Native valve endocarditis

Article written and reviewed by Dr Luca Moretti

Native valve endocarditis is infection of a valve that has not been replaced by a prosthesis, with possible extension to the chordae, papillary muscles, annulus, and adjacent structures. It may develop on a degenerative valve, a congenitally abnormal valve, or a valve damaged by rheumatic disease, but also in the absence of previously recognized heart disease. The characteristic lesion is an infected vegetation, which may be accompanied by perforation, chordal rupture, and perivalvular invasion. The absence of artificial material therefore does not necessarily make the condition less aggressive or more readily curable with antibiotics alone.

Mitral and aortic involvement mainly predispose to left-sided regurgitation, heart failure, and systemic embolization; tricuspid, and more rarely pulmonary, involvement has specific pathophysiology and indications discussed in detail on the page about right-sided endocarditis. The site should be specified together with the causative organism and acquisition setting. Healthcare-associated native valve endocarditis due to Staphylococcus aureus differs from subacute community-acquired streptococcal disease, even when both involve the mitral valve. The treatment plan arises from these differences and from the complications present.

Epidemiology reflects age and the healthcare system. In high-income countries, degenerative valvular disease, hemodialysis, vascular access, and healthcare exposures have increased the relative importance of staphylococci and comorbidities; elsewhere, rheumatic heart disease remains a relevant substrate. The onset of symptoms at home does not exclude healthcare acquisition. Contemporary cohorts document a heterogeneous disease in which prognosis depends on heart failure, invasion, causative organism, embolic injury, and the feasibility of intervention more than on the distinction between native and prosthetic valves alone.

Etiology, pathogenesis, and pathophysiology

The classic substrate is endothelial alteration favored by shear stress, abnormal jets, and valvular lesions. Platelets and fibrin are deposited on the exposed matrix, creating a site to which microorganisms may adhere during bacteremia. Calcific degeneration, bicuspid aortic valve, prolapse with regurgitation, and previous infectious damage are examples of predisposition. Colonization, however, is not an inevitable outcome of every bacteremic episode: duration, inoculum, adhesive capacity, and host defenses all matter. Evaluation of the portal of entry should therefore also seek persistent sources, such as a catheter or skin lesion, rather than stopping at a remote procedure.

Staphylococcus aureus can invade endothelium and tissues even in the absence of known valvular disease and tends to produce a rapid course with destruction and metastatic foci. Staphylococcal bacteremia requires active investigation for endocardial involvement, especially when persistent, without a controlled source, or associated with emboli. Staphylococcus lugdunensis may behave aggressively despite belonging to the coagulase-negative staphylococci. By contrast, other coagulase-negative staphylococci isolated sporadically require assessment for possible contamination: species, number of sets, chronology, and clinical picture should be considered together.

Oral streptococci are often associated with a subacute course and predisposing substrates, but identification at group level is not sufficient to define treatment: susceptibility must be documented. S. gallolyticus should prompt colorectal evaluation, whereas Granulicatella and Abiotrophia require attention to culture difficulties and susceptibility. Oral health is relevant because repeated bacteremias may also arise from daily activities in the presence of gingival inflammation. This mechanism explains why prevention cannot be reduced to prophylaxis for a single dental procedure.

Enterococcus faecalis is important in older adults and in the presence of gastrointestinal or genitourinary disease or procedures. Recurrent bacteremia, absence of a clear source, and valvular lesions increase the probability of cardiac involvement. Enterococci exhibit tolerance characteristics that make synergistic combinations and high-level aminoglycoside resistance relevant. HACEK organisms, other Gram-negative bacteria, fungi, and intracellular pathogens are less frequent but require specific pathways. Negative cultures after antibiotics remain compatible with common bacterial causes and do not automatically identify one of these less usual microorganisms.

Within the vegetation, microorganisms and the platelet-fibrin matrix form a focus with a high inoculum and areas of low metabolic activity. The surface may continue to release bacteria and emboli while the center is relatively protected from the host response. Susceptibility of the isolate is therefore necessary but not sufficient to predict eradication: exposure, duration, and the presence of abscess cavities are equally relevant. Infection may cross the leaflet or annulus and transform an apparently localized lesion into invasive disease, with mechanical consequences that antibiotics cannot correct.

