Infectious endocarditis is the inflammation of the endocardium, the inner lining of the heart, as well as the valves that separate each of the four chambers within the heart. It is primarily a disease caused by bacteria and has a wide array of manifestations and sequelae. Without early identification and treatment, a myriad of intracardiac and far-reaching extracardiac complications can develop. Therefore, careful evaluation, including a thorough history and physical exam, can help diagnoses cases and guide management, limiting mortality and morbidity.
The vast majority of infectious endocarditis cases stem from gram-positive streptococci, staphylococci, and enterococci infection. Together, these three groups account for 80 to 90% of all cases, with Staphylococci aureus specifically responsible for around 30% of cases in the developed world. In addition to various streptococci species, other common colonizers of the oropharynx, such as the HACEK organisms (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella) can less frequently be the culprit bacteria. Numerous other bacteria have been previously identified as well but comprise only about 6% of total cases. Finally, fungal endocarditis represents only about 1% of cases but can be a typically fatal complication of systemic Candida and Aspergillus infection in the immunocompromised population.
Risk factors and the environmental setting of bacterial acquisition, healthcare versus community, provide hints towards the underlying infectious etiology. The definition of nosocomial infections remains controversial, but in general, healthcare-related cases emerge in the setting of early prosthetic valve endocarditis (typically defined as occurring within the first 60 days since surgery) or following recent vascular catheterization, hemodialysis, hospitalization, or extra-cardiac operative procedures. In these situations, S. aureus represents the predominant pathogen, responsible for around 50% of nosocomial infections. The less virulent coagulase-negative staphylococci, such as S. epidermidis, stereotypically stem from indwelling vascular devices or recently implanted prosthetic valves. Enterococcal infection emerges with similar frequency in both nosocomial and non-nosocomial infections, comprising about 15% and 18% of cases, respectively.
Community-acquired infections tend to develop in the setting of immunosuppression, intravenous drug use, poor dentition, degenerative valve disease, and Rheumatic heart disease. Intravenous drug use, which underlies almost 10% of infectious endocarditis cases, suggests repeated inoculation with skin flora such as S. aureus and S. epidermidis, with S. aureus demonstrating a predilection for healthy, native tricuspid valves. While fairly uncommon in healthcare-related infections, Viridans group streptococci underlie about 20% of community-acquired infections. Classically, infections with Streptococcus gallolyticus (bovis) organisms should raise suspicion for underlying colon carcinoma.
Infectious endocarditis is a rare condition with an estimated yearly incidence of 3 to 10 cases per 100,000 people. Historically, this disease process has demonstrated a predilection for males, with a male tofemale ratio of nearly 2 to 1. The average age of infectious endocarditis patients is now greater than 65 years old. This preponderance for the elderly likely corresponds to the increased prevalence of predisposing factors such as prosthetic valves, indwelling cardiac devices, acquired valvular disease, hemodialysis, and diabetes mellitus within this demographic. Although previously a major risk factor, rheumatic heart disease now underlies less than 5% of all cases in the modern antibiotic era. Recreational intravenous drug use represents a growing risk factor that now accounts for about 10% of all infectious endocarditis cases.
The intact, healthy endocardium is typically resistant to bacterial seeding. Overall, the development of infectious endocarditis requires prodromal endocardial injury followed by a period of bacteremia. The preliminary endocardial disruption may emerge secondary to turbulent flow around diseased valves or from the direct mechanical trauma caused by catheter or electrode insertion. In the setting of intravenous drug use, repetitive valvular barrage by co-injected particulate matter generates the necessary injury. As evidenced by the predilection for vegetations to form on the ventricular surface of the aortic valve and the atrial surface of the mitral valve, hemodynamics play an important role in the pathogenesis. The vegetations are localized immediately downstream from regurgitant flow, leading to the hypothesis that hypoperfusion of the intima predisposes these areas to endocardial injury. Furthermore, infectious endocarditis is more common with high turbulence lesions such as a small ventricular septal defect with a jet lesion or stenotic valves; presumably, the high-pressure flow creates more local damage than defects associated with large surface areas or low flow. The damaged endocardium serves as a nidus for platelet aggregation and activation of the coagulation cascade, which fosters the formation of a sterile, non-bacterial thrombotic vegetation.
