Infective Endocarditis

IE is defined as an infection of the endocardial surface of the heart, which may include 1 or more heart valves, the mural endocardium, or a septal defect. The history of IE can be divided into several eras. In 1674, Lazaire Riviere first described the gross autopsy findings of the disease in his monumental work Opera Medica Universa. In 1885, William Osler presented the first comprehensive description of endocarditis in English. Lerner and Weinstein presented a thorough discussion of this disease in their landmark series of articles, “Infective Endocarditis in the Antibiotic Era.”[20, 21, 22]  These authors documented that IE was most commonly subacute in nature with streptococci and enterococci as the most common pathogens. Rheumatic fever or congenital heart disease were the most frequent underlying valvular abnormalities. Accordingly, it manifested itself in young adulthood. 

In the late 1980s, the nature of IE fundamentally changed. This was brought about by the ever-increasing availability of prosthetic heart valves, intracardiac pacemakers, and Swan-Ganz catheters. It became much more acute in nature and affected older individuals with a wider spectrum of pathogens. These included especially S aureus, both MSSA and MRSA, gram negative rods, and fungi. IE can appropriately be described as infective endocarditis in the era of intravascular devices that is intensified by changes in the gut and oral microbiome and by the widespread inflammatory response initiated by many of the valvular pathogens. IE continues to pose significant clinical challenges,[3, 23, 24]  with an overall mortality rate of 30%. 

SBE results from "wear and tear" platelet/fibrin microthrombi of the endothelial surface of the heart.[24]  IE develops when a transient bacteremia seeds this thrombus. Pathologic effects of infection can include local tissue destruction and embolic phenomena. Secondary autoimmune effects, such as immune complex glomerulonephritis and vasculitis, can also occur. 

Types of infective endocarditis

Endocarditis has evolved into several variations, keeping it near the top of the list of diseases that must not be misdiagnosed or overlooked. Endocarditis can be broken down into the following categories[2, 3, 24] :

• Native valve endocarditis (NVE), acute and subacute 
• Prosthetic valve endocarditis (PVE), ^{[2, 3]}  early and late
• Intravenous drug abuse (IVDA) endocarditis

Other terms commonly used to classify types of IE include pacemaker IE and nosocomial IE (NIE).

The classic clinical presentation and clinical course of IE has been characterized as either acute or subacute. Indiscriminate antibiotic usage and an increase in immunosuppressed patients have blurred the distinction between these 2 major types; however, the classification still has clinical merit.

Acute NVE frequently involves normal valves and usually has an aggressive course. It is a rapidly progressive illness in healthy and debilitated persons alike. Virulent organisms, such as S aureus and group B streptococci, typically are the causative agents of this type of endocarditis. Underlying structural valve disease may be absent.

Subacute NVE primarily affects abnormal valves. Its course, even in untreated patients, usually is more indolent than that of the acute form and may extend over many months. Alpha-hemolytic streptococci or enterococci, usually in the setting of underlying structural valve disease, typically are the causative agents for this type of endocarditis.

Prosthetic valve endocarditis accounts for 10-20% of IE cases. Eventually, 5% of mechanical and bioprosthetic valves become infected. Mechanical valves are more likely to be infected within the first 3 months of implantation, and, after 1 year, bioprosthetic valves are more likely to be infected. The valves in the mitral valve position are more susceptible than those in the aortic areas.[2, 3, 25]

Early PVE occurs within 60 days of valve implantation. Traditionally, coagulase-negative staphylococci (CoNS), gram-negative bacilli, and Candida species have been the common infecting organisms. Late PVE occurs 60 days or more after valve implantation. Staphylococci, alpha-hemolytic streptococci, and enterococci are the common causative organisms. Data suggest that S aureus now may be the most common infecting organism in both early and late PVE.

In 75% of cases of IVDA IE, no underlying valvular abnormalities are noted, and 50% of these infections involve the tricuspid valve.[25]  Staphylococcus aureus is the most common causative organism. Hospitalizations and associated valvular surgeries increased 12-fold between 2007 and 2017.[2, 3, 26] With newer methodology, many carriers of S aureus have this pathogen widely distributed throughout their epidemic.[10]

Analogous to PVE are infections of implantable pacemakers and cardioverter-defibrillators. Usually, these devices are infected within a few months of implantation. Pacemaker infections include those of the generator pocket (the most common), the proximal leads, and the portions of the leads in direct contact with the endocardium.[10]

This last category represents true pacemaker IE, is the least common infectious complication of pacemakers (0.5% of implanted pacemakers) and is the most challenging to treat. Of pacemaker infections, 75% are produced by staphylococci, both coagulase-negative and coagulase-positive.

Healthcare associated IE is defined as an infection that manifests 48 hours after hospitalization or that is associated with a hospital, based on a procedure performed within 4 weeks of the clinical disease onset of disease. 

Two types of HCIE have been described. The right-sided variety affects a valve that has been injured by placement of an intravascular line (eg, Swan-Ganz catheter). Subsequently, the valve is infected by a nosocomial bacteremia. The second type develops in a previously damaged valve and is more likely to occur on the left side. Staphylococcus aureus has been the predominant pathogen of HCIE since the prevalence of intravascular devices. Enterococci are the second most isolated pathogens and usually arise from a genitourinary source.

The underlying valvular pathology has also changed. Rheumatic heart disease accounts for less than 20% of cases, and 6% of patients with rheumatic heart disease eventually develop IE. Approximately 50% of elderly patients have calcific aortic stenosis as the underlying pathology. Congenital heart disease accounts for 15% of cases, with the bicuspid aortic valve being the most common example.[27]

Other contributing congenital abnormalities include ventricular septal defects, patent ductus arteriosus, and tetralogy of Fallot. Atrial septal defect (secundum variety) rarely is associated with IE. Mitral valve prolapse is the most common predisposing condition found in young adults, and it is the predisposing condition in 30% of cases of NVE in this age group. Infective endocarditis complicates 5% of cases of asymmetrical septal hypertrophy and usually involves the mitral valve.

Infective endocarditis develops most commonly on the mitral valve, closely followed in descending order of frequency by the aortic valve, the combined mitral and aortic valve, the tricuspid valve, and, rarely, the pulmonic valve. Mechanical prosthetic and bioprosthetic valves exhibit equal rates of infection.

All cases of IE develop from a commonly shared process, as follows:

1. Bacteremia (nosocomial or spontaneous) that delivers the organisms to the surface of the valve
2. Adherence of the organisms
3. Eventual invasion of the valvular leaflets

The common denominator for adherence and invasion is nonbacterial thrombotic endocarditis, a sterile fibrin-platelet vegetation. The development of subacute IE depends on a bacterial inoculum sufficient to allow invasion of the preexistent thrombus. This critical mass is the result of bacterial clumping produced by agglutinating antibodies.

In acute IE, the thrombus may be produced by the invading organism (ie, S aureus) or by valvular trauma from intravenous catheters or pacing wires (ie, HCIE). S aureus can invade the endothelial cells (endotheliosis) and increase the expression of adhesion molecules and of procoagulant activity on the cellular surface. Nonbacterial thrombotic endocarditis may result from stress, renal failure, malnutrition, systemic lupus erythematosus, or neoplasia.

The Venturi effect also contributes to the development and location of nonbacterial thrombotic endocarditis. This principle explains why bacteria and the fibrin-platelet thrombus are deposited on the sides of the low-pressure sink that lies just beyond a narrowing or stenosis.

In patients with mitral insufficiency, bacteria and the fibrin-platelet thrombus are located on the atrial surface of the valve. In patients with aortic insufficiency, they are located on the ventricular side. In these examples, the atria and ventricles are the low-pressure sinks. In the case of a ventricular septal defect, the low-pressure sink is the right ventricle, and the thrombus is found on the right side of the defect.

Nonbacterial thrombotic endocarditis also may form on the endocardium of the right ventricle, opposite the orifice that has been damaged by the jet of blood flowing through the defect (ie, the MacCallum patch).

The microorganisms that most commonly produce endocarditis (ie, S aureus; Streptococcus viridans; groups A, C, and G streptococci; enterococci) resist the bactericidal action of complement and possess fibronectin receptors for the surface of the fibrin-platelet thrombus. Among the many other characteristics of IE-producing bacteria demonstrated in vitro and in vivo, some features include the following:

• Increased adherence to aortic valve leaflet disks by enterococci, S viridans, and S aureus
• Mucoid-producing strains of S aureus
• Dextran-producing strains of S viridans
• Streptococcus viridans and enterococci that possess FimA surface adhesin
• Platelet aggregation by S aureus and S viridans and resistance of S aureus to platelet microbicidal proteins

The pathogenesis of pacemaker IE is similar. Shortly after implantation, a fibrin-platelet thrombus (similar to the nonbacterial thrombotic endocarditis described above) involves the generator box and conducting leads. After 1 week, the connective tissue proliferates, partially embedding the leads in the wall of the vein and endocardium. This layer may offer partial protection against infection during a bacteremia.

Bacteremia (either spontaneous or resulting from an invasive procedure) infects the sterile fibrin-platelet vegetation described above. Bloodstream infections develop from various extracardiac types of infection, such as pneumonias or pyelonephritis, but most commonly from gingival disease. Of those with high-grade gingivitis, 10% have recurrent transient bacteremias (usually streptococcal species). Most cases of subacute disease are secondary to the bacteremias that develop from the activities of daily living (eg, tooth brushing, bowel movements).

The skin is quite resistant to S aureus infection, largely owing to its production of antimicrobial peptides. Soong et al discovered that, in vitro, the secretion of alpha toxin by S aureus allows the organism to successfully penetrate the keratinocyte layer. This could explain the presence of staphylococcal bacteremia in the absence of any gross damage to the epithelial layer.[26]

Bacteremia can result from various invasive procedures, ranging from oral surgery to sclerotherapy of esophageal varices to genitourinary surgeries to various abdominal operations. The potential for invasive procedures to produce a bacteremia varies greatly. Procedures, rates, and organisms are as follows:

• Endoscopy - Rate of 0-20%; coagulase-negative staphylococci (CoNS), streptococci, diphtheroids
• Colonoscopy - Rate of 0-20%; Escherichia coli, Bacteroides species
• Barium enema - Rate of 0-20%; enterococci, aerobic and anaerobic gram-negative rods
• Dental extractions - Rate of 40-100%; S viridans
• Transurethral resection of the prostate - Rate of 20-40%; coliforms, enterococci, S aureus
• Transesophageal echocardiography - Rate of 0-20%; S viridans, anaerobic organisms, streptococci

The incidence of nosocomial bacteremias, mostly associated with intravascular lines, has more than doubled in the last few years. Up to 90% of BSIs caused by these devices are secondary to the placement of various types of central venous catheters. Hickman and Broviac catheters are associated with the lowest rates, presumably because of their Dacron cuffs. Peripherally placed central venous catheters are associated with similar rates.

Intravascular catheters are infected from 1 of the following 4 sources:

• Infection of the insertion site
• Infection of the catheter
• Bacteremia arising from another site
• Contamination of the infused solution

Bacterial adherence to intravascular catheters depends on the response of the host to the presence of this foreign body, the properties of the organism itself, and the position of the catheter. Within a few days of insertion, a sleeve of fibrin and fibronectin is deposited on the catheter. Staphylococcus aureus adheres to the fibrin component.

Staphylococcus aureus also produces an infection of the endothelial cells (endotheliosis), which is important in producing the continuous bacteremia of S aureus BSIs. Endotheliosis may explain many cases of persistent methicillin-susceptible S aureus (MSSA) and MRSA catheter-related BSIs without an identifiable cause.

Staphylococcus aureus catheter-related BSIs occur even after an infected catheter is removed, apparently attributable to specific virulence factors of certain strains of S aureus that invade the adjacent endothelial cells. At some point, the staphylococci re-enter the bloodstream, resulting in bacteremia.[28, 29, 30, 31]

Four days after placement, the risk for infection markedly increases. Lines inserted into the internal jugular vein are more prone to infection than those placed in the subclavian vein. Colonization of the intracutaneous tract most likely is the source of short-term catheter-related BSIs. Among lines in place for more than 2 weeks, infection of the hub is the major source of bacteremia. In some cases, the infusion itself may be a reservoir of infection.

