Definition

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 known to infectious disease clinicians, but it might not be recognized by a busy general internist who is unlikely to encounter more than several cases a year.

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Prevalence and risk factors

The incidence of infective endocarditis in a general population has been estimated at between 2 and 6 cases per 100,000 person-years, but it is clearly higher in patients with underlying valvular heart diseases 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.

Although historically rheumatic valvulitis was considered a frequent predisposing factor for endocarditis, times have changed. Mitral valve prolapse, aortic sclerosis, and bicuspid aortic valvular heart disease are now more frequent causes. In addition, prosthetic valvular heart disease accounts for about one third of all cases of endocarditis, and occurs in 1% to 3% of patients after valvular heart surgery.

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

One study has demonstrated a high frequency of S. aureus endocarditis secondary to preventable sources.³ Of 59 cases reported from Duke University, 23 were caused by intravascular catheters and 14 by infected surgical wounds. Approximately 25% of vascular catheter-associated bacteremias caused by S. aureus may result in endocarditis.

A significant risk factor for endocarditis is IVDA. Patients who use injection drugs tend to be younger and may be coinfected with human immunodeficiency virus (HIV). Cases of IVDA-associated endocarditis usually respond quickly to antibiotic therapy, but recurrence is common.¹

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Pathophysiology

Although uncertain, it is believed that cardiac valves and other endocardial surfaces become infected after exposure to microemboli from bacteria or fungi circulating in the bloodstream. Dextran-producing bacteria, such as Streptococcus mutans, have a virulence factor that promotes adherence to endovascular surfaces. Coagulase-negative staphylococci may 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, or pacemaker wires provide a favorable environment for thrombus formation. Over time, microorganisms proliferate in the thrombus, resulting in a classic vegetation. Microorganisms are released into the circulation, usually on a continuous basis, which often results in interesting findings.

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Signs and symptoms

The disease often begins as a flulike 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 1). Surprisingly, most patients, especially younger ones, do not seek medical advice until fatigue or fever becomes 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 postoperative complications.

A careful physical examination may disclose skin or mucosal lesions in about 50% of cases (Fig. 1). These include subconjunctival and soft palate petechiae, hemorrhages within the nail beds (splinter hemorrhages), painful subcutaneous nodules on the palms or soles (Osler’s nodes), and generalized rashes. Patients may also present with painful embolic lesions on the fingers or toes, which may be visible.

Almost always, a regurgitant heart murmur is heard, usually in the mitral or aortic valve position. New or changing murmurs in patients with preexisting murmurs are noted in about 30% of cases. A widening of the pulse pressure may be a sign of aortic valve dehiscence, an indication for urgent surgical intervention. Similarly, bradycardia progressing to complete heart block can be caused by a septal abscess, which also requires open surgical débridement and drainage.

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

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Diagnosis

Diagnostic clues noted by Sir William Osler in 1908 included remittent fever with a valvular heart lesion, embolic findings, skin lesions, and progressive cardiac changes, and these are pertinent today. However, in Osler’s time, the diagnosis was confirmed at autopsy, because few, if any, patients survived. Without pathologic evidence, clinical findings are not specific for the diagnosis. Fortunately, with the use of modern blood culture techniques, the diagnosis can usually be confirmed in the microbiology laboratory. A majority of patients with confirmed bacterial endocarditis have positive blood cultures within a 2-day period, provided that they had not recently been on antibiotics. Therefore, it is not necessary to continuously collect blood cultures beyond this point. Three sets should suffice. Recovery of organisms is enhanced with the BACTEC system (Becton Dickinson, Sparks, Md) for gram-negative bacilli and yeasts.

In 1981, Von Reyn and associates published an important article that laid out strict criteria for the diagnosis of endocarditis.¹¹ A positive valve culture or histology was defined as definite endocarditis. Major criteria for probable endocarditis were 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 the use of echocardiography. Transesophageal echocardiography is preferred over the transthoracic approach because it usually provides superior imaging for detecting vegetations and abscesses.

Durack and associates² at Duke University have subsequently found that an echocardiogram clearly showing vegetations or abscesses of the endocardium is a major criterion, as is positive serology for Coxiella burnetii (Box 1).

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Treatment

Medical Treatment

Streptococci, especially Streptococcus viridans, have historically been responsible for the largest percentage of cases of native valve endocarditis (Table 2). However, in more recent series, S. aureus may be as common, or even more common. Certain viridans streptococci, such as 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. Enterococci are responsible for up to 10% of cases; some strains may be not only resistant to penicillin, but to vancomycin and aminoglycosides.

