Continuing Education Activity

Prosthetic valve endocarditis (PVE) is one type of infectious endocarditis (IE). It accounts for 20% of all cases of endocarditis. It is important to achieve an early diagnosis and initiate the treatment as early as possible. This activity provides a review of this disease's etiology, the clinical presentation, and the appropriate management. The early diagnosis and initiation of treatment improves outcome and decreases complications and mortality.

Objectives:

• Describe the different types of prosthetic valve endocarditis, and explain the etiology of each type.
• Explain the clinical presentation and physical findings in patients with prosthetic valve endocarditis.
• Review the appropriate steps in establishing a diagnosis of prosthetic valve endocarditis and guide in selecting appropriate treatment.
• Outline some interprofessional team strategies that can benefit patients who present with prosthetic valve endocarditis.

Introduction

Prosthetic valve endocarditis (PVE) is a microbial infection of the endovascular that occurs on parts of a prosthetic valve or on the reconstructed native valve of the heart.[1] PVE accounts for 20% of infective endocarditis. It is the most severe form of infective endocarditis and is associated with high morbidity and mortality.[2]

Based on the time of the disease acquirement, this disease is classified into two types, early and late PVE. The early PVE is acquired within one year of the surgery, while the late PVE is acquired after one year. The clinical importance of this classification is the distinct microbiological profiles between the former and the latter.

Etiology

Early PVE occurs as a result of direct intraoperative contamination or due to hematogenous spread to the valve in the first days to weeks of the surgical procedure. Paravalvular abscess formation is common in both mechanical and bioprosthetic valves.[3] After 2 months of surgery and up to 12 months, the infection occurs due to late-onset nosocomial infection or due to a community-acquired infection.

In the first two months after the surgical intervention, Staphylococcus aureus accounts for the highest number of PVE cases, followed by coagulase-negative staphylococci, these are followed by gram-negative bacilli and Candida species. In the period of 2 months to 12 months of the surgical intervention, streptococcus, staphylococcus aureus, and coagulase-negative staphylococcus are the most common pathogens, these are followed by enterococcus.[4] Staphylococcus epidermidis is the most common coagulase-negative staphylococcus in this period, and mostly are methicillin-susceptible.[5][6]

Late PVE occurs due to community-acquired infection, and pathogens are similar to native valve endocarditis. The most frequent pathogens are streptococci and S. aureus, followed by coagulase-negative staphylococci and enterococci. Mortality in late PVE is high in patients with multiple comorbidities who acquire the endocarditis when admitted to hospitals for other reasons.[7][6]

Culture negative endocarditis may occur with both early and late PVE. Other etiologies of PVE can be related to nontuberculosis mycobacteria ( Mycobacterium chimera) and enterovirus.[8][9]

Epidemiology

PVE is responsible for about 20% of endocarditis cases. It occurs in up to 6% of patients who have valve prosthesis.[4]

Epidemiology of the aortic PVE is different if the valve replacement was done surgically ( surgical aortic valve replacement SAVR) or transcatheter aortic valve replacement (TAVR).

In SAVR, the rate of incidence of PVE is 6 per 1000 cases.[10] the rate of PVE is higher in patients who had bioprosthetic SAVR than patients with mechanical SAVR.[11][12]

In TVAR, the incidence rate of PVE in the bioprosthetic valve is similar to the SARV PVE with a bioprosthetic valve.[13]

Healthcare-associated infection is associated with late PVE and occurs due to nosocomial infection when patients are admitted due to other medical conditions or due to exposure in an outpatient facility exposure as in infusion centers, nursing homes, or during hemodialysis.[4]

Pathophysiology

In early PVE, the microorganism can directly invade the prosthetic vale intraoperatively due to contamination, or it can spread hematogenous in the initial days to weeks after the procedure. The organisms during the first days after the valve implementation have direct access to the prothesis-annulus interface and the tissue along the suture in the paravalvular area. The organism can adhere to the fibrinogen and fibronectin in the paravalvular area, which causes the formation of abscesses in both mechanical and bioprosthetic valves.