Colonization of heart valves by microorganisms is a complex process. Most transient bacteremias are short-lived, are without consequence, and often are unpreventable. Bacteria rarely adhere to an endocardial nidus before the microorganisms are removed from the circulation by various host defenses.

Once microorganisms establish themselves on the surface of the vegetation, the process of platelet aggregation and fibrin deposition accelerates at the site. As the bacteria multiply, they are covered by ever-thickening layers of platelets and thrombin, which protect them from neutrophils and other host defenses. Organisms deep in the vegetation hibernate because of the paucity of available nutrients and therefore are less susceptible to bactericidal antimicrobials that interfere with bacterial cell wall synthesis.

Complications of subacute endocarditis result from embolization, slowly progressive valvular destruction, and various immunologic mechanisms. The pathologic picture of subacute IE is marked by valvular vegetations in which bacteria colonies are present both on and below the surface.

The cellular reaction in subacute bacterial endocarditis primarily is that of mononuclear cells and lymphocytes, with few polymorphonuclear cells. The surface of the valve beneath the vegetation shows few organisms. Proliferation of capillaries and fibroblasts is marked. Areas of healing are scattered among areas of destruction. Over time, the healing process falls behind, and valvular insufficiency develops secondary to perforation of the cusps and damage to the chordae tendineae. Compared with acute disease, little extension of the infectious process occurs beyond the valvular leaflets.

Levels of agglutinating and complement-fixing bactericidal antibodies and cryoglobulins are markedly increased in patients with subacute endocarditis. Many of the extracardiac manifestations of this form of the disease result from circulating immune complexes. These include glomerulonephritis, peripheral manifestations (eg, Osler nodes, Roth spots, subungual hemorrhages), and, possibly, various musculoskeletal abnormalities. Janeway lesions usually arise from infected microemboli.

The microscopic appearance of acute bacterial endocarditis differs markedly from that of subacute disease. Vegetations that contain no fibroblasts develop rapidly, with no evidence of repair. Large amounts of both polymorphonuclear leukocytes and organisms are present in an ever-expanding area of necrosis. This process rapidly produces spontaneous rupture of the leaflets, of the papillary muscles, and of the chordae tendineae.

The complications of acute bacterial endocarditis result from intracardiac disease and metastatic infection produced by suppurative emboli not due to any immunological mechanisms.

The different types of IE have varying causes and involve different pathogens.

Native valve endocarditis

The following are the main underlying causes of NVE:

• Rheumatic valvular disease (30% of NVE) - Primarily involves the mitral valve
• Congenital heart disease (15% of NVE) - Underlying etiologies include a patent ductus arteriosus, ventricular septal defect, tetralogy of Fallot, or any native or surgical high-flow lesion
• Mitral valve prolapse with an associated murmur (20% of NVE)
• Degenerative heart disease - Including calcific aortic stenosis resulting from a bicuspid valve, Marfan syndrome, or syphilitic disease

Approximately 70% of infections in NVE are caused by Streptococcus species, including S viridans, S bovis, and enterococci. Staphylococcus species cause 25% of cases and generally demonstrate a more aggressive acute course.

Prosthetic valve endocarditis

Early prosthetic valve endocarditis (PVE), which presents shortly after surgery, has a different bacteriology and prognosis than late PVE, which presents in a subacute fashion similar to NVE.

Infection associated with aortic valve prostheses is particularly associated with local abscess and fistula formation, and valvular dehiscence. This may lead to shock, heart failure, heart block, shunting of blood to the right atrium, pericardial tamponade, and peripheral emboli to the central nervous system and elsewhere.

Early PVE may be caused by a variety of pathogens, including S aureus and S epidermidis. These nosocomially-acquired organisms often are methicillin-resistant (eg, MRSA).[29] Late disease most commonly is caused by streptococci. Overall, CoNS are the most frequent cause of PVE (30%).

Staphylococcus aureus causes 17% of early PVE and 12% of late PVE.

Corynebacterium, nonenterococcal streptococci, fungi (eg, C albicans, Candida stellatoidea, Aspergillus species), Legionella, and the HACEK (ie, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae) organisms cause the remaining cases.[32]  

OUD infective endocarditis

Diagnosis of endocarditis in those who abuse IV drugs can be difficult and requires a high index of suspicion. Two thirds of patients have no previous history of heart disease or murmur on admission. A murmur may be absent in those with tricuspid disease, owing to the relatively small pressure gradient across this valve. Pulmonary manifestations may be prominent in patients with tricuspid infection: one third have pleuritic chest pain, and three quarters demonstrate chest radiographic abnormalities

Staphylococcus aureus is the most common (< 50% of cases) etiologic organism in patients with IVDA IE. MRSA accounts for an increasing portion of S aureus infections and has been associated with previous hospitalizations, long-term addiction, and nonprescribed antibiotic use. Groups A, C, and G streptococci and enterococci also are recovered from patients with IVDA IE.

Gram-negative organisms are involved infrequently. Pseudomonas aeruginosa[24] and the HACEK family are the most common examples.

Please see COVID-19's Effect on Infective Endocarditis in People Who Inject Drugs.

Healthcare-associated infective endocarditis

Endocarditis may be associated with therapeutic modalities involving intravascular devices such as central or peripheral intravenous catheters, rhythm control devices such as pacemakers and defibrillators, hemodialysis shunts and catheters, and chemotherapeutic and hyperalimentation lines. These patients tend to have significant comorbidities, more advanced age, and predominant infection with S aureus. The mortality rate is high in this group.

The gram-positive cocci (ie, S aureus, CoNS, enterococci, nonenterococcal streptococci) are the most common pathogens of HCIE

Fungal endocarditis

Fungal endocarditis is found in IV drug users and intensive care unit patients who receive broad-spectrum antibiotics.[2]  Blood cultures may be negative. Microscopic examination of large emboli may detect the organism.

Candida auris is particularly concerning since most infections are recognized in healthcare facilities and can rapidly spread throughout a given facility and between that facility and previously uninfected sites. There were at least 8200 cases in the United States in 2022. Cleaning or disinfecting infected surfaces, including patient's skin, is ineffective. The organism typically is resistant to many antifungals.[33, 34]

Culture negative endocarditis

Many cases are due to inappropriate institution antibiotics prior to obtaining adequately drawn blood cultures.[35]  

Clinical features associated with different pathogens

Table 1. Clinical Features of Infective Endocarditis According to Causative Organism (Open Table in a new window)

Risk factors

The most significant risk factor for IE is residual valvular damage caused by a previous attack of endocarditis.

In the United States, the incidence of IE is approximately 12.7 cases per 100,000 persons per year.[36]  The incidence of IE in other countries is similar to that in the United States. The proportion of patients with intracardiac devices has increased from 13.3% to 18.9%, whereas the proportion of cases with a background of HIV infection has decreased.

The mean age of patients has increased from 58.6 to 60.8 years and continues to rise; more than 50% of patients are older than 50 years.[31]  Mendiratta and colleagues, in their retrospective study of hospital discharges of patients aged 65 years and older with a primary or secondary diagnosis of IE, found that hospitalizations for IE increased 26%, from 3.19 per 10,000 elderly patients to 3.95 per 10,000. IE is 3 times more common in males than in females. There appears to be no racial predilection.[37, 38]

Prognosis largely depends on whether complications develop. Early detection and appropriate treatment of this uncommon disease can be lifesaving. The overall mortality rate has remained stable at 14.5%. There has been no overall improvement in outcomes of IE of congenital heart disease. 

Cure rates for appropriately managed (including both medical and surgical therapies) NVE are as follows:

• For S viridans and S bovis infection, the rate is 98%.
• For enterococci and S aureus infection in individuals who abuse intravenous drugs, the rate is 90%.
• For community-acquired S aureus infection in individuals who do not abuse intravenous drugs, the rate is 60-70%.
• For infection with aerobic gram-negative organisms, the rate is 40-60%.
• For infection with fungal organisms, the rate is lower than 50%.

For PVE, the cure rates are as follows:

• Rates are 10-15% lower for each of the above categories, for both early and late PVE.
• Surgery is required far more frequently.
• Approximately 60% of early CoNS PVE cases and 70% of late CoNS PVE cases are curable.

Anecdotal reports describe the resolution of right-sided valvular infection caused by S aureus infection in individuals who abuse IV drugs after just a few days of oral antibiotics.

The role of early valvular surgery in reducing mortality among patients with IE has become somewhat clearer. Challenges to resolving this question include the necessity of performing multicentered studies with an apparent difficulty of ensuring that the patients' preoperative assessments and surgical approaches are comparable. The largest study to date indicates that in cases of IE complicated by heart failure, valvular surgery reduces the 1-year mortality rate. More recent studies document that early surgery in patients, especially those with large vegetations, significantly reduces the risk for death from any cause.[39, 40, 41, 42]

Mortality rates in NVE range from 16-27%, and mortality rates in patients with PVE are higher. More than 50% of these infections occur within 2 months after surgery. The fatality rate of pacemaker IE ranges up to 34%.[43, 44, 45, 46, 47]

Increased mortality rates are associated with older age, infection involving the aortic valve, development of congestive heart failure, central nervous system complications, and underlying disease such as diabetes mellitus. Catastrophic neurological events of all types resulting from IE are highly predictive of morbidity and mortality.

Mortality rates vary with the infecting organism. Acute endocarditis caused by S aureus is associated with a high mortality rate (30-40%), except when it is associated with IV drug use,[26]  whereas IE resulting from streptococci has a mortality rate of approximately 10%.[48]

Surveys indicate that an appallingly small number of patients who are at risk of developing IE understand antibiotic and nonpharmacologic (ie, appropriate oral hygiene) principles. Drug rehabilitation for patients who use IV drugs is critical.

The United Kingdom’s National Institute for Health and Clinical Excellence (NICE) addresses patient education in its guideline on prophylaxis against IE in adults and children undergoing interventional procedures. The NICE guideline recommends that healthcare professionals teach patients about the symptoms of IE and the risks of nonmedical invasive procedures such as body piercing and tattooing, explain the benefits and risks of antibiotic prophylaxis and the reasons that it is no longer routine, and emphasize the need to maintain good oral health.[49]  

COVID-19 infections may occur concurrently with, precede, or follow cases of IE. Most were males with a mean age of 52.2 years. The most common pathogens were S aureus (38.1%), E faecalis (14.3 %), and Strep minis (2%); 33% required cardiac surgery and 2.8% died.[13]  S aureus IE has been mistakenly diagnosed as Multisystem Inflammatory Response Syndrome.[8, 11]  Symptoms, chest x-ray findings, vital signs, and screening laboratory tests are shared by both. In such situations, the best approach is the application of SA that would indicate performing a COVID-19 test as well as screening for IE as discussed above.

Cardiac infection may present months after active COVID in individuals with no previous predisposing conditions. It can present as myocarditis with persistence of the virus in the myocardium, bacterial IE, or as non- bacterial thromboendocarditis. The cause of both is related to the viral infection and the intense systemic inflammatory and thrombotic response triggered by it.[50]  

COVID-19 infection may lead to IE by its ability to produce visceral thrombosis. These can occur prior to treatment in the community or as the individual is receiving treatment in a variety of healthcare institutions. The primary cause of such is a variety of intravascular lines, any of which can lead to a transient BSI resulting in endocardial infection.

The initial fevers of COVID-19 usually are due to the virus and the resulting thrombotic and inflammatory processes. At the 7-day mark, bacterial or fungal infections must be ruled out including a thorough reevaluation for IE that includes echocardiography.

Please see COVID-19's Effect on Infective Endocarditis in People Who Inject Drugs.

Table 2. Differential Diagnoses of IE During the COVID-19 Pandemic (Open Table in a new window)

Acute disease has become the predominant type of valvular infection because of the rise in intravascular devices such as prosthetic valves and pacemakers. The opioid crisis and the increase of hepatitis C virus infection among injection drug users accounts in large part for this shift, especially among the younger patients. The social isolation brought about by COVID-19 appears to be accelerating this process.[15, 50]

Its clinical history is highly variable, especially among cases with subacute IE. The symptoms often are vague and constitutional in nature. They may focus on primary cardiac effects or secondary embolic phenomena. Fever and chills are the most common symptoms. Anorexia, weight loss, malaise, headache, myalgias, night sweats, shortness of breath, cough, and joint pains are commonly observed.[27]  Signs and symptoms of congestive heart failure may be due to valvular insufficiency. Focal neurologic complaints of embolic stroke(20% of cases ) or the back pain associated with vertebral osteomyelitis may be present.

