Overview of Infective Native Valve Endocarditis

Infective native valve endocarditis is rare, with an incidence of approximately 2-10 cases/100,000 person-years. The initiating event is presumed to be an injury to the valvular endothelium or endocardium. This lesion exposes the subendothelial collagen and other molecules of the matrix, where the adhesion of platelets and fibrin is favored, forming a microthrombotic lesion called sterile vegetation .

Bacteria circulating in the bloodstream bind and colonize this lesion. In the absence of an effective host response, bacteria replicate in situ, stimulating increased deposition of platelets and fibrin, to form infected vegetations that is the hallmark of infective endocarditis.

Vegetations create a protective microenvironment that is poorly accessible to neutrophils and host defense molecules. The vegetations are loaded with bacteria in very high densities (, 109, 1010 colony-forming units [CFU] per gram of vegetation) that promote high-grade bacteremia and greater growth of the vegetations, which become friable and fragment easily. in circulation.

These conditions (high bacterial density, growing vegetation, and friability and fragmentation of growing vegetation) drive the four mechanisms that are responsible for most of the clinical features of infective endocarditis and its complications: valvular destruction, paravalvular extension of the infection and heart failure; microvascular and large vessel embolization; metastatic infection of target organs (e.g., brain, kidneys, spleen, and lungs); and immunological phenomena such as hypocomplementemic glomerulonephritis and false-positive serological results for rheumatoid factor, antineutrophil antibodies, or VDRL.

Cardiac conditions that predispose to infective endocarditis include congenital diseases (eg, ventricular septal defect and bicuspid aortic valve) and acquired valvular disease (eg, degenerative valve disease, aortic stenosis, and rheumatic heart disease).

Rheumatic heart disease , the most common predisposing condition for infective endocarditis in developing countries, is rare in developed countries, where the most common predisposing heart diseases are degenerative valvular disease, congenital abnormalities, and intracardiac devices.

Non-cardiac risk factors are : poor dentition, intravenous drug use, hemodialysis, chronic liver disease, diabetes, immunodeficiency, neoplastic diseases, and indwelling intravascular devices.

Fever and heart murmur, the two hallmarks of infective endocarditis, are present in almost 90% and 75% of patients, respectively.

Infective endocarditis can present acutely, and evolve in a rapidly progressive manner, complicated by congestive heart failure, stroke, systemic or pulmonary embolization, severe sepsis or subacute septic shock with nonspecific symptoms such as low fever, malaise, chills, sweats, dyspnea. , back pain, arthralgia, and weight loss over a period of weeks to sometimes months.

Microembolic or immunological phenomena such as splinter hemorrhage, conjunctival hemorrhage, Osler’s nodules (distal vasculitis lesions of the fingers and toes), Janeway lesions (vasculitis lesions of the palms and soles), and spots Roth’s (retinal hemorrhagic lesions) are present in 5-10% of patients.

Worldwide, gram-positive bacteria account for almost 80% of cases of infective native valve endocarditis.

These bacteria include Staphylococcus aureus (35-40%), streptococci (30-40%), namely: Streptococcus viridans (20%) and Streptococcus gallolyticus [formerly S. bovis and other streptococci (10%).

Coagulase-negative staphylococci, a common cause of prosthetic valve infective endocarditis, are rare in native valve infective endocarditis, with the exception of S. lugdunensis, which is clinically similar to S. aureus .

Only in 5% of cases are HACEK species (Haemophilus, Aggregatibacter [formerly Actinobacillus species], Cardiobacterium, Eikenella corrodens , and Kingell species), fungi, polymicrobial infection, and, rarely, aerobic gram-negative bacilli isolated.

> Evaluation and diagnosis

The modified Duke criteria are the basis for the diagnosis of infective endocarditis.

