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Infective Endocarditis Michael Klein and Andrew Wang J Intensive Care Med published online 15 October 2014 DOI: 10.1177/0885066614554906 The online version of this article can be found at: http://jic.sagepub.com/content/early/2014/10/14/0885066614554906

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Infective Endocarditis Michael Klein, MD1 and Andrew Wang, MD1

Abstract Infective endocarditis (IE) is a noncontagious infection of the endocardium and heart valves. The epidemiology of IE has shifted recently with an increase in health care-associated IE. Infective endocarditis requiring intensive care unit stay is increasing, and nosocomial IE is frequently responsible. Diagnosis of IE requires multiple clinical data points encompassing history and physical examination, microbiology, and cardiac imaging as no one test is sufficiently sensitive or specific. The modified Duke criteria algorithm is the standard of care in the clinical diagnosis of IE. Complications from IE are common, particularly so in the critical care setting, and include congestive heart failure, embolism, septic shock, invasive infection, prosthetic valve dehiscence, heart block, and mycotic aneurysm. A multidisciplinary care team of infectious disease, cardiology, and cardiac surgery physicians is recommended to reduce complications. Intravenous antibiotics are first-line therapy with cardiac surgery being reserved for certain complications of IE and/or for clinical situations in which there is a high risk of complications. Timing of surgery for IE remains controversial and depends on a variety of clinical factors. Keywords infective endocarditis, intensive care, complications, diagnosis, treatment

Definition and Incidence Infective endocarditis (IE) is a noncontagious infection of the endocardium and heart valves or of a prosthetic valvular implant.1 Infective endocarditis is classified as acute or subacute based on the rapidity of progression of the illness prior to diagnosis. The presentation of IE is related both to the virulence of the causative organism and to the patient’s immune response to the infection. Acute IE is a severe condition that develops over days to weeks. Patients with acute IE commonly present with marked toxicity. In contrast, subacute IE follows a more indolent course, progressing slowly over weeks to months.2 Infective endocarditis can also be classified by the type of intracardiac infection as native valve, prosthetic valve, or cardiac implantable electronic device (CIED) infection of a permanent pacemaker or implantable cardioverter-defibrillator.

Incidence Infective endocarditis has an estimated incidence ranging from 2.4 to 11.6 per 100 000 person-years and a high in-hospital mortality rate of approximately 20%, despite medical and surgical advances.1,3 The contemporary epidemiology of IE has changed significantly compared to earlier eras, and these changes have had important influences on the evaluation and outcome of this condition. In the large, prospective, multinational International Collaboration on IE (ICE) registry, the mean age of diagnosis of IE was found to be in the sixth decade, with approximately 2:1 male predominance and IE frequently

occurs in the presence of comorbid conditions such as kidney disease and diabetes mellitus.4 The incidence of native valve IE increases with age. The average age of the patient with IE has increased over time, likely related to the decreased prevalence of rheumatic heart disease and increased prevalence of degenerative valvular disease in the aging population.5 The major predisposition to IE in the modern era is underlying degenerative valvular disease (particularly mitral valve disease). This risk factor is present in approximately 30% of cases. Rheumatic heart disease is a strong risk factor; however, its prevalence in IE in the modern era is low due to the drop in the overall prevalence of rheumatic heart disease.4 A common, but often overlooked, predisposing heart condition for developing native valve IE is bicuspid aortic valve. A multicenter study from 2 tertiary centers in France showed that patients with IE involving a bicuspid aortic valve were younger, had fewer comorbidities, and a higher frequency of aortic paravalvular abscess (50%).6 Due to the severity of IE in these patients, special consideration should be given to early

1 Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA

Received April 4, 2014, and in revised form August 19, 2014. Accepted for publication August 21, 2014. Corresponding Author: Andrew Wang, Division of Cardiology, Department of Medicine, Duke University Medical Center, DUMC 3428, Durham, NC 27710, USA. Email: [email protected]

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surgical intervention when IE develops. Another important predisposing condition is the presence of a prosthetic cardiac valve. Prosthetic valve endocarditis (PVE) is often described with respect to the time from prosthetic valve implantation: early PVE occurring within 1 year of implantation and generally caused by staphylococcal species acquired in the perioperative period or late PVE, with higher percentages of nonstaphylococcal causative microorganisms. A number of patient characteristics have been associated with developing IE. Intravenous drug abuse is associated with tricuspid valve and, also, left-sided valvular IE, even in the absence of underlying valve disease.7 A high percentage of patients have some form of valvular or congenital structural heart disease predisposing them to development of IE.8,9 Other conditions associated with IE include poor dentition, leading to more frequent transient bacteremia, as well as states of immunosuppression including liver cirrhosis, malignancies, or solid organ transplant.10 Increasingly, health care-associated infection, including infections related to hemodialysis, indwelling central venous catheters, and outpatient medical care, is recognized as contributing to IE in up to one-third of the cases. The presence of pacemaker or ICD leads across the tricuspid valve may serve as an initial nidus of infection and lead to involvement of the valve.11 There has also been a significant shift in the microbiology of IE. In earlier eras, streptococcal species were the predominant cause of native valve IE. However, increasing patient age and the rise in health care-associated infection have led to major changes in the microbiology of IE.12 In the ICE registry in a cohort of nearly 1200 cases of IE, the plurality of cases were attributable to Staphylococcus aureus (32%), with 18% viridans streptococci, 11% enterococci, and 11% coagulase-negative staphylococci.13 Importantly, among those with S aureus IE, health care-associated infection accounted for a staggering 39% of cases.13 Staphylococcus aureus has also been found to be the commonest cause of prosthetic valve IE in the modern era.14 As a result, there has been a shift toward acute rather than subacute presentation of IE at the time of diagnosis.4

