Continuing Education Activity

Infective endocarditis occurs globally and is defined by the infection of the endocardial surface of the native valve, prosthetic heart valve, or an implanted cardiac device such as a permanent pacemaker or a defibrillator. This activity outlines the etiology, evaluation, and medical treatment of infective endocarditis and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Describe the etiologic pathogens commonly associated with infective endocarditis.
• Outline the common signs and symptoms associated with infective endocarditis.
• Summarize the management of infective endocarditis based on pathogen susceptibility.
• Explain the importance of interprofessional team strategies for improving care coordination and communication to aid in the diagnosis and management of infective endocarditis and improving outcomes in patients diagnosed with the condition.

Introduction

Infective endocarditis occurs globally and is the infection of the endocardial surface of the native valve, prosthetic heart valve, or an implanted cardiac device such as a permanent pacemaker or a cardioverter-defibrillator.[1] Over the past few decades, there has been a change in both the host and the pathogen. Staphylococcus aureus has surpassed Streptococcus as the most common etiologic pathogen worldwide and especially in the developed world given its common association with healthcare contact and invasive procedures. Changes in the host include older and sicker patients who carry a high burden of comorbidities. Resistance to antibiotics is another challenge threatening healthcare worldwide and seems to be growing.

Despite technological advances in diagnostic and therapeutic modalities, the overall mortality has not improved. Aortic valve infective endocarditis is a life-threatening disease associated with high mortality and morbidity. In this chapter, we will provide an overview of infective endocarditis with a particular emphasis on aortic valve endocarditis. The term native valve endocarditis denotes a cardiac infection that involves the leaflets of the valves, the endocardial surface, chordae tendinae, congenital defects, and anastomosis sites. Prosthetic valve endocarditis is defined by an infection involving artificial valves, conduits, catheters, assist devices, pacemakers, defibrillators, or other artificial intracardiac structures.

Etiology

The etiology of infective endocarditis has its basis on whether the valve is native or prosthetic and for prosthetic valve endocarditis, the etiology is dependent upon the timing with the early phase defined as less than two months and the late phase defined as greater than 12 months. The native valve infective endocarditis is most commonly caused by Streptococcus viridans and Staphylococcus aureus. For the early phase, prosthetic valve endocarditis causative agents include coagulase-negative staphylococci (Staphylococcus epidermidis) and Staphylococcus aureus whereas for the late phase the key culprits include Streptococcus viridans and Staphylococcus aureus. Enterococci enter the bloodstream as a consequence of gastrointestinal or genitourinary tracts manipulation. Streptococcus bovis and Clostridium septicum are associated with colonic malignancies whereas HACEK group agents (Haemophilus, Aggregatibacter (previously Actinobacillus), Cardiobacterium, Eikenella, Kingella) infect patients with poor dental hygiene or from needle contaminate with saliva in intravenous drug users. Fungal endocarditis is the gravest form of infective endocarditis, and the risk factors include prosthetic heart valves, intravenous drug use, and an immunocompromised state.

Epidemiology

Infective endocarditis can be community-acquired, or it can be related to healthcare exposure. The epidemiological trends and disease patterns of infective endocarditis have evolved across the globe. In developing countries, rheumatic heart disease remains the key risk factor, affected patients are usually younger, and community-acquired, penicillin-sensitive streptococci typically cause the infection.[1] In the developed world degenerative valve disease, malignancy, intravenous drug use, diabetes mellitus, and congenital heart disease are the predominant risk factors, and the mean age of the patients is older than the ’70s. The cases of healthcare-acquired infective endocarditis due to Staphylococcal infection have surged over the past two decades owing to an increase in the use of invasive procedures, cardiovascular implantable electronic devices, long-term intravenous lines, percutaneous, minimally invasive, and prosthetic heart valves.[2] There has been an increased incidence of infective endocarditis after minimally invasive aortic valve surgery or percutaneous transcatheter aortic valve replacement.[3]

