Enteroccocus and Endocarditis

Abstract

Infective endocarditis (EI) produced by enterococci ranks third among infectious endocarditis and is a severe infection with usually subacute onset, often complicated with valvular lesions, systemic emboli and immunological changes. EI caused by enterococcus is produced in 90% of cases by Enterococcus faecalis and much less often by Enterococcus faecium or other species. Most cases are acquired in the community, but enterococcal EI can also be nosocomial. Enterococcal endocarditis is more common in the elderly or may appear against the background of some associated conditions: colorectal cancer, liver cirrhosis, diabetes, immunosuppressive treatments. Transthoracic echocardiography combined with blood cultures is the basis of the diagnosis of infective endocarditis, but in difficult cases, transesophageal ultrasound and new imaging methods such as computer tomography, PET-CT or cardiac MRI can be the solution for establishing the diagnosis. Enterococci are very tolerant to bactericidal antibiotics and their eradication requires prolonged therapy (up to 6 weeks) with synergistic bactericidal combination of cell wall inhibitors with aminoglycosides, they can also be resistant to many antibiotics, including beta-lactams, aminoglycosides and vancomycin. E. faecium is often resistant to vancomycin and beta-lactams. Linezolid may be effective in the treatment of vancomycin-resistant enterococcal endocarditis, but also daptomycin, dalbavancin and oritavancin seem promising.

1. Introduction

Endocarditis is a medical condition characterized by inflammation and infection of the endocardium, which is the inner lining of the heart chambers and heart valves [1]. The endocardium is a smooth membrane that lines the inside of the heart, providing a protective barrier between the heart muscle and the blood that flows through it.

In cases of endocarditis, microorganisms such as bacteria, fungi, or other infectious agents invade the endocardium, often entering the bloodstream from other parts of the body. Once inside the heart, these microorganisms can attach themselves to damaged heart valves or other areas of the endocardium, leading to inflammation and the formation of infected masses known as vegetations [2].

Endocarditis can be acute or chronic, and it may occur in individuals with pre-existing heart conditions or those who have undergone certain medical procedures that increase the risk of bloodstream infections [3]. Common symptoms of endocarditis include fever, fatigue, shortness of breath, chest pain, and changes in heart murmur [1, 2, 3]. Prompt diagnosis and treatment, usually involving a course of antibiotics, are essential to prevent complications such as heart valve damage, heart failure, or septicemia [4]. In severe cases, surgical intervention may be necessary to repair or replace damaged heart valves [5, 6].

Enterococcus is a genus of bacteria that includes species like Enterococcus faecalis and Enterococcus faecium. These bacteria are normally found in the intestines and are generally harmless. However, they can cause infections when they enter the bloodstream, particularly in the context of certain medical procedures, surgeries, or if there is a pre-existing heart valve abnormality and can cause 10–15% of all cases of endocarditis [6, 7]. Enterococcus faecalis is one of the main causes of bacterial endocarditis in the world, generating a high mortality rate in the elderly and immunocompromised people and is the most common causative organism isolated in endocarditis in patients who have undergone a transcatheter aortic valve implantation [7, 8, 9, 10, 11]. Enterococcal endocarditis was mainly community-acquired, but there is a significant increase in the incidence of healthcare acquisition [9, 10], particularly in patients with colorectal neoplasms [11, 12].

Diagnosis involves blood cultures to identify the bacteria causing the infection. Treatment typically includes antibiotics, often intravenous (IV), to target the specific strain of Enterococcus involved. The choice of antibiotics may depend on the susceptibility of the bacteria to different drugs. In severe cases, especially when there is valve damage or other complications, surgical intervention may be necessary to repair or replace the affected heart valve.

It’s crucial to seek medical attention promptly if there are symptoms of endocarditis, as delayed treatment can lead to serious complications, including heart failure or septicemia. The specific treatment plan will depend on factors such as the patient’s overall health, the severity of the infection, and the strain of Enterococcus causing the endocarditis [13, 14].

2. Etiology

The etiology of endocarditis refers to the underlying causes or origins of the condition. The most common causative agents are bacteria, but fungi and, less commonly, other microorganisms can also lead to endocarditis [13].

2.1 Bacterial endocarditis

• Streptococcus species: often associated with subacute endocarditis. Examples include Streptococcus viridans.

• Staphylococcus aureus: known for causing acute endocarditis.

• Enterococcus species: such as Enterococcus faecalis and Enterococcus faecium.

• HACEK group: an acronym representing Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species.

• Other bacteria: Various other bacteria may also be implicated, depending on factors such as patient risk factors and health status.

2.2 Fungal endocarditis

• Candida species: Common fungi associated with fungal endocarditis, especially in individuals with compromised immune systems.

• Aspergillus species: Less common, but it can cause endocarditis in certain populations.

2.3 Other microorganisms

Viruses: While viral endocarditis is rare, it can occur, often in the context of a pre-existing viral infection.

Rickettsia and Chlamydia: Certain species of these intracellular bacteria can also cause endocarditis.

3. Risk factors for endocarditis

• Pre-existing Heart Conditions: Structural abnormalities of the heart, such as congenital heart defects, damaged heart valves, or prosthetic heart valves, can increase the risk.

• Medical Procedures: Certain invasive medical procedures, such as dental work or surgeries, can introduce bacteria into the bloodstream, increasing the risk of endocarditis.

• Immunocompromised States: Individuals with weakened immune systems are more susceptible to infections, including endocarditis.

• Intravenous Drug Use: The use of contaminated needles can introduce infectious agents into the bloodstream [1, 5].