Dyspnea, cough, and chest pain are common complaints of intravenous drug users due to the predominance of tricuspid valve endocarditis in this group and secondary embolic showering of the pulmonary vasculature.

A key concern is the distinction between subacute and acute IE.[51, 52, 53, 54]  The diagnosis of subacute IE is suggested by a history of an indolent process characterized by fever, fatigue, anorexia, back pain, and weight loss. Less common developments include cerebrovascular accident or congestive heart failure.

Question the patient about invasive procedures and recreational drug use that may be causing the bacteremia. Most subacute disease caused by S viridans infection is related to dental disease, with most cases not caused by dental procedures but by transient bacteremias secondary to gingivitis. In 85% of patients, symptoms of endocarditis appear within 2 weeks of dental or other procedures.

The interval between the onset of disease and diagnosis averages approximately 6 weeks. The fact that less than 50% of patients have previously-diagnosed underlying valvular disease significantly limits the effectiveness of antibiotic prophylaxis.

Acute IE is a much more aggressive disease. The patient notices the rapid onset of high-grade fevers and chills and a rapid onset of congestive heart failure. Again, a history of antecedent procedures or illicit drug use must be investigated.

The distinction between these 2 polar types of IE has become less clear. Intermittent use of antibiotics aimed at treating misdiagnosed endocarditis can suppress bacterial growth within the valvular thrombus, giving rise to the state of muted IE. This often is the case of HCIE, also referred to as healthcare-associated IE [HCIE]), which commonly manifests with elements of a sepsis syndrome (ie, hypotension, metabolic acidosis, fever, leukocytosis, and multiple organ failure).

The source of the bacteremia may be an infection in another organ (eg, pneumonia, pyelonephritis) or in a central venous catheter. These patients most often are in the intensive care unit. Approximately 45% of cases of HCIE occur in patients with prosthetic valves. Muted IE caused by S aureus infection may resemble IE that results from S viridans infection.

Subacute native valve endocarditis

The symptoms of early subacute native valve endocarditis (NVE) usually are subtle and nonspecific. They include low-grade fever (absent in 3-15% of patients), anorexia, weight loss, influenzalike syndromes, polymyalgia-like syndromes, pleuritic pain, syndromes resembling rheumatic fever (eg, fever, dulled sensorium as in typhoid, headaches), and abdominal symptoms (eg, right upper quadrant pain, vomiting, postprandial distress, appendicitis-like symptoms).

When appropriate therapy is delayed for weeks or months, additional clinical features, embolic or immunologic in origin, develop.

Signs and symptoms secondary to emboli include acute meningitis with sterile spinal fluid, hemiplegia in the distribution of the middle cerebral artery, regional infarcts that cause painless hematuria, infarction of the kidney or spleen, unilateral blindness caused by occlusion of a retinal artery, and myocardial infarction arising from embolization of a coronary artery.

The emboli of right-sided IE commonly produce pulmonary infarcts. The rate of embolization is related to the organism, the size of the vegetation and its rate of growth or resolution, and its location.

The vegetations of S aureus, Haemophilus influenzae, H parainfluenzae, and the fungi are much more likely to embolize than those of S viridans. Those larger than 10 mm in diameter and mobile or prolapsing have a high rate of embolization. A vegetation that grows during therapy is associated with a significant increase in the risk for embolization but with the persistence of bacteremia.

Clinically separating the importance of the absolute size and the rate of change in the size of the vegetation from the causative organism is difficult. The vegetations of the mitral valve are much more likely to embolize than those in any other location. The risk for embolization markedly decreases after 1 week of appropriate antibiotic therapy.

The deposition of circulating immune complexes in the kidney may produce interstitial nephritis or proliferative glomerulonephritis, with renal failure progressing to the point of uremia at the time of the patient’s presentation. Similarly, various musculoskeletal symptoms (44% of patients) arise from immunologically mediated synovitis.

Osler nodes and Roth spots arise from immune-mediated vasculitis. Patients may experience palpitations, ie, the symptoms of an immune-mediated myocarditis.

The origin of lumbosacral back pain in patients with subacute IE (15%) is unclear but probably results from the deposition of immune complexes in the disk space; however, antibiotic therapy rapidly abolishes these symptoms. In 50% of patients with cerebral emboli, this event is the first manifestation of IE and is associated with a mortality rate that is 2 to 4 times higher. Stroke in younger individuals should always raise the possibility of underlying IE.

Bacteria-free infective endocarditis

Rarely observed today, the bacteria-free state of IE is one in which patients have multiple negative blood culture results in the presence of severe congestive heart failure, renal failure, multiple sterile emboli, massive splenomegaly, severe anemia, brown facial pigmentation, bilateral thigh pain, and massive leg edema. These patients usually are afebrile. This process appears to indicate prolonged and unchecked stimulation of the immune system.

Acute infective endocarditis

The clinical symptoms of acute IE result from either embolic or intracardiac suppurative complications. The onset of illness is abrupt, with rapidly progressive destruction of the infected valve. The valvular leaflets are quickly destroyed by bacteria that multiply rapidly within the ever-growing friable vegetations. Complications develop within a week. These include the dyspnea and fatigue of severe congestive heart failure and a wide spectrum of neuropsychiatric complications resulting from CNS involvement.

Acute bacterial endocarditis caused by Staphylococcus aureus with perforation of the aortic valve and aortic valve vegetations. Courtesy of Janet Jones, MD, Laboratory Service, Wichita Veterans Affairs Medical Center.

Acute bacterial endocarditis caused by Staphylococcus aureus with aortic valve ring abscess extending into myocardium. Courtesy of Janet Jones, MD, Laboratory Service, Wichita Veterans Affairs Medical Center.

Opioid Use Disorder Infective Endocarditis (OUDIE)

Patients with right-sided intravenous drug abuse (IVDA) IE (53% of cases) frequently present with pleuropulmonary (pneumonia and/or empyema) manifestations. Symptoms from metastatic infection develop early in a disease course caused by S aureus. Right-sided disease is associated with a low rate of congestive heart failure and valvular perforation.[54]

Infection with P aeruginosa has a high rate of neurologic involvement, with 2 distinctive features: (1) mycotic aneurysms with a higher-than-average rate of rupture and (2) panophthalmitis (10% of patients). The course of infection with P aeruginosa is much slower than that of S aureus.

The course of left-sided IVDA IE is similar to that of non-IVDA disease.

Approximately 5-8% of febrile individuals who abuse IV drugs have underlying IE. Many users of illicit drugs may lose their fever within a few hours of hospitalization. This phenomenon, termed cotton wool fever, is probably caused by the presence of adulterants contained within the injected drugs.

Prosthetic valve endocarditis

Clinical features of PVE closely resemble those of NVE. Early PVE is defined as infection occurring within 60 days of valve implantation; late PVE occurs after this period. For valvular infection with CoNS, this division should be extended to 12 months.

Congestive heart failure occurs earlier and is more severe in persons with PVE. The patient may present with symptoms of myocarditis or pericarditis, and the rate of embolic stroke is high in the first 3 days of PVE.

Pacemaker infective endocarditis

The clinical presentation in a person with a pacemaker infection and pacemaker IE depends on several factors, including the site of infection (eg, generator pocket vs intravascular leads or epicardial leads), the type of organism, and the origin of the infection (eg, pocket erosion, localized infection of the generator pocket, bacteremia from a remote site). The risk of developing IE is directly associated with the complexity of the permanent pacemaker. The risk associated with internal cardiac defibrillators was almost twice that of single-chamber pacemakers. Mortality also was greater in the former group.

Half of cases of right-sided IE associated with a cardiac device are a result of CoNS.[55]

Early infections, within a few months of implantation, manifest as acute or subacute infections of the pulse-generator pocket. Bacteremia may be present even in the absence of clinical signs and symptoms. Fever is the most common finding and may be the only finding in approximately 33% of patients.

Late infections of the pocket may be due to erosion of the overlying skin without systemic involvement. Such erosions always indicate infection of the underlying device.

The most significant late infections involve the transvenous or epicardial leads. With epicardial infection, signs and symptoms of pericarditis or mediastinitis may be present along with bacteremia. Infection of the transvenous electrode produces signs and symptoms of right-sided endocarditis. Those that occur early after implantation (33% of cases) show prominent systemic signs of infection, often with obvious localization to the pacemaker pocket.

Late infections have much more subtle manifestations. They may occur up to several years after implantation or reimplantation.

Fever is almost universal in persons with pacemaker IE. Signs of right-sided endocarditis (ie, pneumonia, septic emboli) are observed in up to 50% of patients.

Healthcare infective endocarditis (HCIE)

Healthcare infective endocarditis commonly presents with elements of sepsis (ie, hypotension, metabolic acidosis, fever, leukocytosis, and multiple organ failure). The source of bacteremia may develop from an infection in another organ (eg, pneumonia, pyelonephritis) or from a central venous catheter. These patients most often are in the intensive care unit.

The aging of the population is associated with an increased incidence of staphylococcal healthcare-associated endocarditis, in addition to an increased mortality rate linked to the disease.[43]

Approximately 45% of cases of HCIE occur in patients with prosthetic valves.

Infective endocarditis associated with dialysis catheters has a fairly high rate of MRSA involvement. Eighty percent of cases involve the mitral valve.[47]  

General findings

Fever, possibly low-grade and intermittent, is present in 90% of patients. 

The American Heart Association (AHA; endorsed by the Infectious Diseases Society of America [IDSA]) guideline on cardiovascular implantable electronic device (CIED) infections and their management recommends that patients with CIED who develop unexplained fever or BSI should seek evaluation for CIED infection by cardiologists or infectious disease specialists.[55]

Heart murmurs are present in 85% of patients. Change in the characteristics of a previously noted murmur occurs in 10% of these patients and increases the likelihood of secondary congestive heart failure.

One or more classic signs of IE are found in as many as 50% of patients. They include the following:

• Petechiae - Common but nonspecific finding
• Subungual (splinter) hemorrhages - Dark red linear lesions in the nailbeds
• Osler nodes - Tender subcutaneous nodules usually found on the distal pads of the digits
• Janeway lesions - Nontender maculae on the palms and soles
• Roth spots - Retinal hemorrhages with small, clear centers; rare and observed in only 5% of patients.

A middle-aged man with a history of intravenous drug use who presented with severe myalgias and a petechial rash. He was diagnosed with right-sided staphylococcal endocarditis.

Signs of neurologic disease occur in as many as 40% of patients. Embolic stroke with focal neurologic deficits is the most common etiology. Other etiologies include intracerebral hemorrhage and multiple microabscesses.[1]

Signs of systemic septic emboli result from left heart disease and are more commonly associated with mitral valve vegetations. Multiple embolic pulmonary infections or infarctions are due to right heart disease.

Signs of congestive heart failure, such as distended neck veins, frequently are due to acute left-sided valvular insufficiency.

Splenomegaly may be present.

Other signs include the following:

• Stiff neck
• Delirium
• Paralysis, hemiparesis, aphasia
• Conjunctival hemorrhage
• Pallor
• Gallops
• Rales
• Cardiac arrhythmia
• Pericardial rub
• Pleural friction rub

Subacute infective endocarditis

Approximately 3-5% of patients with subacute IE (primarily elderly and chronically ill individuals) have normal or subnormal temperatures. Most patients have detectable heart murmurs. The presence of a murmur is so common (99% of cases) that its absence should cause clinicians to reconsider the diagnosis of IE. The major exception is right-sided IE, in which only one third of patients have a detectable murmur.[20, 21, 22, 51]

As many of these murmurs are hemodynamically insignificant and have been present for years, their role in the patient’s illness may be underestimated. In SBE, only 15 % of preexisting murmurs are documented to change. 

The peripheral lesions of subacute IE are observed in only approximately 20% of patients, compared with 85% in the preantibiotic era. The most common of these is petechiae. They may occur on the palpebral conjunctivae, the dorsa of the hands and feet, the anterior chest and abdominal walls, the oral mucosa, and the soft palate.

