycin should be substituted for penicillin if the isolate is susceptible. For vancomycin-resistant enterococci (VRE), anectdotal success has been reported using streptogramin quinupristin-dalfopristin (Synercid) either alone, or in combination with doxycycline and rifampin.¹⁵ A newer antimicrobial agent, linezolid (Zyvox), which is an oxazolidinone, has in-vitro activity against VRE and methicillin-resistant Staphylococci auerus. It has proven successful in the treatment of skin and soft tissue infections. Although an animal model looks promising, it has not been widely studied in treatment for endocarditis.¹⁶

The preferred treatment for NVE due to methicillin-susceptible staphylococci is oxacillin or cefazolin for 4-6 weeks.¹² If the organism is methicillin-resistant, vancomycin is used. Gentamicin may be given for the first 3-5 days to reduce the duration of bacteremia; however, it does not improve the cure rate and, if continued longer, may cause renal toxicity.

Antibiotic therapy for staphylococcal PVE must be more aggressive because of the greater likelihood of treatment failure or relapse (Table 10). When the isolate is methicillin-susceptible, oxacillin plus rifampin is given for six weeks; and gentamicin for the first two weeks. When the isolate is methicillin-resistant, vancomycin is substituted for oxacillin.

Endocarditis due to Staphylococcus aureus associated with IVDA is generally more responsive to short-course antibiotic therapy. In one study, a cure rate of 89% was reported after a two week course of intravenous cloxacillin (not available in US).¹⁷

The preferred treatment for the HACEK group of bacterial is either ceftriaxone (Rocephin) alone or ampicillim plus gentamicin for four weeks.¹² (Table 11). Patients with late-onset PVE may be cured medically without requiring valve surgery.

Fungal endocarditis has a poor prognosis. In a recent series of prosthetic-valve endocarditis reported from the Cleveland Clinic, a 67% survival rate was reported.¹⁸ Cases not only had aggressive surgery and intravenous amphotericin B (Fungizone), but lifelong suppression with an oral antifungal afterward.

About ten percent of patients with clinically-suspected endocarditis will have negative blood cultures. One should consider an empiric trial of ampicillin plus gentamicin for NVE or vancomycin plus ampicillin and gentamicin for PVE. Although the usual organisms are not recovered from blood, they may be seen on smear or cultured from vegetations taken at surgery. About fifty-percent of patients with negative blood culture will respond, but if they do not, one must probe further.

Indications for Surgery:

Death from infective endocarditis is usually due to congestive heart failure, often accompanied by valve dysfunction. In the last quarter century, aggressive surgery has been the most important advance in therapy. Surgery during acute infection does not increase mortality; in fact, restoration of a failing pump improves function and outcome. Valve failure causing moderate to severe congestive heart failure (New York Heart Association Class III or IV) is a strong indication for urgent surgery. An endocardial abscess, which can involve the aortic root, valve ring, or ventricular septum, is another indication for urgent intervention. Other conditions favoring surgery include vegetations larger than one centimeter in diameter, a major embolic event, and failure or relapse of medical therapy.

Even though surgery may not be required during hospitalization, it may be needed later on because of progressive valve damage from healed-endocarditis. In one study, 47% of patients eventually required surgery, usually within two years after completing medical therapy.¹⁹

Persistant fevers during treatment of endocarditis are worrisome (Table 12). Annular or ring abscesses may cause this, and are strong indications for surgery.²⁰ Other causes of fever include myocarditis, pulmonary and systemic emboli, and intravascular-catheter site infections. Drug fevers without other manifestations, such as rash and renal findings, are unusual, but must also must be considered.

Neurologic complications from endocarditis are rather common, and can present difficult and sometimes vexing management dilemmas (Table 13).²¹ Leading causes are stroke, encephalopathy, and retinal emboli.¹⁷ Brain abscess and mycotic aneurysms are relatively infrequent. As a general rule, anticoagulation should be avoided because of the increased risk of intracranial bleeding. One may elect to continue anticoagulation in patients with mechanical heart valves, but dosing should be in the low therapeutic range to minimize the risk of bleeding. Fortunately, most mycotic aneurysms do not require surgery, and usually resolve after appropriate antimicrobial therapy.

Although the risk of side effects outweighs the benefit in low-risk groups, prophylaxis remains an accepted standard practice. Guidelines are published periodically by the American Heart Association and are soon to be updated.²⁵ Only cases at high or moderate risk should receive prophylaxis (Table 15). Example of procedures where prophylaxis is indicated are shown in Table 16. For dental, oral, respiratory tract, or esophageal procedures, amoxicillin (Amoxil) two grams orally, is recommended one hour before the procedure. For penicillin-allergic patients, clindamycin (Cleocin), 600mg orally; cephalexan (Biocef, Keflex, Keftab), 2 grams orally; or azithromycin (Zithromax), 500mg orally may be substituted (Table 17). No post-procedure dose is needed.

For high-risk patients undergoing genito-urinary and gastrointestinal procedures, ampicillin, 2 grams intramuscularly or intravenously, plus gentamycin, 1.5mg/kg (not to exceed 120mg), should be given within 30 minutes of the procedure, and a single dose of amoxicillin, 1 gram orally six hours later (Table 18). For penicillin-allergic patients, vancomycin, 1 gram intravenously is substituted for ampicillin. A second dose is not needed. For moderate-risk patients, amoxicillin, 2 grams orally, should be given one hour before the procedure, or ampicillin, 2 grams intramuscularly or intravenously, within 30 minutes of the procedure. Vancomycin, 1 gram intravenously, is substituted for penicillin-allergic patients.

For patients undergoing cardiac valve surgery, preoperative prophylaxis with a first or second-generation cephalosporin is recommended. This should be given within 30 minutes prior to making the skin incision. If the operation is longer than four hours, a second dose can be given intraoperatively before skin closure. Prophylaxis should not be continued longer than 24 hours after surgery. Surgeons who operate at hospitals where there is a high prevelance of methicillin-resistant Staphylococcus aureus or Staphylococcus epidermidis, should use vancomycin instead.

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* "Guideline" type references, based on expert opinion rather than evidence-based medicine.

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