Understanding the specific microorganism causing the infection is crucial for determining the appropriate treatment, as different pathogens respond to different antibiotics or antifungal medications. Prompt diagnosis and treatment are essential to prevent complications associated with endocarditis [14].

4. Endocarditis with Enterococcus

Enterococcus is a genus of bacteria, and within this genus, there are several species. The two primary species of clinical significance are Enterococcus faecalis and Enterococcus faecium. These bacteria are gram-positive cocci (spherical-shaped) and are facultative anaerobes, meaning they can grow in both the presence and absence of oxygen [15]. These species share some similarities, but also have distinct characteristics. Here is a basic classification of Enterococcus:

Genus: Enterococcus

4.1 Enterococcus faecalis

Characteristics:

• Most clinically relevant species within the genus.

• Part of the normal flora in the gastrointestinal tract of humans.

• Opportunistic pathogen causing various infections, including urinary tract infections, wound infections, and endocarditis.

• Generally more susceptible to antibiotics compared to Enterococcus faecium.

4.2 Enterococcus faecium

Characteristics:

• Also part of the normal flora in the gastrointestinal tract but less prevalent than Enterococcus faecalis.

• Increasingly recognized as a cause of healthcare-associated infections.

• Demonstrates higher levels of antibiotic resistance compared to Enterococcus faecalis.

• Often associated with nosocomial infections and is a concern due to its resistance to multiple antibiotics.

4.3 Other Enterococcus species

In addition to Enterococcus faecalis and Enterococcus faecium, there are other less clinically significant species within the genus, including:

• Enterococcus avium

• Enterococcus gallinarum

• Enterococcus casseliflavus

• Enterococcus durans

• Enterococcus hirae

These species may also be found in the environment, in animals, or as part of the normal flora in humans.

4.4 Clinical significance

Enterococci are considered opportunistic pathogens, meaning they can cause infections in individuals with compromised immune systems or underlying health conditions. Enterococcus infections can range from relatively mild, such as urinary tract infections, to more serious conditions like endocarditis. The ability of Enterococcus species to develop antibiotic resistance, especially in healthcare settings, poses challenges for treatment. It’s important to note that classification and understanding of Enterococcus continue to evolve, particularly in the context of emerging antibiotic resistance patterns. Microbiological laboratories perform detailed identification and susceptibility testing to guide clinicians in selecting appropriate antibiotics for the treatment of Enterococcus infections.

Enterococcus is a genus of bacteria that includes several species commonly found in the intestines of humans and animals. While these bacteria are typically harmless in their natural environment, they can cause infections when they enter other parts of the body, particularly the bloodstream. Enterococcus species are known for their ability to survive in challenging conditions, such as those encountered in the gastrointestinal tract, and their resistance to certain antibiotics. Among enterococci, the most clinically abundant species, Enterococcus faecalis, accounts for approximately 5–8% of hospital-associated bacteremia and approximately 5–20% of all cases of endocarditis [15, 16, 17].

Key points about Enterococcus include:

Normal Flora: Enterococci are part of the normal microbial flora in the gastrointestinal tract of humans and animals.

Opportunistic Pathogens: While Enterococcus species are generally considered opportunistic pathogens, they can cause infections in individuals with compromised immune systems or underlying health conditions.

Infections: Enterococci are known to cause a variety of infections, including urinary tract infections, intra-abdominal infections, wound infections, and endocarditis. Enterococcal endocarditis is a serious condition that often involves infection of the heart valves.

Antibiotic Resistance: Enterococcus species are notorious for their intrinsic and acquired resistance to antibiotics. This resistance can make treatment challenging, especially in healthcare settings.

Nosocomial Infections: Enterococci are commonly associated with healthcare-associated infections (nosocomial infections), particularly in settings like hospitals and long-term care facilities.

Transmission: The primary mode of transmission is through the fecal-oral route. In healthcare settings, transmission can also occur through contaminated medical equipment.

Treatment: Treatment of enterococcal infections often involves antibiotics, and the choice of antibiotics is guided by susceptibility testing. Due to increasing antibiotic resistance, combination therapy or the use of specific antibiotics may be necessary.

It’s important to note that Enterococcus faecalis and Enterococcus faecium can exhibit different patterns of antibiotic resistance, and susceptibility testing is crucial to determine the most effective treatment. Additionally, preventive measures, such as proper hygiene practices and infection control measures in healthcare settings, are important to reduce the risk of Enterococcus infections.

5. Pathogenesis

The pathology of endocarditis involves the inflammatory and infectious processes that affect the endocardium, the inner lining of the heart chambers and valves. The condition is characterized by the formation of infected masses known as vegetations, which can lead to various complications, including damage to heart valves [1, 17, 18]. Here is an overview of the pathology of endocarditis:

5.1 Formation of vegetations

• Infection Entry: Microorganisms, most commonly bacteria, enter the bloodstream through various means, such as dental procedures, surgeries, or infections in other parts of the body.

• Attachment to Endocardium: Bacteria can adhere to the endocardium, especially in areas with damaged or abnormal heart valves. The turbulent blood flow around these areas can facilitate the attachment of microorganisms.

• Vegetation Formation: Microorganisms, blood platelets, fibrin, and inflammatory cells accumulate, forming vegetations on the valve leaflets or other endocardial surfaces. These vegetations can vary in size and composition [18, 19, 20, 21].

5.2 Inflammatory response

• Immune Activation: The body’s immune system responds to the presence of microorganisms by activating an inflammatory response.

• Cellular Infiltration: Inflammatory cells, such as white blood cells, infiltrate the affected areas, contributing to the formation of vegetations and causing tissue damage [19, 20, 21].

5.3 Valve damage

• Direct Damage: The inflammatory process and the presence of vegetations can directly damage the valve leaflets, leading to structural changes.

