Bacteria

Fungi

Fungi are rarely a cause of endocarditis, but fungal IE has high mortality. Candida species are responsible for most cases of fungal IE. Aspergillus species are also seen. Fungal IE tends to occur in patients with cardiac abnormalities, medical devices (prosthetic valves, long-term indwelling vascular catheters), some level of compromised immunity (human immunodeficiency virus, malignancy, organ transplantation), and injection drug use.⁹ Fungal IE usually produces large vegetations and is an indication for surgical intervention.

Classic Triad

The triad consisting of fever, heart murmur, and anemia has classically been ascribed to the diagnosis of IE. Unfortunately, the sensitivity and specificity of these findings for endocarditis are poor. The clinician must combine these findings with high-risk patient characteristics (see Box 62.2).

Organ-Specific Clinical Findings

Most commonly, patients with IE have symptoms of malaise and fatigue in the setting of a low-grade fever. Most of this probably reflects the immunologic response to constant bacteremia. Patients may complain of generalized weakness with anorexia and weight loss. Without high clinical suspicion, a nonspecific viral syndrome may often be diagnosed.

Ophthalmologic Signs and Symptoms

The eye is not immune to endocarditis. Both embolic and immune phenomena can affect the optic nerves, ophthalmic vessels, conjunctivae, and retina. Initial complaints may include painless conjunctival hemorrhages, visual field cuts, and even monocular blindness. Emboli can cause infarction of the ophthalmic or retinal vessels and lead to loss of vision. Hemorrhages with pale cotton-wool centers known as Roth spots can be visualized on the retina (Fig. 62.3). EPs should be aware that these spots are not pathognomonic for IE but rather, if seen, should raise suspicion for this disease. Painless subconjunctival hemorrhages (Fig. 62.4), or petechiae involving the conjunctivae, can also be present and again are not specific.

Fig. 62.3 Roth spots.

Septic microemboli to the retinal arteries result in infarction. The ischemic cotton-wool centers are surrounded by hemorrhagic halos (arrows). These spots are not pathognomonic for endocarditis.

(From Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 6th ed. Philadelphia: Churchill Livingstone; 2005.)

Fig. 62.4 Subconjunctival hemorrhages (arrow) in patient with viridans group streptococcal endocarditis.

(Courtesy Marc E. Grossman, MD, FACP.)

Dermatologic Signs and Symptoms

The skin can give great clues to the presence of IE. Classic findings are Janeway lesions, Osler nodes, and splinter hemorrhages.

Janeway lesions are small, painless hemorrhages with a macular or slightly nodular character (Fig. 62.5). They are found on the thenar and hypothenar eminences of the palms and soles. The histologic findings are generally consistent with septic microemboli. Bacteria have been cultured from these lesions. Janeway lesions are usually present for days to weeks before healing. They are most often associated with acute IE from S. aureus.

Fig. 62.5 Janeway lesions.

These nontender, often hemorrhagic lesions (arrows) are most commonly associated with Staphylococcus aureus endocarditis. They result from septic microembolization. The lesions are usually macular to slightly nodular and involve the soles (A) and the thenar and hypothenar eminences of the palms (B).

(From Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 6th ed. Philadelphia: Churchill Livingstone; 2005; B, courtesy Marc E. Grossman, MD, FACP.)

Osler nodes are small, tender, red to purple nodules. They are most often found on the pulp of the distal phalanges of the fingers and toes, the soles, and the thenar and hypothenar eminences of the palms (Fig. 62.6). Preceding the appearance of the nodes, patients often experience neuropathic pain. Although these nodes were initially believed to be purely immunologic in nature, reports have now isolated bacteria from them. It has been postulated that early microembolization with microabscess formation is followed by an immune-mediated hypersensitivity vasculitis. Osler nodes can appear at any point in the course of IE and can last a few hours to several days. They tend to be associated with subacute IE.

Fig. 62.6 Osler nodes.

(From Cohen J, Powderly WG, editors. Infectious diseases. 2nd ed. Philadelphia: Mosby; 2004.)

Splinter hemorrhages are linear petechiae visible on the nail beds of affected patients (Fig. 62.7). They do not blanch when pressure is applied to the nail and are seen better if a bright light is shone directly onto the distal tip of the digit.

