CHAPTER 67: INFECTIVE ENDOCARDITIS

Infective endocarditis (IE) is a disease caused by a microbial infection involving the endothelial lining of intracardiac structures such as the heart valves. The infection is invariably fatal if untreated. Infection commonly resides on one or more of the heart valve leaflets, but may involve mural endocardium, chordal structures, deeper layers of the myocardium, and/or the pericardium. The presence of an intracardiac or endovascular device provides a nidus for infection, as well as a barrier to eradication. Despite significant advances in the diagnosis and treatment of IE, 6-month mortality still approaches 25%.^1,2 Changes in both patient demographics and microbial biology involving an increased incidence of antibiotic-resistant organisms create challenges for contemporary physicians. Prompt recognition and diagnosis, triggered by a high index of clinical suspicion in susceptible patients, trigger aggressive treatment and represent the critical components of a successful management strategy. Combined medical and surgical intervention leads to improved outcomes for selected patients. However, recent years have not seen improved clinical outcomes, despite medical and surgical advances.³ Patient education, attention to general oral-mucosal hygiene, and the appropriate limited use of prophylactic antibiotics are the mainstays of a preventive strategy. IE is often a complex disease with abnormal function in a number of organ systems. Management by a team of physicians and allied healthcare providers is usually required.^3,4

Our current understanding of IE began with the observations of Sir William Osler, who made several important advances in the understanding of this illness, as summarized in his famed Gulstonian lectures of 1885.^5,6 Osler defined IE as a primary “mycotic” process and provided the first formal description of two clinical variants of the disease—the acute and fulminating form versus the chronic and insidious form. Despite his extensive knowledge of the disease, Osler acknowledged the reality of diagnostic uncertainty in many cases.

In the first half of the 20th century, IE was predominantly a complication of rheumatic heart disease and poor dentition. In developing countries, rheumatic heart disease remains the most frequent predisposing cardiac condition.⁷ However, the epidemiologic features of IE in developed countries have changed considerably in recent decades. The aging of the population has been paralleled by increases in the prevalence of degenerative heart valve disease and in the use of prosthetic heart valves and other intracardiac devices. The numbers of patients with chronic, predisposing medical comorbidities, such as diabetes, human immunodeficiency virus (HIV) infection, end-stage renal disease, and immunosuppressive therapy, have markedly increased, as has the commensurate risk of exposure to nosocomial bacteremia, often with antibiotic resistance.^8,9,10 A recent prospective study of 2781 adults with IE found that 25% of cases were associated with recent healthcare exposure.² These changing demographics are reflected in two observations. First, the median age of patients with IE has gradually increased from 30 to 40 years in the preantibiotic era to 47 to 69 years in the late 20th century.^2,11,12 Second, the incidence of IE in developed countries has remained unchanged, despite the dramatic reduction in the incidence of rheumatic heart disease over the past half century. The Nationwide Inpatient Sample database for the years 2000 to 2011 for the United States found 457,052 IE-related hospitalizations, with a steady increase in incidence.^12,13 The number of cases of staphylococcal IE per million population was stable, but cases of streptococcal IE increased during this time period, perhaps as a result of altered recommendations for antibiotic prophylaxis. This report also noted an increasing rate of valve replacement for patients with IE.

The incidence of IE has been difficult to estimate, principally due to the challenges of accurate case definition and identification of representative populations at risk (eg, urban vs rural, injection drug users [IDUs], young vs elderly). Over recent years, a number of well-designed epidemiologic studies have attempted to address these problems^{9,10,11,12,13,14,15} and are summarized in Table 67–1. A number of these studies suggest that the incidence of IE is increasing among the elderly.^16,17 Increased patient longevity and the increased use of healthcare interventions predict that the incidence of IE throughout the world will continue to rise.¹⁸

Infective Endocarditis in Selected Patient Populations

The Elderly

The incidence of IE among the elderly, often due to nosocomial infection, appears to be rising.¹⁹ A heightened index of suspicion is required to make the diagnosis in this population because the presentation may be atypical.²⁰ There is a higher incidence of degenerative, calcific valve disease, usually aortic, which can decrease the specificity of echocardiographic imaging for the lesions of IE. Transesophageal echocardiography (TEE) imaging is often required for more accurate delineation of valve pathology.²¹ IE caused by Enterococcus faecalis may be more common among the elderly.²² Although there are conflicting reports, advanced age appears to predict mortality in IE,^19,23,24,25 particularly with Staphylococcus aureus infection.²⁶

Injection Drug Users

IE is a dreaded complication of injection (ie, intravenous or subcutaneous) drug use. The incidence of IE among IDUs is approximately 2% to 5% per year, and IE is responsible for 5% to 20% of hospital admissions and 5% to 10% of overall mortality in this group.²⁷ The incidence of IE and the causative agents in this population are related to contaminated injection technique (eg, sharing or licking of hypodermic needles), the injection of unsterile particulate material (eg, talcum), and the high prevalence of HIV infection. Staphylococcus aureus is the most common etiologic agent, causing more than 60% of IE cases in IDUs.²⁷ IE caused by gram-negative bacilli (notably Pseudomonas aeruginosa) and fungi is also more common among IDUs. The distinctive feature of IE in IDUs is that it frequently involves the right heart, with 60% to 70% of cases involving the tricuspid valve. The tricuspid valve may be particularly susceptible to bacterial infection as a result of chronic degenerative changes caused by the repetitive injection of irritants (eg, talcum) into peripheral veins. Septic pulmonary emboli are common in IDUs with IE. Despite the high frequency of Staphylococcus aureus infection, isolated right heart involvement in IDUs partially explains the lower mortality in this population (4%) compared with other IE patient subsets. Nevertheless, left-sided infection does occur and can result in major complications, such as systemic emboli, paravalvular abscess, and severe valvular destruction. IDUs with uncomplicated right-sided IE may be eligible for short-course parenteral antibiotic therapy (2-4 weeks), a regimen that would not be considered in patients with left-sided IE.²⁸ Because the administration of a 4-week parenteral antibiotic regimen in IDUs can be challenging, combination oral therapy with ciprofloxacin plus rifampin can be used safely and effectively in selected patients with uncomplicated right-sided staphylococcal IE.²⁹ Given the relative efficacy of antibiotic cure for isolated right-sided IE in IDUs, surgical therapy is infrequently indicated and is reserved for cases of severe right heart failure caused by tricuspid regurgitation, refractory bacteremia, and persistent tricuspid vegetations > 20 mm with recurrent septic pulmonary emboli or left-sided valve involvement.³⁰ IDU is not an absolute contraindication to surgery for patients with IE, and studies have shown that surgery can be performed in these patients safely and with acceptable outcomes.³¹