Subungual hemorrhages (ie, splinter hemorrhages) are linear and red. They usually are caused by workplace trauma to the hands and feet rather than by valvular infection. Hemorrhages that do not extend for the entire length of the nail more likely are the result of infection rather than trauma.

Osler nodes are smallish tender nodules that range from red to purple and are located primarily in the pulp spaces of the terminal phalanges of the fingers and toes, soles of the feet, and the thenar and hypothenar eminences of the hands. Their appearance often is preceded by neuropathic pain. They last from hours to several days and remain tender for a maximum of 2 days. The underlying mechanism is probably the circulating immunocomplexes of subacute IE. They have been described in various noninfectious vasculitides.

Clubbing of fingers and toes almost universally was found, but it now is observed in less than 10% of patients. It primarily occurs in those patients who have an extended course of untreated IE.

The arthritis associated with subacute IE is asymmetrical and is limited to 1 to 3 joints. Clinically, it resembles the joint changes found in patients with rheumatoid arthritis, Reiter syndrome, or Lyme disease. The fluid is usually sterile.

Splenomegaly is more commonly observed in patients with long-standing subacute disease and may persist long after successful therapy.

Roth spots are retinal hemorrhages with pale centers. The Litten sign represents cotton-wool exudates.

Acute infective endocarditis

In approximately one third of patients with acute IE, murmurs are absent. The most common type is an aortic regurgitation murmur. Because of the suddenness of onset, the left ventricle does not have a chance to dilate. In this situation, the classic finding of increased pulse pressure in significant valvular insufficiency is absent.

Fever is always present, and it usually is high.

Janeway lesions are irregular erythematosus and painless macules (1-4 mm in diameter). They most often are located on the thenar and hypothenar eminences of the hands and feet. Janeway lesions usually represent an infectious vasculitis of acute IE resulting from S aureus infection.

Acute septic monoarticular arthritis in patients with acute IE most often is caused by S aureus infection.

Purulent meningitis may be observed in patients with acute IE, compared with the aseptic type observed in patients with subacute disease. Other neurologic findings are similar to those observed in patients with subacute disease.[52, 53, 54, 56, 57, 58, 59, 60, 61]

The following are potential complications of IE [51, 52, 53, 54, 56, 57, 58, 59, 60, 61, 62] :

• Myocardial infarction, pericarditis, cardiac arrhythmia
• Cardiac valvular insufficiency
• Congestive heart failure
• Sinus of Valsalva aneurysm
• Aortic root or myocardial abscesses
• Arterial emboli, infarcts, mycotic aneurysms
• Arthritis, myositis
• Glomerulonephritis, acute renal failure
• Stroke syndromes
• Mesenteric or splenic abscess or infarct
• Myocarditis or IE related to COVID-19 infection

Congestive heart failure caused by aortic valve insufficiency is the most common intracardiac complication of subacute endocarditis. It develops after months of untreated disease but may occur a full year following microbiological cure.

The complication of arterial embolization is second in frequency to congestive heart failure for both subacute and acute IE. The frequency of this complication has decreased, from 80% in the preantibiotic era to 15-35% today. The emboli usually are sterile because of the minimally invasive nature of the causative organisms (eg, S viridans).

Those most at risk are younger (20-40 years), have mitral or aortic valve (native or prosthetic) involvement, and are infected with certain organisms such as Candida or Aspergillus species, S aureus, Haemophilus parainfluenzae, group B streptococci, and nutritionally variant streptococci.

The prevalence of embolization appears to be the same for both types of disease. The most common areas of deposition include the coronary arteries, kidneys, brain, and spleen. Infarction at the site of embolization is common; abscess formation is not. Cerebral emboli occur in 33% of patients and the middle cerebral artery is involved most often.

Other neurologic embolic damage includes cranial nerve palsies, cerebritis, and mycotic aneurysms caused by weakening of the vessel walls and produced by embolization to the vasa vasorum. Mycotic aneurysms may occur in the abdominal aorta and the splenic, coronary, and pulmonary arteries.

In acute IE, the frequency of aneurysms and other suppurative intracardiac complications is high. In addition to valvular insufficiency, other intracardiac complications of acute IE include (1) aortocardiac and other fistulas, (2) aneurysms of the sinus of Valsalva, (3) intraventricular abscesses, (4) ring abscesses, (5) myocardial abscesses, (6) mycotic aneurysms, (7) septic coronary arterial emboli, and (8) pericarditis.

In patients with acute disease, especially disease caused by S aureus infection, emboli almost inevitably lead to abscesses in the areas where they are deposited. Multiple abscesses can occur in almost every organ, including the kidneys, heart, and brain. Mycotic aneurysms may occur in almost any artery. Paradoxically, they are less common in patients with acute IE.

It appears that older patients have higher rates of myocardial infarction and death but lower rates of neurological complications. 

The metabolic products of the gut and the oral microbiomes(fecal and mouth flora) may have significant positive and/or negative effects on the host. Much more is known about that of the gut. Initially, it was felt that the organisms of the gut microbiome were restricted to the surface biofilm of the intestinal tract. In some patients, they may invade the deeper tissue of the intestinal tract, where they may replicate. This process may be quite sloppy. Such can result in significant resistance to the available antibiotics and antifungals.

The pathogens of the microbiomes may also trigger widespread sterile inflammation that can persist after the valvular infection is eradicated. The patient may have pain along with elevation in various inflammatory markers. Microthrombi and aneurysms often are present, but clinically are usually "silent". The key in recognizing this phase is that the patient will state that the pain and other symptoms differ significantly from his or her valvular infection. The issue of anticoagulation in this situation must be decided on a case-by-case basis.

This 2-stage "attack " has been best worked out for S gordonii, a member of the S viridans group that migrated to the United States from Norway since the turn of 21st century. In reviewing several valvular infections, with this sterile inflammatory response much time was spent obtaining follow-up imaging studies prompted by over reading of these marginal findings.[53, 54, 61]

To improve the functioning of the microbiome, probiotics and prebiotics are added to many of the commercial foods that we ingest. Probiotics are living organisms that hopefully will improve the quality of the gut flora. Prebiotics are nutritional substances that are meant to nourish the probiotics. There is limited evidence that they are very helpful.[63]

The effects of probiotics on IE are becoming more apparent. Probiotics are substances or foods that contain live organisms. The mechanism of this is not clear, but the use of probiotics is extremely widespread and needs to be re-examined.[64]

There is evidence that altered antibiotics that reside in the deep gut microbiome may also subvert the beneficial effects of the probiotic flora.

The role of the oral microbiome has not been as well established. Procedures that disrupt the oral biofilm (tonsillectomy, gum surgery, dental extractions) are significant events.[61]  

The traditional diagnostic standard has been the documentation of a continuous bacteremia (> 30 min in duration). The need for indirect diagnostic techniques that are both specific and sensitive is increasing. The numbers of fastidious organisms has increased, and the rate of the classic peripheral stigmata of IE is much lower. Patients who are elderly, chronically ill, or immunosuppressed often are afebrile and unable to mount a significant fever or exhibit the classic stigmata of valvular infection.

A major clinical challenge is that at least 25% of S aureus BSIs represent IE or metastatic infections. The question is whether a continuous bacteremia in the presence of an intravascular line represents a valvular infection. Blood cultures should be drawn through intravascular lines only for the purpose of diagnosing catheter-related BSIs. Even then, they have limited value.

Because of the ability of S aureus to produce endotheliosis, the presence of a continuous bacteremia does not necessarily indicate an infected valvular vegetation. The attending has the strongest obligation to disprove such.

An important clue to continuous bacteremia/IE is the presence of S aureus bacteriuria associated with hematuria. Hematuria in the setting of IE results from embolic renal infarction or immunologically mediated glomerulonephritis. Echocardiography has become a useful tool for meeting this clinical challenge. 

Twenty-five percent of patients with staphylococcal bacteremia and 23% of those with catheters as the primary focus have evidence of IE on the basis of transesophageal echocardiography (TEE) findings, in the absence of clinical and transthoracic echocardiography (TTE) findings.[10]

Perform baseline studies, such as complete blood count (CBC), electrolytes, creatinine, blood urea nitrogen (BUN), glucose, and coagulation panel, and send to the laboratory for testing.

Anemia is common in subacute endocarditis, and leukocytosis is a hallmark of acute endocarditis. Erythrocyte sedimentation rate (ESR), although not specific, is elevated in more than 90% of cases. Decreased C3, C4, and CH50 are reported in SBE.

Rheumatoid factor (ie, “poor man’s circulating immune complex”) becomes positive in 50% of patients with subacute disease and resolves after successful treatment.

Proteinuria and microscopic hematuria are present in approximately 50% of cases.

Appropriate blood testing for COVID -19 should be performed.

Patients with PVE or right-sided disease may not have a continuous bacteremia. Five percent to 10% of patients have false-negative blood culture due to recent antibiotic use. Other causes include fastidious organisms and inadequate blood volume; a blood-to-broth ratio of 1:10 is recommended. With modern automated blood culture systems, fastidious organisms such as nutritionally variant streptococci and members of the HACEK group rarely cause culture-negative IE.

As many as 50% of positive blood culture results have been estimated to be falsely positive. This rate probably has decreased, but false-positive blood culture results remain a major diagnostic challenge. One such result can lead to 4 days of unnecessary patient hospitalization.

The significance of positive blood culture results correlates with the following:

• The type of organism
• The clinical setting (CoNS are significant in patients with prosthetic valves but not in those with native valves.)
• Multiple blood cultures positive for the same organism
• Shorter incubation time for recovery
• The degree of severity of clinical illness

Procedure

Never draw only 1 set of blood cultures; 1 is worse than none. Two sets of blood cultures have greater than 90% sensitivity when bacteremia is present. Three sets of cultures improve sensitivity and may be useful when antibiotics have been administered previously.

The AHA (endorsed by IDSA) guideline update on CIED infections and their management recommends drawing at least 2 sets of blood cultures at evaluation before starting antimicrobial therapy.[27]

For diagnosing subacute IE, draw 3 to 5 sets of blood cultures over 24 hours. This helps detect 92-98% of cases in patients who have not recently received antibiotics. In the case of acute IE, 3 sets may be drawn over 30 minutes (with separate venipunctures) to help document a continuous bacteremia.

Using various types of blood culture bottles (with resins added to interfere with antibiotic action) probably has little advantage. Some of these may interfere with bacterial growth.

When blood culture results fail to show an infectious agent after blood is drawn 48 hours after the discontinuation of antibiotic therapy, the second set of blood for cultures should be drawn approximately 7 days later. If these later culture results remain negative, the diagnosis of IE must be reconsidered. In general, blood for culture should not be drawn through IV lines unless this is part of an approach for diagnosing line infection.[65, 66, 67, 68, 69, 70]

Catheter infection

The diagnosis of catheter infection may be made in 1 of 2 ways. Culturing the device via the roll-plate semiquantitative method is the most common approach but requires a catheter removal. In the case of long-term catheters, blood may be drawn simultaneously through the line and the peripheral vein. If it is impossible to draw blood from a peripheral vein in the presence of a multilumen catheter, 1 sample may be obtained through each of 2 catheter lumens.

In a catheter infection, the colony count of the sample obtained from the suspected port is threefold greater than that drawn from a peripheral vein or from another port of the catheter. Retrieval of organisms from blood drawn from a catheter hub at least 2 hours before their growth is detected in the blood obtained from peripheral vein meets the differential time to positivity criteria of a catheter infection.

A sterile culture of the insertion site has a highly negative predictive value for line infection.[66, 67, 68]

Culture-negative infective endocarditis

Approximately 5% of cases of possible IE yield negative blood culture results (ie, culture-negative IE). Patients with culture-negative IE occasionally present with signs and symptoms highly suggestive of IE, but the blood cultures remain negative.

Culture-negative IE may have noninfectious causes (eg, vasculitis) or may be caused by fastidious organisms. Modern blood culture systems recover the vast majority of pathogens within 4 to 5 days, including members of the HACEK group and Abiotrophia species. Overall, the most common cause of culture-negative IE is prior antimicrobial therapy that can suppress bacterial growth within the vegetation but is insufficient to eliminate the valvular infection.

In certain populations, infections with Coxiella burnetii (in southern France and Israel) and Bartonella species (among homeless persons) have become more frequent causes of culture-negative IE. The blood culture results in fungal valvular infections often are sterile. In S aureus IE, the results of blood cultures may be negative when the organism burrows deep within the thrombus, leaving the surface of the valvular thrombus sterile (surface sterilization).