Pathophysiology

The pathophysiologic underpinning of infective endocarditis involves the following steps: bacteremia (spontaneous or hospital-acquired) that delivers the pathogen to the surface of the valve, adherence of the circulating pathogen to the prepared valve surface and ultimately the invasion of the valvular leaflets. Circulating pathogens do not adhere to the normal endothelium. Injury of the valve alters the architecture of the endothelial cells rendering them susceptible to colonization with bacteria.[4]

History and Physical

History is crucial, and patients describe fevers, chills, dyspnea, orthopnea, night sweats, fatigue, and weight loss. Patients can also present with a transient ischemic attack, stroke, myocardial infarction, or heart failure symptoms. On physical exam, patients with aortic valve endocarditis may demonstrate an aortic insufficiency diastolic murmur (new or change in preexisting murmur), and signs of heart failure if aortic valve function is compromised. Other sequelae may include neurological findings such as vision loss, weakness, or peripheral stigmata of the disease as described above including splinter hemorrhages, Osler nodes, Roth spots, Janeway lesions, organomegaly, and hematuria if kidneys are involved.

Signs of neurological dysfunction due to an embolic stroke may be found in at least 1/3rd of patients. Other features of infective endocarditis include confusion, delirium, pallor, lethargy, arrhythmias, and anorexia.

Evaluation

The Modified Duke Criteria are applicable in the evaluation of patients suspected of infective endocarditis. Three categories include definite infective endocarditis, possible infective endocarditis, or rejected infective endocarditis.[5]

Definite infective endocarditis further subclassifies into[6][5][7]:

• Definite infective endocarditis by pathological criteria: where microorganisms are present on culture or histologic examination of the vegetation, embolized vegetation or an intracardiac abscess, or pathological lesions demonstrating active endocarditis
• Definite infective endocarditis by clinical criteria: defined by the presence of two major criteria, one major criterion plus three minor criteria, or five minor criteria in The Modified Duke Criteria

Major clinical criteria are defined as follows[5]:

• Multiple positive blood cultures, single positive culture for Coxiella burnetii or antiphase I IgG antibody titer greater than 1 to 800
• Endocardial involvement (presence of new valvular regurgitation)
• Presence of vegetation, abscess, or dehiscence (worsening or a change of pre-existing murmur does not meet criteria)

Minor clinical criteria are as follows[5]:

• Predisposing heart condition or use of intravenous drug use
• Fever with body temperature greater than 38 degrees C (100.4 degrees F)
• Vascular phenomena: arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesion
• Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor, and
• Positive blood culture that does not meet the major criteria

Possible infective endocarditis criteria are when there are one major criterion and one minor criterion or three minor criteria present. Rejected infective endocarditis is defined when there is likely an alternative diagnosis, or there is no pathological evidence of IE with fewer than 4 days of antibiotic therapy or there is the resolution of clinical symptoms with fewer than 4 days of antibiotic therapy.[5]

It is important to note that prior antibiotic therapy may mask the histopathological evidence of infective endocarditis. Vegetation on an echocardiogram is an oscillating intracardiac mass on the valve or supporting structures, in the path of regurgitant jets. The presence of abscess or partial dehiscence of the prosthetic valve also fulfills echocardiographic criteria of infective endocarditis. A transthoracic echocardiogram should be validated by transesophageal echocardiogram in the evaluation of patients with suspected infective endocarditis whenever indicated.

Significant echocardiographic findings include:

• Myocardial abscess
• New-onset valvular regurgitation
• Oscillating intracardiac mass on a valve
• Partial dehiscence of a prosthetic valve

The ECG may show a conduction block or delay in about 10% of patients. A new conduction block usually indicates the involvement of the septum and is a poor prognostic sign.

CT of the head is done in patients who exhibit neurological deficits.