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

S. aureus, in addition to causing endocarditis, may result in a severe sepsis syndrome, with a fulminating coagulopathy. Metastatic foci of infection spread to the brain, lungs, liver, and kidneys, sequelae that result in a high mortality rate. The organism is also a cause of early-onset prosthetic valve endocarditis (PVE), but is not as common as Staphylococcus epidermidis (Table 3). This form of endocarditis, occurring within 1 year after surgery, is usually the result of intraoperative contamination by skin bacteria. Currently, 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. Staphylococcus lugdunensis is also coagulase-negative, but behaves more like S. aureus clinically. Death is almost certain unless infected valves are removed.

The HACEK group of gram-negative bacteria may cause endocarditis. These fastidious microorganisms include Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella species. Patients can be ill for months and may present with a painful embolic lesion to an extremity.

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 organism responsible is Candida albicans, followed by Candida parapsilosis. Endocarditis caused by Histoplasma capsulatum or Aspergillus spp. is rare.

Finally, unusual cases of endocarditis should be considered when standard microbiologic techniques fail to provide a diagnosis. Q fever endocarditis caused by Coxiella burnetii is an example. Patients may not have fever, but they frequently have underlying valvular heart disease and are on immunosuppressive therapy. Vegetations are rarely detected on the 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 populations. Blood cultures are negative, but again serology may be helpful. Identification by polymerase chain reaction (PCR) assay on resected valve tissue has been reported, but this test is not readily available in most clinical laboratories.

Antimicrobial Selection Guidelines

The penicillins, often in combination with gentamicin, remain the cornerstones of therapy for endocarditis caused by penicillin-susceptible streptococci (Table 4).⁴ For penicillin-allergic patients, vancomycin is substituted. IV ceftriaxone (Rocephin), given once daily for 4 weeks, is another option, and even a 2-week course in combination with gentamicin has proven successful. However, short-term therapy is not indicated for patients who have PVE, major embolic complications, or symptoms for longer than 2 months. Furthermore, in this study, 24% of patients required urgent valvular heart surgery within 1 to 5 weeks after beginning treatment. Therefore, careful follow-up is essential, especially for patients who leave the hospital to complete antibiotic therapy at home.

For relatively penicillin-insensitive streptococci (minimal inhibitory concentration >0.1-0.5 µg/mL), the penicillin dosage is higher and duration of therapy is 2 weeks (Table 5).⁴ Gentamicin is given for the first 2 weeks; treatment for endocarditis caused by enterococci is longer; both penicillin and gentamicin are given for 6 weeks (Table 6). Patients who are penicillin-allergic, should receive vancomycin, provided the isolate is susceptible. For vancomycin-resistant enterococci (VRE), anecdotal success has been reported using streptogramin quinupristin-dalfopristin (Synercid) either alone or in combination with doxycycline and rifampin. A newer antimicrobial agent, linezolid (Zyvox), has in vitro activity against VRE, and has been reported successful in the treatment of a small series of cases. Daptomycin may also be a promising antibiotic for VRE endocarditis, but has not yet been field tested.

The preferred treatment for native valve endocarditis (NVE) caused by methicillin-susceptible staphylococci is oxacillin or cefazolin for 4 to 6 weeks. If the organism is methicillin-resistant, vancomycin is used. Gentamicin may be added for the first 3 to 5 days. This will shorten the duration of the bacteremia; however, if continued longer, it does not improve the cure rate and may cause renal toxicity.

Antibiotic therapy for staphylococcal PVE must be more aggressive because of the greater likelihood of treatment failure or relapse (Table 7). When the isolate is methicillin-susceptible, oxacillin plus rifampin is given for 6 weeks and gentamicin for the first 2 weeks. When the isolate is methicillin-resistant, vancomycin is substituted for oxacillin.

Endocarditis caused by S. 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 2-week course of IV cloxacillin (not available in the United States).

The preferred treatment for the HACEK group of bacterial endocarditis is ceftriaxone for 4 weeks. Other options are ampicillin-sulbactam or ciprofloxacin (Table 8). Patients with late-onset PVE may be cured medically without requiring valve surgery, provided that only the valve cusps or leaflets are involved.

Fungal endocarditis has a poor prognosis. In a series of prosthetic valve endocarditis reported from the Cleveland Clinic, a 67% survival rate was reported.¹² Survivors not only required aggressive surgery and IV amphotericin B (Fungizone), but received lifelong suppression with an oral antifungal afterward.

From 10% to 20% percent of patients with clinically suspected endocarditis will have negative blood cultures. An empirical trial of ampicillin-sulbactam plus gentamicin for NVE or vancomycin plus ciprofloxacin and gentamicin for PVE should be considered. Although staphylococci or streptococci may not be recovered from blood cultures, they may be seen on smears or recovered from vegetations taken at surgery. About 50% of patients with negative blood cultures will respond to empirical therapy. If not, further investigation is warranted, and unusual microorganisms or noninfectious causes of endocarditis should be considered.