• Secondary Changes: The immune response and inflammation can lead to secondary changes in the valve structure, such as fibrosis and scarring.

5.4 Complications

• Valvular Insufficiency: Severe cases of endocarditis can result in valvular insufficiency, where the affected valve no longer functions properly, leading to regurgitation of blood.

• Embolization: Portions of the vegetations or infected material can break off and travel through the bloodstream, causing embolisms. These emboli can lodge in smaller blood vessels and cause damage in distant organs. The occurrence of septic emboli can be monitored both echocardiographically and by biological markers such as D-Dimer, troponin, C-reactive protein, neutrophil-to lymphocyte ratio and by determining anti-B2-glicoprotein antibodies [22].

5.5 Healing and scar formation

• Resolution: With appropriate treatment, the infection can be controlled, and the inflammatory response may subside.

• Scar Formation: The healing process may lead to the formation of scars or fibrous tissue on the valve leaflets, potentially affecting the long-term function of the valve.

Enterococcus faecalis it is involved in the formation of a bacterial biofilm on native or altered valves, which leads to an increase in resistance to antibiotics [23]. E. faecalis colonizes the surface of the intestinal epithelium, producing biofilm microcolonies in the gastrointestinal tract, but it can also colonize the surface of the native valve, causing the development of infectious endocarditis [24]. Understanding the pathology of endocarditis is crucial for diagnosis and management. Treatment often involves antibiotics or antifungal medications, and in severe cases, surgical intervention may be necessary to repair or replace damaged heart valves. Early detection and intervention are essential to prevent long-term complications and improve outcomes.

6. Risk factors for Enterococcus endocarditis

Several risk factors increase the likelihood of developing endocarditis with Enterococcus:

• Pre-existing Heart Conditions:

  Individuals with underlying heart conditions, especially those involving damaged or abnormal heart valves, have an increased risk of endocarditis. These conditions create areas where bacteria, including Enterococcus, can attach and initiate infection.

• Prosthetic Heart Valves:

  Individuals with prosthetic heart valves, whether mechanical or bioprosthetic, are at an elevated risk. Prosthetic materials provide surfaces where bacteria can adhere and form vegetations.

• Previous Episodes of Endocarditis:

  Individuals who have experienced endocarditis in the past are at a higher risk of developing recurrent episodes. Enterococcus species may be involved in both primary and recurrent cases.

• Congenital Heart Disease:

  Certain congenital heart diseases, especially those with abnormal blood flow patterns or defects involving heart valves, increase the risk of endocarditis.

• Immunocompromised States:

  Conditions or medications that compromise the immune system, such as HIV/AIDS, chemotherapy, or immunosuppressive medications, can increase susceptibility to infections, including endocarditis.

• Chronic Illnesses:

  Chronic illnesses, such as diabetes, that weaken the immune system or affect blood flow can contribute to an increased risk of endocarditis.

• HemodiaLysis:

  Individuals undergoing hemodialysis, especially those with vascular access, are at an elevated risk of bloodstream infections, which can lead to endocarditis.

• Intravenous (IV) Drug Use:

  The use of intravenous drugs, particularly when done in a manner that introduces bacteria into the bloodstream, increases the risk of endocarditis. Enterococcus faecalis is one of the bacteria commonly associated with drug-related endocarditis.

• Age and Gender:

  Elderly individuals and males tend to have a higher incidence of endocarditis. The reasons for these associations are complex and multifactorial.

• Invasive Medical Procedures:

  Certain medical procedures that breach the normal barriers of the body, such as dental procedures, surgeries, or invasive diagnostic tests, can introduce bacteria into the bloodstream, increasing the risk of endocarditis [25, 26]. It’s important to note that while these factors increase the risk of endocarditis, not everyone with these risk factors will develop the condition [26]. Additionally, the risk factors may interact, and the overall risk varies among individuals. Early identification of risk factors and appropriate preventive measures, such as antibiotic prophylaxis in certain cases, can help reduce the risk of developing endocarditis.

7. Endocarditis diagnosis

Diagnosing endocarditis involves a combination of clinical evaluation, imaging studies, and laboratory tests. Since prompt and accurate diagnosis is crucial for effective treatment and to prevent complications, healthcare professionals use a variety of methods to confirm the presence of endocarditis. The diagnosis of endocarditis caused by Enterococcus involves a combination of clinical, laboratory, and imaging studies [27]. Here are the key steps in the diagnostic process:

7.1 Clinical evaluation

Medical History: The healthcare provider will gather information about the patient’s symptoms, medical history, and any recent procedures or conditions that may increase the risk of endocarditis.

Physical Examination: A thorough physical examination may reveal signs such as fever, heart murmurs, and other clinical indicators of endocarditis.

Symptoms of endocarditis caused by Enterococcus may include:

• Fever

• Fatigue

• Shortness of breath

• Chest pain

• Swelling in the legs or abdomen

• Changes in heart murmur (a sound heard during a heartbeat examination)

7.2 Blood cultures

Collection of Blood Samples: Blood cultures are essential for identifying the causative microorganism. Multiple blood samples are typically collected over a period of time.

Identification of Enterococcus: Once blood cultures show bacterial growth, the specific microorganism responsible for the infection, such as Enterococcus faecalis or Enterococcus faecium, can be identified. This information is crucial for determining the appropriate antibiotic treatment.

7.3 Imaging studies

Echocardiography: Echocardiograms, including transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), are crucial for visualizing the heart structures. These imaging studies can help identify vegetations, abscesses, or other signs of endocarditis. In some cases, other imaging studies such as CT scans or MRI may be used to assess the extent of damage or complications associated with endocarditis.