Treatment / Management

The American Heart Association published its updated guidelines for infective endocarditis in 2015.[8] In those guidelines, specific recommendations are for the following[8]:

• Native valve highly susceptible (MIC less than or equal to 0.12 mcg/ml) viridans group streptococci (VGS) infective endocarditis
• VGS and S. gallolyticus (bovis) with MIC greater than 0.12 to less than 0.5 mcg/ml
• A defective and Granulicatella species, and VGS with penicillin MIC greater than or equal to 0.5 mcg/ml
• VGS or S. gallolyticus involving prosthetic material
• Staphylococci, Staphylococci involving prosthetic material
• Enterococci, HACEK micro-organisms
• Non-HACEK gram-negative bacilli, culture-negative endocarditis, and fungi

Recommendations for antimicrobial therapy, according to the causative pathogen are complex and well summarized in the 2015 American Heart Association practice guidelines.[8] Treatment for left-sided infective endocarditis (aortic and mitral) is similar, and the recommendations are based on the pathogen, its susceptibility, timeline (acute vs. subacute), and whether it is native or prosthetic valve infective endocarditis. Generally speaking, for subacute native valve infective endocarditis, S. viridans and enterococci need to be covered, and the usual treatment involves IV penicillin (2.4 g, every 4 hours) for up to 4 weeks with gentamicin (1 mg/kg, every 12 hours) for 2 weeks (for suspected aminoglycoside-susceptible enterococci).

Adjunctive therapy with aminoglycosides for native valve infective endocarditis is not recommended because of the risk of renal toxicity and because it doesn’t decrease mortality. Likewise, rifampin is not recommended because of the risk of hepatotoxicity. However, if the culprit is aminoglycoside-susceptible enterococci, then gentamicin can be added to the regimen.[9] Additionally, for prosthetic valve infective endocarditis, the combination therapy of vancomycin and aminoglycoside or rifampin is acceptable. For acute native valve, infective endocarditis treatment S. aureus needs to be covered. The treatment includes nafcillin for methicillin-susceptible S. aureus (MSSA) or cefazolin if patients are allergic to nafcillin. For methicillin-resistant Staphylococcus aureus (MRSA), vancomycin is the recommended antibiotic. The alternative is daptomycin, which requires closer monitoring for dosing. Candida and Aspergillus may respond to medical therapy 5-fluorouracil and amphotericin B respectively, however, these patients frequently require surgical therapy. Among patients with mechanical valve endocarditis who have experienced a central nervous system embolic event, it is reasonable to discontinue for 2 weeks all forms of anticoagulation.[8]

If medical therapy fails, surgical intervention is often necessary. Class I indications for surgery in patients with infective endocarditis include valvular dysfunction with symptoms of congestive heart failure, left-sided infective endocarditis caused by Staphylococcus aureus, fungal, or other highly resistant microorganisms, infective endocarditis with conduction defects or heart block, annular or aortic abscess, persistent infection 5 to 7 days after initiation of antibiotic therapy [10]. For native valve endocarditis, eradication of the infected valvular tissue with subsequent valve repair or replacement is the primary therapy. 

Indications for Surgery

• CHF that is refractory to treatment
• Fungal endocarditis
• Recurrent septic emboli despite antibiotic treatment
• Persistent sepsis despite antibiotic treatment
• Rupture sinus of Valsalva aneurysm
• Conduction defect due to a septal abscess

There are several options for treating aortic valve endocarditis depending on the surgeon's experience and preferences. In the past, cryopreserved homografts were often utilized and had good outcomes. But these homografts have fallen out of favor because of recalcification and the need for another surgery. In addition, the implantation of a homograft does require skill. Today, aortic valve endocarditis is managed with the use of biological stentless valves. These valves have a long shelf life and are available in many sizes. However, they still require some technical skills to get the best outcomes.

