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Infective Endocarditis, from Imaging to Management

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Duval County Medical Society CME Portal, November 2019

Infective Endocarditis, from Imaging to Management

Daniel C. DeSimone, MD,2
Rizwan M. Sohail, MD,2,4
James Newman, MD3
and Sorin V. Pislaru, MD, PhD4
1Department of Cardiovascular Diseases, Mayo Clinic Florida, Jacksonville, Florida
2Department of Infectious Diseases, Mayo Clinic, Rochester, Minnesota
3Department of Hospital Internal Medicine, Mayo Clinic, Rochester, Minnesota
4Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota

Address Correspondence to:

Anca Chiriac, MD, PhD
Assistant Professor of Medicine
Mayo Clinic Florida
David 7- MEDS7
4500 San Pablo Road, Jacksonville, FL 32224
Email: 
chiriac.anca@mayo.edu

Date of Release: Nov. 1, 2019
Date Credit Expires: Nov. 1, 2021
Estimated Completion Time: 1 hour
Background:

The Duval County Medical Society (DCMS) is proud to provide its members with free continuing medical education (CME) opportunities in subject areas mandated and suggested by the State of Florida Board of Medicine to obtain and retain medical licensure. The DCMS would like to thank the St. Vincent’s Healthcare Committee on CME for reviewing and accrediting this activity in compliance with the Accreditation Council on Continuing Medical Education (ACCME). This month, the DCMS CME Portal includes an article, “Infective Endocarditis, from Imaging to Management: A Case-Based Review” authored by Anca Chiriac, MD, PhD, Daniel C. DeSimone, MD, Rizwan M. Sohail, MD, James Newman, MD, and Sorin V. Pislaru, MD, PhDwhich has been approved for 1 AMA PRA Category 1 credit.TM For a full description of CME requirements for Florida physicians, please visit www.dcmsonline.org.

Faculty/Credentials:

Anca Chiriac, MD, PhD, Cardiology Fellow and Assistant Professor of Medicine, Mayo Clinic, Daniel C. Desimone, MD, Assistant Professor of Medicine, Consultant in Infectious Diseases, Mayo Clinic, Rizwan M. Sohail, MD, Professor of Medicine, Consultant in Infectious Diseases, Mayo Clinic, James Newman, MD, Department of Hospital Internal Medicine, Mayo Clinic, Sorin Pislaru, MD, PhD, Professor of Medicine, Consultant in Cardiovascular Diseases, Mayo Clinic

Needs Assessment:

The diagnosis of infective endocarditis can be challenging and needs a high index of suspicion, and a correct sequence of diagnostic testing. Physicians should understand the latest recommendations for infective endocarditis management, with a focus on detailed imaging modalities and treatment. It is also important to learn the latest AHA recommendations for endocarditis prophylaxis.

Objectives:
  1. Recognize how to diagnose infective endocarditis in a timely manner.
  2. Understand the current recommendations for treating infective endocarditis.
  3. Learn how to recognize high-risk cases of infective endocarditis and ensure they receive the appropriate prophylaxis.
CME Credit Eligibility:

A minimum passing grade of 70% must be achieved. Only one re-take opportunity will be granted. If you take your test online, a certificate of credit/completion will be automatically downloaded to your DCMS member profile. If you submit your test by mail, a certificate of credit/completion will be emailed within 4 weeks of submission. If you have any questions, please contact the DCMS at 904-355-6561 or dcms@dcmsonline.org. 

Faculty Disclosure:

Anca Chiriac, MD, PhD, Daniel C. Desimone, MD, Rizwan M. Sohail, MD, James Newman, MD, and Sorin Pislaru, MD, PhD report no significant relations to disclose, financial or otherwise with any commercial supporter or product manufacturer associated with this activity.

Disclosure of Conflicts of Interest:

St. Vincent’s Healthcare (SVHC) requires speakers, faculty, CME Committee and other individuals who are in a position to control the content of this educational activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly evaluated by SVHC for fair balance, scientific objectivity of studies mentioned in the presentation and educational materials used as basis for content, and appropriateness of patient care recommendations.

Joint Sponsorship Accreditation Statement:

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of St. Vincent’s Healthcare and the Duval County Medical Society. St. Vincent’s Healthcare designates this educational activity for a maximum of 1 AMA PRA Category 1 credit.TM Physicians should only claim credit commensurate with the extent of their participation in the activity.

Objective: To review the clinical diagnosis, choice of imaging modalities, and management of infective endocarditis (IE) in an inpatient setting.

Methods: Representative case illustrations and review of the literature.

Results: IE carries a high mortality rate requiring prompt recognition and early intervention by specialists in cardiology, infectious diseases, and cardiovascular surgery. Temporal trends have demonstrated an increasing incidence of IE, despite improved modalities of diagnosis and treatment, most likely due to an aging population and multiple co-morbidities such as diabetes, cancer, immunosuppression, advanced renal failure, valvular heart disease, prosthetic heart valves, and cardiac implanted electronic devices (CIEDs). Advances in technology and increasing use of CIEDs have led to device-related IE with its own management challenges. Referral to a center of excellence with capabilities in cardiac surgery and valve repair and the ability to extract infected devices may decrease the risk of complications.