Infective Endocarditis in Hospitalized and Critically Ill Patients A previous multicenter study reported that 16% of cases with IE were health care-associated.15 As these cases are predominantly in older patients with an increased burden of comorbidities and are more likely to be due to staphylococcal infection, health care-associated IE may be more likely to lead to critical illness. Vascular access is the main source of bacteremia responsible for health care-associated IE. Peripheral venous catheter infection was the cause in one-third of these cases. Health care-associated IE was associated with a much higher rate of in-hospital mortality than community-acquired infection (45% vs 24%).15 In patients with health care-associated IE, the presence of septic shock and the absence of surgical intervention were associated with higher mortality.15 Thus, it is critically important to avoid unnecessary vascular access

catheters and to maintain appropriate sterile procedures in order to reduce the poor outcomes associated with health care-associated IE in those with risk factors. Nosocomial IE has also been reported to have an increasing incidence, with staphylococci as the predominant cause in nearly 60% of the cases.16 Again, the main sources of infection were intravascular procedures or catheter-related infections (55%). Nosocomial IE was associated with an in-hospital mortality of 30%, 3-fold higher than native IE. The number of patients with IE requiring intensive care unit (ICU) admission has also been growing in recent years.17,18 In a study of consecutive patients admitted to an ICU in France between 1993 and 2000, 3% were diagnosed with IE18 and 21% of these cases with IE were nosocomial in origin. Staphylococcus aureus was the isolated organism in half of the cases and complications were common. In-hospital mortality was extremely high at 45%. Another study found that among ICU patients admitted with IE, 45% were diagnosed after admission to the ICU.19 In-hospital mortality was 54% overall in this cohort and rose to 85% in those who did not undergo surgery. Undiagnosed IE has been found to be a leading, missed diagnosis in a large autopsy series of ICU patients, found in 8 cases of 154 in which there were discrepancies between clinical diagnosis and autopsy findings in ICU patients. This finding underscores the importance of high clinical suspicion for the practicing intensivist.20

Pathophysiology The sine qua non of IE is endothelial damage. This damage promotes the deposition of fibrin and platelets to which infectious microorganisms can adhere. Commonly the location of endothelial injury is the valve coaptation site due to higher mechanical stress at this point.21 Endothelial erosion may also occur because of lesions causing turbulent jet flow such as at the left atrial wall due to mitral regurgitation, at the mitral chordal apparatus due to aortic regurgitation, or at the septal leaflet of the tricuspid valve due to a ventricular septal defect.21 Importantly, endothelial damage may result from iatrogenic trauma such as indwelling catheters, emphasizing the importance of appropriate placement and prompt removal of temporary indwelling catheters and devices. These deposits of fibrin and platelets form the nidus for vegetations. Bacteria may adhere to these deposits during periods of bacteremia (even subclinical transient episodes) and thus form an infected vegetation. The major host factor related to the development of IE is the presence of a valvular or endocardial condition that potentiates this risk of endothelial damage. Once bacteremia is induced, the chance of microbial adhesion to the denuded endothelium is dependent on specific properties of the microorganism which are variable between different organisms. For example, both fibronectin and biofilm formation have been implicated as important virulence factors for S aureus.22,23 These and other factors may explain the rise in frequency of S aureus IE as well as the severity of this type of IE. In sum, IE requires a confluence of (1) predisposing host

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factors leading to endothelial damage and (2) subsequent infection of the intracardiac lesions by microorganisms with pathogenic factors.