Valvular vegetations may be detected during cardiac ultrasonographic examinations, but the blood culture results are persistently negative. In this situation, 3 separate blood cultures spaced over a 24-hour period usually are sufficient to detect microorganisms in the blood. Additional blood cultures usually are not helpful.

Many pathogens once considered to be fastidious are no longer classified as such (see above). Bartonella, Legionella, and C burnetii remain significant causes of culture-negative IE. These require special culture media or a prolonged incubation period for retrieval.

Serology for Chlamydia, Q fever (C burnetii), and Bartonella may be useful in culture-negative endocarditis. Serologic tests often are the most practical means for diagnosing valvular infection with fastidious organisms (eg, C burnetii and Chlamydia, Brucella, and Legionella species).[65] Buffered charcoal and yeast agar are required for the isolation of Legionella. Brucella species require up to 6 weeks.

It appears that Tropheryma whipplei, which causes Whipple disease, is becoming a more common cause of culture-negative endocarditis. Thuny and colleagues[71]  have developed an algorithm for the workup of negative blood cultures. The first stage is to obtain serologies for Q fever and Bartonella.

Rheumatoid factor and antinuclear antibody testing are performed to rule out rheumatologic diseases. If testing is negative, a dedicated polymerase chain reaction (PCR) test for Bartonella species and T whipplei should be performed as well as a broad range PCR for the detection of fungi, especially in the setting of a prosthetic valve. If there is no yield from this second tier, especially with a history of antecedent antibiotic therapy, a SeptiFast (Roche Diagnostics, Mannheim, Germany) blood PCR should be performed to detect any staphylococci. In addition, serologic testing for Mycoplasma pneumoniae, Legionella pneumophila and Brucella melitensis should be carried out. 

Fungal infective endocarditis

Cases of fungal IE often have a low rate of positive blood culture results. Only 50% of cases of Candidal blood cultures are positive. Histoplasma and Aspergillus almost never are retrieved from the bloodstream. Fungal endocarditis always must be considered in the clinical setting of culture-negative IE that fails to respond to appropriate antibiotic therapy.[72]

Pacemaker infective endocarditis

Establishing the diagnosis of pacemaker IE is difficult because of its subtle presentation, especially late-onset disease. The addition of pocket infection and the presence of pulmonary emboli to the Duke criteria have increased the rate of diagnosis from 16% to 87.5% of cases. Fever and/or a positive blood culture result without evidence of a primary source in patients with a pacemaker or implantable cardioverter-defibrillator should be considered to represent device-associated IE until proven otherwise. 

The AHA guideline on CIED infections recommends that, when the CIED is explanted, culture of the lead tip and Gram stain and culture of the generator-pocket tissue be obtained; however, percutaneous aspiration of the generator pocket should not be performed for diagnostic evaluation of CIED infection.[43, 51, 73]

The development of the MALDI-TOF allows the ability to identify bacterial or fungal species directly on the culture plates as quickly as they become evident. There is no proven effect on limiting the development of antimicrobial resistance. It does not provide information on the resistance/sensitivity patterns of the detected organisms.

The recent availability of molecular diagnostics such as PCR, multiplex PCR nanoparticle probes, and PNA FISH allow bypass of the incubation step of traditional culture methods. It does so by identifying organisms’ specific DNA/RNA directly. It allows multiple targets to be detected from one sample and provides some information on resistance factors inherent in the isolated organisms. Its advantages besides reduced turnaround time are greater accuracy than offered by Maldi-Tof systems as well as providing genetic information regarding sensitivity and resistance patterns. Their limitations include being susceptible to contamination. In polymicrobial cultures, they may not cover all the possible causative pathogens and do not provide phenotypic susceptibility profiles. There is a little data supporting the impact on clinical outcomes or proven effectiveness on limiting the development of antibiotic resistance.[74]

Echocardiography has become the indirect diagnostic method of choice, especially in patients who present with a clinical picture of IE but who have nondiagnostic blood culture results (eg, some patients with fungal endocarditis). The diagnosis of IE can never be excluded on the basis of negative echocardiogram findings, either from transthoracic echocardiography (TTE) or from TEE.

The AHA guideline on CIED infections recommends TEE to evaluate the left-sided heart valves for all adults suspected of having CIED-related endocarditis, even if TTE has shown lead-adherent masses. If TTE views are good, TTE may be sufficient for pediatric patients. Patients with positive blood culture results or negative blood culture results taken after recent antimicrobial therapy should undergo TEE for CIED infection or valvular endocarditis. 

Visible vegetation suggests a worse prognosis. Both TTE and TEE are highly specific for valvular vegetations; however, sensitivity differs.

Two-dimensional cardiac Doppler ultrasound testing is a significant advance for the diagnosis and evaluation of IE. It provides information about the presence and size of vegetations, which helps in diagnosis and, to some extent, in predicting embolization.

Transthoracic echocardiography is more sensitive for detecting anterior myocardial abscesses and quantitating the degree of valvular dysfunction.

The Doppler method can be used to detect distorted blood flow and certain types of cardiac pathology not otherwise visualized by standard echocardiography. It is good for visualizing jet lesions and differentiating cusp perforation from valvular insufficiency.

The combination of TEE and color Doppler is excellent for detecting intracardiac fistulas. The resolution of both TEE and TTE in real time is approximately 2 mm.

Conditions that are positively related to the detection of valvular thrombi include the location (ie, right-sided structures are poorly visualized, especially by TTE); disease lasting longer than 2 weeks; abscesses of the valves or myocardium; and aneurysms of the sinus of Valsalva.

Transthoracic echocardiography generally has had a sensitivity of approximately 60% for identification of valvular lesions in patients with NVE; however, sensitivity was as high as 82% in a recent series where advanced harmonic imaging and digital processing techniques were used.[69] Transthoracic echocardiography has a sensitivity of only 20% in patients with PVE.

This is a magnified portion of a parasternal long axis view from a transthoracic echocardiogram. There is a small curvilinear vegetation on the mitral valve as indicated. The patient presented with a headache and fever, and CT scan of the brain revealed an occipital hemorrhage. The patient had a history of intravenous drug use and multiple blood cultures grew Staphylococcus aureus.

Transesophageal echocardiography was developed to overcome the problems in visualizing prosthetic valve thrombi and right-sided events. It eliminates the need for the operator to find a clear field for the beam. The use of higher-frequency waveforms is permitted because of the decreased distance between the heart and the probe. The sensitivity of TEE in detecting the vegetations of NVE is 90-100%. In patients with PVE, the sensitivity of TEE under optimal circumstances is greater than 90%.

Transesophageal echocardiography successfully visualizes vegetations of the leads or of the tricuspid valve in more than 90% of cases of pacemaker IE, compared with less than the 50% achieved by TTE.

Neither TEE nor TTE should be used for screening purposes (ie, patients with fever of unknown origin or those with positive blood culture results and no other signs or symptoms of IE), because nearly 60% of vegetations revealed are sterile. Approximately 15% of positive study results are false positives because the images are, in reality, not those of vegetations but of thickened valves, nodules, or valvular calcifications.

Echocardiography is useful for predicting the potential complications of IE, especially those that are embolic in nature.

Echocardiographic predictors of systemic embolization in patients with IE are the following:

• Large valvular vegetations (>10 mm in diameter)
• Multiple vegetations
• Mobile pedunculated vegetations
• Noncalcified vegetations
• Vegetations that are increasing in size
• Prolapsing vegetations

Echocardiography is also highly useful for detecting abscesses. As with valvular lesions, the transesophageal technique is generally more sensitive.[75, 76, 77, 78, 79, 80, 81]

In summary, the indications for performing echocardiography with Doppler in patients with IE are to provide a baseline in proven or highly suggestive cases of IE and to provide a means of documenting complications during therapy.

In most cases, TTE is sufficient. Transesophageal echocardiography is indicated when mechanical prosthetic valves are present; to detect right-sided lesions; and to visualize myocardial abscesses. Because of the endoscopic portion of the test, TEE carries the risk factor of inducing bacteremias. Approximately 15% of IE cases do not demonstrate any detectable vegetations at the time of the echocardiographic study.

Pulmonary embolic phenomena on radiographs strongly suggest tricuspid disease.

A young adult with a history of intravenous drug use, endocarditis involving the tricuspid valve with Staphylococcus aureus, and multiple septic pulmonary emboli. Pulmonary lesions on chest radiograph are most prominent in the right upper lobe with both solid and cavitary appearance.

Multiple embolic pyogenic abscesses may be visualized.

Ventilation/perfusion scanning may be useful in right-sided endocarditis.

Electrocardiography may help detect the 10% of patients who develop a conduction delay during IE by documenting an increased P-R interval. Nonspecific changes are common. First-degree atrioventricular (AV) block and new interventricular conduction delays may signal septal involvement in aortic valve disease; both are poor prognostic signs.

Updating of the Duke Criteria was conducted by a working group of the International Society for Cardiovascular Infections{ISCVID} in 2023.[6]  These criteria incorporated recognition of new microbiological techniques, new imaging studies, and direct intraoperative inspection as major criteria. Organisms that only infect implanted material are now to be classified as "Typical."

Standards for the timing and separation of individual blood cultures were abolished, and predisposing conditions such as prior IE were clarified.

These standards are to be updated as required and documented online to maintain it as a "living" document.

Concerns:

The criteria may undermine the significance of supporting the keystone characteristic of IE, that of a continuous bacteremia.

The criteria may not recognize the limitations of scanning modalities.

Not recognizing the role that the same pathogen that caused the IE can prolong the patient's suffering by triggering a massive inflammatory response; this often is the case in S gordonii infections.

To the author, the most concerning factor is that this approach will be regarded as artificial intelligence (AI) and mandated by third parties..

Experience has been gained with completing the last 2 to 3 weeks of antibiotic treatment via the oral route. Candidates for this switch are those who had rapidly cleared their BSI; rapidly defervesced; and showed no evidence of embolization or growth of their vegetations. There is no apparent need for cardiac surgery in the near future. Antibiotics are given orally for long-term suppression of an infected device that cannot be removed. At least 1 of the prescribed agents must be documented to achieve bactericidal levels when taken by mouth. There must be no evidence of malabsorption. There should be no concerns about compliance with the treatment regimen (eg, cases of OUDIE). The evidence that supports the oral route is best established for gram-positive pathogens such as enterococci, MRSA, and CoNS.[72, 82]

The major goals of therapy for IE are to eradicate the infectious agent from the thrombus and to address the intra and extracardiac complications of valvular infection. The latter includes both the intracardiac and extracardiac consequences of IE. Some of the effects of IE require surgical intervention. Emergent care should focus on making the correct diagnosis and stabilizing the patient. General measures include the following:

• Treatment of congestive heart failure
• Supplemental oxygenation if required
• Hemodialysis may be necessary in the setting of severe renal failure

No special diets are recommended for patients with endocarditis. The presence of congestive heart failure calls for a sodium-restricted diet. Activity limitations are determined by the severity of the illness, complications (eg, stroke), and the presence of significant congestive heart failure.

General principles

All positive blood cultures should be evaluated by rapid diagnostic technology such as Malditof can identify pathogens(bacterial or fungal) within hours of documenting a positive gram stain. E-plex technology enhances traditional culture and sensitivity results by detecting specific resistance factors of a given pathogen. E-plex complements traditional methods of culture and sensitivity because it only surveys select pathogens and genes.[83] There may be disagreement between detected resistance markers and sensitivity patterns. This could be due to mechanisms simply not tested for or intrinsic resistance to a given antibiotic.[84]  

All patients with proven or highly suspected IE initially should be assessed by and actively followed by at least an infectious diseases consultant, especially as regards initial antibiotic therapy and any changes in such during the entire therapeutic course.

Generally avoid synergistic combinations except for those pathogens for which such therapy is clearly indicated, such as enterococci, S viridans, HACEK isolates, and infections of intracardiac devices. For other pathogens, true synergistic effect seldom is achieved, and possible side effects are more frequent. A possible exception may be the combination of daptomycin and fosfomycin in severely immunosuppressed individuals (eg, patients being treated for acute leukemia).[85]

In general, avoid the use of vancomycin. It is extremely challenging to achieve and sustain therapeutic levels in situations of unstable renal function. Gentamicin may need to be added because a growing degree of tolerance of staphylococci and enterococci to vancomycin may induce partial resistance of bacteria to daptomycin and other antibiotics by inducing cellular wall thickening.