Conclusion: IE is often first suspected in a general internal medicine setting when a patient presents with an infectious syndrome, a cardiac murmur, or subtle and non-specific multisystem complaints. Diagnosis of IE requires a high degree of clinical suspicion. Once diagnosed, patients with IE should undergo evaluation by a multidisciplinary team at a tertiary center comprised of cardiologists, cardiovascular surgeons, and infectious diseases specialists

Descriptions of infective endocarditis (IE) are found in the medical literature since the beginning of the Modern Age, however, the condition remained universally fatal until the advent of antibiotics in the second half of the 20th century.1 In 1908, Osler described the case of a patient with a systolic murmur and preexisting mitral insufficiency, likely due to rheumatic heart disease, with lower extremity edema and dyspnea on exertion. She had small, erythematous, tender and indurated nodes on her hands and feet, often found on fingertips and disappearing within hours.2 This immunologic phenomena would later be known as Osler’s nodes. In 1994, Durack et al. at Duke University established the role of echocardiography (equivalent to histological evidence of vegetation) in the diagnosis of IE and systematized the diagnostic criteria into three categories: definite, possible and rejected.3

In 2000, the Duke criteria were modified to improve sensitivity and specificity.4 The modified Duke criteria included either microbiological or histological evidence of vegetation which was identified either directly from surgical specimens, or from echocardiographic, immunologic, or microbiologic major and minor criteria. (Figure 1).

 

Figure 1: The modified Duke Criteria (adapted from the AHA guidelines, Baddour et al., Circulation 2015). Definitive IE, based on clinical criteria, is defined as fulfilling 2 major criteria, 1 major criterion and 3 minor criteria, or 5 minor criteria; possible IE fulfills 1 major criterion and 1 minor criterion, or 3 minor criteria. IE is rejected if there is a clear alternative diagnosis, the above criteria are not met, or the abnormalities resolve after less than 4 days of antibiotics.

 

The original and the modified Duke criteria were primarily developed for classification of patients in research studies and had a sensitivity of 80 percent when evaluated at the end of treatment for epidemiological purposes. However, these criteria have a lower accuracy for the initial diagnosis of IE in clinical practice; this is particularly true for prosthetic valve IE and CIED-IE.5,6

In addition to echocardiography, several complementary imaging modalities have been incorporated in the workup for IE, including cardiac or whole body computed tomography (CT), brain magnetic resonance imaging (MRI), F18-fluorodeoxyglucose (FDG) positron emission tomography /computer tomography (PET/CT) and radiolabeled autologous leucocytes – single-photon emission computed tomography (SPECT/CT). These imaging tools have helped to improve the sensitivity of the modified Duke criteria, especially in difficult clinical situations.5,6,7,8 These additional imaging modalities can identify silent septic endocardial lesions not seen on transesophageal echocardiogram (TEE), thus transforming a diagnosis of possible IE into definite IE. In fact, the recent European Society of Cardiology guidelines propose considering a paravalvular abscess seen on cardiac CT or increased uptake around the site of a prosthetic valve or device on PET/CT or SPECT/CT as a major criterion. Furthermore, septic emboli detected by MRI, CT, or nuclear imaging should count as a minor criterion.6

 In 2007, the American Heart Association (AHA) updated its IE prevention guidelines prior to invasive procedures. In these updated guidelines, the need for prophylactic antibiotics prior to gastrointestinal or genitourinary procedures was eliminated, and recommendations to use antibiotics prior to invasive dental procedures were limited to select high-risk cardiac conditions. These include patients with a history of previous IE, prosthetic cardiac valves, unrepaired cyanotic congenital heart defects, or valvular regurgitation and structurally abnormal valves on cardiac allografts.9

The guidelines for management of IE and valvular heart disease have recently been updated.5,6,10,11 This review aims to summarize the rationale and provide guidance for cardiac imaging and management of IE as typified by three illustrative cases.

Case 1

A 45-year-old man with a history of hypertension, morbid obesity, COPD and sleep apnea was admitted to the hospital after a prolonged unidentified illness. Six months prior to this presentation, he was started on atenolol for an “aortic stenosis murmur” and a small ascending aortic aneurysm. A few weeks later, he developed anorexia, intermittent fevers, and diarrhea; atenolol was stopped, however, diarrhea persisted for several months and prompted an extensive gastroenterology evaluation including CT scans and colonoscopies. No pathology was found. He continued with low-grade fevers, anorexia, and lost 50 pounds over the next six months. During this time, the patient developed worsening normocytic anemia, splenomegaly, and a transient erythematous rash on his extremities, followed by skin desquamation which eventually resolved. He then developed peripheral neuropathy, back pain, and arthralgias. Serum antinuclear antibody (ANA) was elevated. A neurologist started him on a six-week trial of steroids which improved his neuropathy. However, his overall constitutional symptoms persisted and he presented for a second evaluation.

On arrival, the patient looked chronically ill and examination revealed jugular venous distension, a 3/6 mitral regurgitation murmur, an aortic flow murmur, and bilateral lower extremity edema. Initial blood cultures grew Streptococcus mitis after 15 hours. He was started on IV Ceftriaxone 2gm Q12h. The patient’s constellation of symptoms raised the suspicion for subacute infective endocarditis, embolic seeding, and endocarditis-related immunologic phenomena. Given the high clinical suspicion for IE, the next diagnostic step was to pursue a TEE (Figure 2).

 

Figure 2: Rational Use of Echocardiography Algorithm. 

 

TEE revealed vegetations on the anterior and posterior mitral valve leaflets, the largest measuring 1.8x1.0 cm, as well as significant mitral regurgitation (Figure 3). Brain MRI demonstrated small septic emboli in the right occipital lobe. Specialists from cardiology and cardiothoracic surgery evaluated the patient and he met criteria for surgical intervention given the large vegetation size, valvular damage, and embolic phenomena. Specialists from oral maxillofacial surgery were consulted and several decaying teeth were extracted prior to valvular intervention.