Fig. 62.7 Splinter hemorrhages.

These lesions appear as narrow, red to reddish brown hemorrhages beneath the nails that tend to run in the direction of nail growth. Most commonly caused by trauma, splinter hemorrhages are associated with endocarditis and may represent vessel damage from vasculitis or microemboli.

(A and B, Courtesy Marc E. Grossman, MD, FACP; C, used with permission from Johns Hopkins University and obtained online from www.vasculitis.med.jhu.edu/typesof/polyangiitis.html/.)

Differential Diagnosis

Because of the many clinical manifestations of IE, the list of differential diagnoses is overwhelmingly large. Broad areas include infectious and febrile illnesses, as well as cardiovascular, neurologic, psychiatric, GI, renal, dermatologic, and immunologic disorders (Box 62.3). Most interestingly, IE can lead to manifestations that are diagnoses; the EP must think past that initial diagnosis and identify IE as the underlying cause. For example, a cerebrovascular accident or myocardial infarction may be secondary to the embolization or mycotic aneurysms of IE; this fact is important because therapy must also focus on treating the IE.

The most common illness in the differential diagnosis list for IE is febrile illness of any source. Viral syndromes, pneumonia, and urinary tract infections may cause fever, weakness, behavioral abnormalities, and even hemodynamic instability.

The most life-threatening entities are aortic catastrophes, myocardial infarction (with or without acute valve failure), complete heart block, massive pulmonary embolism, cerebrovascular accident, and sepsis.

As mentioned frequently in this chapter, high clinical suspicion guided by knowledge of risk factors (see Box 62.2) is the key to including IE in this long, complex list of differential diagnoses.

Medical Decision Making

Contributing to the complexity of IE is the fact that there is neither a single rapid test to diagnose the disorder nor any routine ancillary test that hints at the diagnosis. Some physical findings might clue the EP to this diagnosis, but they are nonspecific. For the EP, the most important tool for diagnosing IE is clinical suspicion. Elements of the history known to identify patients at high risk for endocarditis must trigger this suspicion and lead the EP to focus on physical findings typical of endocarditis. When suspicious for IE based on the history and physical findings, the EP must order serial blood cultures and an echocardiogram to confirm the diagnosis. A diagnostic algorithm is presented in Figure 62.8.

Fig. 62.8 Diagnostic algorithm for the emergency department management of patients in whom infective endocarditis (IE) is suspected.

*Echocardiography can be performed via either the transthoracic (TTE) or transesophageal (TEE) technique. TEE is more invasive but is more sensitive for detecting vegetations and complications of IE, such as perivalvular abscesses; it is recommended for prosthetic valves; for situations in which optimal visualization by TTE will be difficult, such as emphysema and morbid obesity; for high suspicion of IE but normal TTE findings; and for high suspicion of a complication of IE, such as perivalvular abscess. Normal findings with either technique do not exclude IE if clinical suspicion is high. Echocardiograms can be repeated in an attempt to identify problems such as vegetations and abscesses that may not be noted initially. ABCs, Airway, breathing, and circulation; CBC, complete blood count; CHF, congestive heart failure; CVA, cerebrovascular accident; ECG, electrocardiogram; ESR, erythrocyte sedimentation rate; ICU, intensive care unit.

The most accepted diagnostic schema for IE is the modified Duke criteria (Box 62.4).¹⁰ Unfortunately for the EP, this approach relies heavily on blood culture and echocardiography, the results of which are rarely available to EPs at the outset of care. With recent efforts to bring ultrasonography skills to the ED bedside, echocardiography may become more readily available as an initial evaluation tool, but for now, the procedure requires cardiology consultation and is often not available during the first few hours of care.

According to the modified Duke criteria (see Box 62.4), an echocardiogram positive for IE along with presence of three minor criteria would allow the EP to actually make a “definite diagnosis” of IE in the ED. In all other cases, an echocardiogram positive for IE enables the diagnosis to be “possible IE” as the clinician awaits the results of blood cultures or serologic analysis. It must be emphasized, however, that normal echocardiographic findings would not eliminate the diagnosis of IE, especially in the setting of high clinical suspicion (high-risk patient, strongly suggestive findings). Evaluation should continue until the diagnosis of IE is “rejected” according to the modified Duke criteria. This often means establishment of an alternative diagnosis or the finding of sterile blood cultures after appropriate incubation procedures (proper media and incubation times) and resolution of the illness.