Human Immunodeficiency Virus Infection and the Immunocompromised Host

Although HIV infection and intravenous drug use commonly coexist, HIV infection appears to be an independent risk factor for the development of IE.³² Patients with low CD4 counts (< 200 cells/mL) tend to have an increased risk of IE,³³ as well as a higher associated mortality.^27,34 IDUs who are HIV positive have a higher incidence of left-sided valvular involvement and complications compared with HIV-negative IDUs.³⁴ Although they rarely cause IE, Bartonella species can cause opportunistic infections, including IE, in patients with acquired immunodeficiency syndrome (AIDS).³⁵ There is a paucity of data on the characteristics of IE in the non–HIV-infected immunocompromised host. However, immunocompromised patients with gram-negative bacteremia or fungemia may be at risk for IE as a result of these organisms.

Hemodialysis Patients

There are more than 300,000 patients in the United States who are receiving hemodialysis. Infectious complications of vascular access are a major cause of morbidity and mortality in hemodialysis patients. In this population, there is an alarming rate of bacteremia, approaching nearly 1.0 episode per 100 patient-care months. Few other medical conditions, with the exception of chemotherapy-induced neutropenia and intravenous drug use, are associated with such high rates of bacteremia. As a result, IE occurs in approximately 2% to 6% of patients receiving hemodialysis. Staphylococcal species are the predominant organisms and gain access to the bloodstream via infected central venous catheters, arteriovenous (AV) grafts, or AV fistulae. Primary AV fistulae have the lowest rates of infections and are the access of choice if vascular anatomy allows for this approach. Indwelling central venous catheters have the highest rate of infection and are often associated with more serious metastatic complications.³⁶ Access-related infections are the most common cause for the loss of dialysis vascular access, causing nearly 10% of deaths (second only to ischemic heart disease) in this patient population.³⁷ Patients with end-stage renal disease have a high incidence of calcific degeneration of the aortic and mitral valves,³⁸ which may predispose to bacterial colonization of the endocardium. Such degenerative valvular disease may render echocardiographic detection of vegetations extremely challenging.²¹ Vancomycin is often used as a first-line agent because of the high incidence of methicillin-resistant Staphylococcus aureus (MRSA) in this population and the ease of administration of this drug with hemodialysis. Treatment of catheter-related bloodstream infections with antibiotics alone yields poor results, and removal of infected catheters or grafts is necessary in most circumstances.³⁹ Effective prevention of bacteremia in the hemodialysis population hinges on early referral for primary AV fistula placement (preferably before dialysis is needed) and strict adherence to sterile technique with access catheter manipulation.

Cardiac Device–Related Infective Endocarditis

The rates of pacemaker and implantable cardiac defibrillator (ICD) placement have markedly increased over the past 10 years, given the growing number of evidence-based indications for their use. However, the increasing rate of device infection appears to be disproportionate to the increased rate of device implantation.⁴⁰ The overall incidence of cardiac device–related infective endocarditis (CDRIE) lies between that of native valve endocarditis (NVE) and prosthetic valve endocarditis (PVE).^41,42 Staphylococcal species are the causative organism in more than 70% of cases.^43,44 Infection with coagulase-negative staphylococci (CoNS) can be particularly difficult to eradicate. The vast majority of cardiac device infections are apparently a result of pocket site contamination at the time of device placement. Hematogenous seeding from a distant focus of infection, particularly when due to Staphylococcus aureus, can cause late-onset infection. The clinical presentation may be misleading initially, with prominent respiratory or rheumatologic symptoms, as well as local signs of infection.⁴⁴ Septic pulmonary embolism is a frequent complication and contributes to the high mortality associated with CDRIE.⁴⁵ CDRIE is one of the most difficult forms of IE to diagnose; the Duke criteria in this setting lack adequate sensitivity. Modifications of the Duke criteria have been proposed to include signs of local (generator pocket, subclavian vein) infection and septic pulmonary embolism as major criteria.^44,46

There are several important imaging considerations in patients with suspected intracardiac device infections. With transthoracic echocardiography (TTE), it can be difficult to differentiate infected vegetations from noninfected device-related thrombus. TEE is often required for adequate visualization, and it is essential that echocardiographic data be integrated with clinical and microbiologic data. The device and leads should be imaged throughout their entire course within the cardiac chambers and proximal veins, with special attention to their relationship to the tricuspid valve. Device leads that track through the superior vena cava should be visualized as close to the origin of the generator as possible.¹⁸ In addition to TEE, preliminary experience with intracardiac echocardiography for the detection of lead vegetations has recently been reported.⁴⁷ Although no prospective studies have been conducted, management with parenteral antibiotics and complete device removal are the standards of care.⁴³ Cardiac device extraction can be performed percutaneously without the need for surgical intervention in the majority of patients, although percutaneous approaches may be more difficult when the device has been in place for a number of years. Pulmonary embolism of vegetative material during extraction occurs frequently, particularly when vegetations are large.^46,48 However, these episodes are frequently asymptomatic, and percutaneous extraction remains the procedure of first choice, even in cases with large vegetations,^45,46,48 because the overall risks are even higher with surgical extraction.^30,44 Increased experience with evolving percutaneous lead-extraction techniques may aid in the management of infected devices.⁴⁹ When there is documented valvular IE in a patient with an implanted device, there is a high likelihood of concomitant device infection, which usually necessitates extraction of the device at the time of valve surgery. The American Heart Association has recently published a scientific statement that provides recommendations for the prevention, diagnosis, and management of cardiovascular implantable electronic device (CIED) infections.⁵⁰ Decisions regarding optimal timing and site of device reimplantation are complex and must be adapted to the individual patient.^{40,41,42,43,44,45,46,47,48,49,50,51} A retrospective analysis of patients undergoing pacemaker implantation suggests that antibiotic prophylaxis before device implantation can prevent infectious complications.⁵² The current scientific statement recommends that prophylaxis with an antistaphylococcal agent should be administered at the time of CIED placement.⁵⁰ Antimicrobial prophylaxis for the prevention of CIED infections is not recommended for dental or other invasive procedures not directly related to device manipulation.⁵⁰