Subsequent bacteremia then allows for colonization of the vegetation. The necessary bacteremia can stem from an established, distant source of infection or emerge transiently secondary to intermittent hematogenous inoculation of oral flora from dental/gingival manipulation. Although the minimum bacterial burden remains unknown, experimental models have precipitated cases of infectious endocarditis with slow 1mL infusions of 106 colony-forming units of bacteria. Even in the setting of endocardial injury and bacteremia, pathogenesis still requires a virulent organism capable of binding to and facilitating platelet-fibrin deposits. For instance, three S. aureus proteins (clumping factors A, B, and serine-aspartate repeat protein) have been found to independently mediate platelet aggregation. In theory, expanding the originally sterile platelet-fibrin deposits protects pathogens from the host’s immune response and allows the vegetation to grow.
Mature vegetations consist of an amalgamation of inflammatory cells, fibrin, platelets, and erythrocyte debris. The initial platelet-fibrin clot provides a nidus for bacterial adherence and further platelet aggregation. Confocal laser scanning microscopic analysis of infected valve tissue demonstrates bacterial biofilms embedded with platelet collections. In a self-revolving fashion, platelets facilitate bacterial colonization, which in turn propagates further bacterial aggregation through the binding of surface proteins. In the acute setting, vegetations remain avascular; however, once healing commences, neovascularization, fibroblasts, and fibrosis may start to emerge in the affected valve.
Both the gross and histologic appearance of valvular tissue will vary based on the infecting organism. Virulent pathogens such as S. aureus characteristically generate an inflammatory milieu predominated by neutrophils and large bacterial colonies. A macroscopic evaluation may demonstrate friable tissue with frank destruction. The inflammation associated with less virulent organisms such as Viridans group streptococci involves more mononuclear cell infiltration.
The staining of histologic samples will often demonstrate focal bacterial colonies. Although rarely culture-positive following initiation of antibiotic therapy, valve tissue Gram staining remains positive in over 60% of cases undergoing active treatment. In the case of strep and staph endocarditis, hematoxylin and eosin staining will reveal basophilic cocci. Although typically used for fungal identification, the Grocott-Gomori methenamine silver stain will highlight the contours of strep cocci and provide increased sensitivity for detecting bacteria in valve tissue than Gram staining. Periodic acid-Schiff staining also offers greater sensitivity than Gram staining and best accentuates the foamy macrophages characteristic of T. whipplei endocarditis.
In regard to prosthetic valve endocarditis, one study found that the associated inflammatory cells remain relegated to the vegetation on the surface of the valve cusp. Compared to the inflammatory response that characterizes degenerative valve calcification, prosthetic valve endocarditis primarily involves neutrophilic infiltrates rather than macrophages and lymphocytes.
Clinically, infective endocarditis may present with a myriad of signs and symptoms, and clinicians should consider this diagnosis in any patient with risk factors who presents fever or sepsis of unknown origin. Patients will often describe the insidious onset of fevers, chills, malaise, and fatigue that generally prompts medical evaluation within the first month. Fever, typically defined as a temperature over 38.0 degrees C (100.4 degrees F), was found in over 95% of all patients in a large, multi-national prospective cohort study. However, immunosuppression, old age, antipyretic use, or previous antibiotic courses may prevent manifestation and lower the frequency of this finding. Other nonspecific symptoms indicative of systemic infection such as anorexia, headache, and generalized weakness may also be present. Symptoms that help localize to the cardio-pulmonary system—chest pain, dyspnea, decreased exercise tolerance, orthopnea, paroxysmal nocturnal dyspnea—occur less commonly and should raise concern for underlying aortic or mitral valve insufficiency. In the event of acute valvular incompetence, patients may present in extremis with abrupt onset of the symptoms of heart failure.
History often reveals predisposing conditions and risk factors that aid with diagnosis. Current or previous indwelling catheterization, intravenous drug use, recent pacemaker placement, or history of prosthetic valves suggests predisposing endocardial injury. The clinician should also inquire about known degenerative valve disease such as calcific aortic stenosis or mitral valve prolapse, which underlie about 30% of all cases. Previously a major risk factor for infectious endocarditis, rheumatic heart disease precedes the onset of less than 5% of infective endocarditis cases in the developed world today. In North America, diabetes mellitus represents one of the most common comorbidities.
A thorough physical exam may identify stigmata that reinforce the diagnosis and highlight complications of peripheral embolization. As discussed above, a fever will often be present, but tachypnea and tachycardia may also emerge in the setting of underlying valvular insufficiency or systemic infection. Hypotension can similarly develop secondary to either septic or cardiogenic shock in the event of acute valve perforation. Although classically associated with infectious endocarditis, a new or worsening murmur presents in less than 50% of all cases; nonetheless, identification will help localize valve involvement. If severe mitral or aortic valve regurgitation develops, auscultation can demonstrate bilateral pulmonary rales. The dermatologic exam may show the classic immunologic and hemorrhagic cutaneous sequela of infectious endocarditis. However, Osler nodes (painful subcutaneous nodules typically found on the palm), subungual splinter hemorrhages, and Janeway lesions (painless hemorrhagic plaques on the palms/soles) are each individually observed in less than 10% of all cases. The abdominal exam can reveal splenomegaly or even localized peritonitis, which suggests bowel perforation from mesenteric arterial occlusion. Intracerebral embolization can present with focal motor or sensory deficits that correspond to the impacted vascular territories.
