Table of Contents

 

Patients with infective endocarditis (IE) can present to the ED with many varied and sometimes subtle complaints: fevers, malaise, abscess, embolic phenomena, heart failure, sepsis, and even stroke. Blood cultures should be performed, but they will not result in time to aid diagnosis. Nonetheless, a thorough surgical, device, and drug history for these patients will help determine effective ED management.

What is the symptom present in 80% of patients with IE?

Why are the “classic” signs and symptoms of IE present in fewer than 10% of patients?

What are the differences in vascular and immunologic phenomena and how can they offer clues for diagnosis?

For a patient with a prosthetic valve, what does the evidence say regarding “early” and “late” classification, and how does this affect treatment?

How can the Duke Criteria be used for ED evaluation?

When should POCUS be used? TTE? TEE? In what order? If urgent TEE is unavailable, what are the next steps?

What are the conditions that require urgent surgical consultation?

What is the current evidence on antibiotic prophylaxis before dental, respiratory, or soft-tissue procedures?

Is there evidence that outpatient antibiotic therapy is effective?

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Etiology and Pathophysiology
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. History
   2. Physical Examination
9. Diagnostic Studies
   1. Diagnostic Criteria
   2. Imaging
      1. Transthoracic Echocardiography and Transesophageal Echocardiography
      2. Computed Tomography
      3. Magnetic Resonance Imaging
      4. Nuclear Molecular Imaging
   3. Blood Tests and Blood Cultures
10. Treatment
    1. Antimicrobial Treatment
       1. Alternative Antibiotics
       2. Antibiotic Treatment Duration
    2. Surgical Treatment
11. Special Circumstances and Populations
    1. Antibiotic Prophylaxis
    2. Infective Endocarditis-Related Neurologic Complications
    3. Transcatheter Valve Repair-Associated Infective Endocarditis
    4. Infective Endocarditis and Implantable Devices
    5. Infective Endocarditis in Children
12. Controversies and Cutting Edge
    1. Outpatient Therapy for Infective Endocarditis
       1. Partial Oral Therapy for Infective Endocarditis
    2. Catheter-Assisted Vegectomy
    3. Infective Endocarditis Teams
    4. Risk Scores
13. Disposition
14. Summary
15. Time- and Cost-Effective Strategies
16. Risk Management Pitfalls for Infective Endocarditis in the Emergency Department
17. Case Conclusions
18. Disclaimer
19. Clinical Pathway for Emergency Department Management of Patients With Infective Endocarditis
20. Tables and Figures
    1. Table 1. Risk Factors for Infective Endocarditis
    2. Table 2. History and Physical Elements Suggestive of Infective Endocarditis
    3. Table 3. Vascular and Immunologic Phenomena in Infective Endocarditis
    4. Table 4. Duke Criteria for Infective Endocarditis, With Definitions
    5. Table 5. Imaging Modalities Useful in Diagnosing Infective Endocarditis
    6. Table 6. Empiric Antimicrobial Therapies for Infective Endocarditis
    7. Table 7. Indications for Specific Antimicrobial Therapies for Infective Endocarditis
    8. Table 8. Indications for Surgical Consultation for Infective Endocarditis
    9. Table 9. High-Risk Conditions Mandating Antibiotic Prophylaxis
    10. Table 10. Procedures Requiring Antibiotic Prophylaxis for Infective Endocarditis in High-Risk Patients
    11. Figure 1. Changes in Infective Endocarditis Epidemiology
    12. Figure 2. Splinter Hemorrhages
    13. Figure 3. Janeway Lesions
    14. Figure 4. Osler Nodes
    15. Figure 5. Aortic Valve Vegetation and Pseudoaneurysm as Seen on Ultrasound
    16. Figure 6. Cardiac Multislice Computed Tomographic Imaging of Infective Endocarditis
21. References

Abstract

Recognition of infective endocarditis in the emergency department continues to be a challenge, as its signs and symptoms can be subtle, laboratory results are limited, and it can involve or lead to many other serious conditions. With the increase in use of medical access devices, implantable cardiac devices, and the rise of intravenous drug use, the epidemiology of infective endocarditis is changing. Diagnostic imaging has evolved, and the use of point-of-care ultrasound and transthoracic echocardiography are critical in making an early diagnosis. This review provides a best-evidence approach to diagnostic strategies, antibiotic recommendations, and surgical treatment recommendations for infective endocarditis.