Additional Aspects of Infective Endocarditis Epidemiology

Patients who recover from an episode of IE are unfortunately still at risk for late complications.⁵³ Shih et al⁵³ observed that patients with successfully treated IE were at higher risk for the late occurrence of ischemic and hemorrhagic stroke, myocardial infarction, hospitalization for heart failure, and sudden death compared with a cohort of matched controls without IE. The diagnosis of IE is also a substantial marker for the presence of occult cancer.⁵⁴

Normal vascular endothelium resists colonization by bacteria. Damaged vascular endothelium can be colonized by circulating bacteria with specific adhering qualities.⁵⁵ The hallmark of IE is persistent endocardial or endovascular infection causing continuous bacteremia. Importantly, IE is a relatively uncommon consequence of transient bacteremia, and not all organisms can effectively colonize or invade the endovascular space. It is apparent that a complex series of host-pathogen interactions conspire in the development of IE lesions, including the integrity of the vascular endothelium, the host immune system, hemostatic mechanisms, cardiac anatomical characteristics, microbial properties, and the peripheral events that cause the bacteremia.^18,55 There are substantial experimental data to suggest that host endothelial damage is the key predisposing insult, with subsequent platelet and fibrin deposition and creation of a receptive milieu for bacterial colonization during episodes of transient bacteremia. That endothelial damage is the inciting event is further supported by the observation that vegetations are most likely to form in areas where blood-flow injury is likely to occur—on the ventricular side of semilunar valves and the atrial side of AV valves.^56,57 Jet lesions from regurgitant valves or intracardiac shunts may also damage endothelium, and vegetations may form on such sites of injury, including the mitral chordae with aortic regurgitation, the mural left atrial endocardium with mitral regurgitation, or the septal leaflet of the tricuspid valve with ventricular septal defect.^18,53 Figure 67–1 illustrates the classic locations of endocardial flow injury that are associated with vegetation formation in IE.⁵⁷

Once endothelial injury has occurred, bacteria must gain access to the intravascular space to seed the lesion. Common sources of bacteremia include skin, surgical wounds, the periodontal space, indwelling intravascular catheters, and the urinary and gastrointestinal tracts. Bacteremia is common after both toothbrushing and tooth extraction. More bacteria are released into the bloodstream after extraction than after toothbrushing. However, because toothbrushing is so much more common than extraction, it may well be a common source for the initiation of IE.⁵⁸ Bacteria that have entered the bloodstream must be able to adhere to the damaged endothelium, exposed extracellular matrix, or areas of fibrin deposition.⁵⁹ This adherence is mediated by microbial surface components recognizing adhesive matrix molecules, which, in turn, recognize a variety of host proteins such as fibronectin, collagen, and integrins. Certain organisms appear to preferentially express these molecules, enabling them to adhere more effectively and colonize the injured endocardium.^52,60 The fact that Staphylococcus aureus can induce endothelial tissue factor expression may partially explain why this organism can adhere to relatively normal heart valves.⁶⁰ Particulate material that may be injected may also promote Staphylococcus aureus adherence by stimulating matrix protein expression on valvular endothelium.⁵⁹ In a Streptococcus rat model of endocarditis, extracellular neutrophil “traps” form with the aid of activated platelets and specific immunoglobulin G. Pathogens, in this case streptococci, actually promoted the formation of these extracellular traps, which form part of the characteristic vegetation. These neutrophil traps aid in promoting and expanding the vegetations of IE.⁶¹

A factor in the pathogenesis of device-related intravascular infections is biofilm formation, which impedes microbial clearance by host mechanisms, and thus often mandates device removal for eradication of the infection. Staphylococcus epidermidis and Staphylococcus aureus have been studied most extensively in this regard, with characterization of a responsible intercellular adhesin and its gene cluster.⁶² Once adherent, certain strains of bacteria are able to evade the host immune system, destroy host tissue, or occasionally enter the cytosolic compartment of endothelial cells. Repetitive cycles of bacterial proliferation, fibrin-platelet deposition, and host tissue destruction create an infected vegetation, within which bacteria can reach extremely high concentrations (10⁹-10¹¹ organisms per gram of tissue; Fig. 67–2). These dense vegetations are a source of continuous bacterial seeding of the bloodstream. Figure 67–3 shows a gross pathologic specimen of the heart with a large, complex vegetation attached to the left atrial surface of the anterior mitral leaflet. After successful antimicrobial therapy, vegetations will resolve completely or contract in size and persist indefinitely as a sterile and frequently calcified mass adherent to valve tissue.

The various systemic manifestations of IE are the result of showers of bacteria-laden emboli that often cause satellite areas of infection with subsequent abscess formation. Osler and Janeway lesions are the result of these infected emboli and not the result of immunologically induced vasculitis.⁶³ That small, often clinically unnoticed, embolic phenomena are occurring with considerable frequency was documented by Cooper et al,⁶⁴ who observed with magnetic resonance imaging (MRI) scans that the majority of their patients with definite left-sided IE had subclinical brain lesions highly suggestive of embolic events.