Most patients with endocarditis present with nonspecific symptoms such as fatigue, fever, or chest pain. These symptoms correspond to multiple serious conditions, and the workup must necessarily be broad. Patients with chest pain or dyspnea warrant early consideration of other potentially life-threatening cardiopulmonary processes such as acute coronary syndrome, pulmonary embolism, and pneumonia. Whereas those appearing floridly septic should undergo rapid, guideline-directed evaluation following validated protocols.
For those presenting primarily with chest pain or dyspnea, initial acquisition of a 12-lead ECG is a rapid and cheap means to evaluate for underlying ischemia, dysrhythmias, or structural disease that may be confounding the diagnostic picture. The typical ECG in infectious endocarditis appears normal. ST-elevation can be seen in infectious endocarditis but should be considered a marker of myocardial infarction and handled consistent with ST-segment myocardial infarction even in previously diagnosed cases of infectious endocarditis. A two-view chest X-ray can reveal evidence of pulmonary abscesses, infiltrates, or pleural effusions. In the case of severe left-sided valvular insufficiency, frank cardiopulmonary edema, cardiomegaly, or cephalization of pulmonary vasculature may be appreciated. Investigating possible pulmonary parenchymal disease, empyema, or arterial embolization may require more advanced chest imaging such as a contrasted CT scan or CT angiogram. For patients with presentations concerning for myocardial ischemia or myocarditis, cardiac biomarkers remain critical for elucidating underlying infarction.
In the acute setting, a broad laboratory workup is often indicated, given the nonspecific presenting symptomatology. A complete blood count often demonstrates a leukocytosis that points towards an underlying infectious process. Cases with more subacute-chronic presentations may have normocytic anemia consistent with anemia of chronic disease. Although nonspecific, inflammatory markers such as the erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) are elevated in around 60% of cases. A chemistry panel should be obtained to identify electrolyte derangements requiring correction during the initial resuscitation.
Following exclusion of more immediately life-threatening etiologies, diagnosis of infectious endocarditis anchors on both microbiologic and echocardiograph evidence of infection. Diagnosis has long been predicated on the Modified Duke Criteria. Divided into major and minor criteria, diagnosis requires satisfaction of either two major criteria, one major and three minor criteria, or five minor criteria. The first major criterion involves confirmation of bacteremia. More specifically, the Modified Duke Criteria requires two separate blood cultures positive for typical pathogens such as Viridans group strep, Strep gallolyticus, HACEK organisms, S. aureus, or community-acquired enterococci in the absence of a primary focus. If other culprit pathogens are suspected, blood cultures must remain persistently positive as defined by either two positive cultures drawn more than 12 hours apart or positive results of all three or majority of 4 or more separate cultures (with first and last samples drawn one hour apart). Additionally, a recent update by the American Heart Association (AHA) allows satisfaction of this criterion with single positive blood culture for Coxiella burnetii or an anti-phase 1 IgG antibody titer greater than or equal to 1:800.
The second major criterion involves sonographic evidence of endocardial involvement. Echocardiogram must demonstrate a vacillating intra-cardiac mass fixed to a valve, supporting structure, or implanted material. Initial evaluation with a transthoracic echocardiogram (TTE) is common; however, the American Heart Association (AHA) recommends obtaining a more sensitive and specific transesophageal echocardiogram if suspicion for infectious endocarditis remains high despite a negative TTE (Class I, Level of Evidence B). Circumstances such as comorbid chronic obstructive pulmonary disease, previous thoracic surgery, obesity, and prosthetic valve involvement may hamper visualization via the transthoracic approach and should prompt more expeditious attainment of a TEE.
Regarding the five minor criteria, these include the following. Predisposing conditions such as underlying valvular abnormalities, structural heart disease, or intravenous drug use. Fever defined by temperature greater than 38 degrees celsius. Evidence of vascular phenomena such as mycotic aneurysms, intracranial hemorrhage, Janeway lesions, major arterial emboli, or septic pulmonary infarcts. Evidence of immunologic phenomena such as Osler’s nodes, Roth spots, glomerulonephritis, or positive rheumatoid factor. Or positive blood cultures that do not satisfy the aforementioned major criterion or serologic evidence of infection consistent with infectious endocarditis.