Diagnosis Clinical Presentation of IE The clinical presentation of IE is highly variable and therefore a high suspicion must be maintained in order to ensure that cases do not go undiagnosed. Clinical evidence for the diagnosis of IE can be broken down into the following 3 general categories: (a) signs and symptoms suggestive of IE, (b) bacteremia or other evidence of bloodstream infection, and (c) evidence of cardiac vegetations and/or infection on cardiac imaging. None of the clinical signs and symptoms of IE are highly sensitive or specific to that diagnosis, and therefore a constellation of findings is often required to support a diagnosis of IE. Approximately 85% of patients present with fever, although this finding may not be present in patients with immunosuppression and in patients who have previously been on antibiotic therapy. Other clinical features include chills (42%-75%), sweats (25%), anorexia (25%-55%), weight loss (25%-35%), malaise (25%-40%), dyspnea (20%-40%), and cough (25%). The detection of a heart murmur with auscultation has been reported in 80% to 85% of patients with confirmed IE.24 The relatively high sensitivity of this finding affirms the importance of a careful cardiac examination as other signs may be lacking. Therefore, a new or changing regurgitant murmur combined with the presence of fever of uncertain origin should prompt further evaluation for IE. Peripheral stigmata of IE, due to embolic and/or immunemediated events, are infrequently present in IE but can include petechiae, splinter hemorrhages, Janeway lesions (10%), Osler nodes (10%-25%), and Roth spots. Janeway lesions are nontender, small, macular, or nodular skin lesions due to microabscess formation beneath the epidermis. Osler nodes are painful red skin lesions caused by immune complex deposition. Roth spots are retinal hemorrhages usually due to immune-mediated vasculitis. Because clinical history and examination findings of IE may lack sensitivity and specificity, a high suspicion for underlying IE should be maintained when critically ill patients present with complications of unknown etiology such as systemic embolism or heart block. A history of antibiotic exposure is all too common due to the nonspecific nature of the infectious symptoms caused by IE. An early study of consecutive cases of IE found that 53% of patients had been exposed to antibiotics in the 2 weeks prior to diagnosis.25

Ancillary Testing Readily available laboratory results may support the diagnosis of IE yet do not represent standard diagnostic criteria for IE. Such nonspecific laboratory data include normocytic, normochromic anemia (70%-90%) due to chronic inflammation, thrombocytopenia (5%-15%), and leukocytosis (30%).

Erythrocyte sedimentation rate and C-reactive protein concentrations are usually elevated.26 Imaging modalities may detect septic emboli in various organs. Pulmonary septic emboli are not infrequently encountered in patients with right-sided IE and are apparent on chest X-ray or chest computed tomography (CT). Head CT or brain magnetic resonance imaging (MRI) may reveal multifocal ischemic lesions and contrasted examination may reveal abscesses in those presenting with neurologic abnormalities. Abdominal CT studies may show evidence of splenic or renal infarcts or abscesses. Thus, especially in the ICU patients, it is important to think of IE as a systemic disease rather than a cardiac disease.

Diagnostic Criteria for IE The diagnostic standards for IE are the modified Duke criteria, which have demonstrated superior sensitivity and specificity compared to earlier case definitions and diagnostic criteria27 and have been well validated.27-32 The modified Duke criteria weight the microbiologic, imaging, and clinical evidence of IE and place patients into the following 3 categories based on their probability of IE: definite, possible, and rejected (Table 1).

The Use of Echocardiography and Other Cardiac Imaging Modalities Echocardiography is the standard method for assessing not only the presence of IE but also identifying its common cardiac complications such as valvular incompetence and abscess formation. As mentioned previously, echocardiographic evidence is among the major criteria for IE according to the modified Duke criteria. The hallmark finding on echocardiography is a vegetation which appears as an independently mobile, echogenic mass attached to endocardial structures, typically the cardiac valves. Of note, echocardiography cannot provide any evidence as to the presence of infection of such a vegetation and hence microbiologic evidence remains critically important even in those with vegetations on echocardiography. Transthoracic echocardiography (TTE) is appropriate to perform in all patients with suspected IE.33 However, the sensitivity of TTE for the visualization of an intracardiac vegetation or abscess is insufficient to exclude IE, and thus the diagnosis of IE cannot be excluded on the basis of a negative TTE. The use of TTE specifically in patients admitted to the ICU is not well studied but may be even less sensitive in the setting of mechanical ventilation and suboptimal patient positioning both of which can quite significantly limit examination quality. In a multicenter review of echocardiographic examination in ICU patients, TTE was diagnostic in only 33% and a subsequent transesophageal echocardiography (TEE) was required in 91% to confirm the diagnosis or to fully delineate the extent of disease.34 Transesophageal echocardiography has greater spatial resolution based on the ultrasound transducer’s closer proximity to most of the cardiac valves allowing for better evaluation of the

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Table 1. The Modified Duke Criteria for Diagnosis of Infective Endocarditis.a Major criteria