In late PVE, the prostheses do not allow the organism to adhere to leaflets as long as there is no evidence of thrombotic material. The sewing ring and sutures become endothelialized after few months of the valve implementation. Alterations in the valve and the paravalvular surface can lead to the formation of microthrombus, to which the bacterial organisms can adhere and cause an infection.[14]

History and Physical

Patients with PVE present with symptoms similar to other types of infectious endocarditis (IE), including fever and chills, shortness of breath, pleuritic chest pains, anorexia, and weight loss. Patients may experience other symptoms such as malaise, headache, myalgias, arthralgias, night sweats, abdominal pain, and cough.

Cardiac murmurs are more common in PVE than other types of IE. Splenomegaly and cutaneous manifestations such as petechiae or splinter hemorrhages are other common findings on physical exam. Petechiae are observed in up to 40 percent of patients; they can present as skin findings on an extremity or mucosal surfaces of the palate and conjunctivae. Findings on nail beds can include Splinter hemorrhages, which appear as red to brown lines that are non-blanching under the nail bed.

Other less common clinical manifestations are Janeway lesions – non-tender erythematous macules on the palms and soles, Osler nodes: subcutaneous violaceous nodules mostly on the pads of the fingers and toes, Roth spots: Exudative, edematous hemorrhagic lesions of the retina with pale centers.

Evaluation

When a patient is suspected of having PVE due to clinical manifestations, workup should always be started with obtaining blood cultures. The presence of bacteremia in a febrile patient with a history of prosthetic valve replacement raises the probability of the PVE. Three blood cultures from different sites are required. A transthoracic echocardiogram TTE should follow this.[15] 

The modified Duke criteria (DC) are accepted criteria to establish the diagnosis of PVE.[16]

The use of transesophageal echo TEE is recommended when TTE fails to make the diagnosis.[17] If the initial TEE is negative, it is recommended to repeat it in 3-5 days when the clinical suspicion is high for PVE. As shielding from the prosthesis prevents the adequate images of TTE, TEE provides better diagnoses of PVE.[18][15] TEE's role is to help identify vegetations, characterize the valve dysfunction, identify the spread of infection in the periprosthetic area, determine the preoperative prognosis and timing for surgery, and follow up on PVE after management.[18] TEE has better sensitivity than TTE in the diagnosis of infectious endocarditis, especially PVE.[19] TEE should be done if there is suspicion about intracardiac complications in patients with positive IE on TTE.[15] And TEE should be repeated if there are any clinical features of the development of new intracardiac complications.[15]

Other diagnostic modalities may be required as part of the workup for patients with PVE; a chest X-ray can be ordered to evaluate for lung infiltrates, and an electrocardiogram to evaluate PR prolongation and possible AV blocks.

Cardiac computed tomography angiogram CTA can be used to diagnose PVE if the TEE fails to provide the diagnosis, cardiac CT is better than TEE to detect perivalvular abscess, CTA can be used as next step in diagnosis for patients who have negative TTE and have contraindications to perform TEE.[20][21][22]

18F-FDG PET/CT can be used to diagnose PVE if TTE/TEE fails to make the diagnosis, and there is a high probability of the infection. It improves the diagnostic accuracy of the modified DC and yields high diagnostic performance.[23] Promising data showed 18F-FDG PET/CT to help as a follow-up modality after completing IE antibiotic treatment.[24][25]

Magnetic resonance imaging MRI of the brain is considered the best diagnostic tool when septic emboli to the brain are suspected. CT of the chest and abdomen can also be considered when septic emboli are suspected.[25]

Treatment / Management

The valvular vegetations associated with PVE are usually larger than those found in native valve endocarditis (NVE). For the antibiotics to penetrate the total vegetation, they should be used in the dosages, which result in maximum, non-toxic serum concentrations.[1]

When starting the treatment for a patient with PVE, it is required to identify the causing microorganism, select the appropriate antibiotic, evaluate for any complications of the endocarditis, and evaluate the need for surgical intervention if the antibiotics treatment fails, the infection causes a valvular abscess.