Effective treatment hastens endocardial vegetation eradication and limits or prevents secondary complications. However, those presenting in extremis with acute decompensated heart failure, septic shock, or stroke require stabilization and resuscitation, prioritizing the tenets of airway, breathing, and circulation. Following initial stabilization, subsequent treatment concentrates on prolonged bactericidal antibiotic regimens and possible cardiothoracic surgical intervention.
Antibiotic treatment duration and selection depends on the nature of the valve involved and resistance pattern of the infecting organism. In the case of native valve endocarditis with penicillin-susceptible Viridans group strep or Strep gallolyticus, the shortest proposed treatment regimen involves a two-week course of ceftriaxone 2 gm IV every 24 hours plus gentamicin 3 mg/kg IV every 24 hours. [Class IIa, level of evidence B] For this same patient population, other possible regimens include ceftriaxone 2 gm every 24 hours IV for four weeks or aqueous penicillin G 12 to 18 million units every 24 hours via continuous IV drip or in 4 to 6 equally divided doses. In the case of prosthetic valve involvement, these same pathogens typically require a minimum of a 6-week course of 24 million units of penicillin G every 24 hours or ceftriaxone 2 gm with or without gentamicin 3 mg/kg every 24 hours.
Patients at risk for staphylococcal infection typically require more prolonged antibiotic therapy. Patients with native valve methicillin-sensitive S. aureus (MSSA) infections can receive 6-week courses of either nafcillin 2gm every four hours or cefazolin 2 gm every 8 hours. In cases of methicillin-resistant S. aureus (MRSA) infections, a standard course involves vancomycin 15mg/kg every 12 hours or daptomycin 8 mg/kg daily for 6-weeks. Of note, gentamicin dual-therapy is no longer recommended for MSSA or MRSA infections given lack of clinical benefit and associated renal toxicity. Overall, therapy for prosthetic valve Staphylococcal infections are quite similar but require augmentation with rifampin and gentamicin. Prosthetic valve MSSA disease should receive gentamicin 3 mg/kg IV in 2 to 3 divided doses plus rifampin 900 mg IV in 2 to 3 equally divided doses every 24 hours for 2-weeks and 6-weeks, respectively, in addition to the above-described nafcillin regimen. In addition to vancomycin, MRSA cases should receive this same course of gentamicin and rifampin.
Since beta-lactam monotherapy does not possess bactericidal activity against enterococci, both native and prosthetic valve enterococcal infections require combination regimens. Examples include ampicillin or penicillin G plus an aminoglycoside such as gentamicin for 4 to 6 weeks. Interestingly, a dual beta-lactam regimen such as ampicillin plus ceftriaxone achieves appropriate bactericidal activity against Enterococci faecalis and may be utilized. Of note, penicillin resistance warrants combined vancomycin-gentamicin therapy; however, emerging penicillin, gentamicin, and vancomycin resistance may require treatment with linezolid or daptomycin.
Overall, antimicrobial treatment guidelines remain ever-evolving and should be routinely reviewed. To further guide and help develop appropriate antibiotic therapy courses, early infectious disease consultation is encouraged. As an additional principle of medical management, two blood cultures should be drawn every 24 to 48 hours to ensure clearance of bloodstream infection and direct ongoing antimicrobial therapy.
In general, early surgical intervention, including valve repair versus replacement, is indicated in the event of acute heart failure, extensive infection with localized complications, and recurrent arterial embolization. Acute valvular compromise manifesting with heart failure symptomatology typically warrants operative intervention within 24 hours. However, AHA/ACC also recommends early surgical treatment before completion of the initial antibiotic course in the event of an associated atrioventricular block, paravalvular abscess, or presence of destructive infiltrative lesions. [Level IB]Prevention and treatment of recurrent embolic events represent a major impetus for surgical intervention. At this time, AHA/ACC also recommends early surgery if patients experience recurrent embolic events or demonstrate large, mobile native valve vegetations less than 10 mm, respectively. One large prospective cohort study found the initiation of antimicrobial therapy alone decreased the incidence of stroke from 4.82 per 1000 patient days to 1.71 per 1000 patient days over one week. However, Kang and colleagues found early surgical intervention within 48 hours significantly reduced the overall in-hospital mortality (3% compared to 23% in the conventional therapy group) as well as the 6-week risk of embolic events (0% compared to 21%). Today, this mortality benefit means that almost half of all infectious endocarditis cases undergo some type of surgery.