Minor criteria    



Blood culture evidence  Typical microorganisms growing in blood cultures from at least 2 separate inoculations  Persistently positive blood cultures; at least 2 positive cultures >12 hours apart or at least 3 of 3 or majority of 4 positive blood cultures >1 hour apart  Single positive blood culture for Coxiella burnetii or IgG titer > 1:800 Endocardial involvement evidence  Oscillating intracardiac mass on endocardial structures, structures involved with turbulent jets, or implanted foreign material on echocardiography  Evidence of abscess on echocardiography  New valvular regurgitation in absence of previous murmur  New prosthetic valvular dehiscence Predisposing heart condition or IVDU Temperature > 38 C Microbiologic evidence not meeting major criteria Vascular phenomena: – Arterial emboli – Pulmonary infarcts – Mycotic aneurysm – Intracranial hemorrhage – Conjunctival hemorrhages – Janeway lesions Immunologic phenomena: – Glomerulonephritis – Osler’s nodes – Roth’s spots – positive rheumatoid factor titer

Abbreviations: IgG, immunoglobulin G; IVDU, intravenous drug abuse; IE, infective endocarditis. a Definite IE diagnosis when any of the following are found: (a) direct pathologic evidence of IE; (b) 2 major criteria; (c) 1 major criterion and 3 minor criteria; (d) 5 minor criteria. Possible IE diagnosis when any of the following are found: (a) 1 major criterion and 1 minor criterion and (b) 3 minor criteria.

presence of vegetations (Figure 1). As a result, TEE should be performed in patients with a high likelihood of IE and a negative TTE.35,36 Although TTE and TEE have been found to have concordant results in approximately half of patients with suspected IE, TEE can offer additional diagnostic information in some patients, particularly those with prosthetic valves.37 However, dependent upon technical issues, TTE can at times provide some hemodynamic data that TEE may not offer in certain patients and often is better able to visualize the tricuspid valve due to its close proximity to the chest wall. Therefore, TTE and TEE can often be thought of as providing complimentary information rather than redundant information. In addition to the enhanced sensitivity of TEE for the diagnosis of IE, TEE may be beneficial after the diagnosis of IE when complications that may warrant surgical intervention, particularly paravalvular complications of abscess, regurgitation, dehiscence of a prosthetic valve, and fistula formation are suspected (Figure 2). The

Figure 1. A patient with vegetation involving the mitral valve. Upper, Transthoracic echocardiogram demonstrating a vegetation adherent to the atrial side of the mitral valve (arrow). Lower, Transesophageal echocardiogram in the same patient with better characterization of vegetation due to proximity of the transducer to the lesion. LA indicates left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

American College of Cardiology/American Heart Association (ACC/AHA) have published guidelines for the use of echocardiography in cases of potential IE (Table 2) and a simple clinical algorithm for determining what if any testing should be performed.38 It is important for ICU physicians to note that the optimal use of echocardiography in all patients with methicillinresistant S aureus (MRSA) bacteremia, but without known IE, remains uncertain. The most recent Infectious Diseases Society of America (IDSA) guidelines on MRSA infection state that echocardiography, either TTE or TEE, should be performed in adult patients with MRSA bacteremia.39 However, others have recently suggested that simple, clinical algorithms for assessing the appropriateness of echocardiography in these patients could reduce the overuse of imaging in the absence of high clinical suspicion.40 A suggested algorithm for the use of echocardiography for diagnosis of IE is shown in Figure 3. In general, repeat echocardiography during or after treatment of IE should be performed if there is clinical evidence of worsening or refractory symptoms or signs of progressive cardiac dysfunction.

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Figure 2. Transesophageal echocardiogram in a patient with infective endocarditis (IE) complicated by fistula formation between the aorta and the left atrium. Upper (still frame during systole), A prominent systolic flow jet (arrow) is seen traveling from the aorta just above the aortic valve in to the left atrium. Lower (still frame during diastole), The continuous jet (arrow) remains apparent during diastole due to the pressure gradient between the aorta and the left atrium.

Other imaging modalities can be useful in certain situations. Recently, positron emission tomography–computed tomography imaging has been used to confirm IE in cases where the diagnosis was uncertain after standard evaluation41 and may be particularly helpful in suspected prosthetic valve or cardiac device infection, when thrombus or postsurgical changes may be difficult to differentiate from an infected vegetation. Cardiac magnetic resonance imaging and cardiac CT have been used to detect aortic root abscess. However, clinical experience with these techniques in patients with IE is limited, and their clinical utility is not well defined.42-44

Complications Leading to Critical Illness Infective endocarditis continues to have a high rate of complications which contributes to the severity of illness and