Empiric treatment with antibiotics should be started after 3 blood cultures are obtained. This treatment should consider coverage of gram-positive and gram-negative bacteria. This empiric treatment should include vancomycin, gentamycin, and anti-pseudomonal carbapenem or cefepime. When the causing organism is identified, treatment should be tailored towards the coverage of this causative agent. American Heart Association recommends at least six weeks of antibiotics treatment.[25][15]

When PVE is caused by staphylococcus, recommendations from AHA are to start triple antibiotical treatment.[25][26] In the staphylococcus induced PVE, either S. aureus or S. epidermidis, the susceptibility to methicillin is the main consideration in selecting the combination therapy. When PVE is caused by methicillin-sensitive staphylococcus, the triple antibiotic regimen will include nafcillin or oxacillin (total of six weeks) combined with both gentamicin (which is given for the first 2 weeks of treatment only) and rifampin (total of six weeks of treatment). If the patient reports being allergic to penicillin without evidence of anaphylaxis, a first-generation cephalosporin should be the next choice.

In the case of methicillin-resistant staphylococcus, vancomycin should be combined with both gentamycin and rifampin. If the bacteria is resistant to gentamycin, another aminoglycoside should be selected depending on the antibiotic susceptibilities.[25] A fluoroquinolone can be an alternative to the aminoglycoside in case of pan resistance to all aminoglycosides.[27] Rifampin has a unique effect on staphylococcus invasion of foreign bodies and is used in staphylococcus induced IE.[28]

In streptococcal induced PVE, the combination therapy with a beta-lactam antibiotic and an aminoglycoside is the treatment of choice. This combination provides a synergistic killing of the causative bacteria.[17] If a penicillin-susceptible Streptococcus causes the PVE, the penicillin-gentamycin combination is recommended. For penicillin-allergic patients, vancomycin or cephalosporine are the choices. If the patient's penicillin allergy is not severe (does not include anaphylaxis), a cephalosporin should be used first. If the aminoglycoside is contraindicated, PVE can be treated with a single-agent (penicillin, cephalosporine, or vancomycin)

If the streptococcus is resistant to penicillin, an aminoglycoside can be used alone for the entire treatment duration.[15] If the organism is resistant to aminoglycoside, recommendations are for treatment with vancomycin as a single agent.

In enterococcal induced PVE, the combination of cell wall-active agent (penicillin, ampicillin, or vancomycin) and an aminoglycoside (gentamycin or streptomycin) is considered. In penicillin allergy, vancomycin is considered a better alternative than cephalosporine combined with an aminoglycoside, as cephalosporins are not effective against enterococcus.[29]

In the setting of aminoglycoside resistance, the enterococcus PVE should be treated with a cell wall-active agent (penicillin, ampicillin, or vancomycin) alone for a longer period (8 to 12) weeks.[30]

In the setting of vancomycin-resistant Enterococcus faecium (VRE), daptomycin and linezolid are considered acceptable choices for treatment.[31]

When PVE is caused by Haemophilus, Aggregatibacter (previously Actinobacillus), Cardiobacterium, Eikenella, or Kingella (HACEK), third-generation cephalosporins are usually the first line of treatment and used for a total treatment period of six weeks. Ampicillin can be used if the organism showed sensitivity to the cultures. A fluoroquinolone can be used in the case of allergy to cephalosporins and ampicillin.[15]

Treatment of gram-negative bacilli induced PVE is usually combination therapy with a beta-lactam (penicillins, cephalosporins, or carbapenems) and either a fluoroquinolone or an aminoglycoside. The recommended duration of treatment is 6 weeks.[25]

For patients with culture-negative PVE onset ≤1 year, the antibiotics coverage should consider the possibility of infection due to staphylococci, enterococci, and aerobic gram-negative bacilli. The antibiotics combination should include vancomycin, gentamicin, cefepime, and rifampin as per AHA recommendations.[15]

 AHA recommends patients with culture-negative PVE onset >1 year after surgery to receive infection coverage due to staphylococci, viridans group streptococci, enterococci, and HACEK organisms. The empiric combination should include vancomycin and ceftriaxone.[15]

 AHA recommends repeating 2 blood cultures every 24 to 48 hours till blood cultures are negative and start the count of antibiotics treatment days after the first negative blood culture is achieved.