Case Presentations

A 25-year-old man presents to the ED with general malaise and fever for the preceding 3 weeks. He was seen recently at an outpatient clinic, diagnosed with pneumonia, and treated with azithromycin; however, he continues to have fevers. His history is remarkable for heroin addiction with recurrent treatment in rehabilitation over the past 3 years. He is ill-appearing, with a temperature of 39°C (102.2°F); heart rate, 120 beats/min; blood pressure, 100/60 mm Hg; respiratory rate, 26 breaths/min; and oxygen saturation of 90% on room air. He has diffuse crackles bilaterally; you do not auscultate any heart murmurs. Chest x-ray reveals the presence of multifocal infiltrates. Broad-spectrum antibiotics are administered, and the patient is admitted to the hospital with a diagnosis of multifocal pneumonia and sepsis. The more you contemplate the case, though, you wonder whether there is a diagnostic test that could have been done...

On a morning shift, a 55-year-old woman arrives in severe distress. Her husband informs you that she has had a decrease in energy over the past month and that her past medical history is notable for poorly controlled lupus and mitral valve prolapse. She was evaluated the week prior and discharged with a diagnosis of influenza. Her heart rate is 122 beats/min; blood pressure, 80/60 mm Hg; temperature, 38.0° (100.4°F); respiratory rate, 28 breaths/min; and oxygen saturation, 88% on room air. You auscultate crackles bilaterally and a loud holosystolic murmur most prominent at the cardiac apex. Chest x-ray reveals bilateral infiltrates. The patient improves initially with fluid resuscitation but rapidly decompensates, requiring intubation and vasopressor support. You administer 2 g of ceftriaxone IV and 1 g of vancomycin IV and admit her to the ICU for sepsis secondary to post–influenza pneumonia, but knowing that sepsis outcome is linked to administration of the correct antibiotic, you wonder whether there is a diagnostic test that would help in identifying the etiology...

A 62-year-old man presents to your ED complaining of oral pain. He has poor dentition and several past dental abscesses as well as a prosthetic aortic valve. Today, he presents with what appears to be a simple, superficial dental abscess that is amenable to drainage. Just as you are ready to incise and drain, you wonder whether you should give prophylactic antibiotics and, if so, which one...

Introduction

Infective endocarditis (IE) can be difficult to diagnose in the emergency department (ED) because its signs and symptoms can represent many different and comorbid conditions. Although diagnostic and treatment therapies have advanced over the decades, the mortality rate has changed very little. The epidemiology of IE has changed greatly, however, due to evolving cultural, social, and technological factors, and it is essential to be aware of these factors in order to prevent, recognize, and treat this disease.¹ Not only are there diagnostic difficulties associated with identification of patients with IE, but there is debate over the best courses of treatment and when to advance to more aggressive therapies. In addition, treatment presents a variety of social challenges, as the burden of injection drug use increases in the United States.

There have been recent guideline changes and technical advances in identification and management of IE. Epidemiologic studies of the effects of recently implemented recommendations have been carried out, and the results are presented here. Key presentations and risk factors for IE are discussed, to help in the clinical decision-making needed to maximize outcomes for patients with IE. This issue of Emergency Medicine Practice reviews the best available evidence regarding the diagnosis and treatment of patients with IE, and provides evidence-based recommendations for treatment.