The definitive pathological diagnosis can be made when a vegetation, intracardiac abscess, or peripheral embolus is identified by histological analysis or culture, or if evidence of an intracardiac vegetation or abscess is confirmed by histological analysis with signs of captive endocarditis. The clinical diagnosis of definitive or possible infective endocarditis is based on a combination of major and minor criteria, based on microbiological, echocardiographic, and clinical metrics.

The sensitivity of the modified Duke criteria for infective endocarditis reaches 80% for defined cases, and even more cases are included. These criteria are less sensitive when it comes to infections related to a prosthetic valve or cardiac device, right heart endocarditis, and infectious culture-negative endocarditis. The negative predictive value is approximately 90% when the criteria for definite or possible infective endocarditis are not met.

Blood cultures are the most important microbiological tests for the diagnosis and treatment of infective endocarditis, and are an important Duke criterion. Antimicrobial therapy depends largely on the isolate in the blood culture and its antimicrobial susceptibility. Almost 90-95% of cases of infective native valve endocarditis are positive blood cultures.

Before initiating antibiotics and to maximize recovery of a pathogen, 3 separate sets of blood cultures, drawn 30 minutes apart, are recommended.

Cases of negative blood cultures are most frequently caused by recent administration of antimicrobial agents or by microorganisms that grow poorly or do not develop on standard blood culture media (e.g., Bartonella species , Coxiella burnetii , Tropheryma whipplei , and Legionella ). .

If blood cultures are negative, serological and molecular tests for probable pathogens should be performed. These tests are guided by epidemiological clues (e.g., C. burnetii infection may be related to exposure to farm animals and Bartonella quintana infection may be associated with homelessness).

Molecular diagnosis is based on the amplification of nucleic acids by polymerase chain reaction (PCR), either with primers specific for a particular species or genus, or with broad-range primers targeting microsomal RNA Gene 16S ( rRNA) for bacterial pathogens, or the 18S rRNA gene for fungi. For PCR diagnostic tests, reported sensitivities are 33 to 90% and specificities are 77 to 100%.

It is hoped that next-generation sequencing can be done in the coming years, with the hope that it will be more precise than PCR-based methods. The preferred sample for molecular testing is an excised valve or vegetation. Plasma DNA amplification assays can help make the microbiological diagnosis of cases whose pathogen is difficult to determine.

Echocardiography is a fundamental tool for the diagnosis and treatment of infective endocarditis. Transthoracic echocardiography (TTE) has a sensitivity of 50-60% for detecting vegetations in infective native valve endocarditis while transesophageal echocardiography (TEE) yields ≥90%.

The specificities of both are approximately 95%. Because TTE is also less sensitive than TEE in detecting intracardiac complications (e.g., paravalvular abscess), ruling out infective endocarditis in patients with suspected this condition, and evaluating intracardiac complications, TEE is preferred.

Among newer imaging, the most widely studied is cardiac 18F-fluorodeoxyglucose positron emission tomography (PET) plus computed tomography (CT). PET-CT is more applicable to the diagnosis and evaluation of prosthetic valve infective endocarditis; Its role in infective native valve endocarditis is poorly studied and unclear.

> Antimicrobial therapy recommendations for

Infective endocarditis is based almost entirely on observational studies rather than randomized clinical trials. These recommendations are based on 4 basic principles: ability of the regimen to kill the pathogen, administration of a prolonged course of therapy (weeks instead of days), intensive dosing to ensure adequate drug exposure, and source control.

In general, in patients with native valve infective endocarditis, vancomycin plus ceftriaxone is a reasonable combination for empiric therapy to cover probable pathogens until culture results are received.

For susceptible strains, beta-lactam antibiotics are the cornerstone of definitive therapy.

These agents are preferred over others unless the patient cannot take them without adverse effects or there is a documented immediate hypersensitivity reaction (type I). Infective endocarditis caused by penicillin -nonsusceptible strains of Sstreptococci viridans , S. gallolyticus, abiotrophia, or granulicatella can be treated with a combination of penicillin or ceftriaxone with gentamicin; Vancomycin monotherapy is an option, although in general, experience with this agent is less.