mortality. Complications of IE may involve cardiac structures when the infection spreads within the heart or involve extracardiac structures when there are embolic events or metastasis of infection. About 57% of patients with IE experience 1 or more complications.23 Congestive heart failure (CHF) complicates IE in approximately one-third of cases. It results from the destructive lesions of IE on cardiac valves, resulting in acute and progressive regurgitation (Figure 4). Due to acute and often severe regurgitation, no ventricular compensation is possible, leading to increased filling pressures and reduced cardiac output. Clinical characteristics associated with CHF in IE include older age, health care-associated infection, new or worsening murmur, left-sided native-valvular infection with new aortic or mitral regurgitation, and paravalvular complications.45 Congestive heart failure in IE should be considered a surgical emergency, as patients often decompensate quickly. For severe left-sided valve regurgitation, medical therapy, including diuresis and afterload reduction with an intravenous, short-acting vasodilator (eg, nitroprusside or hydralazine), may stabilize a patient transiently. In patients with acute, severe mitral valve regurgitation, intra-aortic balloon counterpulsation may provide additional afterload reduction, but this therapy is contraindicated if significant aortic regurgitation is present. Systemic embolization has been estimated in 22% to 50% of cases with left-sided IE. Systemic emboli may be clinically silent, and brain MRI may show subclinical brain embolization in nearly half of patients with left-sided IE.46 Embolic risk has been associated with several clinical characteristics including diabetes, atrial fibrillation, embolism before antibiotics, vegetation length, and S aureus infection. Cerebral embolism is the serious extracardiac complications of IE.15,24 Clinically apparent cerebral complications are estimated to occur in 15% to 20% of patients with IE and 60% precede the clinical diagnosis of IE.25 Recent multicenter data from ICU patients have shown that neurologic complications are even more common in the ICU population, occurring in approximately 55% of critically ill patients with IE.17 Periannular abscess is a serious complication of IE and has been estimated to occur in 15% of cases.4 In native valve IE, aortic valve involvement is more strongly associated with abscess. In prosthetic valve IE, abscess may be the only endocardial evidence of infection, as vegetations are less frequently visualized than in native valve IE. Abscess may be suspected clinically by persistent fever or new electrocardiographic conduction abnormalities, particularly in cases of aortic valve IE. Although high-degree or complete heart block may be rapidly recognized by cardiac monitoring, the majority of new conduction abnormalities, such as first-degree atrioventricular block, are subtle changes yet may indicate invasive infection and abscess formation. However, the specificity of these ECG findings is highly variable (53%-97%). Transesophageal echocardiography is the test of choice for the noninvasive diagnosis of an intracardiac abscess (Figure 5), although surgery is the gold standard confirmation. Septic shock complicates IE in approximately 17% of cases. In a large series of patients with IE, septic shock was associated

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Table 2. ACC/AHA Guideline Indications for Transthoracic Echocardiography in Infective Endocarditis. Class I    

Class IIa

To detect valvular vegetations  To diagnose infective with or without positive blood endocarditis of a prosthetic cultures valve in the presence of persistent fever without To characterize the hemodynamic bacteremia or a new murmur severity of valvular lesions To assess complications of infective endocarditis To reassess high-risk patients (eg, those with a virulent organism, clinical deterioration, persistent or recurrent fever, new murmur, or persistent bacteremia)

Class IIb

Class III

 To re-evaluate prosthetic  valve endocarditis during antibiotic therapy in the absence of clinical deterioration

Transthoracic echocardiography is not indicated to re-evaluate uncomplicated (including no regurgitation on baseline echocardiogram) native valve endocarditis during antibiotic treatment in the absence of clinical deterioration, new physical findings, or persistent fever

Abbreviation: ACC/AHA, American College of Cardiology/American Heart Association.

with diabetes mellitus, S aureus infection, acute renal insufficiency, vegetation size 15 mm, signs of persistent infection, and supraventricular tachycardia. Patients who developed this complication had an in-hospital mortality of 73%.47 Other less frequent complications include mycotic aneurysm, due to infection of an arterial vessel wall with possibility of rupture and bleeding, and prosthetic valve dehiscence. Prosthetic valve dehiscence may be diagnosed by echocardiography based on an unstable rocking motion of the valve prosthesis relative to cardiac motion (Figure 6).

Treatment Multidisciplinary Team Management Especially for the critically ill patients, it is essential to utilize multidisciplinary care teams for determining treatment strategies. Multidisciplinary care teams consisting of infectious disease, cardiology, and cardiac surgery physicians that apply professional society guidelines have been shown to decrease renal failure, multisystem organ failure, death from embolic events, and overall mortality.48 The effect of this strategy was likely due to more appropriate selection of antibiotic regimens and surgical intervention. Surgical consultation should be obtained for all cases of complicated, native IE and for all cases of prosthetic IE.

The Role of Antibiotics Given the significant morbidity and mortality associated with IE, it is prudent to initiate appropriate empiric antimicrobial therapy as soon as the diagnosis is considered. However, in order to accurately diagnose IE, it is necessary to obtain the requisite blood culture samples prior to starting antibiotic therapy. In cases of blood culture-negative endocarditis, it is important to remember that fastidious organisms may be responsible and may take much longer than expected to grow in culture, if at all. The diagnostic utility of serologic analysis for Bartonella and Coxiella as well as blood polymerase chain reaction testing in selected cases has been demonstrated in a