7.4 Laboratory tests

Inflammatory Markers: Blood tests measuring inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can indicate the presence of inflammation in the body.

Complete Blood Count (CBC): Abnormalities in white blood cell count or other blood cell components may suggest an ongoing infection [27, 28, 29].

7.5 Duke criteria

The Duke Criteria, which include major and minor criteria, are used to categorize cases into possible, definite, or rejected endocarditis [30, 31]. These criteria consider clinical, microbiological, and echocardiographic findings.

7.5.1 Major criteria

• Positive Blood Cultures:

• Microorganisms typically found in blood cultures drawn from two separate occasions.

• Persistent bacteremia, typically defined as the isolation of the same microorganism in multiple blood cultures or isolation of a microorganism from a single blood culture for a recognized pathogen.

• Evidence of Endocardial Involvement on Imaging Studies:

• Positive Echocardiogram Findings: Evidence of a vegetation, abscess, dehiscence of a prosthetic valve, or a new valvular regurgitation.

7.5.2 Minor criteria

• Predisposition:

  Presence of a predisposing heart condition or use of intravenous drugs.

• Fever:

  Temperature higher than 38.0°C (100.4°F).

• Vascular Phenomena:

  • Emboli: Clinical evidence of arterial emboli (e.g., petechiae, splinter hemorrhages).

  • Janeway Lesions: Non-tender hemorrhagic lesions on the palms or soles.

  • Mycotic Aneurysm: An aneurysm that results from an infection.

• Immunologic Phenomena:

  • Glomerulonephritis: Evidence of glomerulonephritis, such as hematuria, proteinuria, or cellular casts.

  • Osler’s Nodes: Tender subcutaneous nodules on the pads of the fingers or toes.

• Microbiological Evidence:

  Positive blood culture not meeting major criteria or serological evidence of an active infection with an organism consistent with endocarditis [32, 33].

7.5.3 Diagnosis categories

Definite Infective Endocarditis:

• Two major criteria.

• One major criterion and three minor criteria.

• Five minor criteria.

Possible Infective Endocarditis:

• One major criterion and one or two minor criteria.

• Three minor criteria.

Rejected Case:

• Firm alternate diagnosis explaining clinical findings.

• Resolution of symptoms with <4 days of antimicrobial therapy.

• No pathological evidence of infective endocarditis at surgery or autopsy.

The new modified 2023 Duke Criteria included new microbiology diagnostics assay like polymerase chain reaction, metagenomic sequencing and in situ hybridization. They also added some new imaging techniques like positron emission computed tomography and cardiac magnetic resonance or computed tomography [31].

These criteria provide a structured approach to the diagnosis of endocarditis, taking into account clinical, microbiological, and imaging findings. It’s important to note that the diagnosis is often complex and may require the collaboration of multiple healthcare professionals, including infectious disease specialists, cardiologists and radiologist. Prompt and accurate diagnosis is crucial for initiating appropriate treatment and improving outcomes for individuals with endocarditis.

7.6 Other tests

Serological Tests: Serological tests may be performed to detect antibodies against Enterococcus or other specific microorganisms. These tests can provide additional information about the immune response and aid in the diagnosis.

Electrocardiogram (ECG): An ECG may be done to assess the heart’s electrical activity and rule out other cardiac conditions.

7.6.1 Molecular diagnostic techniques

Polymerase Chain Reaction (PCR) and other molecular techniques may be used to detect the genetic material of the infecting microorganism in blood or tissue samples. These methods can be valuable for identifying the specific species and strain of bacteria causing endocarditis [34].

7.6.2 Next-generation sequencing (NGS)

NGS technologies are increasingly being explored for their potential in identifying pathogens directly from clinical samples. This approach may enhance the speed and accuracy of identifying the causative microorganism.

7.6.3 Nuclear medicine imaging

Positron Emission Tomography-Computed Tomography (PET-CT) scans with radiolabeled glucose analogs may be used to identify areas of infection and inflammation, including cardiac involvement [31, 35].

7.7 Consultation with specialists

Infectious disease specialists and cardiologists are often involved in the diagnostic process, especially for cases involving endocarditis. Prompt and accurate diagnosis is crucial for initiating appropriate treatment and improving outcomes for individuals with endocarditis.

8. Echocardiography

Echocardiography plays a crucial role in the diagnosis and management of infective endocarditis, including cases caused by Enterococcus species [35, 36]. Both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) are commonly used imaging modalities to visualize cardiac structures and detect abnormalities associated with endocarditis [36, 37, 38, 39].

8.1 Transthoracic echocardiography (TTE)

TTE is often the initial imaging modality used in the evaluation of suspected infective endocarditis. It is a non-invasive procedure that uses ultrasound waves to create images of the heart from the chest wall. TTE can detect large vegetations, valve abnormalities, abscesses, and regurgitant jets. It is particularly useful for identifying abnormalities on the right side of the heart and for screening for endocarditis.

Limitations: TTE may have limitations in visualizing structures in certain patients, especially if there are factors such as obesity or lung disease that limit the acoustic window [35, 36, 38, 40].

8.2 Transesophageal echocardiography (TEE)

TEE is a more sensitive and specific imaging modality compared to TTE. It involves inserting an ultrasound probe into the esophagus, providing clearer and closer views of cardiac structures. TEE allows for detailed visualization of cardiac valves, identifying smaller vegetations and complications such as abscesses and perforations. It is particularly useful for evaluating the left side of the heart, including the mitral and aortic valves.

Advantages: TEE is often considered the gold standard for the diagnosis of infective endocarditis due to its higher sensitivity and specificity [35, 36, 38, 39].