The drug of choice for infective endocarditis caused by methicillin-susceptible strains of S. aureus (MSSA) is an antistaphylococcal penicillin (oxacillin). Randomized controlled trials have shown that combination therapy with an antistaphylococcal penicillin and gentamicin or rifampin does not improve outcomes and is associated with adverse events; therefore, this combination is not recommended.

Cefazolin is a reasonable alternative for patients. with MSSA who cannot receive penicillin without adverse effects. The disadvantage of cefazolin is that some strains have an "inoculum effect", defined as an increase in the minimum inhibitory concentration (MIC) of the culture broth dilution, from ≥16 μg/ml at an inoculum of 5 × 107 CFU /ml (100 times the standard inoculum of approximately 5 × 105 CFU/ml). This inoculum effect, which is due, at least in part, to the hydrolysis of cefazolin by staphylococcal penicillinase, may be associated with clinical failure.

The recommended treatment for native valve infective endocarditis caused by MRSA is monotherapy with daptomycin or vancomycin. The benefit of combination therapy remains unproven. For MRSA bacteremia, a randomized trial comparing vancomycin (8 patients) alone, or in combination with an antistaphylococcal beta-lactam antibiotic (mainly flucloxacillin), in 363 patients (including 42 with infective endocarditis) showed no benefit from the combination.

The group treated with the antibiotic combination had higher 90-day mortality and a significantly higher incidence of acute kidney injury. Anecdotal data suggest that combining a second agent (e.g., ceftaroline) with vancomycin or daptomycin may benefit patients with persistent or unresponsive bacteremia. However, the best combination is currently unknown. For the treatment of infective endocarditis due to enterococci, combination therapy is recommended.

Penicillin or ampicillin combined with gentamicin is synergistic at low doses and has been the standard treatment for decades. The utility of this regimen is limited by gentamicin toxicity and an increasing incidence of high-level gentamicin resistance, indicating a lack of synergy.

Observational data suggest for infective endocarditis caused by ampicillin-susceptible strains of E. faecalis , an acceptable therapeutic alternative is a 6-week course of ampicillin plus ceftriaxone. If the combination of ampicillin plus gentamicin is used, the effectiveness of combination therapy for 2 weeks, followed by ampicillin alone for 4 to 6 weeks may be similar to that of the standard combination regimen for 4 to 6 weeks, and is less toxic .

> Surgical management

Multivariable analysis adjusted for coexisting conditions, performed in a prospective cohort study with patients with infective endocarditis in native valve, showed that the indication for surgery without being followed by performance of surgery was an independent predictor of death. Surgery is not well defined and is a highly individualized decision, best made by an experienced multidisciplinary team.

A small randomized controlled trial compared early surgery at the start of hospitalization and within 48 hours of randomization (37 patients) with conventional treatment (39 patients) in patients with left heart endocarditis, severe valvular insufficiency (without heart failure) and large vegetations (>10 mm in diameter).

Early surgery significantly reduced the risk of the composite endpoint of in-hospital death or embolic events within 6 weeks of randomization, but this decreased risk was driven entirely by the decreased risk of systemic embolism.

The limitation of this trial was that patients had few underlying diseases and patients with streptococcal infections and infective mitral valve endocarditis were overrepresented.

Two meta-analyses showed that early surgery, compared with conventional therapy (medical treatment or delayed surgery >20 days) was associated with a 40-60% reduction in death from any cause. However, it is still unclear how best to identify patients most likely to benefit from valve surgery.

The modified Duke Criteria for the clinical diagnosis of infective endocarditis are not based on the results of molecular diagnostic tests. As these methods improve in accuracy and become more available for daily practice, their diagnostic utility will need to be taken into account.

It has not yet been established whether routine brain MRI and other advanced imaging techniques such as PET-CT improve diagnosis, treatment, and outcomes in patients with native valve infective endocarditis.