 

Figure 3: Pre- and post-bypass images of mitral valve endocarditis. Left panels (pre-bypass) demonstrate a large vegetation on the posterior mitral valve leaflet and torrential mitral regurgitation. Right panels (post-bypass) demonstrate lack of vegetation, a posterior annuloplasty band and trivial mitral regurgitation.

 

The patient underwent vegetectomy and mitral valve repair with a posterior annuloplasty band (Figure 3). After surgery, he completed four weeks of IV Ceftriaxone 2gm Q12h (dosing for IE); follow-up TTE at the completion of therapy demonstrated good mitral valve repair and normal cardiac function.

Nonspecific signs and symptoms and multisystem involvement are problems commonly encountered by internists. However, a prolonged febrile illness and a cardiac murmur should raise the suspicion for IE. This patient underwent an extensive unrelated workup first, including GI, rheumatologic, neurologic, and hematologic evaluations. However, the acuity of the physical exam on admission and the high pretest probability of IE prompted the TEE and clinched the diagnosis. Streptococcus mitis, part of the viridans group of Streptococci, is found in the human oral flora and can present as a smoldering subacute infection making initial diagnosis challenging.

 

What is the Clinical Approach to IE?

Whenever IE is suspected, the AHA guidelines recommend obtaining at least three sets of blood cultures from different venipuncture sites, with at least one hour between the first and last culture, ideally prior to the initiation of antibiotic therapy.5 The imaging modality of choice is echocardiography, either transthoracic (TTE) or transesophageal (TEE), depending on clinical suspicion and circumstances (Figure 2).

Obtaining early Infectious Disease consultation is essential in determining the optimal treatment strategy, tailored to the clinical scenario and to the microorganism identified in cultures. Furthermore, the AHA has published clear guidelines for antimicrobial management.5

 

The Role of Echocardiography

Both TTE and TEE are frequently performed during the initial evaluation of IE and provide complementary information. Figure 2 illustrates a practical algorithm for choosing the initial imaging modality. TEE is better suited to identify left sided valvular vegetations, perivalvular extension, myocardial abscesses, mycotic or pseudoaneurysms, valve perforation and prosthetic valve dehiscence, vegetations on CIED leads, and should be performed first in these situations.12 However, TTE is superior in determining the presence of ventricular dyssynchrony and visualizing the tricuspid valve, the right ventricular outflow tract, and estimating pulmonary arterial pressures. Right sided vegetations may be better seen on TTE.13

While necessary in evaluating the majority of patients suspected of having IE, TEE is an invasive procedure and is not without risks, as opposed to TTE. A screening TTE may be more expeditiously obtained after working hours, when the patient has not fasted, or when the patient is unstable or needs general anesthesia for TEE. These additional considerations will influence the choice of initial imaging. Importantly, if TTE reveals findings suggestive of IE, this could guide prompt initiation of treatment and activation of the multidisciplinary IE team without delay.

If clinical suspicion is low, a TTE should be performed (Figure 2); if this is negative, an alternative diagnosis should be sought. However, if the clinical suspicion is high and an initial TTE is performed and is negative, this cannot rule out endocarditis. TEE should be performed in cases with high clinical suspicion (persistent fever or high-grade bacteremia with the typical microorganisms, i.e. Staphylococcus aureus, viridans group Streptococci, Enterococci), presence of prosthetic devices (prosthetic valves or CIEDs), or cases where the sensitivity of TTE is low (difficult anatomy, morbid obesity, severe COPD).

Both TTE and TEE can yield false negative results if performed early in the disease course or if the vegetation has already embolized. If the clinical suspicion remains high and blood cultures are persistently positive, a TEE should be repeated in 5-7 days or sooner if there are new clinical developments (worsening murmur, acute decompensated heart failure, new septic emboli).

Echocardiography may also yield false positive results in cases of previous valvular scarring, thrombi, Lambl’s excrescence, fibroelastoma, degenerative or myxomatous valve disease, Libman-Sacks endocarditis, or marantic endocarditis. In these cases, it is the correlation with microbiological data that will help identify the correct diagnosis.

Three dimensional transesophageal echocardiography (3D-TEE) provides an accurate representation of vegetations, 3D volumes of cardiac structures, and the special relationships of the vegetation with the surrounding anatomy, thus providing a better prediction of the embolic risk and facilitating surgical planning.14 3D-TEE may be particularly useful in outlining perivalvular extension, leaflet perforation, or prosthetic valve dehiscence.6 Furthermore, intraoperative TEE is of paramount importance during valve surgery.5

 

What are the Indications for Valve Surgery?

Echocardiographic and clinical indicators of high risk IE and urgent need for surgical evaluation include large vegetations (>10 mm in length), highly mobile vegetations, location on the anterior mitral valve leaflet, severe valvular insufficiency, leaflet perforation, perivalvular abscess, pseudoaneurysm, heart block, prosthetic valve dehiscence, cerebral or peripheral emboli, and evidence of acute decompensated heart failure.5 Bacteriological factors may also play a role in the decision to proceed with early surgery, e.g. IE caused by fungi or highly resistant organisms (vancomycin-resistant enterococcus, multidrug-resistant Gram-negative bacilli), or persistent bacteremia and fever for >5-7 days after the start of appropriate antibiotic therapy (i.e., failure of antibiotic therapy).

 

Case 2

A 72-year-old woman with a complicated past medical history including atrial fibrillation on Coumadin, hypertension, dyslipidemia, coronary artery disease and previous myocardial infarction, chronic systolic heart failure status post implantable cardioverter-defibrillator (ICD), and type 2 diabetes mellitus treated with insulin, presented to the emergency department complaining of left foot pain, difficulty walking, and several weeks of subjective fevers. A left foot ulceration and cellulitis were discovered on exam. She was admitted to the hospital on the internal medicine service for further workup. 