8.3 Key echocardiographic findings in endocarditis

• Vegetations:

  Vegetations are abnormal masses of infected tissue and bacteria attached to heart valves or other endocardial structures. They are a hallmark finding in endocarditis. Echocardiography helps visualize the size, location, and characteristics of vegetations.

• Valve Abnormalities:

  Echocardiography can identify valve regurgitation, stenosis, and structural abnormalities resulting from infective endocarditis.

• Perivalvular Abscess:

  In cases of more severe infection, echocardiography can help identify abscess formation in the perivalvular region.

• Valve Perforation:

  Echocardiography can reveal valve perforations, a complication of endocarditis.

• Complications:

  Echocardiography helps assess for complications such as emboli, which may appear as mobile echogenic masses.

8.4 Monitoring and follow-up

Serial echocardiograms may be performed to monitor the progression of the infection and assess the response to treatment.

Echocardiography findings play a crucial role in deciding whether surgical intervention is necessary, such as valve repair or replacement.

Echocardiography, especially TEE, is an integral part of the Duke Criteria, which are widely used for diagnosing infective endocarditis. It helps guide treatment decisions and surgical interventions based on the severity and complications of the infection. The imaging findings obtained through echocardiography contribute significantly to the overall management and prognosis of patients with infective endocarditis, including those caused by Enterococcus species.

Transesophageal echocardiography is superior to transthoracic echocardiography in the diagnosis of protected valvular endocarditis, but a negative result cannot exclude it. New non-invasive diagnostic imaging methods are increasingly used in the diagnosis of endocarditis. Nuclear medicine imaging techniques are superior to echocardiography in the diagnosis of infective endocarditis on prosthetic valves and implantable cardiac electronic devices. Computed tomography angiography is useful for evaluating paravalvular complications and in cases with inconclusive echocardiography [40].

9. Treatment on Enterococcus endocarditis

Once a diagnosis is confirmed, appropriate treatment can be initiated. Treatment typically involves antibiotics effective against Enterococcus, and the choice of antibiotics may be guided by the results of susceptibility testing. In severe cases or when complications arise, surgical intervention may be necessary to address damaged heart valves. Early detection and treatment are crucial for improving outcomes in cases of endocarditis caused by Enterococcus.

Treatment of E. faecalis endocarditis is often difficult since they have acquired multiple resistance mechanisms including plasmids from other bacteria and also produce a bacterial biofilms over prosthetic devices [41, 42, 43, 44, 45]. These resistance mechanisms have led to a decrease in the sensitivity of enterococci to traditional antibiotics and to the appearance of more cases of relapse compared to other etiologies [41, 42, 46, 47, 48]. Patients with enterococcal endocarditis need to be monitored for a longer period of time because relapses can sometimes occur several months after the end of treatment [49].

The treatment of endocarditis typically involves a combination of antimicrobial therapy and, in some cases, surgical intervention. The specific treatment plan depends on various factors, including the causative microorganism, the severity of the infection, the presence of complications, and the overall health of the patient. Here are the key components of the treatment for endocarditis:

9.1 Antimicrobial therapy

Empirical Treatment: Initially, broad-spectrum antibiotics are often started while awaiting the results of blood cultures. Empirical therapy is based on the most likely pathogens, taking into consideration patient characteristics and risk factors.

Definitive Treatment: Once the causative microorganism is identified through blood cultures, the antibiotic regimen can be adjusted to target the specific pathogen and its susceptibility profile.

Duration of Treatment: The duration of antibiotic therapy varies but is generally prolonged, often lasting several weeks. The decision on the duration depends on factors such as the type of microorganism, the presence of complications, and the response to treatment.

9.2 Selection of antibiotics

The treatment of endocarditis caused by Enterococcus species often involves a combination of antimicrobial therapy. Enterococci, particularly Enterococcus faecalis and Enterococcus faecium, are known for their intrinsic and acquired resistance to multiple antibiotics, making treatment decisions challenging [50].

Several classes of antibiotics are commonly used to treat Enterococcus infections, with the choice of antibiotic depending on factors such as the specific species of Enterococcus, the site of infection, and the antibiotic susceptibility of the strain [51, 52]. Please note that the landscape of available drugs and their clinical use is subject to change, and new drugs may have been developed or approved.

Here are some classes of antibiotics commonly used to treat Enterococcus infections, and potential newer drugs that may be considered:

9.2.1 Beta-lactam antibiotics

• Penicillins (Ampicillin, Penicillin G): Ampicillin is often used in combination with an aminoglycoside for Enterococcus faecalis infections [49, 52, 53].

• Cephalosporins: Some cephalosporins (ceftobiprole and ceftaroline) may be effective against Enterococcus, but their use is often limited [48, 54, 55].

9.2.2 Ceftaroline

• Ceftaroline is a cephalosporin with activity against Gram-positive bacteria, including some strains of Enterococcus. Its role in the treatment of Enterococcus infections, especially endocarditis, is not well established [48].

Beta-lactam monotherapy was associated with a poor outcome in patients with endovascular infections [52, 56]. The bactericidal activity is rarely achieved with beta-lactam monotherapy and some enterococcal strains produce a “paradoxical response” killing enterococcus only at a specific concentration, above which the killing effect decreases [57].

9.2.3 Aminoglycosides

• Gentamicin, Streptomycin: Aminoglycosides are used in combination with beta-lactam antibiotics for synergistic effects, especially in Enterococcus faecalis infections.

Although enterococci are considered resistant to aminoglycosides due to their structure, the combination with agents that inhibit peptidoglycan synthesis will increase the permeability of the bacterial wall, resulting in a synergism between beta-lactams/vancomycin and aminoglycosides, with improved clinical results [58, 59, 60].