large, prospective series of blood culture-negative endocarditis.49 In cases complicated by sepsis, valvular dysfunction, conduction disturbances, or embolic phenomena, empiric antimicrobial therapy should be initiated immediately after obtaining blood cultures.10,50 Detailed empiric and culturespecific antimicrobial treatment regimens have been defined based on a synthesis of the available clinical data and expert opinion in several society guidelines (Table 3).38,51 After initial inpatient therapy and determination of antibiotic appropriateness as well as clearance of blood cultures, stable patients can be successfully treated with outpatient intravenous antibiotic infusion. There are 3 basic tenets of treatment that should guide antibiotic therapy. First, a prolonged course of antibiotic treatment is necessary owing to high bacterial concentrations and because organisms deep within vegetations are inaccessible to phagocytic cells.52 Native valve IE is treated at a minimum for 4 weeks with intravenous antimicrobial therapy, whereas prosthetic valve IE is universally managed with at least 6 weeks of intravenous antibiotic therapy, due to the greater difficulty in antibiotic penetration of the lesions which inhabit the prosthetic surface. The beginning of the determined duration of treatment should begin on the first day of negative blood cultures in cases where blood cultures had been positive. For patients who undergo valve replacement if the excised native valve tissue is culture negative, then the recommended antibiotic choice and duration of treatment should be consistent with recommendations for PVE rather than native valve IE.10 Second, parenteral administration of antibiotic therapy for the full duration of therapy is recommended no matter the underlying substrate or organism. Oral therapy for IE has been described in certain situations but is not recommended, particularly for left-sided IE.53,54 Third, in cases of IE where the causative organism demonstrates antimicrobial resistance, combination therapy is recommended, commonly involving a b-lactam and an aminoglycoside antibiotic. Both antibiotics should be administered at roughly the same time of the day so that maximum synergistic bactericidal effect is obtained.10 However, careful monitoring for renal dysfunction and other adverse effects should be

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Figure 3. Diagnostic algorithm in cases of possible infective endocarditis.

performed.55 It should be noted that alternate regimens and shortened aminoglycoside administration duration have demonstrated reasonable efficacy in Enterococcus faecalis IE48,56 and may be given consideration in situations in which there is higher risk of adverse effects from aminoglycoside administration such as in the elderly patients and those with renal dysfunction.

Prognosis and Indications for Surgery Many observational studies have evaluated clinical characteristics associated with higher in-hospital mortality in IE. In

general, host factors, particularly comorbid conditions, causative micro-organism, and IE complications, predominate among risk factors for mortality. In one of the largest, prospective, and contemporary series from the ICE group of investigators, in-hospital mortality was associated with age, prosthetic valve involvement, staphylococcal infection, and complications of pulmonary edema or paravalvular complications. In another observational study of clinical characteristics near the time of IE diagnosis, higher mortality was predicted by male sex, diabetes mellitus, and acute physiology (Acute Physiology and Chronic Health Evaluation II score) at admission, S aureus infection, and embolic event.57

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Figure 4. A patient with aortic valve endocarditis. Upper, Transesophageal echocardiogram demonstrates an aortic valve that is incompetent due to aggressive infection. . Lower, With color Doppler, the turbulent, regurgitant blood flow through this space is seen as a mosaic color pattern (arrow). Ao indicates aorta; LV, left ventricle.

There are no randomized studies of surgery versus antibiotic therapy alone as treatment of IE. Many of the complications of IE, such as heart failure and abscess, are unlikely to be cured by antibiotic treatment alone. Observational comparisons of mortality between surgically or medically treated IE are confounded by differences in patient characteristics and selection bias. After adjustment for these differences, a survival benefit during hospitalization for surgery has been reported for patients with complicated IE,58 particularly if heart failure occurs.45,59 Although S aureus IE carries a higher risk of mortality, surgery is performed less commonly than for other bacterial causes58 likely related to the adverse host factors associated with S aureus IE. Based on these observational data and expert clinical opinion, guidelines have been published by professional societies to identify patients who may benefit from valve surgery for IE (Table 4). The ACC/AHA Valvular Heart Disease Management Guidelines recommend surgical intervention for IE with complications that are unlikely to be cured by antibiotic therapy alone: heart failure due to valve dysfunction, left-sided IE with resistant

Figure 5. A patient with an aortic paravalvular abscess. Upper, Transesophageal echocardiogram demonstrates an area of ring-like echogenicity surrounding a central echolucent area adjacent to the aorta (Ao) near the aortic valve, typical for aortic paravalvular abscess (arrow). Lower, A nearly orthogonal view shows marked thickening of the tissue (arrow) separating the left atrium (LA) from the aorta (Ao). This is highly suggestive of paravalvular extension of infection in a patient with infective endocarditis (IE).