A wide range of microorganisms can cause IE, but only a few species account for the vast majority of cases. Streptococci and staphylococci are the cause of greater than 80% of IE cases in which a responsible organism is identified. Streptococcal species were historically the most common group of pathogens, but more recent data identify Staphylococcus aureus as the most frequently isolated microbial agent worldwide.²⁶ Moreover, the rate of antibiotic resistance among causative organisms is increasing.^26,65

Native Valve Endocarditis

Streptococci

Viridans group streptococci, or α-hemolytic streptococci, are a frequent cause of community-acquired NVE. Viridans streptococci are responsible for 30% to 65% of cases of NVE in older children and adults.^65,66 They are normal residents of the oropharynx and easily gain access to the circulation after dental or gingival trauma. The viridans streptococci comprise several species, of which Streptococcus sanguinis, Streptococcus gallolyticus (formerly bovis), Streptococcus mutans, and Streptococcus mitior are most commonly isolated in cases of IE. The viridans streptococci are usually highly sensitive to penicillin, as defined by a minimum inhibitory concentration of < 0.1 μg/mL, and thus can often be eradicated with penicillin monotherapy.⁶⁶

S gallolyticus, a normal inhabitant of the human gastrointestinal (GI) tract, is noteworthy because IE caused by this organism is strongly suggestive of GI malignancy,⁶⁷ polyp formation, or diverticular disease. Colonoscopy should be performed when this organism is detected in the blood. When meticulously investigated, GI pathology is discovered in as many as 60% of patients with S gallolyticus IE.⁶⁰

Nutritionally deficient streptococci, now known as Abiotrophia species and Granulicatella species, require specialized isolation and culture techniques for growth (supplemental thiol compounds or active forms of vitamin B₆) and now account for approximately 5% to 7% of streptococcal IE cases.⁶⁸ IE caused by these organisms is virtually always indolent in onset and associated with pre-existing heart disease. Therapy remains difficult, and prognosis is poor because these organisms are generally less sensitive to penicillin than the viridans group streptococci.⁶⁹ Treatment often requires synergistic therapy with an aminoglycoside.

The Enterococcus species, formerly classified as group D streptococci, are now defined as a distinct genus. They are responsible for 5% to 18% of cases of native valve IE, the vast majority of which are caused by E faecalis (80%) or Enterococcus faecium (10%). These organisms are normal inhabitants of the GI and genitourinary tracts, and may enter the bloodstream after manipulation of the colon, urethra, or bladder (eg, Foley catheterization, colonoscopy). The incidence of enterococcal endocarditis appears to be rising, likely as a result of the increased genitourinary and GI instrumentation in older adults and the increased use of indwelling central venous catheters and prosthetic implants. These organisms can infect both normal and diseased heart tissue, as well as prosthetic materials. Indeed, among the most relevant risk factors for development of enterococcal IE is the presence of an implanted device. The pathogenesis of such infections is poorly understood, but several virulence factors have been proposed. The ability to form biofilm has recently been shown to be one of the most prominent features of this microorganism, allowing colonization of inert and biological surfaces and preventing antibiotic penetrance. The disease typically runs an indolent course, and cure is challenging because the organism has limited susceptibility to many antibiotics, including β-lactam drugs. There is an alarming incidence of nosocomial bacteremia with these organisms and a growing problem with drug resistance (to both vancomycin and aminoglycosides). Although synergistic antibiotic therapy, as predicated by susceptibility testing, should be considered,⁶⁹ there is some debate regarding its efficacy.⁶⁹

Group A Streptococcus rarely causes IE. Streptococcus pyogenes, the causative organism in childhood pharyngitis, scarlet fever, impetigo, cellulitis, erysipelas, fasciitis, and myositis, is not associated with IE in adults. Before 1945, Streptococcus pneumoniae caused approximately 10% of IE cases; however, the current incidence of pneumococcal IE is very low. Streptococcus pneumoniae bacteremia often begins with respiratory infection, and nearly half of patients with pneumococcal IE suffer from chronic alcoholism.⁷⁰ Streptococcus pneumoniae can infect normal valve tissue and usually results in an acute, fulminant illness often associated with severe valve damage, perivalvular extension, embolic complications, pericarditis, meningitis, and high mortality (25%-50%).⁶³

Group B streptococci (eg, Streptococcus agalactiae) are chiefly responsible for infections in the neonate and parturient, although these organisms can be isolated from diabetic foot ulcers. Risk factors for group B streptococcal bacteremia in adults include obstetric complications,⁷¹ diabetes, carcinoma, liver failure, alcoholism, and IDU.⁷² These organisms are generally less sensitive to penicillin than group A isolates and require higher doses for treatment.

Staphylococci

Staphylococcus aureus causes 80% to 90% of staphylococcal IE and is the most common cause of acute IE. Recent prospective data from the International Collaboration on Endocarditis (ICE) suggest that Staphylococcus aureus has become the leading cause of IE worldwide and more often presents as an acute disease.^2,26 The mucous membranes of the anterior nasopharynx are the most common sites of colonization, and approximately 30% of normal persons carry Staphylococcus aureus. Carrier rates are higher among persons with more frequent exposures to the organism and those who are at risk for breakdown of the normal mucocutaneous barrier. Rates of Staphylococcus aureus infection, particularly bacteremia associated with healthcare contact, have increased in hospitalized patients and among those receiving outpatient medical therapy.^73,74 Although only a fraction of patients with Staphylococcus aureus bacteremia will develop NVE,⁷⁵ populations at increased risk include patients on dialysis,³⁷ patients with type 1 diabetes, burn victims, persons with HIV,³² IDUs,²⁷ patients with certain chronic dermatologic conditions, and patients with recent surgical incisions (including median sternotomy for valve replacement). Despite the frequency of nosocomial Staphylococcus aureus acquisition, community-acquired infection appears to be an independent risk factor for the development of IE and metastatic disease.^76,77 Staphylococcus aureus is respected as a highly virulent organism and has the capacity to infect and destroy normal endocardial surfaces (see Fig. 67–2). A number of virulence factors help this organism enter the bloodstream, adhere to endothelial and prosthetic surfaces, and evade host defense.⁵⁵ Staphylococcus aureus IE is frequently fulminant when it involves left-sided cardiac valves and often results in major complications such as valve destruction, heart failure, perivalvular extension with conduction disturbances, embolization, and metastatic infection.⁷⁸ Not surprisingly, Staphylococcus aureus as a causative organism is an independent predictor of poor prognosis in IE⁷⁸ and is associated with a 25% to 30% mortality.^1,26 As many as 50% of patients with left-sided NVE as a result of Staphylococcus aureus will require surgery. Right-sided (tricuspid valve) IE with Staphylococcus aureus, by contrast, is most frequently associated with IDUs and is associated with a high incidence of septic pulmonary embolization, but only a 2% to 4% case fatality rate.