9.2.4 Vancomycin

• Vancomycin is effective against Enterococcus, including strains that are resistant to beta-lactam antibiotics. However, the emergence of vancomycin-resistant Enterococcus (VRE) is a concern. Strains of enterococci are considered sensitive to vancomycin (MIC < 4 mg/L), intermediate (MIC = 8–16 mg/L) or fully resistant (MIC > 16 mg/L). There are several genotypes with resistance to vancomycin, the most common being the vanA operon [61, 62, 63, 64].

9.2.5 Teicoplanin

• Teicoplanin is a glycopeptide that have a long elimination half-life which permits once-daily dosing and has the advantage of much lower renal toxicity [65, 66].

• Teicoplanin, associated or not with gentamicin, could be used especially in patients allergic to beta-lactams. In addition, it has the advantage of less renal toxicity and the possibility of administration or data per day, being able to be used in the treatment of patients at home [67, 68].

9.2.6 Daptomycin

• Daptomycin is a lipopeptide antibiotic that is active against Enterococcus, including VRE. It is often used for complicated skin and soft tissue infections [69, 70, 71].

9.2.7 Linezolid

• Linezolid is an oxazolidinone antibiotic effective against Enterococcus, including VRE. It is used for various infections, including skin and soft tissue infections and pneumonia. Linezolid has been recommended for the treatment of enterococcal endocarditis caused by strains resistant to beta-lactam, aminoglycosides, and vancomycin [72, 73].

• One of the disadvantages of this antibiotic is the fact that in the elderly it can cause peripheral neuropathy and myelotoxicity in long-term use [74].

9.2.8 Tedizolid

• Tedizolid is another oxazolidinone antibiotic with activity against Enterococcus. It is indicated for skin and soft tissue infections [75, 76, 77, 78].

9.2.9 Quinolones

• Fluoroquinolones (Ciprofloxacin, ofloxacin, moxifloxacin and levofloxacin) have a moderate activity against enterococci and moxifloxacin is more potent against Gram-positive bacteria [79, 80, 81].

• Delafloxacin is a new quinolone active against Methicillin-resistant staphylococcus aureus (MRSA) and Methicillin-susceptible Staphylococcus aureus (MSSA), but there is not enough evidence that it would be active in enterococci and would be effective in enterococcal endocarditis [82, 83, 84].

9.2.10 Streptogramins

• Quinupristin/Dalfopristin: This combination antibiotic has activity against Enterococcus, including VRE. It is used in certain situations, such as complicated skin and skin structure infections [85].

9.2.11 Dalbavancin and oritavancin

• These are long-acting lipoglycopeptide antibiotics similar to vancomycin and have been used for the treatment of certain Gram-positive infections. While they are not specifically indicated for Enterococcus endocarditis, they may be considered in some situations [86, 87, 88].

• Dalbavancin could be used as an outpatient treatment, either with a loading dose of 1000 mg and then 500 mg/week or the first dose of 1500 mg followed by 1000 mg every 2 weeks [89, 90, 91].

• Oritavancin is active on enterococci, including those with VanA- and VanB-mediated vancomycin resistance, and can be administered as a single dose of 1200 mg followed by sequential doses of 800 mg weekly. Oritavancin and Dalbavancin can also be active on the biofilm created by enterococcus [92, 93, 94, 95, 96, 97].

9.2.12 Tigecycline

• This bacteriostatic drug, blocking bacterial protein synthesis, have a therapeutic effect against multi-drug-resistant Gram-positive bacteria including VRE and MRSA, with very few resistances for E. faecalis and E. faecium, the main mutations occurring in various efflux pumps or through deletions in ribosomal protein gene [98, 99, 100, 101].

9.2.13 Fosfomycin

Fosfomycin intravenous can be used in combination with ceftriaxone, teicoplanin, daptomycin or tigecycline in treatment of MSSA and MRSA endocarditis. Fosfomycin demonstrated activity against biofilm-forming Enterococcus faecalis when the drug was used in combination with gentamicin and daptomycin and could be used in the future in enterococcal endocarditis [102, 103, 104, 105].

9.2.14 Combination therapies

Some studies explore combination therapies to improve efficacy or overcome antibiotic resistance [103, 106, 107, 108, 109]. Due to the increasing antibiotic resistance of Enterococcus, combination therapy with two antibiotics is often recommended [102, 109, 110, 111, 112]. Ampicillin is usually used in combination with an aminoglycoside [106]. Vancomycin-resistant Enterococcus (VRE) is a concern. If the strain is resistant to vancomycin, alternative antibiotics such as linezolid or tedizolid may be considered.

Current guidelines recommend for the treatment of enterococcal endocarditis the combination of ampicillin with ceftriaxone, a regimen that is synergistic, effective and with less toxicity [113, 114, 115, 116].

It’s important to emphasize that the treatment of endocarditis is complex, and decisions on antibiotic therapy should be individualized based on factors such as the specific strain of Enterococcus, antibiotic susceptibility testing, the patient’s overall health, and the presence of complications.

The acquisition of resistance to multiple antibiotics has made enterococcal endocarditis a life-threatening clinical challenge, and this highlights the need for alternatives to current antibiotic strategies. In this regard, alternative approaches that could be considered include immunoprophylaxis or immunotherapy targeting proteins that are expressed in vivo and that are important for virulence. The first step in the infection process of extracellular pathogens such as E. faecalis is generally considered to be the attachment and colonization of host tissue surfaces. Evidence from other gram-positive pathogens suggests that microbial surface component proteins that recognize the family of adhesive matrix molecules may serve as potential antigenic candidates for the development of new immunotherapies [104, 105].