In the setting of acute IE, institute antibiotic therapy as soon as possible to minimize valvular damage. Three to 5 sets of blood cultures are obtained within 60 to 90 minutes, followed by the infusion of the appropriate antibiotic regimen. If molecular blood testing is not available, the initial antibiotic choice is arrived at by SA and attention to local resistance patterns. 

Native valve endocarditis (NVE) has often been treated with penicillin G and gentamicin for synergistic coverage of streptococci. Patients with a history of IV drug use have been treated with nafcillin and gentamicin to cover for methicillin-sensitive staphylococci. The emergence of methicillin-resistant S aureus (MRSA) and penicillin-resistant streptococci have led to a change in empiric treatment.

Prosthetic valve endocarditis (PVE) usually is caused by MRSA or CoNS.[28]  

Vancomycin and gentamicin classically have been administered despite the risk for renal insufficiency. Rifampin is necessary for individuals with infection of prosthetic valves or other intravascular devices because it penetrates the biofilm that protects the primary pathogens of these devices (CoNS, MSSA, MRSA). These latter 2 agents serve to prevent the development of resistance to the rifampin.

Linezolid or daptomycin are options for patients with intolerance to vancomycin or resistant organisms.[86] Organisms with a minimum inhibitory concentration (MIC) to vancomycin of 2 mcg/mL or higher should be treated with alternative agents. Appropriate regimens should be devised in consultation with a specialist in infectious diseases.

In the cases of SBE, treatment generally may be safely delayed until culture and sensitivity results are available. If the patient's condition is stable, waiting does not increase the risk for complications in this form of the disease.

Eradicating bacteria from the fibrin-platelet thrombus is extremely difficult because of (1) the high concentration of organisms present within the vegetation (ie, 10-100 million bacteria per gram of tissue), (2) their position deep within the thrombus, (3) their location in both a reduced metabolic and reproductive state, and (4) the interference of fibrin and white cells with antibiotic action. For all these reasons, bactericidal antibiotics are considered necessary for cure of valvular infection.

Evidence has shown that patients with left-sided endocarditis in stable condition who received at least 10 days of intravenous antibiotics could be switched to oral administration for the remainder of their therapeutic course.[82]  Anecdotally, highly absorbed antibiotics such as linezolid have been used when intravenous access has been impossible to procure.

Treat all patients in a hospital or skilled nursing facility to allow adequate monitoring of the development of complications and the response to antibiotic therapy.

The American Heart Association (AHA) has developed guidelines for treating IE caused by the most frequently encountered microorganisms.[87] The below represents an updating of the guidelines of the AHA that is necessitated by changing sensitivity patterns of the infecting organisms. In addition, the value of IV/PO linezolid and minocycline in the treatment of gram-positive cocci and transitioning to oral therapy is clearer. 

Antibiotic doses are predicated on normal renal function.

Adult NVE caused by penicillin-susceptible S viridans, S bovis, and other streptococci (MIC of penicillin of ≤0.1 mcg/mL) should be treated with 1 of the following regimens:

• Administer penicillin G at 12-18 million units/day (U/d) IV by continuous pump or in 6 equally divided doses for 4 weeks.
• Administer ceftriaxone at 2 g/d IV for 4 weeks. It may be given intramuscularly (IM) for short periods if venous access problems develop; ceftriaxone allows once-a-day outpatient IV therapy for clinically stable patients.
• Administer penicillin G and gentamicin at 1 mg/kg (on the basis of ideal body weight) every 8 hours for 2 weeks; short-course therapy with ceftriaxone and gentamicin for 2 weeks is a cost-effective regimen and is effective in selected patients; short-course therapy is recommended for those with uncomplicated NVE caused by sensitive S viridans and of less than 3 months’ duration.
• In patients who are allergic to penicillin, give vancomycin at 30 mg/kg/d IV in 2 equally divided doses for 4 weeks; the vancomycin dose should not exceed 2 g/d unless serum levels are monitored and can be adjusted to attain a peak vancomycin level of 30-45 mcg/mL 1 hour after completion of the intravenous infusion of vancomycin.

For NVE caused by relatively resistant streptococci (MICs of penicillin of 0.1-0.5 mcg/mL), the following regimens are recommended:

• Administer penicillin G at 18 million U/d IV, either by continuous pump or in 6 equally divided doses, for 4 weeks.
• Administer cefazolin at 6 g/d IV in 3 equally divided doses for 4 weeks.
• Both of the above regimens are combined with gentamicin at 1 mg/kg (on the basis of ideal body weight) IM or IV every 8 hours for the first 2 weeks of therapy.
• For patients who are allergic to penicillin, administer vancomycin at 30 mg/kg/d IV in 2 equally divided doses (usually, do not exceed 2 g/d unless serum levels are monitored) for 4 weeks; peak vancomycin levels of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.

​Enterococcal Therapy

Infective endocarditis caused by nonresistant enterococci, resistant S viridans (MICs of penicillin G of >0.5 mcg/mL), or nutritionally variant S viridans and PVE caused by penicillin-G–susceptible S viridans or S bovis should be treated as follows:

• Administer penicillin G at 18-30 million U/d IV, either by continuous pump or in 6 equally divided doses daily, combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4-6 weeks.
• Alternatively, administer ampicillin at 12 g/d by continuous infusion or in 6 equally divided doses daily, combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4-6 weeks.
• In patients who are allergic to penicillin, administer vancomycin at 30 mg/kg/d in 2 equally divided doses (usually, do not exceed 2 g/24 h unless serum levels are monitored). This may be combined with gentamicin for 4-6 weeks of treatment. A peak vancomycin level of 30-45 mcg/mL should be attained 1 hour after completion of the intravenous infusion.

Enterococcal PVE generally responds as well as disease involving native valves. Six weeks of treatment is recommended for patients with symptoms of enterococcal IE of more than 3 months’ duration, with relapsed infection, or with PVE. Combination treatment for resistant E faecium with ceftriaxone 2 grams every 24 hours for at least 8 weeks plus ampicillin 12 g every 24 hours for at least 8 weeks appears to be the preferred approach.

A combination of an inhibitor of cell wall synthesis (ie, penicillin) with an aminoglycoside (ie, gentamicin, streptomycin) is necessary to achieve bactericidal activity against the enterococci. Tobramycin or amikacin do not act synergistically with antibiotics active against the bacterial cell wall.

Increasing numbers of enterococci have aminoglycoside-inactivating enzymes that make them relatively resistant to the usual synergistic combinations. These aminoglycoside-resistant strains have an MIC of 2000 mcg/mL or more for streptomycin and 500 mcg/mL or more for gentamicin. Of gentamicin-resistant enterococcal strains, 25% are susceptible to streptomycin.

Continuously infused ampicillin (serum level of 16 mcg/mL) is probably the best therapy for aminoglycoside-resistant enterococci. Alternative choices are imipenem, ciprofloxacin, or ampicillin with sulbactam. Vancomycin does not appear to be as useful as the aforementioned antibiotics.

Double beta-lactam therapy (ampicillin 2 g IV every 4 hours and ceftriaxone 2 g IV every 12 hours) is recommended for treatment of enterococci susceptible to penicillin and gentamicin when the creatinine clearance is less than 50 mL/min. This combination may be effective against enterococcal isolates that are resistant to high doses of gentamicin.

High peak levels of gentamicin are not necessary to establish synergistic bactericidal activity against enterococci. Peak gentamicin levels of 3-5 mcg/mL, with a trough of less than 2 mcg/mL, frequently can be obtained with a dose of gentamicin of 1 mg/kg IV every 8 hours. Once-a-day gentamicin dosing should not be used because a prolonged postantibiotic effect against gram-positive organisms does not occur, and synergistic killing requires the simultaneous presence of an agent active in the cell wall and an aminoglycoside.

A study indicates that gentamicin usage, even for synergy, is associated with decreasing renal function[86] ; however, overall mortality does not appear to be increased. Certainly, gentamicin therapy should be continued to achieve synergy against enterococci, but the practice of administering gentamicin for 5 days in the treatment of S aureus IVDA IE should be questioned.

Vancomycin-resistant isolates of Enterococcus faecium and Enterococcus faecalis (ie, vancomycin-resistant enterococci [VRE]) produce some of the most challenging nosocomial infections. No therapy has been proven highly effective for IE caused by strains of VRE.

NVE caused by methicillin-sensitive S aureus (MSSA) should be treated as follows:

• Administer nafcillin or oxacillin at 2 g IV every 4 hours for 4-6 weeks.
• Administer cefazolin at 2 g IV every 8 hours for 4-6 weeks.
• For patients who are allergic to penicillin, administer vancomycin at 30 mg/kg (usually, do not exceed 2 g/24 h unless serum levels are monitored) for 4-6 weeks and obtain a peak vancomycin level of 30-45 mcg/mL 1 hour after completion of the IV infusion.

Vancomycin therapy is associated with a significant failure rate (up to 35%) in the treatment of MSSA and MRSA BSI/IE. It appears that vancomycin should not be used to treat infections with staphylococci with an MIC of greater than 1.5-2 mcg/mL. In these cases, alternative agents such as linezolid or daptomycin should be used.

Outpatient treatment of nonenterococcal streptococci, MSSA, MRSA, VISA, CoNS, and VSE IE may be facilitated by use of dalbavancin, which requires IV administration every 7 days.[88]

Treat PVE caused by MSSA as follows:

• Administer nafcillin or oxacillin at 2 g IV every 4 hours for 6 weeks or longer.
• Alternatively, administer cefazolin at 2 g IV every 8 hours for 6 weeks or longer.
• Each of these options should be combined with rifampin at 300 mg orally every 8 hours for 6 weeks or longer and with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for the first 2 weeks.
• Treat PVE caused by MRSA with vancomycin at 30 mg/kg (not to exceed 2 g/d unless serum levels are monitored) for 6 weeks or longer combined with rifampin and gentamicin as outlined above; a peak vancomycin level of 30-45 mcg/mL should be attained 1 hour after completion of the IV infusion; a significant concern is that MRSA may become resistant to vancomycin.

Treatment with linezolid appears to result in outcomes superior to those with vancomycin against many types of infections caused by MRSA and MSSA. Another advantage of linezolid is that its dose does not need to be adjusted in patients with renal failure. Its excellent GI absorption facilitates transition to complete treatment orally. White blood cell counts, red blood cell counts, and platelet counts need to be monitored frequently while the patient is on linezolid. The risk of developing serotonin syndrome is low.

After the fourth week of therapy, the risk for hematologic and neuropathic complications rapidly increases.

Daptomycin (6 mg/kg/24 h) has been approved for the treatment of S aureus BSI and right-sided IE. Higher doses of daptomycin (12 mg/kg/24 h) are more effective, with little increase in adverse effects. Patients who have received vancomycin have a higher rate of resistance to daptomycin.

Treat HACEK microorganisms as follows:

• Administer ceftriaxone at 2 g/d IV for 4 weeks.
• Alternatively, administer ampicillin at 12 g/d by continuous pump or in 6 equally divided doses daily; this may be combined with gentamicin at 1 mg/kg (based on ideal body weight) IM or IV every 8 hours for 4 weeks.

Culture-negative NVE is usually treated with vancomycin and gentamicin. In patients who previously have received antibiotics, initial therapy should consist of either ampicillin-sulbactam plus gentamicin (3 mg/kg/d) or vancomycin plus gentamicin and ciprofloxacin. Because of the increased risk for renal failure with gentamicin, the latter regimen is preferred.

Patients with culture-negative PVE should be given daptomycin or meropenem or linezolid targeting possible enterococcal or CoNS infections. In patients with suspected PVE who have previously received antibiotics, therapy should consist of daptomycin or linezolid for 6 weeks and rifampin for 6 weeks. There is a risk of developing resistance to rifampin; therefore, many clinicians would start this antibiotic only after the blood cultures results become negative.