Critical Appraisal of the Literature

PubMed and MEDLINE^®, Google Scholar, and the Cochrane Database of Systematic Reviews were searched for literature published from 2009 to 2020, using specific search terms: infective endocarditis, infectious endocarditis, culture negative endocarditis, bacterial endocarditis, valvular infection, infective endocarditis in injection drug users, and cardiac device infections. Because the disease carries a high risk of morbidity and mortality and affects a broad demographic, there is abundant literature available, as well as many articles discussing the controversies associated with management strategies. Extrapolation of data was limited to meta-analyses, systematic reviews, well-designed clinical trials, large observational studies, and clinical guidelines. Case series and case reports were included only when trends were seen across the literature for specific organisms or populations.

In all, 94 articles were identified, including multiple medical, surgical, and several combined society guidelines. Challenges in the search and assimilation of data included the broad scope of literature, with many publications geared toward inpatient management of already-diagnosed disease and not specifically toward acute management and diagnosis.

Etiology and Pathophysiology

First described in 1646 by Lazar Riviere, IE remains an elusive and deadly disease. Although IE has classically been associated with malformed or damaged heart valves that have been seeded by bacteria (most commonly, streptococci), the increasing burden of intravenous (IV) drug use as well as the use of implantable cardiac devices and medical venous access devices have changed the disease’s etiology and epidemiology. Historically, specific entities of acute and subacute bacterial endocarditis were defined, but it has been recognized that the site of infection (right vs left) and type of bacteria involved are more important factors in classification and management.

More than 70% of IE cases occur in native valves that are either damaged or possess altered flow dynamics that predispose the patient to platelet aggregation. In native valves, mitral valve prolapse is the most common risk factor for IE, and it raises the risk of IE by 8-fold. In the subpopulation of patients with IV drug use, impurities in an injectable drug contribute to valvular damage through micro-trauma that serves as a nidus for infection. Regardless of the initiating factor, platelets provide a surface for bacterial adherence and synergistically act to shelter anchored bacteria from immune mechanisms.²

While often considered a rare disease, with a global incidence of between 1.5 and 11.6 cases per 100,000 people, bias toward the developed world in the literature likely underestimates the worldwide disease burden and mortality.³ The association of IE with rheumatic heart disease is no longer the case in developed countries, where most cases are related to either valvular degeneration, IV drug use, or nosocomial infection.⁴ Due to the increased use of invasive intravenous access medical devices, today the mean age of an IE patient is older than 50 years, whereas a century ago, the mean age was under 30 years.⁵ Currently, hospitalization or recent hospital exposure is associated with 25% of cases of IE.⁵

In a 2013 systematic review of global trends in IE epidemiology over the last 50 years, the percentage of staphylococcal endocarditis had increased significantly, with this organism outpacing viridans group streptococci as the leading cause of endocarditis in the United States. Cases of enterococcal and coagulase-negative staphylococcal (CoNS) endocarditis have also increased over time, and are fast approaching that of viridans group streptococci IE.⁶ (See Figure 1.)

These trends are most evident in North America, where the opioid abuse epidemic has led to an increase in native valve endocarditis caused by Staphylococcus aureus. Currently, 75% of cases of IE are native valve endocarditis, with 80% of all cases involving either the mitral or aortic valves.⁷ In cases of IE in IV drug users, most lesions are located on the tricuspid valve, leading to few systemic manifestations. Cases of native valve endocarditis due to CoNS approximate 8% to 10%, and about half of these cases are healthcare related. Despite differences in virulence, large studies show similar mortality in IE patients infected with S aureus and CoNS.⁸

In addition to risk factors already discussed for IE in general, patients who are immunocompromised, elderly, have had abdominal or genitourinary instrumentation, or prosthetic heart valves seem to be at the highest risk for contracting enterococcal IE.⁹ (See Table 1.) S aureus bacteremia alone is likely an independent risk factor for IE development. In a 2014 systematic review of 3513 patients with S aureus bacteremia, transesophageal echocardiography (TEE) demonstrated that between 14% and 28% of those with bacteremia actually had IE; however, this review may be biased, in that it included only prospective observational studies, and it is likely that clinician suspicion for IE influenced referral for TEE.¹⁰ More-recent reviews reinforce that TEE is useful in undifferentiated or complicated S aureus bacteremia; however, there is a low-risk group of patients who are less likely to benefit from TEE.¹¹ This group includes patients without indwelling lines, patients without cardiac devices or valvular disease, and those with brief bacteremic episodes (< 48 hours duration). If bacteremia persists for more than 3 days, it would be appropriate to consider TEE. If the TEE is negative, it is prudent to repeat the TEE in 2 days if the patient is still febrile and without a source, given that TEE does have a small (but not insignificant) false-negative rate.