9.3 Duration of treatment

Prolonged Course: Treatment duration is often prolonged, typically ranging from several weeks to months. The decision on the duration depends on factors such as the type of microorganism, the presence of complications, and the patient’s response to treatment.

The treatment of enterococcal endocarditis often requires the combination of two synergistic antibiotics, administered in several doses per day, over a prolonged period of time, on average 4–6 weeks. Although in patients with endocarditis on the native valve and without perivalvular extension 4 weeks of treatment might be sufficient, in many cases a treatment shorter than 6 weeks results in relapses [117]. Some studies recommend shortening the treatment with aminoglycosides from 4 to 2 weeks [118, 119].

9.4 Parenteral antimicrobial therapy outpatient

Recent studies reveal the possibility of ambulatory parenteral treatment of infective endocarditis, after the first 2 weeks of hospital treatment, when the risk of complications assessed by echocardiographic monitoring is lower [120, 121]. Treatment at home would reduce the risk of nosocomial infections and improve patient comfort [122, 123, 124, 125, 126].

9.5 Oral treatment

Oral antibiotics with good bioavailability and favorable pharmacodynamic properties could be an alternative to prolonged parenteral therapy in enterococcal endocarditis [127, 128]. Oral treatment of enterococcal endocarditis could be based on the combination of amoxicillin, linezolid, rifampin or moxifloxacin, but these combinations could cause more important adverse effects in elderly patients and increase the risk of Clostridiodes difficile enterocolitis [129, 130].

9.6 Surgical intervention

Indications: Surgery may be considered in cases of severe valve damage, persistent infection despite appropriate antibiotic therapy, heart failure, recurrent emboli, or large vegetations [131].

Procedures: Surgical options include valve repair, valve replacement (mechanical or bioprosthetic), and removal of infected tissue. The choice depends on the specific circumstances of the case [132].

9.7 Monitoring and follow-up

Clinical Monitoring: Continuous monitoring of the patient’s clinical status, laboratory parameters, and imaging studies is essential to assess the response to treatment.

Long-Term Follow-Up: Patients with endocarditis require long-term follow-up to monitor for recurrence, assess valve function, and manage any potential complications.

9.8 Prevention

Prophylactic Antibiotics: Prophylactic antibiotics may be recommended for individuals at high risk of infective endocarditis before certain dental or medical procedures.

9.9 Resistance testing

Antibiotic Susceptibility Testing: Regular testing for antibiotic susceptibility is crucial to guide treatment decisions, especially in the face of increasing antibiotic resistance.

The management of endocarditis caused by Enterococcus is complex and often requires collaboration between infectious disease specialists, cardiologists, and surgeons. Early diagnosis and appropriate, targeted treatment are crucial for optimizing outcomes and preventing complications.

10. Endocarditis complications

Enterococcal endocarditis, caused by Enterococcus species, can lead to various complications that affect the cardiovascular system and other organs [133]. The complications are often similar to those associated with endocarditis caused by other pathogens [134, 135]. Here are some potential complications of enterococcal endocarditis:

• Valvular Damage: Enterococcal endocarditis can cause structural damage to heart valves, leading to valvular insufficiency (regurgitation) or stenosis (narrowing). Severe damage may require surgical intervention for valve repair or replacement.

• Vegetations: Vegetations are abnormal masses of infected tissue, blood clots, and bacteria attached to heart valves. These vegetations can embolize (break off) and travel to other parts of the body, causing secondary infections.

• Systemic Emboli: Emboli from vegetations can travel through the bloodstream and lodge in various organs, leading to infarctions (tissue death) and localized infections. Common sites of emboli include the brain (causing strokes), lungs, spleen, kidneys, and extremities.

• Abscess Formation: In severe cases, the infection may lead to the formation of abscesses in the heart valves or the surrounding tissues (perivalvular abscesses). Abscesses can compromise cardiac function and may require surgical intervention.

• Heart Failure: Valve damage, regurgitation, and impaired cardiac function can contribute to congestive heart failure, a condition where the heart is unable to pump blood effectively.

• Arrhythmias: Endocarditis can disrupt the normal electrical conduction in the heart, leading to arrhythmias (irregular heart rhythms). These arrhythmias can affect the heart’s ability to pump blood efficiently.

• Renal Complications: Infected emboli may affect the kidneys, leading to renal infarctions or abscesses. This can result in impaired kidney function.

• Septicemia: The presence of bacteria in the bloodstream can lead to septicemia (bloodstream infection), causing widespread inflammation and organ dysfunction.

• Neurological Complications: Septic emboli can cause neurological complications, including strokes, seizures, and other manifestations of central nervous system involvement [121].

• Pulmonary Complications: Pulmonary emboli can lead to pneumonia or lung abscesses, causing respiratory symptoms and compromising lung function.

• Rheumatologic Manifestations: Immunological responses to the infection may result in rheumatologic manifestations, such as arthritis and other inflammatory conditions.

• Secondary Infections: The spread of bacteria from the primary site of infection can lead to secondary infections in various organs and tissues.

• Peripheral Emboli: Emboli can also affect peripheral arteries, leading to complications such as ischemia in the extremities [136, 137, 138].

The complications of endocarditis highlight the importance of prompt diagnosis and appropriate management, including antimicrobial therapy and, in some cases, surgical intervention. The choice of treatment depends on the specific causative microorganism, the extent of valve damage, and the presence of complications. Early recognition and aggressive management are essential to improve outcomes and reduce the risk of severe complications. Patients with suspected or confirmed endocarditis often require a multidisciplinary approach involving infectious disease specialists, cardiologists, and sometimes cardiac surgeons.