The patient had a myocardial infarction five years prior to this presentation. Coronary angiography revealed multi-vessel coronary artery disease with left main involvement and a left ventricular (LV) ejection fraction (EF) of 25%. She underwent coronary artery bypass grafting and was started on optimal medical therapy; however, a repeat TTE one month later revealed persistent left ventricular systolic dysfunction and an ICD was placed for primary prevention of sudden cardiac death. The most recent TTE, six months prior to this presentation, revealed a LV EF of 45%, mild calcific aortic stenosis, and moderate tricuspid regurgitation.

For three months prior to this presentation, the patient noticed pain in the left foot and had difficulty ambulating. Her diabetes had been difficult to control of late, despite the initiation of insulin. Over this period, she noted a gradual functional decline, loss of appetite, fatigue, malaise, low-grade fever, chills, night sweats, and a 15 pound weight loss.

On arrival, she was borderline hypotensive, dehydrated, and febrile (T 39.5 C). Physical examination revealed dry mucosae, normal jugular venous pressure, clear lungs, irregularly irregular heart sounds and a 3/6 systolic murmur at the left lower sternal border. She had a normal appearing ICD pocket in the left subclavicular area, with no superimposed erythema, tenderness, or fluctuance. There was a 0.5 x 0.5 cm ulceration on the lateral side of the left big toe and a 1 x 1 cm ulceration with purulent discharge and surrounding cellulitis on the plantar aspect of the foot. Pedal pulses were present but diminished. Laboratory data revealed a leukocytosis with a left shift, elevated inflammatory markers, chronic normocytic anemia, acute kidney injury, and an elevated hemoglobin A1C. Urinalysis revealed micro-proteinuria, but no casts.

 

What is the Appropriate Initial Management?

The patient fulfilled sepsis criteria; blood cultures were obtained, fluid resuscitation was initiated, and empiric IV Vancomycin and Piperacillin/Tazobactam were administered. The suspected source of infection was the diabetic foot ulcer. However, blood cultures grew Gram-positive coccus resembling staphylococcus after nine hours of incubation. Repeat cultures were ordered and antibiotics were continued. A TTE was performed, with focus on the tricuspid valve and device leads, as TEE was not immediately available.

TTE demonstrated severe tricuspid regurgitation, device lead at the right ventricular (RV) apex, and a 1X1 cm highly mobile, lead-adherent vegetation (Figure 4).

 

Figure 4: Right ventricular lead vegetation.

 

The left ventricular ejection fraction was 48%. A TEE was subsequently performed and did not identify valvular involvement, but confirmed the RV lead vegetation. Chest CT was performed, as right sided vegetations tend to embolize to the pulmonary rather than systemic circulation, but did not identify septic pulmonary emboli.

The ICD was removed percutaneously without complications and the patient completed a two-week course of intravenous Vancomycin therapy for lead endocarditis without valvular endocarditis.5 Since TTE demonstrated recovery of LV EF, the patient no longer had an indication for the device and this was not replaced.

 

Overview of CIED Infections

CIED infections can present in two distinct ways: systemic infection with bacteremia, with or without TEE evidence of lead or valvular endocarditis, and localized infection of the device pocket.15 The case above typifies a category of patients with echocardiographic evidence of CIED-IE, which require device explantation. However, there are also cases of bacteremia without vegetations and without clear evidence of device pocket infection (swelling, erythema, dehiscence, or purulent discharge), for which guidelines remain unclear. On the other hand, a “localized” device pocket can progress to lead infection as bacteria migrate along CIED leads and TEE alone may be insufficient to capture the full extent of infection. Furthermore, lead and valvular vegetations may embolize before they are captured on TEE. Therefore, there is a need for complementary imaging modalities to uncover CIED-related infections and septic emboli.

Several studies assessed the role of PET/CT in diagnosing CIED infections and distal emboli, and this test may change management in certain patients (i.e. guide a longer duration of antibiotic therapy, as for valvular IE, and device removal). However, further evidence is needed before recommending routine use of PET/CT in all cases of CIED-related infections.15

 

For CIED-Related Infections and CIED-IE, Device Removal is Essential

Infected CIEDs should be completely removed, as antibiotic therapy alone is associated with higher rates of relapse and morbidity.16 In cases of valvular IE, an existing CIED should also be removed, even in the absence of lead vegetations, to prevent these devices from acting as nidi of infection. Upon removal, cultures should be obtained from the device leads and generator pocket, with the caveat that lead tips may become contaminated at the time of removal (making it difficult to differentiate between lead infection and generator pocket infection). The current AHA guidelines5 recommend swab and tissue Gram-stain and cultures from the device pocket. However, vortex sonication of implants followed by culture of the sonicate fluid has been shown to increase bacterial detection.17 Tissue cultures may be falsely negative as microorganisms tend to concentrate in biofilms of the surface of CIEDs. Identification of the culprit microorganism is essential for optimized treatment and to prevent future antibiotic resistance.

Percutaneous lead removal is preferred to open surgical intervention in most situations. Complications of percutaneous lead extraction are uncommon but may include pericardial tamponade, pneumothorax, hemothorax, lead migration, subclavian vein laceration, pulmonary emboli and death. Contrary to expectations, large vegetation size (defined as vegetations > 10mm) was not found to be a contraindication for percutaneous lead removal.16 However, in certain situations (RV lead vegetations > 20mm), surgical removal may be favored due to the high risk of pulmonary emboli during mobilization.18 Repeat blood cultures should be obtained after device removal to document clearance.