Magnetic resonance imaging is more sensitive than CT in detecting nervous system lesions, and the presence of asymptomatic embolic lesions in patients with suspected infective endocarditis is a minor diagnostic criterion. Brain MRI has been recommended to detect silent CNS emboli in patients candidates for valve surgery, although it is unknown whether this improves outcomes.

Data from randomized controlled trials show that the benefits and risks of oral antimicrobial therapy for infective endocarditis are limited.

Partial oral treatment of endocarditis (POET) showed that in patients with infective endocarditis of the left heart, whose condition had stabilized, treatment with oral antibiotics after an initial course of intravenous antibiotics was noninferior to standard intravenous antibiotic treatment, evaluated 6 months after the end of treatment.

Longer-term follow-up showed no harmful results with oral administration of step therapy. However, only 20% of patients who were screened were enrolled, and few were infected with S. aureus (none with MRSA). More data are needed to clarify the safety and efficacy of this approach in a variety of clinical settings.

In patients with infective endocarditis, the timing of surgery, criteria for postponing surgery, and predictors of surgical mortality and poor outcomes have yet to be well defined.

Most guidelines recommend delaying valve surgery for at least 4 weeks in patients with injuries from a large CNS embolism or intracranial hemorrhage, although early surgery can be safely performed in selected patients despite these conditions, and in patients with small embolic lesions (<2 cm in diameter) without hemorrhage or significant neurological deficits.

Several scoring systems have been proposed to predict surgical mortality and postoperative complications. However, limitations including small sample sizes, data dependency, changes in surgical practice over time (up to decades), and lack of large-scale external validation make it difficult to evaluate the precision of these systems.

The scientific cardiological societies of the USA, Europe and Japan have published guidelines on the diagnosis and treatment of infective endocarditis, and they have guided the present work. In general, these guidelines provide concordant recommendations with relatively minor differences regarding antimicrobial treatment, forms of diagnostic imaging, and indications and timing of surgery.

The patient described in the vignette has community-acquired enterococcal pyelonephritis with bacteremia. On a purely clinical basis: presence of bacteremia plus a murmur in a febrile condition, there is a high suspicion of infective endocarditis.

At presentation, this patient likely meets 3 minor Duke criteria for possible endocarditis: fever; 2 blood cultures positive for E. faecalis (pyelonephritis) and, aortic stenosis, a predisposing cardiac condition.

Additional blood cultures should be obtained, the positive result of which would meet an important criterion for the diagnosis of infective endocarditis-persistently positive blood cultures. Echocardiography should be performed immediately to document the nature of the valvular lesion and the presence of vegetations or complications of infective endocarditis.

Although TEE is much more sensitive than TTE in detecting valvular vegetations and paravalvular complications, a TTE can be started as it is non-invasive and technically simpler; In addition, it provides better information on myocardial function.

If TTE is negative or non-diagnostic, then TEE is indicated, given the strong suspicion of infective endocarditis. If TEE is not diagnostic and the suspicion of infective endocarditis remains high, it should be repeated several times, days later.

It is advisable to convene a multidisciplinary team (cardiologist, cardiovascular surgeon and infectious disease specialist). Combined antimicrobial treatment should be indicated as soon as possible for suspected enterococcal infective endocarditis.

Although it is necessary to confirm the sensitivity of the isolate to gentamicin, this patient’s age, diabetes, and chronic kidney disease put him at high risk of acute kidney injury due to gentamicin, which makes the authors prefer to initiate treatment with ampicillin and ceftriaxone.

Blood cultures should be done to confirm the post-treatment disappearance of bacteremia, and the patient should be carefully evaluated for a probable indication for immediate valve surgery.

Antimicrobial therapy should be continued for 6 weeks. After blood cultures become negative. Screening colonoscopy should also be considered, as some data suggest that, as in S. gallolyticus infective endocarditis , enterococcal infective endocarditis may be associated with colonic neoplasms, although further investigation is required.