The detection of Staphylococcus aureus bacteremia should prompt echocardiography to look for evidence of IE, especially if bacteremia is persistent. Although most patients undergo TTE first, an initial TEE should be considered for patients with catheter-associated Staphylococcus aureus bacteremia as a cost-effective means of determining the duration of antibiotic therapy (ie, 2 weeks vs 4 weeks).⁷⁹ A semisynthetic, β-lactamase–resistant penicillin (eg, nafcillin) is preferred for initial treatment of susceptible Staphylococcus aureus in non–penicillin-allergic individuals, often with a short course of an aminoglycoside. Antibiotic resistance can be a particular challenge with Staphylococcus aureus because more than 90% of clinical isolates produce β-lactamase and are thus penicillin resistant. Semisynthetic penicillin analogs that are unaffected by β-lactamase, such as methicillin, oxacillin, and nafcillin, are first-line agents. Increasing rates of MRSA in both hospital and community settings,²⁶ and the recovery of clinical Staphylococcus aureus isolates resistant to vancomycin,⁸⁰ have complicated the treatment of Staphylococcus aureus IE. Increasing hospital use of vancomycin for the treatment of MRSA is likely one additional reason for the growing incidence of vancomycin resistance among enterococci. Vancomycin, although the best available antibiotic for treatment of MRSA, is only weakly bactericidal and predominantly bacteriostatic. Recently, Staphylococcus aureus isolates with varying levels of vancomycin resistance have been cultured from infected patients and have been associated with IE treatment failures.⁸¹ The new lipopeptide antistaphylococcal agent daptomycin has been approved for treatment of Staphylococcus aureus bacteremia and right-sided IE,⁸² and may have promise for the treatment of left-sided IE caused by resistant organisms. Cases of resistant Staphylococcus aureus IE should always be managed in close collaboration with an infectious diseases specialist.

The CoNS are constituents of normal human skin flora and are much less likely to infect normal endocardial surfaces. Staphylococcus epidermidis is an important causative agent in PVE and device-related endocarditis. NVE caused by CoNS occurs mainly in patients with pre-existing valvular heart disease,⁸³ although exceptions to this generalization do occur (see Fig. 67–3). NVE caused by CoNS has historically been regarded as an indolent disease; however, recent data from the ICE have demonstrated equal rates of heart failure and death for CoNS and Staphylococcus aureus NVE.⁸³ Staphylococcus epidermidis infections of intracardiac devices are extremely difficult to eradicate, and the addition of adjunctive course of rifampin therapy is often recommended. Rare cases of IE caused by other CoNS (eg, Staphylococcus saprophyticus, Staphylococcus capitis) have been reported,^84,85 including a growing number of reports of IE caused by community-acquired Staphylococcus lugdunensis.⁸⁶ S lugdunensis may cause a more virulent form of IE with high morbidity despite uniform in vitro susceptibility to most antibiotics.

Gram-Negative Bacilli

IE caused by gram-negative bacilli is uncommon and tends to occur in IDUs, immunocompromised patients, patients with advanced liver disease, and prosthetic heart valve recipients. The fastidious gram-negative rods of the HACEK group (Haemophilus species, Actinobacillus, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) reside normally in the oropharynx and are responsible for a very small (approximately 1%) proportion of cases of NVE, usually involving abnormal valve tissue. Because of their growth requirements (carbon dioxide), they may take 3 to 4 weeks to grow in culture and have gained notoriety for their implicated role in certain cases of culture-negative IE. The Haemophilus species (Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus) are the most common etiologic agents from this group. They typically form large and friable vegetations that have a tendency to embolize. There are numerous case reports of IE caused by other members of the HACEK group.⁸⁷ The Enterobacteriaceae (eg, Escherichia coli, Klebsiella, Enterobacter, Serratia) are rare causes of IE. Salmonella species have a particular predilection for atherosclerotic plaque and may infect arterial aneurysms.⁸⁸ The vast majority of patients with P aeruginosa endocarditis are IDUs.⁸⁹ The source of Pseudomonas appears to be from standing water that contaminates needles and other drug paraphernalia. Left-sided endocarditis caused by P aeruginosa is difficult to eradicate with antibiotics alone, has a high rate of complications, and often requires early surgery.⁸⁹

The rickettsial organism Coxiella burnetii is the causative agent of Q fever and is a relevant cause of IE in areas where cattle, sheep, and goat farming are common. Cases of IE caused by C burnetii are well documented in the developed world.⁹⁰ The aortic valve is affected in more than 80% of cases, and the infection is difficult to eradicate with antibiotics. Because the organism is extremely difficult to culture, the diagnosis is best made serologically using antibody titers.⁹⁰ Bartonella species (Bartonella quintana, Bartonella henselae, Bartonella elizabethae), the etiologic agents in cat scratch disease, have been recently described as an important cause of IE among both homeless men and HIV-infected patients. The diagnosis can be suspected serologically and confirmed with special culture techniques or by polymerase chain reaction.⁹¹ Brucellae have been implicated in approximately 4% of cases of IE in Spain. These organisms are usually ingested in unpasteurized milk or cheese, and are occupational hazards for veterinarians, shepherds, and livestock handlers. IE is the most common cause of death in patients with brucellosis, and surgery is usually required for cure.⁹²