One notable type of CoNS leading to IE is Staphylococcus lugdunensis (SLuG). SLuG behaves much like methicillin-resistant Staphylococcus aureus (MRSA), with an aggressive course and a propensity to cause perivalvular abscess. Detection of SLuG in a single blood culture indicates IE in approximately 16% of patients, and in 25% of patients with 2 positive cultures. Thus, SLuG should be considered as a cause of IE, especially in a patient with CoNS in peripheral blood cultures and fever without a source. Despite its MRSA-like behavior, SLuG is sensitive to beta-lactam antibiotics.¹²

Other risk factors for IE include subaortic valvular stenosis, ventricular septal defects, pulmonic stenosis, tetralogy of Fallot, and other congenital heart lesions. The risk of IE in adults with congenital heart disease is approximately 1% and is lesion-dependent, with patients having patent ductus arteriosus having the lowest risk.¹³ In children, however, approximately half of all IE cases are related to congenital heart disease.¹⁴

Historical mortality in cases of IE approximates 30%, according to several different analyses. Recent meta-analysis data indicate that although diagnostics and therapeutics have changed, mortality has not been significantly impacted. In a meta-analysis of worldwide outcomes including 22,382 patients, short-term 30-day all-cause mortality for IE was 20%, while long-term post discharge mortality rates approached 37%.¹⁵ In the United States, 90-day mortality rates are approximately 24%.^15,16 Global and regional mortality differences are multifactorial and stem from a combination of healthcare disparities, differences in patient risk factors, valvular involvement, and bacterial virulence.

Differential Diagnosis

Many of the differential diagnoses for IE may present with IE and lead to IE’s reputation as the “great imitator.” Differential diagnoses include pneumonia, sepsis, acute heart failure, acute ischemic stroke, intracranial hemorrhage, meningitis, acute kidney injury, and dysrhythmias, among others. IE may involve or lead to any of these conditions, and the key is for the emergency clinician to consider IE when caring for critically ill patients with multisystem involvement.

Risk Management Pitfalls for Infective Endocarditis in the Emergency Department

1. “I figured the persistent fever was just viral; she looked so well.”

Failing to consider IE in a patient with fever without a source, even if the patient appears well, can lead to missed diagnoses. Often, suspicion of IE is the most difficult part of the workup, and can add significantly to the diagnostic momentum if it is suspected.

2. “My 32-year-old patient had developed acute heart failure, but I assumed it was because he has diabetes and is on hemodialysis.”

Consider IE in any young patient with new-onset acute heart failure, which suggests perivalvular abscess. Other clinical syndromes in young patients that can indicate IE are stroke or multifocal pneumonia, both of which are suggestive of embolic phenomena.

6. “A TTE was negative in the ED, so I assumed that the patient didn’t have IE.”

Imaging modalities such as TTE and POCUS are most useful as rule-in, not rule-out tests. Even if a TEE is negative, in the presence of high suspicion, it should be repeated within a short interval, as it is only 90% sensitive and can miss small lesions, especially right-sided lesions.

Tables and Figures

 

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available. In addition, the most informative references cited in this paper, as determined by the author, are highlighted.

