Infective Endocarditis: Practice Essentials, Background, Pathophysiology

Previous updates of this article have focused on the contribution of the following to infective endocarditis (IE):

1. Antibiotic resistance
2. The increasing implantation of intravascular devices
3. COVID-19
4. Opiate use disorders
5. The growing number of immunosuppressed patients

The current article also focuses on the key role that the microbiome plays in producing many complications of IE including the growing rate of resistance to antimicrobial agents and the "weaponizing" of probiotics and postbiotics against the patient and the ability of infecting microbes to trigger sterile inflammatory responses that mimic the initial valvular infection.

The microbiome is the general term that describes the trillions of various bacteria, fungi, parasites, and viruses that live on and within our bodies. The chief microbiomes are that of the gut, mouth, and skin. The microbiomes of the mouth and gut normally have a flora that promotes the overall health of the surrounding tissue. The most significant of these is that of the gut because it facilitates the absorption of all types of materials that are necessary for health of the host. What is quite challenging is to determine a case of IE that may or may not have any connection to a pathogenic microbiome. 

Infective endocarditis (IE) is the term that denotes a bacterial , viral or fungal infection of the endocardial surfaces of the heart—usually those of 1 or more cardiac valves; to a lesser degree the mural endocardium; or a septal defect. Such may produce severe valvular insufficiency, intractable congestive heart failure, myocardial abscesses, infected and sterile emboli, and a variety of immunological processes. Since approximately 2008, its incidence, morbidity, and mortality have risen dramatically. ^{[1, 2, 3]}

Simultaneously, there has been an ever-growing marked increase in resistance to many types of established antimicrobial therapies. There also is the challenge of dealing with "new" pathogens that originate from outside the United States or that are due to the increase in immunosuppressed individuals. The waves of COVID have increased all types of intravascular infection by increasing the necessity of intravascular lines. 

In response to these realities, the International Society for Cardiovascular Infectious Diseases (ISCVD) has established a multidisciplinary working group to update the Duke Criteria 1994 ^[4]  and its modification of 2000 ^[5]  to meet these current challenges. The 2023 Duke Criteria ^[6]  for diagnosing IE consider the newly available microbiological techniques such as enzyme immunoassays, metagenomic sequencing, and in situations of hybridization, imaging techniques such as metagenomic imaging.

Recently available diagnostic tests, such as enzyme amino assays for Bartonella, PCR, and newer types of imaging, especially [18F]FDG PET/Cardiac Computed Tomography. The finding of valvular infection on direct examination during surgery has become a major criterion. Tables of organisms that are typical of intracardiac infections have been established. The diagnostic significance of IE, that of producing a continuous bacteremia, appears to be minimized in this document. Specific guidelines for the proper drawing of blood cultures have been eliminated; it was proposed that these criteria should be updated on a regular basis to make it a "Living Document." ^[6]

Signs and Symptoms

IE has been classified into subacute and acute categories based on the rate of progression of the process prior to diagnosis. Individuals with untreated SBE can survive up to 1 year, whereas someone with acute infection that is untreated will barely survive 6-8 weeks. ^{[7, 8]}

Subacute infective endocarditis (SBE) 

Fever, often low-grade and intermittent, is present in up to 90% of cases of SBE. Heart murmurs are documented in approximately 85% of patients.

50% of patients may exhibit 1 or more classic signs and symptoms of SBE. These are immunologic and are underappreciated because of their subtle nature. Signs and symptoms of SBE include the following:

• Petechiae 

• Subungual (splinter) hemorrhages: Dark red, linear lesions in the nail beds

• 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)

Signs of neurologic disease include the following ^{[2, 3, 6, 9, 10]} :

• Embolic stroke with focal neurologic deficits (the most common neurologic sign)

• Intracerebral hemorrhage

• Multiple microabscesses

Other signs of IE include the following:

• Splenomegaly

• Stiff neck

• Delirium

• Paralysis, hemiparesis, aphasia

• Conjunctival hemorrhage

• Pallor

• Gallops

• Rales

• Cardiac arrhythmia

• Pericardial rub

• Pleural friction rub

• Low-grade fever (absent in 3-15% of patients)

• Anorexia

• Weight loss

• Influenza-like syndromes

• Polymyalgia-like syndromes

• Pleuritic pain

• Syndromes similar to rheumatic fever, such as fever, dulled sensorium (as in typhoid), headaches

• Abdominal symptoms, such as right upper quadrant pain, vomiting, postprandial distress, appendicitis-like symptoms

Acute bacterial endocarditis 

Cases of acute bacterial endocarditis (ABE) present with far more aggressive symptoms, including the following:

• Sepsis

• Congestive heart failure

• Renal failure

• Stroke

• Septic emboli

Effect of COVID 19 infection in diagnosing IE

Many of the symptoms of COVID -19 and IE overlap. Indeed, both infections can be concurrent. The inflammatory response to COVID -19 may mimic persistence of IE. ^{[11, 12, 13, 14, 15, 16]}

Diagnosis

The Duke diagnostic criteria were developed by Durack and colleagues as a guide for reaching a valid definitive diagnosis of IE. The criteria combine the clinical, microbiologic, pathologic, and echocardiographic characteristics of a specific case. ^{[2, 3, 5, 6, 8, 10]}

Major blood culture criteria for IE include the following:

• Two blood cultures positive for organisms typically found in patients with IE

• Blood cultures persistently positive for 1 of these organisms, from cultures drawn more than 12 hours apart

• Three or more separate blood cultures drawn at least 1 hour apart

Major echocardiographic criteria include the following:

• Echocardiogram positive for IE, documented by an oscillating intracardiac mass on a valve or on supporting structures, in the path of regurgitant jets, or on implanted material, in the absence of an alternative anatomic explanation

• Myocardial abscess

• Development of partial dehiscence of a prosthetic valve

• New-onset valvular regurgitation

Minor criteria for IE include the following:

• Predisposing heart condition or intravenous drug use (IVDA)

• Fever of 38°C (100.4°F) or higher

• Vascular phenomena, including major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, or Janeway lesions

• Immunologic phenomena such as glomerulonephritis, Osler nodes, Roth spots, or rheumatoid factor

• Positive blood culture results not meeting major criteria or serologic evidence of active infection with an organism consistent with IE

• Echocardiogram results consistent with IE but not meeting major echocardiographic criteria

A definitive clinical diagnosis can be made based on the following:

• Two major criteria

• One major criterion and 3 minor criteria

• Five minor criteria

The development of syndromic analysis (SA) better meets the diagnostic and therapeutic challenges of the current profile of IE. Syndromic analysis considers the patient's current and past history, the tempo of the disease's progression, recognition of pertinent findings on physical exam, and nonspecific laboratory testing. The resulting case profile leads to the selection studies that will most quickly produce a definitive diagnosis. ^[7]

Management

There is an ever-growing urgency to diagnose IE and its complications, and to institute the most appropriate antibiotic treatment. The increasing resistance to the "tried and true" empiric regimens is becoming untenable because of the wide development of resistance to multiple classes of agents. This is especially true among those with opioid use disorder (OUD ) and other marginalized groups due to a decreased ability to access healthcare brought about by the multiple effects of COVID-19 on the healthcare system. ^{[8, 11, 12, 13, 14, 15]}

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

Syndromic diagnostic techniques along with updated techniques of rapidly evaluating positive blood cultures show great promise. ^[7]  This is especially so regarding the time required to achieve the final identification and sensitivity of the infecting organism through the standard techniques. Various molecular diagnostics have lessened the turnaround times from greater than hours to 0.75–2.5 hours. Such techniques have become available since approximately 2020. The next best resource is an updated sensitivity pattern of community pathogens. The treatment of a given patient should reflect a collaboration of the microbiology laboratory, treating clinicians, and antimicrobial stewardship teams. ^{[17, 18, 19]}

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

• 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)