 

Always Have a Plan for Device Reimplantation Prior to Removal

From a clinical standpoint, it is important to have a plan for both temporary support and eventual reimplantation prior to removal of an infected CIED. This point is particularly salient in cases of pacemaker dependence. In many instances, this is a time to carefully reconsider the primary indication for device implantation, as studies have shown that in one-third of patients, the device may no longer be necessary.16,19 In certain situations, as demonstrated by Case 2, the patient’s cardiac function recovered and the device was no longer indicated. Alternatively, there is a change in clinical circumstances (more advanced age, multiple comorbidities, advanced malignancy) and the device is no longer consistent with the patient’s goals of care.

 

Considerations for Device Reimplantation

In cases of pacemaker infection in pacemaker-dependent patients, a strategy is established for transcutaneous pacing until a new permanent device can be implanted. A new permanent device, either pacemaker or ICD, is typically placed on the contralateral side, avoiding the original infected pocket. The recommended waiting time is at least 72 hours of negative blood cultures in the case of CIED infection without endocarditis, and at least two weeks of negative blood cultures in the case of valvular endocarditis.7

 

Antibiotic Therapy for CIED Infections

The duration of antibiotic therapy depends on the causative microorganism, the type of infection (valvular IE versus CIED-IE versus CIED infection without IE), and the type of valve involved (native versus prosthetic heart valve). Valvular IE is typically treated with 4-6 weeks of IV antibiotics depending on the microorganism (S. aureus typically requires six weeks of therapy), while CIED infections without valve involvement may be treated with two weeks of IV antibiotics following device removal. However, if repeat blood cultures after device extraction remain positive for more than 24 hours, a longer course of intravenous antibiotics is recommended (typically four weeks, as for valve endocarditis) even if the TEE ruled out valvular vegetations.7

 

Case 3

A 64-year-old man with a history of COPD, non-small cell lung cancer status post right upper lobectomy, palliative radiation to the spine and to left femoral metastatic lesions, and deep vein thrombosis on full dose enoxaparin, was admitted to the intensive care unit with acute hypoxic respiratory failure and septic shock presumed secondary to a healthcare-associated pneumonia. Blood cultures were obtained and intravenous fluids and broad spectrum antibiotics were administered. CT scan of the chest ruled out pulmonary emboli and pneumonic infiltrates, but revealed bibasilar lung fibrosis and honeycombing. Radiation pneumonitis was suspected, although the spine-targeted field should not have affected the lungs to that magnitude.

Bedside TTE, performed due to respiratory failure and shock, demonstrated a bicuspid aortic valve with fusion of the right and left coronary cusps and moderate aortic regurgitation. The left and right ventricular functions were preserved; the inferior vena cava was non-dilated, with normal collapse. The patient stabilized and was transferred to the medical floor after 24 hours. However, blood cultures from admission grew a Gram-positive coccus resembling Staphylococcus after 15 hours of incubation. This was later speciated as Staphylococcus lugdunensis.

On transfer, the patient complained of back pain and left thigh pain consistent with his known metastatic lesions. On examination, there was a mild diastolic murmur of aortic insufficiency, but no jugular venous distension, pulmonary crackles, S3 gallop, or peripheral lower extremity edema. He had painful swelling of the left distal thigh; there were no other obvious sources of infection on detailed examination. Due to the intermittent confusion noted in the intensive care unit, his usual home opiate regimen had been held and he was experiencing a pain crisis. Palliative care was consulted and his regimen was optimized.

Repeat blood cultures two days after admission were still positive for S. lugdunensis after 28 hours of incubation. An infectious diseases specialist was consulted and antibiotics were changed to IV Cefazolin 2gm Q8h, as well as oral Levofloxacin to complete a 7-days course for pneumonia.

 

What is the Most Appropriate Next Diagnostic Modality?

The patient had persistent bacteremia due to S. lugdunesis, a coagulase-negative Staphylococcus. S. lugdunesis is well known to behave clinically as aggressive as S. aureus, however, remains very susceptible to most antibiotic therapies. With an abnormal aortic valve on TTE, a TEE was indicated for evaluation of possible IE.

The patient was sent for TEE; however, he quickly decompensated after receiving intravenous sedation and the procedure was aborted. He returned to the medical floor where his oxygen requirements increased and he required temporary noninvasive positive pressure ventilation. A portable chest X-ray demonstrated worsening bibasilar infiltrates. The patient received IV diuresis with furosemide and antibiotics were broadened to cover for possible aspiration. The TEE was postponed until his respiratory status improved.

 

What are the Recommended Complementary Imaging Modalities?

Cerebral Imaging

Cerebral imaging is recommended for all patients with IE and suspected neurological complications. Detection of cerebral lesions such as stroke, emboli, mycotic aneurysms, abscess, or hemorrhage often leads to a change in therapeutic strategy.5 MRI is superior to CT in identifying cerebral lesions; however, CT may be more expeditiously obtained in critically ill patients. Furthermore, the presence of prosthetic valves or CIEDs often precludes the use of MRI in those cases. If cerebral complications are confirmed, Neurosurgery should be consulted and these should be promptly addressed. Of note, S. aureus IE is more frequently associated with neurological complications compared to other types of organisms.