Laboratory Tests

Though not diagnostic when performed alone, some laboratory tests can be useful in diagnosing endocarditis and managing patients in the ED.

The complete blood cell count is less useful than one might think. Leukocytosis is present only in some cases. Normochromic normocytic anemia may be seen.

An elevated erythrocyte sedimentation rate or C-reactive protein value can be a good though nonspecific clue. Both findings are markers for an ongoing inflammatory process and are nearly always present in patients with IE.

Urinalysis often shows proteinuria and sometimes hematuria. Proteinuria may occur as a result of the immunologic effects of endocarditis. Chronic infection or inflammation leads to the formation of immune complexes and their deposition in the glomeruli. Depending on the duration of this illness, the patient may have glomerulonephritis and renal insufficiency.

Renal function can be affected in patients with IE. A serum creatinine measurement is not useful for the diagnosis of IE, but it is for its management. Antibiotic dosing and the use of intravenous contrast–enhanced computed tomography (CT) are dependent on a patient’s renal function.

Less useful for the EP but part of the modified Duke criteria for IE are serologic tests. Rheumatoid factor may occasionally be found in patients with IE, particularly those with long-standing, indolent cases. Serologic assays can detect the presence of bacteria such as Coxiella, Brucella, Bartonella, Legionella, and Chlamydia. Polymerase chain reaction testing for specific DNA or RNA from blood, urine, or surgically excised tissue can be performed when the potential pathogen is slow growing or cannot be cultured by conventional methods.¹¹

Microbiology

Perhaps the most useful test for the diagnosis and management of IE is serial blood cultures. Unfortunately, the results of cultures are often not available to the EP. Three sets of blood culture specimens should ideally be collected before the initiation of antibiotics at intervals of least 30 minutes and over a period of 3 to 6 hours. There is little increased culture yield beyond three sets of blood cultures as long as they are obtained before the administration of antibiotics.

IE results in a constant, low-grade bacteremia. Therefore, it is not necessary to obtain blood culture specimens only during temperature spikes. Serial blood culture specimens obtained over a period of hours to days (in the absence of antibiotic therapy) should all yield positive results as long as at least 10 mL of blood per culture bottle is collected. In the interest of identifying endocarditis caused by more fastidious organisms, it is recommended that blood cultures be held for 14 to 21 days before being labeled negative.

The EP must remember that antecedent antibiotic treatment can also result in negative blood culture results, so the history should include questions about such treatment.¹¹ In a stable patient with a history of antecedent antibiotic therapy, serial blood culture specimens should be collected over a longer time (even days) before initiation of antibiotic therapy for IE.

The caveat to the timing of serial blood sampling for culture is that withholding antibiotics should be the strategy in a stable patient who has no other indications for antibiotics. In an unstable or acutely ill patient, the three sets of blood culture specimens should be obtained over a period of 5 to 20 minutes and then antibiotics given as early as possible.

Electrocardiography

Acquisition of an electrocardiogram (ECG) is often prompted by abnormalities in vital signs, initial symptoms, or clinical instability. If the EP suspects IE, an ECG must be performed. Abnormalities found on the ECG can be caused by endocarditis, but as with other findings for this diagnosis, these abnormalities are nonspecific. The pathologic findings that can be associated with endocarditis are acute myocardial infarction (secondary to coronary artery involvement), complete heart block, atrioventricular block, and bundle branch blocks. Infarction can occur as a result of direct embolization to the coronary arteries or coronary mycotic aneurysm formation. Conduction abnormalities can arise from direct extension of infection to the conduction system. Most commonly, the ECG in patients with endocarditis is normal or reveals a sinus tachycardia.