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8. Chu VH, Woods CW, Miro JM, et al. Emergence of coagulase-negative staphylococci as a cause of native valve endocarditis. Clin Infect Dis. 2008;46(2):232-242. (Prospective cohort study; 1635 patients)
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45. Claeys KC, Zasowski EJ, Casapao AM, et al. Daptomycin improves outcomes regardless of vancomycin MIC in a propensity-matched analysis of methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob Agents Chemother. 2016;60(10):5841-5848. (Retrospective matched cohort; 262 patients)
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53. Duval X, Hoen B. Prophylaxis for infective endocarditis: let’s end the debate. Lancet. 2015;385(9974):1164-1165. (Editorial)
54. Albes JM. Current practice in prophylaxis of endocarditis: are we running into trouble? Eur J Cardiothorac Surg. 2019;56(1):1-6. (Editorial)
55. Calcaterra G, Crisafulli A, Guccione P, et al. Infective endocarditis triangle. Is it the time to revisit infective endocarditis susceptibility and indications for its antibiotic prophylaxis? Eur J Prev Cardiol. 2019. (Editorial)
56. Grattan MJ, Power A, Fruitman DS, et al. The impact of infective endocarditis prophylaxis recommendations on the practices of pediatric and adult congenital cardiologists. Can J Cardiol. 2015;31(12):1497. (Retrospective cohort study; 439 patients)
57. Cahill TJ, Harrison JL, Jewell P, et al. Antibiotic prophylaxis for infective endocarditis: a systematic review and meta-analysis. Heart. 2017;103(12):937-944. (Meta-analysis; 36 studies)
58. DeSimone DC, Tleyjeh IM, Correa de Sa DD, et al. Incidence of infective endocarditis due to viridans group streptococci before and after the 2007 American Heart Association’s prevention guidelines. Mayo Clin Proc. 2015;90(7):874-881. (Population study)
59. Garg P, Shariff S, Jenkyn KB, et al. Infective endocarditis hospitalizations and antibiotic prophylaxis rate before and after the 2007 American Heart Association guidelines revision. J Am Coll Cardiol. 2017;69(11):1956. (Retrospective; 7551 cases)
60. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;116(15):1736-1754. (Guideline updates)
61. Ong E, Mechtouff L, Bernard E, et al. Thrombolysis for stroke caused by infective endocarditis: an illustrative case and review of the literature. J Neurol. 2013;260(5):1339-1342. (Case report/review)
62. Marquardt RJ, Cho SM, Thatikunta P, et al. Acute ischemic stroke therapy in infective endocarditis: case series and systematic review. J Stroke Cerebrovasc Dis. 2019;28(8):2207-2212. (Review)
63. Asaithambi G, Adil MM, Qureshi AI. Thrombolysis for ischemic stroke associated with infective endocarditis: results from the nationwide inpatient sample. Stroke. 2013;44(10):2917-2919. (Retrospective review; 222 cases)
64. Ambrosioni J, Urra X, Hernández-Meneses M, et al. Mechanical thrombectomy for acute ischemic stroke secondary to infective endocarditis. Clin Infect Dis. 2017;66(8):1286-1289. (Retrospective review)
65. United States Department of Health and Human Services Food and Drug Administration. Label for ACTIVASE [Supplement 5203, Action Date 02/13/2015]. Available at: https://tinyurl.com/y35tvyet. Accessed August 10, 2020. (Drug label)
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67. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016;47(2):581-641. (AHA statement)
68. Brownlee WJ, Anderson NE, Barber PA. Intravenous thrombolysis is unsafe in stroke due to infective endocarditis. Intern Med J. 2014;44(2):195-197. (Review)
69. Gedela M, Shrestha A, Stys T, et al. Prosthetic aortic valve endocarditis following transcatheter aortic valve implantation. S D Med. 2018;71(12):546-549. (Case report/review)
70. Amat-Santos IJ, Ribeiro HB, Urena M, et al. Prosthetic valve endocarditis after transcatheter valve replacement. JACC Cardiovasc Interv. 2015;8(2):334-346. (Retrospective review; 60 patients)
71. Regueiro A, Linke A, Latib A, et al. Association between transcatheter aortic valve replacement and subsequent infective endocarditis and in-hospital death. JAMA. 2016;316(10):1083-1092. (Retrospective review; 250 cases)
72. Arnold CJ, Chu VH. Cardiovascular implantable electronic device infections. Infect Dis Clin North Am. 2018;32(4):811-825. (Review)
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74. Riaz T, Nienaber JJC, Baddour LM, et al. Cardiovascular implantable electronic device infections in left ventricular assist device recipients. Pacing Clin Electrophysiol. 2013;37(2):225-230. (Retrospective review; 247 patients)
75. Bentata Y. Physiopathological approach to infective endocarditis in chronic hemodialysis patients: left heart versus right heart involvement. Ren Fail. 2017;39(1):432-439. (Review)
76. Ursi MP, Durante Mangoni E, Rajani R, et al. Infective endocarditis in the elderly: diagnostic and treatment options. Drugs Aging. 2018;36(2):115-124. (Review)
77. Beteille E, Guarana M, Nucci M. Infective endocarditis in neutropenic patients with viridans streptococci bacteraemia. Clin Microbiol Infect. 2018;24(8):916-917. (Systematic review; 35 studies)
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82. Cervera C, del Río A, García L, et al. Efficacy and safety of outpatient parenteral antibiotic therapy for infective endocarditis: a ten-year prospective study. Enferm Infecc Microbiol Clin. 2011;29(8):587-592. (Prospective cohort study; 392 cases)
83. Fanucchi LC, Walsh SL, Thornton AC, et al. Outpatient parenteral antimicrobial therapy plus buprenorphine for opioid use disorder and severe injection-related infections. Clin Infect Dis. 2019;70(6):1226-1229. (Pilot randomized trial)
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85. Ugwu J, Hussein U, Alliu S, et al. Percutaneous aspiration of a mobile infected thrombus from the right ventricular outflow tract using the angiovac system. Case Rep Cardiol. 2019;2019(6279019):1-4. (Case report)
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90. Kaura A, Byrne J, Fife A, et al. Inception of the ‘endocarditis team’ is associated with improved survival in patients with infective endocarditis who are managed medically: findings from a before-and-after study. Open Heart. 2017;4(2):e000699. (Observational study; 196 patients)
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92. Gatti G, Perrotti A, Obadia JF, et al. Simple scoring system to predict in-hospital mortality after surgery for infective endocarditis. J Am Heart Assoc. 2017;6(7):e004806. (Scoring evaluation; 361 patients)
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Points and Pearls Excerpt