Acute mitral regurgitation may result from perforation, chordal rupture, or flail. The nonadapted atrium receives a substantial portion of systolic output and its pressure rises rapidly, causing congestion and pulmonary edema. The ventricle may appear hyperdynamic because it also ejects blood into a low-resistance chamber, while forward output is reduced. An eccentric wall-hugging jet may be underestimated if severity is judged only by the color Doppler jet area. Mechanism, flow parameters, pulmonary pressure, and clinical tolerance should therefore be integrated.

In acute aortic regurgitation, the regurgitant volume enters a ventricle that has not yet dilated, increasing diastolic pressure and reducing the coronary perfusion gradient. Edema, ischemia, and shock may occur without the classic peripheral signs of the chronic form. Extension of infection toward the aortic root and membranous septum can cause an abscess and atrioventricular block; involvement of the mitral-aortic continuity may add mitral lesions or abnormal communications. Aortic involvement therefore requires attention not only to the leaflet, but to the entire perivalvular region.

Emboli depend on friability, mobility, size, and causative organism, with a high risk before and early in treatment. Mitral location and highly mobile vegetations can be particularly emboligenic; a previous event indicates that the mechanism is already clinically active. Injury may be ischemic or suppurative because the fragment contains microorganisms. Immunologic phenomena, such as glomerulonephritis, may also affect an organ without embolization. Systemic pathophysiology therefore requires an interpretation broader than the visible vegetation alone.

Clinical manifestations

Fever, chills, sweating, fatigue, and weight loss may present acutely or persist over time. The time course guides suspicion but does not identify the causative organism with certainty. Previous antibiotics can attenuate the syndrome and reduce culture yield; immunosuppression and advanced age can make fever inconspicuous. History-taking includes valvular disease, previous infections, vascular access, dialysis, procedures, and skin or oral lesions, while also documenting medications and dates. Identifying an extracardiac cause of bacteremia does not exclude secondary colonization of the valve.

Rapidly progressive dyspnea is a warning sign of a possible valvular complication. Orthopnea, crackles, hypoxemia, hypotension, and oliguria should be linked to an anatomic mechanism, distinguishing sepsis from low output. The murmur may be soft in severe acute regurgitation, especially when gradients fall or cardiac output is low. An apparently preserved ejection fraction is not reassuring in the presence of major regurgitation. Syncope or bradycardia instead requires attention to the conduction system and possible periannular invasion.

A neurologic event may be the first recognized manifestation. Focal deficits, headache, altered consciousness, or seizures require imaging to distinguish ischemia, hemorrhage, abscess, and infectious aneurysm. Abdominal, flank, or limb pain may indicate embolization; persistent low back pain and joint pain suggest metastatic foci or inflammatory phenomena. Examination should not be limited to the valve, because an extracardiac complication may determine urgency and treatment sequence even when the cardiac condition appears stable.

Petechiae, conjunctival hemorrhages, Janeway lesions, Osler nodes, and splenomegaly contribute to the clinical picture without being required. Dark urine or hematuria may result from glomerulonephritis or renal infarction and require targeted testing. A rash and positive autoantibodies should not lead clinicians to overlook infection, which can mimic an immunologic disease. Physical examination also records nutritional status, functional capacity, and signs of congestion, useful both for defining severity and for recognizing deterioration during treatment.

Investigations and diagnosis

Blood cultures should be obtained before antibiotics, generally as three peripheral sets with aerobic and anaerobic bottles and an adequate blood volume. There is no need to wait for a fever spike because bacteremia in endocarditis is usually continuous. In shock, samples are collected rapidly and followed by treatment. Species, number of positive sets, and persistence are more informative than a generic report of Gram-positive cocci. Follow-up cultures document response; to judge treatment failure, it is necessary to verify when actually active therapy began and whether other reservoirs exist.