Cardiac and Whole-Body CT Scan

In aortic valve IE, multislice cardiac CT scan can provide valuable information regarding the size of the aortic annulus, aortic root, ascending aorta and degree of calcification, and it may be superior to TEE in identifying the extent of perivalvular extension.20

In right-sided IE, chest CT may identify pulmonary septic emboli or abscesses. Cardiac CT and coronary CT angiography may play an important role in preparation for valvular surgery. However, routine use of whole-body CT scan in all cases of IE is not recommended; its use is limited by the total radiation exposure and risk of contrast nephropathy in patients who often have underlying renal insufficiency.

 

Role of Nuclear Imaging to Identify Occult Sources of infection

FDG-PET/CT and SPECT/CT may be useful in identifying peripheral emboli and distal infectious complications of IE such as paraspinal abscesses, septic pulmonary emboli, or infected devices.5,6,7 They may also identify occult sites of infection in cases of bacteremia of unclear origin.

SPECT/CT relies on the time-dependent accumulation of the patient’s autologous radiolabeled leucocytes at sites of infection, thus potentially uncovering occult foci. It is a two-day procedure, with collection of the patient’s peripheral blood and tagging of leucocytes on day one, followed by re-injection and imaging on day two. In contrast, PET/CT is performed at a single time point after the injection of F18-FDG glucose, which is actively engulfed by metabolically active cells (activated leucocytes, macrophages, and CD4+ lymphocytes) at the sites of infection.

Of note, nuclear imaging cannot identify small lesions (<5mm) due to the low spatial resolution of current technology. Furthermore, it has limited value shortly after cardiac surgery due to the expected postoperative inflammatory response. It may also yield false positive results in a number of inflammatory conditions such as vasculitis, primary cardiac tumors, cardiac metastases, soft atherosclerotic plaques, and active thrombi. Additionally, PET/CT cannot be used for the diagnosis of cerebral emboli due to the inherently high metabolic activity of the brain.

SPECT/CT is more specific for the diagnosis of IE than PET/CT and is the preferred imaging modality at this time, if feasible. Both modalities have added value in certain cases of IE; however, their routine use is not supported by the current evidence. Therefore, the use of various imaging modalities in cases of suspected IE should be individualized. For the patient described in Case 3, the TEE failed; however, a SPECT/CT was performed.

 

Case 3- Summary and Discussion

The initial TEE could not be performed due the patient’s respiratory decompensation. MRI of the brain, performed due to the patient’s persistent encephalopathy, revealed multiple tiny enhancing lesions in both cerebral hemispheres, suspicious for either septic emboli or early metastases. SPECT/CT demonstrated radiotracer uptake around the distal third of the left femur, with bony and diffuse soft tissue uptake.  There were bibasilar areas of uptake in the lungs, suggestive of pneumonia, and a wedge-shaped photopenic defect in the periphery of the spleen suggestive of splenic infarction (Figure 5).

 

Figure 5: Aortic valve endocarditis. Upper panels demonstrate the bicuspid aortic valve (left) and vegetations on both aortic cusps (right). The left lower panel Doppler-image illustrates an eccentric aortic regurgitant jet. The right lower panel is a SPECT/CT image demonstrating an area of increased uptake in the left femur, bibasilar pulmonary uptake, and a wedge shaped photopenic area in the spleen. 

 

TEE was performed, after the patient was preemptively intubated for airway protection, and demonstrated the bicuspid aortic valve and echo-densities on both leaflets suggestive of vegetations, as well as an eccentric aortic regurgitant jet corresponding to moderate to severe aortic insufficiency (Figure 5).

Due to the patient’s advanced metastatic cancer and comorbidities, definitive treatment that would involve valve surgery and left lower extremity amputation was deferred. Infectious Diseases recommended a palliative strategy with six weeks of IV Cefazolin 2gm Q8h, followed by chronic suppressive therapy with oral Cefadroxil 500mg Q12h. However, the patient developed progressive congestive heart failure and encephalopathy and passed away one week later.

In conclusion, IE remains a high mortality disease despite recent advancements in diagnostic imaging and early initiation of appropriate antibiotic therapy. Early involvement of the multidisciplinary team and well-timed surgical intervention, if appropriate, are essential in curbing the inherently high morbidity and mortality of IE. 

Summary of Recommendations for the Management of Infective Endocarditis

 

1. Obtain at least three sets of blood cultures, with one hour between the first and last culture, prior to the initiation of antibiotics.

2. Echocardiography is the preferred imaging modality in cases of suspected IE. The decision to start with TTE versus TEE is based on clinical scenario, pretest probability, and test availability.

3. Infective endocarditis remains a high-risk, high-mortality disease, often insidious in onset. However, once diagnosed, it requires prompt intervention by a multidisciplinary team of specialists including cardiologists, infectious disease specialists, and cardiovascular surgeons.

4. Valve repair is preferred, if feasible, to valve replacement. The highest risk of embolization is within the first few days of antibiotic therapy.

5. In cases of complicated IE, that may require valve surgery, early transfer to a center with expertise is essential.

6. Infected CIEDs should always be removed for curative intent; antibiotic therapy alone is inadequate.

7. Prior to removal of a CIED, a plan should be in place for the need and timing of reimplantation. In up to one-third of the cases, ongoing CIED therapy is no longer indicated.

8.  Complementary imaging modalities (CT, MRI, PET/CT, and SPECT/CT) provide important additional diagnostic and prognostic information beyond the modified Duke criteria, as well as help with surgical planning.

9.  Cerebral imaging is recommended if there are suspicious neurological changes or if the vegetation has features suggestive of high embolic risk. MRI is more sensitive than CT; however, the presence of prosthetic valves or CIEDs often is a contraindication to MRI. 

10.   Nuclear imaging is increasingly recognized for its potential to uncover occult sources of infection, distal embolic seeding, and evidence of CIED-related infections. 