Early surgical intervention for PVE is indicated if:[15]

• The patient develops heart failure due to valve dehiscence, the development of intracardiac fistula, or the presence of severe prosthetic valve dysfunction. 
• The presence of persistent bacteremia for 5 to 7 days after the appropriate antibiotic regimen, with other bacteremia sources, is excluded. 
• Evidence of heart block, development of abscess (annular or aortic), or presence of destructive penetrating lesions
• Fungi or highly resistant bacterial organisms cause the PVE.

Early surgery is reasonable in PVE in the following scenarios: developing recurrent emboli despite the appropriate antibiotic treatment, relapsing PVE, or large mobile vegetations >10 mm.[15]

Surgical intervention decreases the mortality when performed on patients with PVE who develop heart failure.[32]

Paravalvular invasion of the PVE can be manifested as a complete heart block, annular or aortic abscess, destructive penetrating lesions, or an intracardiac fistula. These complications require early complex reconstructive surgery, which can improve the survival rate by 80%.[33]

S. aureus PVE is associated with high mortality, and often early surgery is indicated when complications are present. Such an early surgical approach was associated with decreased mortality in these patients. Other organisms that may require early surgical intervention are gram-negative (non-HACEK) microorganisms ( Pseudomonas aeruginosa and multidrug-resistant gram-negative bacilli), multidrug-resistant enterococci, and fungi.[34]

After the surgical intervention is completed, six weeks of intravenous antibiotics are recommended if the intraoperative valve culture was positive.[35]

Differential Diagnosis

The differential diagnosis for PVE:

• Native valve endocarditis: Patients usually have a similar clinical picture to PVE patients.
• Atrial myxoma: Patients present with constitutional symptoms secondary to cytokine release or may have systemic disease secondary to the embolic phenomenon.
• Libman-Sacks endocarditis: Patients are commonly asymptomatic and have a history suggestive of a diagnosis of systemic lupus erythematosus SLE.
• Nonbacterial thrombotic endocarditis (NBTE): Endocarditis caused by sterile vegetations deposition on cardiac valves. NBTE can be caused by pancreatic, lung, and colon tumors or from SLE or tuberculosis.[36]
• Rheumatic fever: Jones criteria make the diagnosis: evidence of carditis, presence of polyarthritis, chorea, erythema marginatum, subcutaneous nodules, and evidence of preceding streptococcal infection.[37]

Prognosis

Despite the appropriate diagnosis and use of surgical treatment in PVE, morbidity and mortality remain high; PVE carries the highest mortality rates compared to other types of IE. The strongest predictors of mortality were: persistent bacteremia, heart failure, intracardiac abscess, and stroke development.[4] Persistent bacteremia, and healthcare-associated infection, are associated with S aureus induced IE.[38] 

S. aureus is associated with high mortality in both PVE and native valve endocarditis.[39] Healthcare-associated PVE is another predictor of high in-hospital mortality.[40] Other predictors for higher mortality are large vegetation, poor surgical candidacy, positive valve culture, embolization, and diabetes mellitus.[41][42]

Complications

The most common cardiac complication of PVE is heart failure. This can result from prosthetic valve dehiscence, which leads to valvular insufficiency, or myocardial infarction from emboli.[43] Other cardiac complications are perivalvular abscess formation, intracardiac fistula, and pericarditis.[44]

Non-cardiac complications are usually a result of an embolic event, metastatic abscess formation, or a mycotic aneurysm.

Neurologic complications are stroke (due to an embolus), seizure (abscess or emboli), brain abscess formation, aseptic meningitis, acute encephalopathy, cerebral hemorrhage due to ruptured mycotic aneurysm, or meningoencephalitis.[45][46]

Renal complications are renal infarction due to emboli, renal abscess, glomerulonephritis (as a result of immunoglobulins and complement deposition in the glomerular membrane), and acute interstitial nephritis. All these complications may present as acute renal failure.[47]

Pulmonary complications occur due to right heart PVE; vegetations of the tricuspid or pulmonary valve can lead to embolization, which results in lung abscess, pneumonia, pleural effusion, or pneumothorax. 