Treatment of other microorganisms is as follows:

• For P aeruginosa, administer ceftazidime, cefepime, or imipenem, combined with high-dose tobramycin at 8 mg/kg/d in 3 divided doses, to attain peak blood levels of 15-20 mcg/mL, for 6 weeks.
• For enteric gram-negative rods (eg, E coli, Proteus mirabilis), administer ampicillin, ticarcillin-clavulanic acid, piperacillin, piperacillin-tazobactam, ceftriaxone, or cefepime combined with gentamicin or amikacin for 4-6 weeks.
• For Streptococcus pneumoniae, administer ceftriaxone at 2 g/d IV or vancomycin (if penicillin allergy or high-level penicillin G resistance [MIC of 2 mcg/mL or more]) for 4 weeks.
• For diphtheroids, administer penicillin G at 18-24 million U/d in 6 divided doses or vancomycin combined with gentamicin for 4 weeks.
• For Q fever (C burnetii infection), administer doxycycline combined with rifampin, trimethoprim-sulfamethoxazole, or a fluoroquinolone for 3-4 years.

Prosthetic valve endocarditis is especially difficult to treat, as the microorganisms adhere to the foreign body and may make them impervious to the bactericidal action of agents active in the cell wall. All patients with PVE require at least 6 weeks of antimicrobial therapy. Rifampin is the key drug in the treatment of PVE, as it is one of the only antimicrobial agents that penetrate the biofilm laid down by S aureus and CoNS. As a result of the risk of these organisms developing resistance to rifampin, many clinicians withhold the addition of rifampin until blood cultures have cleared.

Penicillin-sensitive S viridans PVE should be treated with 2 weeks of penicillin G or ceftriaxone combined with gentamicin, followed by 4 weeks of penicillin G or ceftriaxone.

If the S viridans PVE is caused by an organism with a penicillin MIC of 0.2 mcg/mL or more, penicillin G or ceftriaxone combined with gentamicin combination therapy should be administered for 4 to 6 weeks. If the combination therapy is administered for only 4 weeks, penicillin G or ceftriaxone should be continued for an additional 2 weeks. Linezolid may be substituted for penicillin or ceftriaxone if the patient has a history of severe, immediate penicillin hypersensitivity, such as urticaria, anaphylaxis, or angioedema.

Enterococcal PVE therapy is complicated by the multiple types of enterococcal antimicrobial resistance, including beta-lactamase production (rare), different types of aminoglycoside-inactivating enzymes (more common), and VRE (increasingly common). If the enterococci are highly resistant to both gentamicin and streptomycin, ampicillin should be administered for 8 to 12 weeks by continuous infusion.

Patients with PVE must be monitored carefully for signs of valve dysfunction, congestive heart failure, and heart block. They also should be monitored for clinical response to therapy, conversion of positive blood culture results, renal function status, and serum blood levels of vancomycin and aminoglycosides.

Valve replacement surgery should be performed promptly if any of the following occurs: moderate-to-severe congestive heart failure, valve dysfunction, perivalvular or myocardial abscess formation, the presence of an unstable valve that is becoming detached from the valve ring, more than 1 embolic episode with persistent vegetations observed on transesophageal echocardiogram, or the presence of vegetations larger than 1 cm in diameter.

If PVE does not respond to antimicrobial therapy and blood cultures results remain positive or if a relapse of bacteremia occurs after infection, the prosthetic valve should be replaced. In the presence of microorganisms that have no microbicidal agent (eg, VRE, fungi) or in the presence of other recalcitrant organisms (eg, P aeruginosa, S aureus, enteric gram-negative rods, Brucella species, C burnetii), past clinical experience shows that early replacement of the prosthetic valve improves the chances for cure.

Fungal endocarditis is rare, and it primarily occurs after prosthetic valve surgery and in individuals who abuse intravenous drugs. Candida species and Aspergillus species are the organisms most frequently encountered. Available antifungal agents have been unsuccessful in eliminating fungal IE. The only cures for proven fungal IE have resulted when surgical excision of the infected valves was combined with amphotericin B therapy.

Empiric therapy of OUDIE should be aimed at S aureus. The choice between using vancomycin or oxacillin/nafcillin depends on the incidence of MRSA in the community. Generally, gram-negative organisms occur infrequently, and delay in covering them initially is acceptable.

Monitoring During Therapy

Some clinicians obtain peak and trough blood samples during antimicrobial therapy of IE in order to run serum bactericidal tests. These tests are performed by incubating serial 2-fold dilutions of serum that contain antimicrobials with an inoculum of 100,000 colony-forming units per milliliter of the target microorganism that previously has been isolated from the patient’s blood for 24-48 hours.[72, 87, 89, 90, 91, 92, 93]

Peak antimicrobial concentrations that inhibit and kill the bacteria at a 1:32 or greater dilution in serum are a consistent predictor of a favorable clinical response. Antimicrobial dosages are adjusted to try to attain this goal. However, many clinicians feel that the serum bactericidal test does not have a reproducible result, and these clinicians rely on standardized tests of antimicrobial susceptibility (ie, MICs) and serum antimicrobial assays of peak and trough levels to determine whether sufficient amounts of antimicrobial agents are being administered.[72, 82, 86, 87, 89]

The basic criticism of these tests is that they are conducted in an in vitro environment outside the area of infection. Infected tissue can be hypoxic and acidotic with significant levels of inflammation. Such an environment can markedly interfere with the effectiveness of a wide range of antibiotics. It is not rare that after 4-8 weeks of therapy the patient appears to be cured. Two weeks after stopping the antibiotics, the individual relapses. More specific and sensitive laboratory tests must be developed to more accurately monitor therapeutic response.

In the past, management of S aureus bacteremia in the presence of an intravascular catheter required prompt removal of the catheter, initiation of appropriate antibiotic therapy, monitoring of blood culture results in 24 to 48 hours, and performance of transthoracic echocardiography (TTE).

If follow-up blood culture and TTE findings were negative and no evidence of metastatic infection was found, 2 weeks of antistaphylococcal therapy was believed to be appropriate.

If the follow-up blood culture findings are positive, TEE should be performed. If TEE demonstrates findings of valvular infection, the patient is to be treated for 4 to 6 weeks with antistaphylococcal antibiotics.

Individuals with an underlying implantable cardiac device or whose S aureus BSIs developed in the community are at highest risk for IE and therefore should undergo immediate TEE. If the TEE findings are negative, it should be repeated in 5 days[92]  if the cause of persistent BSI is not identified. A good deal of these may be explained by endotheliosis. For the time being, the duration of antibiotic therapy for each case of S aureus catheter-related BSI must be individualized.[91, 92, 93, 94, 95, 96, 97]

Although thrombosis may be a key element of IE, anticoagulation with warfarin (Coumadin, Jantoven) is controversial. Indeed, evidence indicates patients who are anticoagulated have worse outcomes than those who are not anticoagulated. Cases of non-COVID-19 IE that are treated with anticoagulation appear to have a higher rate of intracerebral bleeding. If an established reason for anticoagulation (eg, deep venous thrombosis, presence of a mechanical prosthetic valve) exists, a standard regimen of anticoagulation should be followed.

Please see COVID-19 associated IE.

Approximately 15% to 25% of patients with IE eventually require surgery.

Indications for surgical intervention in patients with NVE are as follows:

• Congestive heart failure refractory to standard medical therapy
• Fungal IE (except that caused by Histoplasma capsulatum)
• Persistent sepsis after 72 hours of appropriate antibiotic treatment
• Recurrent septic emboli, especially after 2 weeks of antibiotic treatment
• Rupture of an aneurysm of the sinus of Valsalva
• Conduction disturbances caused by a septal abscess
• Kissing infection of the anterior mitral leaflet in patients with IE of the aortic valve

Congestive heart failure in a patient with NVE is the primary indication for surgery. A second relapse, during or after completion of treatment, requires replacement of the valve.

Paravalvular abscess and intracardiac fistula almost always require surgical intervention. Patients with culture-negative NVE who remained febrile for more than 10 days should be considered surgical candidates. Persistent hypermobile vegetations, especially those with a history of embolization beyond 7 days of antibiotic therapy, should be treated with surgery. Cardiac surgery should be considered in patients with multiresistant organisms (eg, enterococci).

The indications for surgery in patients with PVE are the same as those for patients with NVE, with the addition of the conditions of valvular dehiscence and early PVE. Orally administered antibiotics have been used as suppressive therapy for incurable valvular infections (ie, inoperable PVE).

Surgery often is required for treatment of metastatic infections (eg, cerebral and other types of aneurysms and macroabscesses of the brain and spleen). Many cerebral abscesses may not be accessible. If this is the case, they can be monitored because 30% may heal when treated medically.

Occasionally, local debridement and the administration of appropriate antibiotics may be sufficient to cure an uncomplicated pacemaker pocket infection; however, most studies indicate that complete removal of the system is necessary for cure in most cases. Many patients in whom this is not possible eventually die of complications from relapsing infection. This aggressive approach is especially necessary when dealing with pacemaker IE.

The AHA guidelines on CIED infections and their management recommend complete removal of infected CIED and leads for the following patients[43] :

• All patients with definite CIED infection, as shown by valvular and/or lead endocarditis or sepsis. ^{[95, 98, 99]}  All patients with CIED pocket infection, as shown by abscess formation, device erosion, skin adherence, or chronic draining sinus without involvement of the transvenous section of the lead system
• All patients with valvular endocarditis without definite involvement of the lead(s), device, or both ^[100]

Patients with occult staphylococcal bacteremia

The guideline states that complete removal is reasonable in patients with persistent occult gram-negative bacteremia despite appropriate antibiotic therapy.[43]

Removal of the device and leads is not indicated in the following cases:

• A superficial or incisional infection that does not involve the device, leads, or both
• Relapsing BSI resulting from a non-CIED source and for which long-term suppressive antimicrobials are required

After removal of the infected device, placing a temporary transvenous pacer is best. Immediate insertion of a permanent pacemaker at a new site can be safely accomplished.

The AHA guideline on CIED infection recommends careful evaluation of each patient to determine if a CIED is still needed. Replacement device implantation should not be ipsilateral to the extraction site. The guideline suggests the contralateral side, the iliac vein, and epicardial implantation as preferred alternative locations.[31, 43]

The AHA guideline recommends that if blood cultures were positive before the device extraction, blood cultures should be taken after the device removal and new device placement should be delayed until blood cultures have been negative for at least 72 hours. If valvular infection is present, placement of new transvenous leads should be delayed for at least 14 days after CIED system removal.

In the past, removal of the intracardiac leads that had been in place for several months often necessitated open heart surgery. The use of laser technology to dissolve the pacemaker lead adhesions has a 94% success rate. The risk of dislodging vegetations during removal of infected leads is negligible. Patients whose leads cannot be removed are started on permanent antibiotic suppression.[71, 101, 102]

The AHA CIED guideline states that long-term suppressive antimicrobial therapy should be considered for patients with CIED infection who are not candidates for CIED removal. Such therapy should not be administered to patients who are candidates for CIED removal.[98, 99, 103, 104, 105, 106]

Approximately 15-25% of IE cases are a consequence of invasive procedures that produce a significant bacteremia. As only 50% of those who developed valvular infection after a procedure were identified as being candidates for antibiotic prophylaxis, only approximately 10% of cases of IE can be prevented by the administration of preprocedure antibiotics. Maintaining good oral hygiene probably is more effective in the overall prevention of valvular infection because gingivitis is the most common source of spontaneous bacteremias.

Since implementation of IE prevention guidelines in 2009 of the European Society of Cardiology, there has been a marked increase in cases of IE, the age of patients with mitral valve involvement, mortality, and associated comorbidities (renal failure, heart failure, diabetes).[107]

A follow-up in 2021 of the American Heart Association Guidelines did not document any increase in S viridans IE.[94]

Antimicrobial prophylaxis against IE should be given in patients at higher risk, including those with the following conditions:

• Presence of prosthetic heart valve
• History of endocarditis
• Cardiac valvulopathy in cardiac transplant recipients 
• Congenital heart disease with a high-pressure gradient lesion

The presence of a coronary artery stent is not considered to place the patient at high risk for endocarditis.

Also consider prophylaxis in patients before they undergo procedures that may cause transient bacteremia, such as the following[108] :

• Any procedure involving manipulation of gingival tissue or the periapical region of teeth, or perforation of the oral mucosa
• Any procedure involving incision in the respiratory mucosa
• Procedures on infected skin or musculoskeletal tissue including incision and drainage of an abscess
• Prophylaxis no longer is routinely recommended for gastrointestinal or genitourinary procedures.