  1. Grinberg M, Solimene MC. Historical aspects of infective endocarditis. Rev Assoc Med Bras. 2011 Mar-Apr;57(2):228-33.

  2. Osler W. Chronic infectious endocarditis. In: Willus FA, Keys TE. Cardiac classics: a collection of classic works on the heart and circulation with comprehensive biographic accounts of the authors. New York: Schuman; 1941. p. 807-11.

  3. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med. 1994 Mar;96(3):200-9.

  4. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000 Apr;30(4):633-8.

  5. Baddour LM, Wilson WR, Bayer AS, 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 Oct 13;132(15):1435-86.

  6. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015 Nov 21;36(44):3075-128.

  7. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation 2010 Jan 26;121(3):458-77.

  8. Amraoui S, Tlili G, Sohal M, et al. Contribution of PET imaging to the diagnosis of septic embolism in patients with pacing lead endocarditis. JACC Cardiovasc Imaging. 2016 Mar;9(3):283-90.

  9. 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 Oct 9;116(15):1736-54.

  10. Nishimura RA, Carabello BA, Faxon DP, et al. ACC/AHA 2008 guideline update on valvular heart disease: focused update on infective endocarditis: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2008 Aug 19;118(8):887-96.

  11. Nishimura RA, Otto CM, Bonow, RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 10;129(23):2440-92.

  12. Reynolds HR, Jagen MA, Tunick PA, et al. Sensitivity of transthoracic versus transesophageal echocardiography for the detection of native valve vegetations in the modern era. J Am Soc Echocardiogr. 2003 Jan;16(1):67-70.

  13. San Román JA, Vilacosta I, Zamorano JL, et al. Transesophageal echocardiography in right-sided endocarditis. J Am Coll Cardiol. 1993 Apr;21(5):1226-30.

  14. Berdejo J, Shibayama K, Harada K, et al. Evaluation of vegetation size and its relationship with embolism in infective endocarditis: a real-time 3-dimensional transesophageal echocardiography study. Circ Cardiovasc Imaging. 2014 Jan;7(1):149-54.

  15. Sohail MR, Baddour LM. Role of PET imaging in management of implantable electronic device infection. JACC Cardiovasc Imaging. 2016 Mar;9(3):291-3.

  16. Sohail MR, Uslan DZ, Khan AH, et al. Infective endocarditis complicating permanent pacemaker and implantable cardioverter-defibrillator infection. Mayo Clin Proc. 2008 Jan;83(1):46-53.

  17. Nagpal A, Patel R, Greenwood-Quaintance KE, et al. Usefulness of sonication of cardiovascular implantable electronic devices to enhance microbial detection. Am J Cardiol. 2015 Apr 1;115(7):912-7.

  18. Smith MC, Love CJ. Extraction of transvenous pacing and ICD leads. Pacing Clin Electrophysiol. 2008 Jun;31(6):736-52.

  19. Sohail MR, Uslan, DZ, Khan AH, et al. Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections. J Am Coll Cardiol. 2007 May 8;49(18):1851-9.

  20. Feuchtner GM, Stolzmann P, Dichtl W, et al. Multislice computed tomography in infective endocarditis: comparison with transesophageal echocardiography and intraoperative findings. J Am Coll Cardiol. 2009 Feb 3;53(5):436-44.

 

To take the test and earn CME credit, click here.

1. Regarding infective endocarditis, which of the following statements is incorrect?

a. Transesophageal echocardiography is the imaging modality of choice in cases with high pretest probability of endocarditis.

b. Evidence of aortic valve vegetations and perivalvular abscess on cardiac CT count as a major Duke criterion for endocarditis.

c. Whenever feasible, valve repair is preferred to valve replacement.

d. In cases of tricuspid valve endocarditis, cerebral imaging should routinely be performed to look for septic emboli.

e. Nuclear imaging, such as SPECT/CT or PET-CT can be used to uncover distal embolic seeding.


2.  Which of the following patients need endocarditis prophylaxis prior to dental cleaning?

a. A 45-year old woman with a bicuspid aortic valve and no prior history of endocarditis.

b. A 40-year old man with a history of stroke, presumed embolic, who is 1-year status post percutaneous patent foramen ovale (PFO) closure with an Amplatzer device.

c. A 60-year old man with atrial fibrillation who had a percutaneous left atrial appendage closure (Watchman device) one month ago.

d. A 26-year old man who is a cardiac transplant recipient with normal allograft function and normal valves.

e. A 51-year old man with Down syndrome, ventricular septal defect, severe pulmonary artery hypertension and cyanosis.

f. An 86-year old woman with a history of severe aortic stenosis status post trans-catheter aortic valve replacement (TAVR).

g. Patients A, B and F

h. Patients B, C, and E

i. Patients A, D, and E

j. Patients C, E and F


3. The following question stem applies to the next 5 questions:

A 68-year old man with recently diagnosed atrial fibrillation status post cardioversion one month prior and anticoagulated with apixaban, hypertension, coronary artery disease, diabetes, dyslipidemia, presents to the emergency department with severe back pain and confusion. Blood pressure is 98/50mmHg, pulse 110 (sinus rhythm), and temperature is 38.5 degrees Celsius. Laboratory data is significant for a mild normocytic anemia, leukocytosis with a left shift, hyponatremia, and acute kidney injury superimposed on stage III chronic kidney disease. Examination reveals a well-healed sternotomy scar and a 3/6 systolic murmur at the 2nd right interspace radiating to the carotids. Outside records reveal that he had a bioprosthetic aortic valve replacement 5 years prior. Non-contrast CT of the head rules out any acute abnormality. He is admitted to the internal medicine service and mental status and laboratory data improve with hydration. On hospital day 2, blood cultures return positive for streptococcus pyogenes. He is started on empirical IV Ceftriaxone.