Enterococcus faecalis infective endocarditis continues to be a very serious disease, with considerable percentages of high-level gentamicin-resistant strains and in-hospital mortality around 20% [139]. Strategies to prevent Enterococcus faecalis EI, improve diagnosis, optimize treatment, and reduce morbidity will be needed to improve overall prognosis.

11. Endocarditis prophylaxis

Endocarditis prophylaxis, also known as antibiotic prophylaxis, refers to the administration of antibiotics to individuals at risk of developing infective endocarditis before certain dental or medical procedures [140]. The goal is to prevent bacterial infection of the heart valves or endocardium, particularly in those with pre-existing cardiac conditions that pose an increased risk of developing endocarditis. It’s important to note that the guidelines for endocarditis prophylaxis have evolved, and recommendations may vary based on regional guidelines and individual patient factors [140, 141, 142].

The most recent guidelines often recommend more restrictive use of antibiotic prophylaxis compared to earlier practices [143]. The focus is on identifying individuals at the highest risk and limiting antibiotic use to situations where the potential benefits outweigh the risks. The American Heart Association (AHA) and other professional organizations provide guidelines for endocarditis prophylaxis [144].

Here are some key points regarding endocarditis prophylaxis:

Enterococcus species, specifically Enterococcus faecalis and Enterococcus faecium, are among the bacteria that can cause endocarditis. However, the recommendations for antibiotic prophylaxis are generally not specific to the type of bacteria causing endocarditis. The decision to prescribe prophylactic antibiotics is more focused on the patient’s underlying cardiac conditions.

11.1 Indications for prophylaxis

• Prosthetic heart valves, including bioprosthetic and mechanical valves.

• Previous episodes of infective endocarditis.

• Certain congenital heart diseases (unrepaired or incompletely repaired cyanotic congenital heart disease).

• Cardiac transplant recipients who develop cardiac valvulopathy.

• Dental Procedures: The focus is on dental procedures that involve manipulation of the gingival tissues or the periapical region of teeth, which could introduce bacteria into the bloodstream.

11.2 Antibiotic regimens

If prophylaxis is deemed necessary, the choice of antibiotics may include amoxicillin or, in individuals with penicillin allergies, alternatives such as cephalexin or clindamycin [143, 144, 145].

Some guidelines recommend a single dose of antibiotics shortly before the dental procedure [146].

Important Considerations:

• Prophylaxis is generally not recommended for routine dental cleanings.

• The decision to administer prophylactic antibiotics should be individualized based on the patient’s specific circumstances, including their cardiac history and the procedure’s characteristics.

• Patients should inform their healthcare providers about their cardiac history, and healthcare providers should stay updated on the latest guidelines to provide the most current and appropriate recommendations.

It’s crucial to note that guidelines may change, and it’s essential for healthcare providers and patients to refer to the most recent recommendations from relevant medical organizations. Additionally, individual patient cases may vary, and decisions about antibiotic prophylaxis should be made in consultation with healthcare professionals based on the most up-to-date clinical guidelines.

12. Conclusions

Infective endocarditis is a serious and potentially life-threatening condition that can lead to various complications, affecting not only the heart valves but also other organs and systems in the body. Enterococcal endocarditis is a serious condition that often requires prompt medical attention.

It’s important to note that the diagnosis of endocarditis is often complex, and a combination of clinical, laboratory, and imaging findings is considered. Additionally, advancements in diagnostic technologies may continue to emerge over time. Healthcare professionals, including infectious disease specialists and cardiologists, play a crucial role in interpreting test results and determining the appropriate diagnostic approach based on individual patient characteristics.

Initially, broad-spectrum antibiotics are often started while awaiting the results of blood cultures. Empirical therapy is based on the most likely pathogens, taking into consideration patient characteristics and risk factors. Once the causative microorganism is identified through blood cultures, the antibiotic regimen can be adjusted to target the specific pathogen and its susceptibility profile. The duration of antibiotic therapy varies but is generally prolonged, often lasting several weeks. The decision on the duration depends on factors such as the type of microorganism, the presence of complications, and the response to treatment.

Treatment of Enterococcal endocarditis involves a combination of antibiotics, often including ampicillin or penicillin, along with an aminoglycoside (e.g., gentamicin). Vancomycin or daptomycin may be used if the strain is resistant to ampicillin. It’s important to note that antibiotic resistance is an ongoing concern, and the choice of antibiotics should be guided by susceptibility testing.

Combinations of beta-lactam antibiotics seem to be beneficial in endocarditis produced by Enterococcus, having good tolerability and fewer side effects in prolonged therapy. The combination of ampicillin + ceftriaxone can be administered safely in the elderly, and the combinations of beta-lactams with daptomycin or fosfomycin seem promising, but require additional studies. Other therapeutic options, such as teicoplanin, could be used in patients allergic to beta-lactams, due to lower renal toxicity and single-dose administration, which makes it useful in the ambulatory treatment of endocarditis. Additionally, newer drugs and treatment approaches may be developed over time. Dalbavancin and oritavancin might be a good choice for treating enterococcal endocarditis in the context of outpatient sequential therapy, but further studies are needed to demonstrate whether these drugs could be used integrally for the treatment of enterococcal endocarditis.

The management of enterococcal endocarditis involves a combination of antimicrobial therapy, often with a combination of antibiotics, and, in some cases, surgical intervention. Prompt diagnosis and appropriate treatment are crucial to reduce the risk of complications and improve outcomes. Patients with enterococcal endocarditis often require close monitoring and a multidisciplinary approach involving infectious disease specialists, cardiologists, and sometimes cardiac surgeons.

Acknowledgments

The author acknowledges the use of Large Language Model Meta AI (Llama) for language polishing of the manuscript.