Transthoracic echocardiography assesses all valves, regurgitation, function, and pressures. Transesophageal echocardiography better evaluates small vegetations, perforations, and perivalvular lesions, and is indicated when suspicion remains high despite a negative or equivocal TTE and to define complications of already recognized left-sided disease. A negative examination does not end the diagnostic pathway when microbiology and clinical findings are strongly suggestive. Repeating the study, generally within 5-7 days and earlier if emboli, conduction block, or hemodynamic deterioration emerge, seeks progression and findings that were initially invisible.

Assessment must explain the mechanism of regurgitation. A jet traversing the leaflet suggests perforation; a flail segment points toward loss of chordal support; a perivalvular defect may indicate invasion. Severity is estimated with a combination of parameters and clinical tolerance, taking eccentric jets, pressures, and loading conditions into account. Vegetation size is measured in multiple planes, recording maximum length and mobility. Serial comparison must distinguish true growth from acquisition differences, especially when a dimensional threshold enters the surgical decision.

Cardiac CT is complementary for abscesses, pseudoaneurysms, fistulas, and relationships with the aortic root and coronary arteries. It can clarify lesions that are not well visualized on transesophageal echocardiography, without replacing it for small mobile findings. PET/CT is less sensitive for native vegetations than for infections involving prosthetic material, and a negative result does not exclude endocarditis; however, it may contribute to the search for extracardiac foci. The clinical question should guide the modality: when a dynamic perforation, a periannular cavity, or spondylodiscitis is suspected, the most informative test is not necessarily the same.

The 2023 Duke-ISCVID criteria organize microbiology, imaging, and systemic manifestations. Typical causative organisms include S. aureus, S. lugdunensis, E. faecalis, streptococci excluding S. pneumoniae and S. pyogenes, Granulicatella, Abiotrophia, Gemella, and HACEK organisms. The criterion of new significant regurgitation requires comparison with previous imaging; a simple increase in previously known regurgitation does not automatically constitute the major criterion. Concordant echocardiography and CT findings belong to the same category, not to two separate major criteria. Classification should be documented and updated, especially in patients who have already received treatment.

2023 Duke-ISCVID clinical combinations:

• Definite endocarditis: two major criteria, or one major and three minor criteria, or five minor criteria.
• Possible endocarditis: one major and one minor criterion, or three minor criteria, without meeting definite or rejected endocarditis.
• Pathologic evidence from appropriate material constitutes a pathway distinct from the clinical combination; an initially nondiagnostic result does not exclude evolving disease.

If cultures remain negative, previous antibiotic use and specimen quality are reconstructed, then serology and molecular tests are selected according to exposures. Coxiella, Bartonella, and T. whipplei require specific attention. In patients undergoing surgery, the specimen is divided between microbiology and histology before formalin fixation; molecular diagnostics may retain yield after antibiotics, but must be interpreted while considering the possible persistence of DNA. The absence of positive cultures does not establish noninfective endocarditis: malignancy, lupus, and antiphospholipid syndrome are alternatives that must be assessed on their own evidence.

Serial ECGs, renal function, urinalysis, complete blood count, inflammatory markers, and liver function tests complete the evaluation. New conduction block with aortic involvement accelerates perivalvular imaging. Brain MRI, vascular imaging, abdominal CT, or spinal MRI are selected according to symptoms and the expected consequences for treatment. Persistent bacteremia requires a search for infected catheters, thrombophlebitis, and deep foci; renal impairment requires distinction among sepsis, emboli, glomerulonephritis, and toxicity. These investigations define the true extent of disease and the safety of treatment, rather than merely providing ancillary findings.

Treatment and prognosis

Empirical therapy is started after blood cultures have been obtained, rapidly in unstable patients, and tailored to community or healthcare acquisition, suspected organism, allergies, organ function, and local resistance patterns. The absence of a prosthesis does not exclude MRSA or Gram-negative organisms in a patient with relevant exposures. Once the microorganism is identified, treatment is changed to a targeted regimen. Dosing must achieve adequate exposure at the endocardial focus and is reassessed as renal function or fluid distribution changes. Discussion with the surgical team proceeds in parallel when mechanical damage or invasion is present.