Echocardiography

Echocardiography is the most important diagnostic tool available to the EP for the early identification of endocarditis and must be performed rapidly in all cases of suspected IE.^6,12 It is one of the major criteria for the diagnosis of IE according to the modified Duke criteria (see Box 62.4 for echocardiographic findings that are diagnostic of IE¹⁰) (Fig. 62.9). In addition, echocardiography allows assessment of disease severity, complications, prognosis, and the need for surgical therapy. It is therefore a critical component in the initial assessment of a patient suspected of having IE.^12,13

Fig. 62.9 Valvular vegetations.

This parasternal long view on a transthoracic echocardiogram shows a large vegetation (thick arrow) on the mitral valve (thin arrow). The large arrow is in the left ventricle and the thin arrow is in the left atrium.

(Courtesy Mark Goldberger, MD.)

Transesophageal Echocardiography

Although it requires more preparation and is more invasive than TTE, transesophageal echocardiography (TEE) has greater sensitivity and specificity (Table 62.3). It can visualize smaller vegetations, as well as myocardial involvement such as abscesses and prosthetic valve vegetations. TEE is recommended for patients with the following findings:

• The TTE result is negative, but clinical suspicion for IE is high.

• The TTE result is positive, but there is concern for the presence of a high-risk complication of IE, such as large or mobile vegetations, significant valvular insufficiency, or a suggestion of perivalvular extension.

• The TTE result is suboptimal because of, for example, morbid obesity, mechanical ventilation, emphysema, or chest wall deformity.

• Prosthetic valves are in place.

Table 62.3 Comparison of the Sensitivity and Specificity of Transthoracic and Transesophageal Echocardiography for the Diagnosis of Cardiac Vegetations

In patients with high clinical suspicion for IE, a normal echocardiographic result is not sufficient to discontinue diagnostic assessment or treatment. TTE or TEE should be repeated within 7 to 10 days. TTE or TEE can be used subsequently to assess the response to treatment or progression of the disease. Please see Figure 62.10 for the echocardiography algorithm.^6,12

Fig. 62.10 Algorithm for the role of echocardiography in the diagnosis of infective endocarditis (IE).

TEE, Transesophageal endocardiography; TTE, transthoracic echocardiography.

(Modified from Habib, G, Hoen B, Tornos P, et al, for the ESC Committee for Practice Guidelines [CPG]. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis [new version 2009]: the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology [ESC]. Eur Heart J 2009;30:2369-413.)

Radiography

Chest radiographs are obtained routinely in most patients with cardiopulmonary symptoms, fever, or both. No specific finding on the chest radiograph is pathognomonic for IE. Multiple bilateral pulmonary infiltrates might be a clue that septic emboli may be present (Fig. 62.11, A).

Fig. 62.11 Septic emboli.

A, A chest radiograph shows two nodular densities (arrows). In this case they are foci of infection from embolization of infected vegetations. B, This non–contrast-enhanced computed tomography scan of the chest demonstrates multiple small infiltrates (arrows) caused by septic embolization.

CT is an excellent tool for the evaluation of symptoms that may be associated with IE. The discovery of ischemic or infectious foci or abscesses, especially multiple lesions, should raise suspicion for a septic focus, such as IE. Contrast-enhanced CT is preferred for differentiating mass lesions with necrotic centers from abscesses.

Chest CT may better identify multiple septic emboli, effusions, or pulmonary abscesses (see Fig. 62.11, B). Brain CT for the evaluation of patients with neurologic or neuropsychiatric symptoms may demonstrate ischemic or infectious foci. Contrast-enhanced abdominopelvic CT might identify ischemia or infarction of the intestines, liver, spleen, or kidneys (Fig. 62.12).

Fig. 62.12 Renal infarction.

A contrast-enhanced abdominopelvic computed tomography scan demonstrates patchy uptake of intravenous contrast agent by the right kidney. Gray areas (white arrow) within the anterolateral aspect of the midpole of the right kidney represent infarction caused by septic emboli from infective endocarditis. This contrasts with the rather homogeneously white, well-perfused left kidney and posterior aspect of the right kidney (black arrows).

(Courtesy Jeffrey Newhouse, MD.)

For identifying the presence of mycotic aneurysms or peripheral embolization, conventional angiography remains the “gold standard,” although screening may be undertaken with CT angiography or magnetic resonance angiography.