Other complications are osteomyelitis, septic arthritis, persistent bacteremia, or candidemia in fungal PVE.[48]

Mortality remains a serious concern after PVE, despite appropriate treatment and surgical interventions.[4]

Consultations

As part of the management of patients with VPE, the treating team must include the right interprofessional team of consultants.

Early involvement of a cardiologist is essential to make the correct diagnosis, review the imaging studies, and give recommendations for the treatment plan.

An infectious disease consult is necessary to direct the initial antibiotics treatment, review the cultures, and redirect the treatment according to the susceptibility results.

Involving the radiologist in the interpretation of the imaging studies is an important step in the management of patients with PVE. Some patients may require advanced imaging studies, and the radiologist will recommend and direct choosing the appropriate type of imaging studies indicated to achieve the diagnosis.

A cardiovascular surgeon should be part of the management team for patients for PVE. The cardiovascular surgeon will need to review the imaging studies, follow the patient's treatment progress, and follow the patient's blood culture response to the antibiotics treatment to determine the need for any surgical intervention.

A pharmacist's early involvement is important in managing PVE patients, direct the antibiotics treatment during hospitalization, checking the drug interactions, and following the patient's treatment course after discharge.

Deterrence and Patient Education

Endocarditis is a type of infection usually caused by bacteria or fungi and affects the heart's inner layer, including the heart's valves. The causative organism most likely a bacteria but can also include some fungi that get to the heart through the bloodstream. Prosthetic valve endocarditis is one type of endocarditis that affects the replaced prosthetic valve. Getting infected heart valves causes damage to the valve and hence malfunction, and that can cause major complications. Early treatment is necessary to prevent bad outcomes. Having surgery for a heart valve increases the risk of infection. Those who inject themselves with IV drug abuse are at higher risk of this type of infection. 

The patient should return to the emergency room if the patient experience any of the following symptoms:

• Tiredness that persists for 2 to 3 days.
• Decreased exercise tolerance.
• Chest pain or shortness of breath.
• Fever over 100.4 degrees F (38.0 degrees C).
• Extensive sweats, especially at night.
• Palpitations.
• Fainting.
• Trouble speaking.
• Weakness in any extremity or face.
• Spots on fingernails, fingertips, whites of the eyes, or other skin areas.
• Symptoms of a stroke such as trouble speaking or inability to move one side of your body.

Enhancing Healthcare Team Outcomes

Prosthetic valve endocarditis is associated with high morbidity and mortality. A comprehensive health care team is required to be cautious in the workup and treatment of this disease.

Treatment of PVE needs to be started early, in an inpatient setting, and monitored by an interdisciplinary team of physicians, nurses, and pharmacists to assure the appropriate treatment and prevent complications. As treatment is usually extended over six to eight weeks, patients will complete treatment in an outpatient setting, at short term nursing facility, or home with home IV infusion.

When a patient presents with suspected PVE, the physician starts the empiric antibiotics treatment, initiates the appropriate workup for confirmation of diagnosis, and identifies the causative organism. Antibiotics should be tailored to target the organism as per susceptibility results. Usually, physicians follow the necessary laboratory testing to prevent any possible renal or liver toxicity and monitor for signs or symptoms of PVE related complications. The pharmacist has to check the antibiotics regimen, monitor for any possible drug to drug interaction, and monitor any possible toxicity. Nurses are responsible for appropriately administering the medications and monitoring for any possible side effects during the hospital stay.

After discharge from the hospital, the team is responsible for appropriate follow-up on the patient’s adherence to treatment and monitoring possible side effects. The Doctor has to order appropriate laboratory tests to monitor possible toxicity and monitor drug levels in coordination with the pharmacist. The home visiting nurse will assure the adherence, will evaluated for appropriate intravenous administration of antibiotics, monitor the IV line side, monitor for any adverse reactions, and evaluate the patient for any possible signs or symptoms of PVE related complications.

If medication compliance was a concern for a certain patient, both pharmacists and nurses should inform the clinician. This also includes drug adverse reactions or changes in a household environment. This comprehensive interprofessional team effort is needed to ensure high-quality patient care and to have the maximum benefits of the regimen.