In disease caused by susceptible streptococci, penicillin G, amoxicillin, or ceftriaxone are reference options. In adults, ceftriaxone 2 g intravenously daily is commonly used for four weeks; other regimens depend on susceptibility and pharmacokinetics. A two-week regimen combined with an aminoglycoside is reserved for rigorously selected patients with uncomplicated infection, a fully susceptible strain, and normal renal function. Reduced susceptibility, deep foci, and nutritionally variant microorganisms require different regimens. Convenience of administration should not take precedence over the microbiologic suitability of the regimen.

For MSSA, oxacillin or (flu)cloxacillin, generally around 12 g/day in adults, or cefazolin, often 6 g/day, are appropriate choices with adjustment for organ function and clinical context. Vancomycin is avoided as an automatic substitute when a beta-lactam can be used. For MRSA, vancomycin with exposure monitoring or specialist regimens with high-dose daptomycin are considered according to susceptibility and response. Gentamicin is not routinely added in native-valve staphylococcal disease; rifampin is not a usual component in the absence of infected prosthetic material. These distinctions reduce toxicity and interactions without demonstrated benefit.

In E. faecalis infection, ampicillin combined with ceftriaxone is an established synergistic regimen; in adults, ampicillin 12 g/day in divided doses and ceftriaxone 2 g every 12 hours are commonly used for six weeks. The combination is also useful when high-level aminoglycoside resistance prevents synergy with gentamicin. If gentamicin is selected, susceptibility, duration, and concentration monitoring must be defined. Comparative observational evidence supports the efficacy of the dual beta-lactam combination and a lower renal burden, without making all Enterococcus species or all resistance profiles interchangeable.

For HACEK organisms, ceftriaxone 2 g/day for four weeks is a reference regimen in native-valve disease. Fungi, non-HACEK Gram-negative organisms, and intracellular pathogens require dedicated regimens and often stronger consideration of surgical source control. In culture-negative disease after antibiotics, empirical therapy reflects plausible usual organisms; when serology or molecular testing identifies Coxiella or Bartonella, treatment changes substantially. Duration is not decided on disappearance of fever alone, but on organism, complications, source control, and microbiologic response.

Monitoring includes cultures until clearance, renal and hepatic function, complete blood count, and agent-specific toxicities: nephrotoxicity and ototoxicity for aminoglycosides, vancomycin exposure, creatine kinase for daptomycin, and interactions according to the regimen. Persistent fever may be due to the drug, embolization, or another infection; persistent bacteremia points more directly to inadequate source control or exposure. The distinction prevents escalation without a target. Duration refers to effective therapy and does not automatically restart after valve replacement; a positive operative culture may instead require a new course.

Surgery for heart failure is urgent when regurgitation or another lesion causes poor hemodynamic tolerance, and emergent in refractory pulmonary edema or shock. Temporary improvement with diuretics does not eliminate a perforation. Apparent systolic function may mask reduced forward output and should not be used as the sole reason to wait. In patients with significant regurgitation but controlled infection and good tolerance, timing can be individualized with close surveillance. Early assessment preserves options before multiorgan failure develops.

Surgery for uncontrolled infection takes abscess, pseudoaneurysm, fistula, anatomic progression, and microbiologic persistence unexplained by other sources into account. Aortic involvement and new conduction block deserve particular attention. For embolic prevention, size, mobility, and previous events are assessed together: persistent vegetations of at least 10 mm after embolization despite appropriate therapy are an important indication. An isolated dimensional threshold does not exhaust the assessment. The benefit of early surgery is greater while the risk of new emboli remains high and operative risk is acceptable.