What is the most appropriate next step in management?

a. Transthoracic echocardiography

b. Transesophageal echocardiography

c. CT of the chest, abdomen and pelvis looking for sources of infection

d. MRI of the brain and of the thoracic spine

e. Two weeks of empirical antibiotics


4.  Transthoracic echocardiography is performed and reveals a bioprosthetic aortic valve with thickened leaflets, mild-moderate aortic stenosis, and no aortic regurgitation. There are no other significant valvular abnormalities and bi-ventricular function is preserved. Repeat blood cultures are negative. Transesophageal echocardiography is discussed, but the patient refuses and leaves against medical advice. He is provided with a prescription for 14 days of Doxycycline.

He returns to the hospital one week later with persistent low-grade fevers, chest pain, profound weakness, fatigue, lightheadedness, and more confusion and back pain. ECG shows sinus rhythm and non-specific repolarization changes. Troponins are elevated, but without a rising and falling pattern. Creatinine is elevated consistent with stage III kidney disease.

What is the most appropriate test to clinch the diagnosis?

a. Coronary angiography

b. Cardiac CT without contrast

c. Coronary CT angiogram

d. Transesophageal echocardiography

e. Repeat blood cultures and initiate IV broad-spectrum antibiotics


5.      Transesophageal echocardiography demonstrates thickened aortic valve leaflets with two small but highly mobile vegetations on the aortic side of the valve and a periaortic abscess. Repeat ECG reveals prolongation of the PR interval from 180ms to 210ms.

Which of the following options are appropriate?

a. Infectious Diseases Consult and antibiotic dosing for endocarditis

b. Cardiothoracic surgery consult to consider early surgery

c. MRI of the brain

d. MRI of the spine

e. All of the above

f. None of the above


6. MRI of the brain reveals multiple small lesions in both hemispheres. MRI of the spine reveals possible lumbar septic emboli. Telemetry now demonstrates rapid atrial fibrillation.

In terms of anticoagulation, which of the following options is the most appropriate?

a. Continue with apixaban at the current dose, 5mg twice daily

b. Decrease the dose of apixaban to 2.5mg twice daily given the renal impairment

c. Discontinue apixaban and start bridging with intravenous unfractionated heparin

d. Anticoagulation should be discontinued


7. Which of the following statements are correct?

a. Progressive PR interval prolongation on ECG is suggestive of perivalvular abscess and can be a hallmark of impending complete heart block.

b. Known septic emboli to the brain or spine are a contraindication to anticoagulation.

c. Surgery is indicated when large vegetations are present, when there is a high embolic risk or there is evidence of existing emboli, with prosthetic heart valves, valve dehiscence, or perivalvular abscess.

d. All of the above.

e. None of the above.


8. The following stem applies to the next 3 questions:

A 72-year old man with a history of permanent atrial fibrillation, status post dual chamber pacemaker placed 12-years prior for bradycardia, heart failure with preserved ejection fraction (left ventricular ejection fraction, 50%), moderate tricuspid regurgitation, and multiple myeloma in remission (status post induction chemotherapy), presents for a planned bone marrow transplant. Other than chronic lower extremity edema, he feels well. He is afebrile and asymptomatic. However, routine pre-transplant blood cultures are positive for staphylococcus (later on identified as methicillin sensitive staphylococcus aureus).

Transthoracic echocardiography reveals poor coaptation of the tricuspid leaflets, torrential tricuspid regurgitation, moderate-severe right ventricular enlargement with moderately reduced systolic function, and preserved left ventricular systolic function. No other valves appear to be involved and there is no pericardial effusion.

Which of the following statements is correct?

a. Transthoracic echocardiography is preferred as the first step in the evaluation of the tricuspid valve.

b. Transesophageal echocardiography is needed to rule out device lead. .endocarditis and for assessment of the left-sided cardiac valves.

c. In the case of confirmed infective endocarditis, any cardiac implantable devices should be removed.

d. A course of IV antibiotics followed by chronic suppressive antibiotic therapy is appropriate.

e. A and B are correct.

f. A, B, and C are correct.

g. A, B, C, and D are correct.


9.  Transesophageal echocardiography demonstrates a thick coat of fibrinous material on the right ventricular lead as it passes through the tricuspid valve, differential diagnosis including thrombus, vegetation or a combination of both. There is no clear evidence of tricuspid valve endocarditis. No other valves are involved.

If the patient is found to be pacemaker-dependent, what is the most appropriate next step after removal of the infected device?

a. Percutaneous removal of the device is preferred to surgical removal.

b. Surgical removal is preferred in cases with large vegetations (>20mm) and a high chance of embolization at the time of lead mobilization.

c. Pacemaker interrogation should be performed to assess whether he is pacemaker dependent.

d. Tricuspid valve vegetations and lead endocarditis are more likely to result in septic emboli to the pulmonary circulation rather than systemic emboli.

e. All of the above.

f. None of the above.


10. If the patient is found to be pacemaker-dependent, what is the most appropriate next step, together with removal of the infected device?

a. Allow for at least 48 hours of device-free time

b. Place a temporary transvenous pacer

c. Place a transcutaneous pacer

d. Plan for a new permanent pacemaker on the contralateral side after at least 2 weeks of negative blood cultures and appropriate antibiotic therapy

e. A and D

f. B and D

g. C and D