organism, persistent bacteremia, heart block, annular or aortic abscess, or destructive penetrating lesion, prosthetic endocarditis with relapsing infection, or recurrent embolic events with persistent vegetation despite antibiotic therapy. Of note, certain microorganisms, particularly S aureus, may be associated with prolonged bacteremia (up to 10 days) after initiation of antibiotic therapy, before clearance of bacteremia. Surgery may also be considered for patients with vegetation greater than 10 mm because of an increased risk of embolic events. A recent, small randomized controlled trial in South Korea found that early surgery (within 2 days) of diagnosis of left-sided, native IE with severe valve regurgitation and vegetation size >10 mm was associated with significantly fewer embolic events than delayed surgery, but no mortality difference was seen at 6-month follow-up.60 Observational data have shown that the risk of embolic event decreases rapidly within the initial 7 days of appropriate antibiotic therapy,61

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9 Table 3. Recommended Empiric Antibiotic Regimen for the Treatment of Presumed Infective Endocarditis. Native valve IE with indolent Amoxicillin 2 g IV q4h and consider presentation gentamicin 1 mg/kg IV (frequency determined by local protocol) Native valve IE with severe Vancomycin IV (dosed per local sepsis protocol) and gentamicin 1 mg/kg IV q12h Vancomycin IV (dosed per local Native valve IE with severe protocol) and meropenem 2g IV q8h sepsis and risk factors for Enterobacteriaceae or Pseudomonas Prosthetic valve IE Vancomycin IV (dosed per local protocol) and gentamicin 1 mg/kg IV q12h and rifampin 300-600 mg IV q12hfs Abbreviations: IE, infective endocarditis; IV, intravenous; q4h, every 4 hours; q12h, every 12 hours; q8h, every 8 hours.

Figure 6. Transthoracic echocardiography demonstrates a dehisced prosthetic aortic valve. Upper (still frame during systole), The plane of the valve prosthesis is seen separated from the native aortic valve plane with a resultant space connecting the sinus of Valsalva (arrow) in the aortic root (Ao) to the left ventricle (LV). Lower (still frame during diastole with color doppler overlay), The prosthetic valve has now partially returned to a normal position but there is still a residual space connecting the sinus of Valsalva to the LV. Color doppler reveals an eccentric diastolic flow connection in this space (arrow).

so surgery for the prevention of embolic events may be of greater benefit soon after the diagnosis of left-sided IE with a large vegetation. Owing to the increase in implanted cardiac devices over the past 2 decades, there has been a concomitant increase in the incidence of CIED infections.62,63 ACC/AHA guidelines regarding the management of CIED infections have been published.64 Any patient with an infected CIED, a CIED in the presence of IE due to resistant organism, IE treated with valve surgery should have complete removal of both generator and leads. The duration of antibiotic treatment should begin at the time of CIED removal and depends on the extent of the infection. It is critical to assess the need for the CIED both in the short and long term in order to determine the necessity of temporary device implantation and/or reimplantation of another device after appropriate antibiotic

administration. If reimplantation of a CIED is required, then it is recommended to delay reimplantation until after successful antibiotic therapy and to reimplant at a distant site. Antibiotic therapy duration is summarized in Table 5. The issue of anticoagulation management often arises in the care of patients with IE who are on chronic anticoagulation. Older observational data suggest that there is a higher mortality due to neurologic complications in patients receiving anticoagulation.65 However, more recent prospective cohort data analysis reported no increase in cerebrovascular complications in patients on anticoagulant therapy.66 Given that these patients should be treated on an inpatient basis during the initial phase of their treatment, a common practice is to discontinue chronic warfarin therapy at the time of IE diagnosis and then to initiate unfractionated heparin when the international normalized ratio is less than 2.0. After antibiotic efficacy and patient stability are established, warfarin can usually be restarted after several days of antibiotic therapy if surgery is not planned. If intracranial hemorrhage occurs and valve surgery is indicated, the Society of Thoracic Surgeons (STS) Clinical Practice Guidelines advise waiting at least 4 weeks to pursue valve surgery.67 In patients with ischemic stroke complicating IE and an indication for anticoagulation, it is common to discontinue oral anticoagulation for a period of 1 to 2 weeks to decrease risk of hemorrhagic conversion. This practice is pragmatic and there are no robust data to support the practice; the risk of thromboembolism must be weighed against the risk of hemorrhagic conversion, particularly in patients with mechanical prosthetic cardiac valves. The short-term risk of thrombosis without anticoagulation is acceptably low in patients with IE, and bileaflet mechanical valves in the aortic position if no other risk factors for thromboembolism (eg, atrial fibrillation, left ventricular systolic dysfunction, and prior thromboembolism) are present. For patients with mechanical mitral valve replacements or other additional risk factors for thromboembolism, use of unfractionated heparin intravenously may be an acceptable option because of its short half-life and reversibility.