A broad array of infectious, inflammatory, neoplastic, and mechanical etiologies should be considered when evaluating for infectious endocarditis. Much will depend upon the presenting symptomatology with appropriately broad differential for chest pain to include evaluation for acute coronary syndrome, acute heart failure, aortic dissection, myopericarditis, pulmonary embolism, pneumonia, and empyema. In patients with previous prosthetic valve replacement, clinicians should consider the possibility of perivalvular thrombosis (especially if there has been an interruption in recommended anticoagulation) or suture dehiscence. Recurrent arterial embolic events following recent myocardial infarction should raise concern for a ventricular mural thrombus. In an otherwise healthy young patient presenting with a new murmur, atrial myxoma should be considered. Although rare, non-bacterial endocarditis associated with sterile valvular thrombi can occur in patients with underlying malignancy (marantic endocarditis) or those with systemic lupus erythematosus (Libman-Sacks endocarditis).
Prognosis can vary widely depending on the virulence of the infective pathogen, the emergence of secondary complications, preexisting comorbidities, and the presence of native versus prosthetic valve. The in-hospital mortality rate hovers around 18%, with one-year mortality reaching up to 40%. In general, cases of prosthetic valve endocarditis occurring within the first 60 days of surgery demonstrate the highest in-hospital mortality rates (about 30%). A large, Japanese prospective cohort study found a staphylococcal infection and heart failure to be the greatest predictors of in-hospital mortality. Although nearly 50% of infectious endocarditis cases now undergo surgical intervention, in of itself, the surgical intervention does not appear to elevate the in-hospital mortality risk.
A host of intracardiac complications can stem from infective endocarditis. Acute valvular incompetence can lead to symptoms of heart failure occur in around one-third of cases. This can occur secondary to acute valve perforation or from the compromise of the chordae tendineae and papillary muscles. Mitral or tricuspid valve regurgitation can lead to atrial enlargement and the subsequent emergence of atrial fibrillation and other supraventricular dysrhythmias as well. Less commonly, intracardiac abscesses (14%) and atrioventricular blocks (8%) emerge.
Peripheral embolization can also have far-reaching extracardiac complications. Right-sided vegetation can lead to arterial emboli that manifest as disseminated pulmonary abscesses, pneumonia, empyema, or focal regions of pulmonary infarctions. Neurologic sequela constitutes the most severe and prevalent extracardiac complications, impacting 15% to 30% of all cases. Potential complications include ischemic stroke, intracranial hemorrhage, meningitis, intracerebral abscess, and infective intracranial aneurysms. Ischemic strokes represent the vast majority of neurologic complications and classically stem from cerebral artery occlusion from embolized mitral/aortic vegetations. Septic embolization into the microcirculation of the vasa vasorum can precipitate vessel wall degradation and subsequent mycotic aneurysms, which typically only become symptomatic in the event of a rupture.
Less common complications include acute renal failure stemming from either immune-mediated glomerulonephritis or focal infarction secondary to occlusive emboli. Splenic infarcts and abscesses, especially in the setting of S. aureus infection, can also occur from infected emboli. Acute mesenteric ischemia and subsequent bowel necrosis and perforation is a feared complication of arterial embolization.
Although antibiotic prophylaxis remains controversial, the AHA/ACC continues to recommend certain individuals undergoing high-risk procedures receive pharmacological prophylaxis. As detailed in the 2017 AHA/ACC focused update, patients with prosthetic cardiac valves, prosthetic material used for valve repair, previous infective endocarditis, unrepaired cyanotic congenital heart disease, repaired congenital heart disease with persistent valvular insufficiency, or cardiac transplants with structurally dysfunctional valves should be considered for antibiotic prophylaxis before any dental procedures requiring mucosal perforation or manipulation of gingival or periapical tissue. A potential prophylactic regimen would include 2 grams of amoxicillin or 600 milligrams of clindamycin (for those with a contraindication to a beta-lactam) less than 60 minutes from procedure start time. Note that current guidelines no longer recommend antibiotic prophylaxis for any cutaneous, genitourinary, and gastrointestinal procedures.
The diagnosis and management of infectious endocarditis can represent a prolonged and complex process. Efficient, safe, and effective patient care is best accomplished by the early involvement of a multi-disciplinary team that includes cardiology, cardiothoracic surgery, infectious diseases, with the primary care provider. Although most cases may be addressed with antibiotics alone, intra-cardiac complications or evidence of peripheral embolization should prompt surgical consultation. Patients with infectious endocarditis secondary to intravenous drug use should receive inpatient counseling as well as access to outpatient treatment and addiction centers. Overall, early diagnosis and guideline-directed management can help limit the morbidity and mortality of this disease.
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