Surgical Treatment

Death from infective endocarditis is usually caused by congestive heart failure, often accompanied by valve dysfunction. In the last 25 years, 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 1 cm 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 2 years after completing medical therapy.¹³

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Outcomes

Persistent Fever

Persistent fever during the treatment of endocarditis is worrisome. Annular or ring abscesses may cause this and are strong indications for surgery. 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 be considered.

Neurologic Complications

Neurologic complications from endocarditis are common and can present difficult and sometimes vexing management dilemmas (Table 9). Leading causes are stroke, encephalopathy, and retinal emboli. Brain abscesses 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.

Survival

In the preantibiotic era, survival after infective endocarditis was unlikely. With effective antimicrobial therapy and surgical intervention, the outcome is no longer bleak. However, despite striking advances in management, mortality remains around 20%. In part, this is because more patients are living longer with prosthetic heart valves and have more comorbidity, and IV drug abuse continues to be a problem. The most frequent cause of death is congestive heart failure, less frequently followed by major embolic events and ruptured mycotic aneurysms. Death is usually not caused by uncontrolled infection. In the past, early-onset PVE mortality was as high as 90% because surgeons were reluctant to reoperate on patients with active infection. Now, with surgical expertise and perioperative support, mortality has been reduced to approximately 25%.

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Prevention

There is a continued debate about the need for and adequacy of antibiotic prophylaxis to prevent infective endocarditis. In 1986, Bayliss and colleagues⁸ reported a presumed dental portal of entry in less than 20% of well-studied cases. Further controversy arose after a case-control study was reported in 1996 from the greater Philadelphia area (Table 10).⁹ Patients with well-defined endocarditis were matched with controls for age, gender, and neighborhood. Information was collected through structured telephone interviews and review of outside medical and dental records. Cases of endocarditis were no more likely than controls to have had dental procedures, except for extractions. Cardiac risk factors were more common in these patients, including mitral valve prolapse, congenital heart disease, rheumatic valvular heart disease, previous cardiac surgery, history of infective endocarditis, and a known heart murmur. In an accompanying editorial, the author suggested that only patients with prosthetic valvular heart disease or a history of endocarditis undergoing dental extractions or gingival surgery would benefit from antibiotic prophylaxis.

Prophylaxis Guidelines

Although the risk of side effects clearly outweighs the benefit in patients at low risk for endocarditis, prophylaxis remains an accepted practice in higher risk patients. Guidelines, published periodically by the American Heart Association, were substantially updated in 2007.¹⁰ After an exhaustive literature search and personal reflections on their own experiences, the expert panel concluded that many of the earlier recommendations had not been based on sound evidence-based studies. They now recommend that prophylaxis should only be given to patients who have the highest risk of complications of endocarditis (Box 2).

Furthermore, the list of procedures for endocarditis prophylaxis has been considerably shortened—for example, only for dental work involving gingival tissue and the periapical regions of the teeth, or for perforations of the oral mucosa (Box 3). Other invasive procedures that might warrant prophylaxis include diagnostic studies or drainage of infected spaces where streptococci, enterococci. or S. aureus are proven or likely pathogens.

For recommended dental procedures, the recommended first-line regimen remains amoxicillin, 2 g PO, or ampicillin 2 g IM or IV, 30 to 60 minutes before the procedure (Table 11). The same regimen should apply for patients undergoing cystoscopy or other genitourinary manipulations who have enterococcal bacteriuria.

However, for high-risk patients undergoing diagnostic studies or procedures such as drainage of empyema, abscesses, or phlegmons in which S. aureus may be present, prophylaxis should be broadened with a penicillinase-resistant penicillin (oxacillin or nafcillin) or first-generation cephalosporin(cefazolin). Vancomycin should be substituted if the pathogen is suspected or proven resistant to oxacillin or methicillin (methicillin-resistant S. aureus [MRSA]).

For patients undergoing cardiac valve surgery, IV preoperative prophylaxis with a first- or second-generation cephalosporin is recommended. This should be given within 30 minutes before opening the skin. If the operation is longer than 4 hours, a second dose can be given intraoperatively before skin closure. Prophylaxis should not be continued longer than 24 hours after surgery. For the penicillin-allergic patient or in hospitals in which there is a high prevalence of MRSA or methicillin-resistant or S. epidermidis, vancomycin should be considered.

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Summary

• Staphylococcus aureus is probably more common now than Streptococcus viridans as the cause of native valve endocarditis.
• A widening pulse pressure and bradycardia are ominous signs that may require early surgical intervention.
• Transesophageal echocardiography is superior to transthoracic imaging for detecting vegetations and abscesses.
• Neurologic complications are frequent but usually do not cause death.
• Antibiotic prophylaxis for invasive dental procedures remains recommended, but only for patients at high risk of complications from endocarditis.

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