Fungal Infective Endocarditis

Fungal endocarditis is a relatively new syndrome associated with exceedingly high mortality (survival rates of < 20%). Patients who develop fungal IE have multiple predisposing conditions that include an immunocompromised state, the use of endovascular devices, and previous reconstructive cardiac surgery. Candida and Aspergillus species are the most common causes of fungal IE and are associated with large, bulky vegetations that can obstruct valve orifices and can also embolize to large vessels (eg, the femoral artery). Blood cultures are usually positive in cases of Candida IE, whereas they are rarely positive with Aspergillus. Fungal endocarditis is an indication for surgical replacement of an infected valve. Cure usually requires combination fungicidal (amphotericin) and surgical treatment, followed by long-term suppressive therapy with an oral antifungal agent.^93,94,95

Culture-Negative Infective Endocarditis

Blood cultures are negative in up to 20% of patients with IE diagnosed by strict criteria.^93,94 Failure to isolate a microorganism may be the result of inadequate culture technique, a highly fastidious organism or a nonbacterial pathogen as the causative agent, or previous administration of antimicrobial therapy before blood culture acquisition. The latter is an extremely important consideration, because the administration of antibiotics before drawing blood cultures can reduce the recovery rate of bacterial pathogens by nearly one-third.^93,94,95,96 There are numerous noninfectious causes of endocarditis that may behave like culture-negative IE, including those that are related to neoplasia (nonbacterial thrombotic endocarditis), autoimmune diseases (antiphospholipid antibody syndrome, systemic lupus erythematosus), or the postcardiac surgical state (thrombi, sutures).^88,93,94,95 Empiric therapy for culture-negative IE remains extremely challenging because the patient may be exposed to potentially toxic antimicrobial therapy while awaiting what is often delayed identification of a causative organism, if one is identified at all. Consultation with an infectious disease specialist to define the most appropriate therapy is recommended.

Prosthetic Valve Endocarditis

PVE represents approximately 10% to 30% of all IE cases.^9,15,65 Although many of the general principles applicable to native valve IE are relevant, there are important considerations specific to PVE. After valve replacement, the incidence of PVE is approximately 1% to 3% at 1 year and 3% to 6% at 5 years. Although the current evidence is not definitive, PVE can be broadly divided into two groups based on the time of onset of the infection after valve surgery—early PVE and late PVE. Early PVE is defined as endocarditis that develops within the first 2 months to 1 year after valve surgery. During this period, the vast majority of causative organisms are nosocomially acquired, with a predominance of staphylococci, notably coagulase-negative species (Staphylococcus epidermidis). Gram-negative bacilli, diphtheroids, and fungal species, although uncommon causes of IE overall, have a predilection to cause PVE during this early period. Late PVE is defined as that occurring beyond 1 year postoperatively. In contrast to early PVE, the spectrum of causative organisms in late PVE resembles that of NVE. In late PVE, cases are predominantly a result of streptococci and enterococci, with a significant decrease in the rate of CoNS and a continued rate of infection with Staphylococcus aureus. Between 2 and 12 months after valve replacement surgery, there is a gradual transition between the early and late microbiologic causes of PVE.

TEE imaging is recommended in cases of suspected PVE (see below). In some cases, both TTE and TEE are performed to provide optimal characterization of the infection, prosthetic valve function, and cardiac performance. Empiric therapy for suspected PVE is similar to that for NVE; however, staphylococcal coverage should always be provided until definitive culture data are available, with particular attention to the likelihood of antibiotic resistance (MRSA). Complication rates with PVE are high, and surgery is often required even in the absence of documented perivalvular extension. For example, Staphylococcus aureus PVE is rarely eradicated with antibiotics alone, and retrospective analyses suggest that combined medical and surgical therapy is more effective than medical therapy alone.^95,96 With proper timing of antibiotic therapy and surgery, the imputed risk of early reinfection of a newly implanted valve is only 2% to 3%.⁹⁷

The history in patients with suspected IE should focus on predisposing factors, such as intravenous drug use, a prior history of IE, recent exposures, the presence of an intracardiac device or indwelling central venous catheter, congenital or acquired valvular heart disease, and other congenital or structural heart disease. The patient may report fever, fatigue, anorexia, weight loss, night sweats, joint pain, or back pain. Often, the nature of the presenting symptoms reflects the severity and type of infection. Patients with Staphylococcus aureus infection, for example, are likely to have a fulminant course with high fever and systemic sepsis, whereas some infections with streptococcal organisms may have a more protracted course. Features on clinical examination that raise suspicion for IE include fever, a new heart murmur indicative of valvular insufficiency, signs of heart failure, and peripheral vascular phenomena. Examples of classic IE-related findings include major arterial emboli with pulse deficits, septic pulmonary emboli (with right-sided IE), mycotic brain aneurysms with intracranial hemorrhage, mucosal or conjunctival petechiae, splinter hemorrhages of the nail beds, palpable purpuric skin rashes (Fig. 67–4), Janeway lesions (small, flat, irregular erythematous spots on the palms and soles), Osler nodes (tender, erythematous nodules occurring in the pad portion of the fingers), Roth spots (cytoid bodies and associated hemorrhage caused by microinfarction of retinal vessels), and urinary red cell casts suggestive of glomerulonephritis (Fig. 67–5).

Although the history and physical examination are useful, the diagnosis of IE rests on the ability to demonstrate endocardial involvement and persistent bacteremia. The proper acquisition of blood cultures before initiation of antimicrobial therapy is essential. In hospitalized patients, the presence of bacteremia with a typical causative organism (eg, Staphylococcus aureus) often provides initial suspicion for IE and prompts further diagnostic evaluation. Echocardiography should be used to seek the presence of endocardial involvement (vegetations, abscess formation, and new valvular regurgitation). These clinical, microbiologic, and echocardiographic features are the foundation for the modified Duke criteria, a set of integrated findings that has become the standard for diagnosis of IE (Tables 67–2 and 67–3).⁹⁸ These criteria are discussed in detail later in this chapter.