Lumbar Puncture

Lumbar puncture is not helpful in making the diagnosis of IE but is mandatory for diagnosing meningitis. Headache, neck stiffness, fever, alteration in mental status, or any combination of these symptoms should make one think of the diagnosis of meningitis. Independent of IE or a complication of IE, the diagnosis of meningitis—especially bacterial meningitis—must be made expeditiously. Lumbar puncture allows the EP to make the diagnosis of meningitis, initiate treatment, and ultimately, identify the causative organism.

Resuscitation

Emergency treatment always begins with the cardinal ABCs of resuscitation—airway, breathing, and circulation. Patients with issues in any of these areas must be stabilized by the usual methods. Supplemental oxygen or endotracheal intubation (or both) should be used as needed. Circulatory instability as a result of either cardiogenic or septic shock should be corrected with volume or pressor support, or both. Refractory cardiogenic shock may require the use of an intraaortic balloon counterpulsation device (contraindicated in patients with aortic insufficiency) or emergency heart surgery.

Empiric Antibiotic Therapy

Antibiotics are the keystone of treatment of IE, and selection of the proper regimen depends on the causative organism. Identification of the specific organism and its resistance pattern allows a properly tailored antibiotic regimen that minimizes the overuse of extended-spectrum agents. With this in mind, EPs should make every effort to obtain serial blood specimens for culture before starting antibiotic treatment. Three sets (aerobic and anaerobic) of blood culture specimens should be obtained. The sets should ideally be collected at least 30 minutes apart and over a period of 3 to 6 hours.

The urgency for empiric antibiotic therapy varies by patient subgroup. In stable patients with subacute manifestations and native valves who have signs and symptoms most consistent with a viral syndrome, antibiotic therapy can be withheld for hours and even days to allow proper culture results to be obtained. Patients with the same stable, subacute findings and viral syndrome–type symptoms but with a prosthetic valve or a history of injection drug use should be admitted to the hospital and receive appropriate empiric antibiotic therapy after the 3- to 6-hour collection of serial blood culture specimens. In a patient with a concomitant infectious process such as meningitis, pneumonia, or abscess and in whom the diagnosis of IE is being entertained, the serial blood culture specimens should still be collected but over a shorter time frame to allow sooner initiation of appropriate empiric antibiotic therapy to cover both the identified infection and the possible IE. Finally, in a patient with an acute, unstable manifestation of suspected IE, empiric antibiotics should not be withheld for collection of serial blood culture specimens. Three specimens can be collected over a 5- to 20-minute period to allow expeditious antibiotic treatment.

Unfortunately for the EP, the causative organism is rarely known because culture results are often not available yet. As with many infections, the EP must choose an empiric regimen. So how does the EP choose the empiric regimen? A group of organisms are known to cause IE (see Box 62.1). Certain of these organisms are more common, depending on the clinical scenario (see Table 62.2). Armed with this knowledge, the EP can tailor the empiric antibiotic regimen to the clinical scenario presented. Examples of such scenarios are native valve involvement, prosthetic valve involvement, injection drug use, history of allergy to antibiotics, prolonged hospitalization, admission to the intensive care unit, and a high prevalence of resistant organisms (Box 62.5). All these factors would influence the antibiotic regimen chosen.

Should the empiric regimen include antibiotics that cover all possible organisms and all resistance patterns? Actually, because many patients with IE have stable, subacute manifestations, the EP is not forced to achieve a perfect match of organism and antibiotic. Changes can be made in 2 to 3 days, when the organisms and resistance patterns become known. In contrast, for unstable, acute cases, EPs should maximize coverage to ensure that they account for all possibilities of organism and resistance. Morbidity and mortality could be influenced by failure to properly treat early.

Initial antibiotic therapy should always be parenteral and bactericidal.¹ Because of growing antibiotic resistance, combination therapy with two or more agents should be used. Recommended empiric antibiotic regimens are listed in Table 62.4.

Table 62.4 Empiric Antibiotic Regimen for Presumed Infectious Endocarditis*†‡

IE, Infectious endocarditis; IM, intramuscularly; IV, intravascularly; PO, orally.