For native valve endocarditis limited to the leaflets/cusps, repair should be performed whenever feasible (Class I) [10]. For prosthetic valve endocarditis that spares the aortic root and annulus after radical resection, implantation of a new prosthetic valve (tissue or mechanical) is reasonable (Class IIa).[10]However, if the annulus is destroyed or if the infection has spread beyond the aortic root, then reconstruction and the use of an allograft or a biologic tissue root is preferable to a prosthetic valved conduit (Class IIa).[10]

Differential Diagnosis

The principal differential diagnoses for infective endocarditis include the following:

1. Nonbacterial thrombotic endocarditis which was formerly known as marantic endocarditis - causes small sterile vegetations on the valve leaflets; predisposing conditions for this include certain malignancies and hypercoagulable states
2. Libman–Sacks endocarditis: causes verrucous vegetations and is associated with systemic lupus erythematosus
3. Vasculitis
4. Connective tissue disease
5. Fever of unknown origin

Prognosis

The in-hospital mortality for infective endocarditis is around 20%.[9] Risk factors for increased mortality include advanced age, infective endocarditis caused by S. Aureus P. aeruginosa, Enterobacteriaceae, or fungi, a heavy burden of comorbidities (end-stage renal disease requiring hemodialysis, prosthetic valve endocarditis, severe heart failure, stroke, abscess, severe immunosuppression due to HIV infection, and development of perivalvular extension or a myocardial abscess).[9] Embolic events to the brain are a significant cause of morbidity and mortality in patients with infective endocarditis. In a study of 1437 consecutive patients with left-sided endocarditis, the incidence of stroke in patients receiving appropriate antimicrobial therapy was 4.82 per 1000 patient days in the first week of therapy and fell to 1.71 per 1000 patient days in the second week suggesting that early initiation of antimicrobial therapy dramatically reduces the risk of stroke.[11]

Complications

Aortic valve endocarditis complications include congestive heart failure due to valve damage, annular abscess, and mycotic aneurysms of the sinus of Valsalva which can result in pericarditis, hemopericardium, cardiac tamponade, or fistulas to the cardiac chambers.[12] Involvement of the conduction system may cause atrioventricular blocks. Neurologic complications include thromboembolic events and mycotic aneurysms from septic embolization of vegetations.[12] Systemic embolization to other organs, including the liver, kidneys, and spleen results in end-organ damage.

Deterrence and Patient Education

Early recognition and timely management of infective endocarditis are imperative to ensure optimal clinical outcomes. Patients should receive education regarding the prognosis, risk factors, signs and symptoms, and management aspects of infective endocarditis. 

Enhancing Healthcare Team Outcomes

Aortic valve infective endocarditis is a life-threatening condition with a poor prognosis. Despite technological advances over the past few decades, mortality remains high. Early recognition and prompt institution of antimicrobial therapy can help optimize patient outcomes. an interprofessional approach involves physicians, specialists, specialty-trained nurses, physician assistants, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]

It is vital that pharmacists, nurses, physician assistants, and primary care clinicians be aware of the latest guidelines for the prevention of subacute bacterial endocarditis. At least 25% of cases are a consequence of an invasive procedure that causes bacteremia. This antibiotic prophylaxis is vital in some patients. In addition, the patient has to be educated about maintaining good oral hygiene. If there is any doubt about antibiotic prophylaxis, a cardiology consult should be sought.

Nurses should be vigilant about central lines as they are also a cause of bacteremia. Nurses should ensure that only dedicated personnel inserts the lines under strict aseptic guidelines. When the line is not being used, it should be removed. The nurse should work with the clinical team in treating patients with endocarditis, monitoring the patients, and contacting the clinician if unexpected fever spikes occur. The pharmacist should assist the clinical team with antibiotic selection and evaluate the patient for potential drug-drug interactions or allergies that may affect treatment. The clinicians, pharmacists, PAs, and nurses should work together to coordinate patient and family education. [Level 5]

Open communication between the clinicians and specialists is vital to ensure that patients with aortic valve endocarditis are treated with the optimal standard of care- as this is one condition that often leads to medical malpractice when complications develop.