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Table 4. ACC/AHA Guideline Indications for Surgical Management of Infective Endocarditis. Class I      

Class IIa

Class IIb

Valve dysfunction causing heart failure  Recurrent embolism and persistent Left sided IE caused by Staphylococcus vegetations, despite antibiotic aureus, fungal or highly resistant organisms therapy Persistent bacteremia or fever >5-7 days IE complicated by heart block, annular or aortic abscess, or other destructive lesions PVE with relapsing infection IE involving permanent pacemaker or implantable cardioverter-defibrillator



NVE with mobile vegetations > 10 mm in diameter with or without evidence of embolic event

Abbreviations: IE, infective endocarditis; ACC/AHA, American College of Cardiology/American Heart Association; NVE, native valve endocarditis; PVE, prosthetic valve endocarditis.

Table 5. ACC/AHA Guidelines for the Management of CIED Infection. Isolated pocket infection Bacteremia and device infection Device-related infective endocarditis

10-14 days of antibiotics after device removal Minimum of 14 days after device removal 4-6 weeks of antibiotics after device removal

Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; CIED, cardiac implantable electronic device.

Timing of Surgery The timing of surgical intervention in IE, even in cases where the indication is serious, is not well defined. A meta-analysis of the patients suggested that mixed findings in studies likely resulted from different patient populations, biases, and statistical methods.68 Subsequently, Kang and colleagues performed a small, randomized controlled trial of early surgery versus standard treatment in patients with left-sided native valve IE, severe valvular regurgitation, and vegetation >10 mm. In this cohort of younger patients with predominantly streptococcal IE, earlier surgery was associated with fewer embolic complications than delayed surgery, but there was no difference in survival during hospitalization or at 6-month follow-up.69 Because of the patient population, extrapolation of the findings to all IE cases is limited. In the large STS registry of surgery for IE, operative mortality was 8% and driven by the urgency of the surgery. Patients treated with surgery after completion of antibiotic therapy had half the mortality rate as those treated during the active phase. However, these timing factors may not be controllable in IE, as mechanical complications may not be stabilized adequately with medical treatment.

great majority (87%) of the deaths occurred during the index hospitalization. The Sepsis-related Organ Failure Assessment (SOFA) score was the only independent predictor of longterm mortality and, perhaps more importantly, was quite effective at discerning probability of death in those who received surgery. There was 100% mortality within 6 months for those with the highest quartile of SOFA score. Importantly, surgical timing was not associated with postoperative outcomes. From a prognostic standpoint, among those with a standard indication for surgery who did not undergo surgery, mortality was 95% confirming the very poor prognosis of these patients. There is little consensus regarding the appropriate timing of cardiac surgery for IE complications after an acute stroke. Earlier data suggested that a 2-week delay for cardiac surgery following stroke was sensible71 The feared complications of surgery in this time frame are hemorrhagic conversion due to the anticoagulation used during cardiopulmonary bypass and perioperative hypotension leading to ischemic stroke extension. More recent studies have challenged this paradigm. In a study of serial patients with CT or MRI verified stroke, early surgery (median timing of 4 days after neurologic event) was not associated with a higher rate of new neurologic events than late surgery. Additionally, the rate of complete neurologic recovery was similar.72 Other studies have shown that early, urgent cardiac surgery is feasible and safe in patients with IE, recent stroke, and minimal neurologic impairment.73,74 Likewise, the risk of mortality in those with transient ischemic attacks or asymptomatic neurologic findings demonstrated on CT scan is low and comparable to those with no evidence of neurologic abnormalities.74 Based on these data, the European Society of Cardiology has updated their guidelines to reflect that in the absence of severe neurologic deficit or coma, ischemic stroke by itself should not delay surgery that is otherwise indicated when hemorrhage has been ruled out by advanced imaging.75

Surgery in the Critical Care Patient With IE There are limited studies examining surgery for critically ill patients with IE. A recent prospective, multicenter, observation study of 198 consecutive ICU patients with IE found 69% mortality at 59.5-month follow-up with a significant reduction in mortality among those who received surgery.70 Notably, the

Follow-Up Including Prophylaxis Data/Guidelines Because of the lack of clinical evidence from randomized studies, the role for IE prophylaxis prior to invasive procedures is a controversial issue. This is particularly relevant to the ICU

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patients who often undergoe invasive procedures related to their critical illness. Statistical modeling has shown that bacteremia and subsequent IE from dental procedures are exceedingly rare with an estimated risk of 1 in 95 000 in the highest risk individuals.76 Although antibiotic prophylaxis reduces the rate of bacteremia, there is no evidence that it reduces the development of IE. The existing professional society guidelines are based primarily on expert opinion. The most recent AHA/ACC guidelines curtailed the recommendations for IE prophylaxis. Importantly for intensivists, invasive dental procedures were the only procedures for which antibiotic prophylaxis is recommended for high-risk patients, including those with previous IE, prosthetic heart valves, unrepaired cyanotic congenital heart disease (including palliative shunts or conduits), or recently repaired congenital heart disease with prosthetic material or residual defect after repair. Specifically, prophylaxis is not recommended for gastrointestinal, pulmonary, or urological endoscopy in the absence of active infections or planned incision of the mucosa in those organs. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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