Prevention of vascular catheter infections is an important prophylactic approach in preventing NIE. Protective factors include the insertion and maintenance of catheters by an infusion therapy team, the use of topical disinfectants and antibiotics, and the practice of coating catheters with antimicrobial agents.

No double-blind studies have been performed to support the use of systemically administered antibiotics for the prevention of pacemaker or intracardiac defibrillator infections. However, awaiting definitive studies, the authors recommend prophylactic antibiotics, as with any implantable device. Of course, strict sterile technique must be followed. Antibiotic prophylaxis is not recommended for prevention of CIED infection in patients with pacemakers or intracardiac defibrillators during invasive procedures not directly related to device manipulation. Pacemaker infection due to transient bacteremias is uncommon.[108]

There has been a significant increase in cardiac device infections and extractions of infected leads, especially among those older than 65 years.[73]  

The use of an absorbable envelope impregnated with rifampin and minocycline shows promise as a prophylactic measure to prevent CIED infections.[109]

American Heart Association guidelines for prophylaxis

The AHA periodically compiles recommendations for IE prophylaxis. It is important to remember that these are not standards but guidelines, and thus they may be modified in particular circumstances. The guidelines remain unproven by randomized controlled clinical trials; indeed, many examples of failure of these recommendations have been noted, even when they are applied appropriately.[31, 74, 75, 76, 77, 78, 82, 85, 87]

The 3 major steps in the pathogenesis of IE that are vulnerable to antibiotic prophylaxis are the following:

1. Killing of the pathogen in the bloodstream before it can adhere to the valve
2. Preventing adherence to the valve/fibrin-platelet thrombus
3. Eradicating any organisms that have attached to the thrombus

Successful antibiotic prophylaxis requires identifying those patients who are at risk, prioritizing the procedures that require prophylaxis, and selecting an appropriate antibiotic regimen. In general, bactericidal antibiotics are used; however, bacteriostatic agents probably are effective in most circumstances.

Although the guidelines are a marked improvement because they prioritize the cardiac conditions and procedures that require antibiotic prophylaxis and emphasize the importance of promoting good oral hygiene, they offer little direction in dealing with the ever-growing problem of antibiotic-resistance patterns of S viridans and enterococci.

The importance of antibiotic prophylaxis of calcific valvular disease in elderly patients also needs to be more fully discussed. Calcific valvular disease is the most common underlying cardiac risk factor for the development of IE in this age group.

The author’s preference is to administer parenteral prophylactic antibiotics to patients with prosthetic valves because of the severe consequences of PVE.

The United Kingdom’s NICE guidelines on prophylaxis against IE differ from the AHA recommendations. The NICE guidelines do not recommend antibiotic prophylaxis for IE in patients undergoing dental procedures; however, they agree with the AHA guidelines in not recommending prophylaxis for those undergoing procedures in the upper and lower gastrointestinal tracts, the genitourinary tract, or the upper and lower respiratory tracts.[49]

Subsequent to the NICE guidelines recommending abolition of all IE antibiotic prophylaxis, prescriptions for such prophylaxis dropped almost 80% without any apparent cases of IE; however, the authors of this article recommend continuing to follow the current AHA guidelines, especially in the presence of an intracardiac prosthetic device.

The rise in the rate of IE cases has called into serious question the validity of abolishing IE antibiotic prophylaxis. This increase has particularly affected individuals who would be deemed at high risk of developing valvular infection.[103, 104]

Failure to consider the diagnosis, especially in patients with a history of IV drug use and a low-grade fever, is a medicolegal pitfall. Many malpractice suits are caused by a failure to diagnose and a delay in diagnosis accompanied by a poor outcome for the patient.

As a rule for primary care clinics, do not administer antimicrobial agents to febrile patients with heart murmurs without first obtaining at least 2 sets of blood cultures.

The outcomes of staphylococcal bacteremia by telephone consults are significantly inferior to those of bedside evaluation.[105]  

The perception that most IE is preventable is incorrect. Frequent episodes of transient bacteremia occur with chewing and other activities of daily life. Proving that a failure to give prophylaxis before dental and surgical procedures resulted in IE is difficult; however, this does not prevent legal action alleging IE as a consequence of failing to give the antimicrobial prophylaxis recommended by the AHA.

When a central venous line is needed, not inserting the line when a patient is known to be bacteremic is advisable. If no alternative to placing the line is available, bactericidal antimicrobial agents should be administered to try to prevent the development of IE.

In general, both a cardiologist and an infectious diseases specialist should be involved in the care of patients with IE. A bedside consultation by an infectious disease specialist results in far better outcomes than the more frequent telephone consultation.[105]  Consulting a cardiothoracic surgeon may be necessary. Personnel in the clinical microbiology laboratory must have the skill to isolate the organism, properly identify it, and perform susceptibility testing appropriate for the growth characteristics and requirements of the organism (with determination of the MIC of clinically relevant antimicrobial agents). 

Monitoring for posttreatment bacteremia

Patients should have blood cultures taken after 3 to 4 days of treatment to document eradication of the bacteremia. Blood cultures during treatment are essential if persistent fever or other signs develop that suggest failing treatment.

Failure to sterilize the bloodstream, despite adequate serum levels of appropriate antibiotics, should prompt a search for metastatic infection (eg, abscesses, especially splenic, or mycotic aneurysms).

Monitoring of inflammatory markers such as CRP should be performed; frequency to be individualized. This would primarily be used to document the noninfectious process tagged by the valvular infection. 

Fever lasting longer than 10 days into therapy with an indicated antibiotic regimen should be of concern and should prompt a search for suppurative complications. Approximately 30% of patients have a return of fever after the initial response. This usually is caused by an intracardiac abscess or metastatic infection. Causes of unresponsive fever include myocardial or septal abscesses, large vegetations that resist sterilization, and metastatic infection. Occasionally, fever in patients with uncomplicated IE may take as long as 3 weeks to abate.

Monitoring for complications

Patients should be monitored for the development of the following complications:

• Valvular dysfunction, usually insufficiency of the mitral or aortic valves
• Myocardial or septal abscesses
• Congestive heart failure
• Metastatic infection
• Embolic phenomenon
• Organ dysfunction resulting from immunological processes

Complications, such as congestive heart failure resulting from valvular insufficiency and embolization, may occur after bacteriologic cure has been achieved. (Note that the diagnosis of developing congestive heart failure or valvular insufficiency is based on clinical findings, not solely on echocardiographic measurements.) The onset of valve dysfunction or moderate-to-severe congestive heart failure should lead to an evaluation for immediate valve replacement.

Monitoring for relapse

Relapse of IE usually occurs within 2 months of finishing clinically effective therapy. Infection with S aureus, enterococci, and gram-negative organisms (especially P aeruginosa) is associated with a high rate of relapse. Enterococcal infection of the mitral valve has the greatest potential for relapse.

Recurrent IE most often occurs in individuals who abuse IV drugs. Valvular infections in these patients recur at a rate of 40%. Those with  pretreatment symptoms of IE of more than 3 months’ duration are at greater risk for relapse. Other significant risk factors for recurrence include a previous episode of IE, the presence of a prosthetic valve, and congenital heart disease.

In general, infected vascular catheters should be removed and should not be replaced over a guidewire. Surgically implanted devices, such as Broviac or Hickman catheters, do not necessarily need to be removed unless evidence of IE, a tunnel infection, or suppurative thrombophlebitis is present or if the infecting organism is a Corynebacterium species, a Pseudomonas species, a fungus, S aureus, or a Mycobacterium species. If bacteremia persists longer than a few days, the catheter must be removed.

Key points of the American Heart Association's guidelines for the treatment of IE in adults are summarized below.[103]

Definition

The diagnosis of IE should be based on syndromic reasoning and includes pathologic criteria and clinical criteria. The diagnosis is differentiated as definite, possible, or rejected IE.

Blood cultures

Blood cultures should be collected at least 3 times from different venipuncture sites. The first and second collections should be taken at least 1 hour apart.

Echocardiography

Transthoracic echocardiography (TTE) should be performed as quickly as possible in all cases of suspected IE. If the initial TTE images are inadequate, or if findings are negative in the setting of persistent suspicion for IE, transesophageal echocardiography (TEE) should be performed. Transesophageal echocardiography also should be performed in patients with possible intracardiac complications in whom TTE findings were initially positive. If the suspicion for IE remains high despite negative TEE findings, a repeat TEE should be performed after 3 to 5 days. Furthermore, repeat TEE should be performed if a new intracardiac complication is suggested by clinical features. Performance of TTE also is reasonable upon completion of antibiotic therapy for the establishment of a new baseline.

Surgical intervention

Especially in challenging cases, as below, in which surgery is considered, the therapeutic approach should be arrived at by a team consisting of infectious disease specialist, cardiologist, and cardiac surgeon. In cases of opioid use disorder (OUD), there should be input of a substance abuse specialist and medical ethicist because of the high rate of recidivism in this group of patients. 

The following features may merit surgical intervention:

• Persistent vegetation following systemic embolization
• Anterior mitral leaflet vegetation, especially larger than 10 mm
• One or more embolic events during the first 14 days of antimicrobial therapy
• Growing vegetation despite appropriate antimicrobial therapy
• Acute mitral or aortic regurgitation with signs of heart failure
• Heart failure that does not respond to medical therapy
• Paravalvular extension
• Valvular dehiscence, rupture, or fistula formation
• New heart block
• Large abscess or extension of abscess despite appropriate antimicrobial therapy

Antimicrobial therapy

The guidelines make specific recommendations for the following:

• Native valve IE caused by highly susceptible (MIC ≤0.12 µg/mL) viridans group streptococci (VGS)
• Viridans group streptococci and S bovis with MIC >0.12 µg/mL to < 0.5 µg/mL
• Abiotrophia defectiva and Granulicatella species, and VGS with penicillin MIC ≥0.5 µg/mL
• Viridans group streptococci or S bovis infection of prosthetic material
• Staphylococcal infection
• Staphylococcal infection of prosthetic material
• Enterococcal infection
• Infection with HACEK micro-organisms
• Infection with non-HACEK gram-negative bacilli
• Culture-negative endocarditis
• Fungal infection
• Early surgery for native valve IE

The following scenarios support early valve surgery for native left-sided IE:

• Signs or symptoms of heart failure as a result of valve dysfunction
• IE caused by fungal infection or highly resistant organisms
• IE complicated by annular abscess, heart block, or destructive perforating lesions
• Persistent infection (bacteremia or fever; >5-7 days) after appropriate antimicrobial therapy has been initiated, if other sources of fever or infection have been ruled out
• Recurrent emboli or persistent/growing vegetations despite appropriate antimicrobial therapy

Early surgery (prosthetic valve IE)

The following scenarios support the consideration of early valve surgery for prosthetic valve IE:

• Signs or symptoms of heart failure resulting from intracardiac fistula, valve dehiscence, or severe prosthetic dysfunction
• Persistent bacteremia (>5-7 days) after the start of appropriate antimicrobial therapy
• Prosthetic valve IE complicated by annular abscess, heart block, or destructive perforating lesions
• Prosthetic valve IE caused by fungal infection or highly resistant organisms
• Recurrent emboli despite appropriate antimicrobial therapy

Anticoagulation

It is reasonable to discontinue all forms of anticoagulation for 2 weeks in patients with a mechanical valve and IE in whom a CNS embolic event has occurred. Antiplatelet therapy should not be initiated as adjunctive therapy upon a diagnosis of IE, although established antiplatelet therapy may be continued in patients with IE who have no bleeding complications.

CNS imaging

CNS imaging should be performed to evaluate for CNS bleeding or intracranial mycotic aneurysm in patients with IE with neurological deficits, severe localized headache, or meningeal signs.

Antibiotics are the mainstay of treatment for infective endocarditis (IE). Goals to achieve to maximize clinical outcomes are early diagnosis, accurate microorganism identification, reliable susceptibility testing, prolonged intravenous (IV) administration of bactericidal antimicrobial agents, proper monitoring of potentially toxic antimicrobial regimens, and aggressive surgical management of correctable mechanical complications.

Please see Treatment and Guidelines.