Once the diagnosis has been made and appropriate therapy initiated, the patient should be monitored closely for complications, especially during the first week of therapy. All patients should have repeat blood cultures after institution of antibiotics to ensure sterility of the blood. Persistent fever beyond 1 week of appropriate therapy should raise the suspicion for intracardiac extension, satellite abscess formation, or an antibiotic-resistant organism. In the absence of complications, the first several days of intravenous antibiotics are administered in the hospital and the remaining course provided via a central venous catheter (eg, peripherally inserted central catheter) as an outpatient with careful follow-up. Patients should be maintained on telemetry while in hospital; the need for surveillance electrocardiograms (ECGs) during outpatient therapy is dictated by the location of the infection and the predicted likelihood of conduction disturbances. Patients should be monitored for antimicrobial toxicity, particularly with aminoglycoside use. Routine surveillance echocardiography during therapy is not necessary unless complications develop or cardiac surgery is being considered (see later section Echocardiography in Infective Endocarditis). At the completion of therapy, TTE may be performed to establish a new “post-IE baseline.”⁶⁵ After successful therapy, patients with IE should be followed longitudinally for the possible development of progressive valvular and/or ventricular dysfunction. Patients with successfully treated IE are at high risk for the development of future episodes of IE and should receive antibiotic prophylaxis before specific dental procedures, as recommended by current guidelines (see later section Antibiotic Prophylaxis for the Prevention of Infective Endocarditis).^3,4,99,100

IE is defined as an infection on any structure within the heart, including normal or damaged endothelial surfaces, prosthetic heart valves, and implanted devices (eg, pacemakers, ICDs, ventricular assist devices, surgical shunts).¹⁸ The diagnosis of IE relies chiefly on the following factors: (1) an initial clinical suspicion, especially in a patient with identifiable risk factors, for example, fever without obvious etiology; (2) microbiologic data (blood cultures demonstrating continuous bacteremia or cultures of vegetative emboli removed surgically); and (3) the results of echocardiographic imaging. Diagnosis is straightforward in only a minority of patients who present with a defined predisposing condition and the classic manifestations of fever, evidence of active valvulitis, peripheral emboli, renal immunologic or peripheral vascular phenomena, and bacteremia. In the majority of patients, IE has an extremely variable clinical presentation.^2,66

Clinical Criteria

Pelletier and Petersdorf¹⁰¹ published the first formal case definition based on their 30-year experience caring for patients with IE in Seattle, Washington. Although this first case definition was specific for the diagnosis of IE, it lacked sufficient sensitivity. Subsequently, von Reyn and colleagues¹⁰² developed the first stratified diagnostic schema in which cases were placed into four categories (rejected, possible, probable, and definite). This approach eventually proved inadequate because of overclassification of cases as “possible” and “probable,” over-reliance on pathologic specimens, and the lack of incorporation of echocardiographic data. In 1994, Durack and colleagues published the Duke criteria¹⁰³ for the diagnosis of IE that incorporated additional clinical factors as well as echocardiographic data. These criteria were revised in 2000 to increase the sensitivity for detection of cases related to Staphylococcus aureus bacteremia, as well as to account for culture-negative IE.⁹⁸ The modified Duke criteria (see Tables 67–2 and 67–3) have become the current standard for diagnosis and clinical research, and have been validated in numerous subsequent studies.^104,105,106 A diagnosis of definite IE is established clinically by evidence of two major criteria, one major plus three minor criteria, or five minor criteria. Patients identified with possible IE (one major criterion plus one minor criterion or three minor criteria) should be treated for IE until the diagnosis is satisfactorily excluded. Application of these criteria in clinical practice will capture the vast majority of cases of IE and render quite remote the possibility of missing a potential case. The modified Duke criteria are both clinically and biologically sound, relying on microbiologic data and evidence of endocardial involvement, with attention to predisposing factors and early complications of a vascular or immunologic nature. Definitions of specific criteria and terms used in the modified Duke criteria are detailed in Table 67–2.^98,100

The importance of obtaining blood cultures by appropriate methods, before the institution of antibiotics, cannot be overemphasized. Three separate sets of blood cultures obtained from different venipuncture sites over 24 hours are recommended. For the most commonly encountered bacterial pathogens (staphylococci, streptococci, enterococci), the first two sets of blood cultures will be positive in the vast majority of cases.¹⁰⁷ Culture-negative IE is most commonly associated with antecedent antibiotic use, but may be caused by fastidious (eg, HACEK) or intracellular organisms that are not readily detected using standard culture techniques,⁸⁷ especially if the laboratory has not been alerted to the possibility of IE and the need to perform additional testing. Identification of the offending pathogen may require special culture media and prolonged incubation times (> 2 weeks).¹⁷ Other indirect measures of active infection with difficult-to-culture organisms (eg, Bartonella, Brucella, Legionella) include positive results of serology, agglutination, immunofluorescence, and polymerase chain reaction amplification assays.^66,87 It should be noted that many of these indirect diagnostic tests may be nonspecific, and careful interpretation is needed to avoid erroneous or false-positive results.

Echocardiography in Infective Endocarditis

All patients with suspected IE should undergo prompt echocardiographic assessment. There are several TTE findings suggestive of endocarditis, including vegetations, evidence of periannular tissue destruction (ie, abscess formation), aneurysms or fistula formation, leaflet perforation, or prosthetic valve dehiscence.¹⁸ Specific definitions of these findings are outlined in Table 67–4.¹⁰⁸ The echocardiographic definition of a vegetation is an irregular-shaped, discrete echogenic mass that must be adherent to, yet distinct from, the endothelial surface to which it is attached. The presence of a vegetation is strongly supportive of the diagnosis of IE if the suspected mass oscillates at a high frequency, independent of other intracardiac structures.