• More than 70% of infective endocarditis (IE) cases occur in native valves as a result of platelet aggregation due to valves that are damaged or have altered flow dynamics.
• Mitral valve prolapse is the most common risk factor and raises risk for IE 8-fold.
• Impurities in injectable drugs cause valvular damage, typically damaging the tricuspid valve through microtrauma. This area subsequently becomes a nidus for infection.
• Staphylococcus aureus is the leading cause of IE. Other major causes are Streptococcus viridans, enterococci, and coagulase-negative staphylococci. Blood-culture-negative IE accounts for one-third of cases.
• IE should be considered in any patient with > 1 week of fever that is consistent or intermittent.

Most Important References

• Moreyra AE, East S, Zinonos S, et al. Trends in hospitalization for infective endocarditis as a reason for admission or a secondary diagnosis. Am J Cardiol. 2019;124(3):430-434. (Retrospective; 21,443 patients) 
• Toyoda N, Chikwe J, Itagaki S, et al. Trends in infective endocarditis in California and New York state, 1998-2013. JAMA. 2017;317(16):1652. (Retrospective population study; 75,829 patients) 
• Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis. Eur Heart J. 2015;36(44):3075-3128. (Guideline) 
• Baddour L, Wilson W, Bayer A, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435-1486. (AHA statement) 
• Pettersson GB, Coselli JS, Pettersson GB, et al. 2016 the American Association for Thoracic Surgery (AATS) consensus guidelines: surgical treatment of infective endocarditis: executive summary. J Thorac Cardiovasc Surg. 2017;153(6):1241-1258.e1229. (Guideline)