The early-surgery trial by Kang and colleagues showed a reduction in the composite outcome of in-hospital death or embolism in selected patients with left-sided endocarditis, severe valvular disease, and large vegetations. The difference was driven mainly by embolic events; the result does not demonstrate that every native-valve case should undergo immediate surgery. In observational comparisons, operated and nonoperated patients differ in frailty and indications and must survive for different periods before the procedure. Each case therefore requires a concrete comparison among a correctable lesion, the risk of waiting, and the possibility of recovery.

Valve repair is preferable when it permits complete removal of infection and a durable result, especially for the mitral and tricuspid valves. A limited perforation or segmental damage may be reconstructable, whereas extensive destruction and annular invasion may necessitate replacement and reconstruction. Valve preservation does not justify leaving infected tissue behind. In invasive aortic disease, debridement may extend to the root and mitral-aortic continuity. Prosthetic material and technique are selected according to anatomy and the patient, not on the assumption that one solution eliminates every future risk.

An ischemic stroke without hemorrhage does not always require postponing a strong cardiac indication; neurologic prognosis, lesion size, and residual embolic risk enter the decision. Intracranial hemorrhage and infectious aneurysms may require a different sequence, with neurovascular assessment. Anticoagulants and antiplatelet agents are not initiated to prevent emboli from the vegetation. An independent indication is reassessed separately. Control of a splenic abscess or other foci must be coordinated with cardiac urgency, avoiding both reinfection of a new prosthesis and delay of a life-saving correction.

Outpatient continuation of treatment requires stability, microbiologic control, absence of unresolved complications, and a reliable program. Transition to oral combinations derives from studies in selected populations, not from defervescence alone; absorption, adherence, and interactions are part of the assessment. OPAT and oral treatment have different risks, including those associated with venous access. Before discharge, follow-up, testing, and the possibility of rapid readmission are defined, the source investigation is completed, and residual valve anatomy and function are documented. Microbiologic cure does not eliminate valvular disease that requires further care.

Prognosis depends on causative organism, heart failure, shock, invasion, emboli, and comorbidities. An echocardiogram at the end of treatment provides the reference for follow-up; new symptoms and fever require reassessment, with cultures before antibiotics whenever possible. Oral health, vascular access management, and treatment of sources reduce the risk of new episodes. After previous endocarditis, the patient belongs to the high-risk categories for which prophylaxis is recommended for indicated dental procedures; this condition differs from the mere initial presence of native valvular disease.

Complications

Perforation and chordal rupture can produce sudden regurgitation and shock, whereas a lesion that is initially tolerated may leave chronic valvular insufficiency. Progression to abscess, pseudoaneurysm, or fistula changes surgical complexity and may involve the conduction system. Temporary pacing or control of congestion addresses the consequences without resolving the focus. The appearance of new signs should therefore lead to anatomic reassessment and discussion of definitive source control.

Cerebral and visceral emboli can leave permanent damage or seed abscesses. Severity depends on the territory involved and the possibility of reperfusion, not only on the size of the mass remaining in the heart. After an event, the risk of hemorrhage or aneurysm rupture may limit some treatments and alter surgical timing. In patients with multiple infarcts, the search for other sources is not negated by the vegetation, but documentation of infection makes the risk of secondary septic foci particularly relevant.

Glomerulonephritis may present with hematuria, proteinuria, and renal insufficiency, sometimes associated with hypocomplementemia or positive autoantibodies. It should be distinguished from emboli, congestion, sepsis, and nephrotoxicity because the priority treatment is control of infection, with nephrology decisions as needed in complex cases. Renal impairment in turn modifies antibiotic exposure and operative risk. Deterioration during therapy should therefore not automatically be attributed to the drug or interpreted as an immediate need for immunosuppression.

Recurrences require comparison of species, susceptibility, and chronology to distinguish relapse from a new infection. Recurrence of the same bacteremia after apparent cure may indicate an undrained cavity, insufficient treatment, or a persistent extracardiac focus. Toxicity, bleeding, vascular-access complications, and malnutrition can impair recovery even after sterilization. The final care pathway therefore includes rehabilitation, prevention of new exposure, and surveillance of the residual valve, in addition to verification that the infectious episode has been controlled.