^* Empiric therapy must be designed on the basis of clinical and epidemiologic clues.

^† The duration of therapy varies with the microorganism and its drug sensitivities, the presence of prosthetic devices, and the response to therapy.

^‡ The pediatric dose should not exceed the normal adult dose.

^§ Penicillin G or ampicillin is added to this regimen because nafcillin/oxacillin and gentamicin may not be adequate coverage of enterococci.

Aminoglycosides such as gentamicin should not be given as single daily doses.

^¶ Doses of vancomycin and gentamicin should be adjusted for reduced renal function, as well as measured serum concentration values.

^** Rifampin increases the warfarin requirement for anticoagulation.

Data from Baddour LM, Wilson WR, Bayer AS, et al, for the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease; Council on Cardiovascular Disease in the Young; Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia; American Heart Association; Infectious Diseases Society of America. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications. A statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005;111:e394-434.

For complex cases, it is advisable to seek the expertise of an infectious disease specialist. In addition, patients with confirmed IE require prolonged antibiotic administration and will probably be discharged with a long-term central intravenous catheter such as a Groshong catheter or peripherally inserted central catheter.

Cardiac Pacing

Any hemodynamically unstable patient with a complete heart block, irrespective of cause, warrants at least temporary cardiac pacing. In the setting of IE, in which a high-degree heart block is unlikely to be a temporary condition, a transvenous pacemaker is preferable to transthoracic pacing.

Anticoagulation

Anticoagulation is not indicated for patients with endocarditis. It prevents neither the formation nor the embolization of vegetations. In the setting of native valve IE, anticoagulation should be avoided because it affords no benefit and might cause harm by converting CNS infarcts from bland to hemorrhagic.

Understanding the risks associated with anticoagulation in the setting of IE, what does the EP do with patients who would normally require anticoagulation? An excellent example would be a patient with IE and an anticoagulation-requiring prosthetic valve. The recommendation is that anticoagulation should be continued, barring the presence of acute hemorrhage, CNS infarction or hemorrhage, or a mycotic aneurysm. Any complaint that may result from these issues should be fully investigated to best inform decisions regarding anticoagulation. CT of the brain should be performed in any patient with possible CNS involvement. Any patient with unexplained abdominal or flank pain should undergo contrast-enhanced abdominal CT to evaluate for the presence of a mycotic aneurysm. Visual complaints warrant a complete funduscopic examination. If contraindications are identified, temporary discontinuation of anticoagulation is appropriate even in patients with a prosthetic valve.^1,13,14 In these circumstances, close consultation with the appropriate specialty services is recommended.

Patients taking warfarin should be switched to intravenous, unfractionated heparin in the event that cardiac surgery is required.

Aspirin has not been shown to prevent embolic events but is probably associated with an increased risk for bleeding. It therefore has no role in early management of IE.¹⁵

Surgical Therapy

There are both early and late indications for surgical intervention in the management of IE. Keeping this fact in mind, the EP should obtain early cardiothoracic surgery consultation if any early indications for surgery exist. The only true indication for early, emergency surgical intervention is severe CHF or cardiogenic shock secondary to valvular insufficiency. Intraaortic balloon counterpulsation devices can be used to temporize all forms of cardiogenic shock except that caused by aortic valve insufficiency. In the case of aortic valve incompetence, valve replacement becomes imperative. The presence of an annular or aortic abscess (with or without a conduction system disturbance), a sinus or aortic true or false aneurysm, or paravalvular leak of a prosthetic valve warrants surgical intervention but need not be performed as an emergency procedure if the patient is otherwise stable.

Other potential indications for surgery in patients with IE are failure of antibiotic therapy, vegetations larger than 10 mm on echocardiography, fungal endocarditis, early prosthetic valve endocarditis (within the first 2 months after surgery), and recurrent embolization despite medical therapy.¹⁴

Removal of Medical Hardware

Blood culture specimens should be obtained via any long-term indwelling intravascular catheter. These devices should then be removed. Decisions to remove prosthetic valves or pacemaker wires are complex and should be made in consultation with cardiology, cardiothoracic surgery, or infectious disease specialists (or all three).