Although there remains some debate regarding the optimal approach, the vast majority of patients should initially undergo transthoracic (TTE) imaging because of its immediate availability and ease of use. A low threshold to pursue transesophageal (TEE) imaging is appropriate, as dictated by the clinical circumstances, the adequacy of the TTE images, and the potential need for early surgical planning and intervention. It is well established that TTE has limited sensitivity for the detection of vegetations (approximately 65%) and intracardiac abscesses (approximately 30%).^21,109 The technique, however, is safe, portable, readily available, and provides useful information regarding ventricular size and function, estimated pulmonary artery systolic pressure, and the appearance and function of uninvolved valves. Another important strength of TTE is its high specificity for the detection of vegetations (approaching 98%).¹⁰⁹ When visualized, vegetations can be characterized further by their size, mobility, texture, and point of attachment. Any associated valvular dysfunction (regurgitation or stenosis) can be assessed with Doppler interrogation and a baseline established against which future comparisons can be made. Nevertheless, as many as one-fifth of patients have technically inadequate TTE images for proper resolution of valvular and endocardial structures.¹⁸ TTE does not provide adequate visualization of prosthetic heart valves (especially in the mitral position) as a result of acoustic shadowing, a situation in which its diagnostic sensitivity is reduced to 15% to 35%.¹¹⁰ Finally, TTE has limited ability to delineate perivalvular extension of infection under most clinical circumstances.^21,110,111

TEE is now performed with increasing frequency in the assessment of patients with suspected or proven IE. Although TEE is invasive and requires conscious sedation, the procedure is generally well tolerated, with low complication rates.¹¹¹ Compared with TTE, TEE has excellent specificity and offers better sensitivity for the detection of vegetations (85%-95%) and intracardiac abscesses (87%) as well as greater spatial resolution.^21,109,110 The sensitivity of TEE for the detection of vegetations in patients with suspected PVE is 82% to 96%,¹¹⁰ and TEE should be considered a first-line imaging modality in cases of suspected PVE. TEE, combined with spectral and color flow Doppler analysis, also provides excellent definition of intracardiac fistulas, valve leaflet perforations, and false aneurysms. The performance characteristics of TTE and TEE are summarized in Table 67–5. TEE should be performed expeditiously in patients with high-risk clinical features at presentation (eg, suspected Staphylococcus aureus infection of the aortic valve and root), known congenital heart disease, or suboptimal TTE images. For patients undergoing cardiac surgery for IE, intraoperative TEE is routine. TEE should also be considered for patients with catheter-associated Staphylococcus aureus bacteremia to predict the indicated duration of antibiotic therapy (ie, 2 weeks vs 4 weeks).⁷⁹ Other analyses have suggested that in patients with an intermediate pretest likelihood of IE, an initial TEE is cost-effective.¹¹²

Because of its superior performance characteristics, it is tempting to pursue TEE in all cases of suspected or proven IE. In several circumstances, however, TTE is sufficient for both diagnosis and clinical decision making. For example, in a patient with mitral valve endocarditis caused by a penicillin-sensitive viridans streptococcal species, an isolated posterior leaflet vegetation of less than 1 cm in length, and mild mitral regurgitation, antibiotic therapy can be initiated with careful follow-up. If clinically indicated, a repeat TTE can be performed to assess for complications or response to therapy. A similar approach could be adopted for a patient who has used intravenous drugs with resultant tricuspid valve IE and no clinical or TTE evidence of left-sided involvement at presentation. Thus, the choice of echocardiographic modality can be tailored to the clinical situation. The indications for TTE and TEE in patients with IE are shown in Tables 67–6 and 67–7.¹⁰⁰ An algorithm for the use of echocardiography in IE is presented in Fig. 67–6.⁶⁶

Although diagnostic echocardiography is recommended for all patients with suspected IE, some studies have suggested that in very low-risk subgroups, echocardiography may be avoided without loss of diagnostic accuracy. Kuruppu and colleagues¹¹³ have shown that 53% of echocardiograms could have been avoided without loss of diagnostic accuracy by using a simple algorithm in patients with a low pretest probability of disease. In another analysis, Greaves and colleagues¹¹⁴ have shown that the negative predictive value of TEE was 1.0 in the absence of five simple clinical criteria: vasculitic/embolic phenomena, presence of central venous access, recent history of intravenous drug use, presence of a prosthetic valve, and positive blood cultures. These studies suggest that routine echocardiographic imaging may not be indicated in a subset of low-risk patients.

The findings on echocardiography alone do not definitively establish or exclude the diagnosis of IE. Infective vegetations may be difficult to distinguish from other intracardiac masses, such as calcified debris, torn chordae, thrombus, fibroelastoma, and the nonbacterial lesions associated with healed IE, nonbacterial thrombotic endocarditis in the setting of systemic malignancy, antiphospholipid antibody syndrome, and systemic lupus erythematosus (Libman-Sacks endocarditis). In addition, an initially nondiagnostic TEE (despite its high negative predictive value) does not exclude the possibility of IE, and a repeat study is indicated in 3 to 5 days if the clinical index of suspicion remains high.¹¹⁵ Accurate diagnosis, therefore, relies on an integrated assessment of the clinical, microbiologic, and echocardiographic data.

In uncomplicated cases of IE, a single echocardiographic study is usually sufficient. However, with complex IE, serial echocardiographic examinations may help determine prognosis and guide surgical intervention. Rohmann and colleagues¹¹⁶ performed serial TEE studies in 83 patients with echocardiographic evidence of IE and followed them prospectively for a mean duration of 6 months and found that vegetations that increased in size were associated with significantly increased risk of complications. Similarly, Thuny et al¹¹⁷ reported that vegetation length was a strong predictor of the occurrence of both embolic events and death. Re-evaluation echocardiographic studies should be performed in patients with complex IE defined as infection with a virulent organism (eg, Staphylococcus aureus), severe hemodynamic compromise, aortic valve involvement, persistent fever or bacteremia, clinical change during therapy, or symptomatic deterioration. The use of re-evaluation studies in uncomplicated IE is less well established.¹¹¹ In the vast majority of cases, no additional diagnostic information is provided with a second echocardiogram.¹¹⁸ Cerebral imaging with MRI can be useful in many patients with IE because it may disclose evidence of brain embolization, leading to possible alteration in the clinical approach to such individuals.¹¹⁹

Biomarkers in the Diagnosis of Infective Endocarditis

Recently, a number of blood biomarkers have been described for increasing diagnostic accuracy in patients with suspected IE. Mueller et al¹²⁰ and Knudsen et al¹²¹ observed that blood procalcitonin levels were elevated in patients with documented IE. Unfortunately, sepsis without endocarditis can also raise blood procalcitonin levels, so the specificity of IE with this test is not high. C-reactive protein (CRP) has also been measured in patients with IE. CRP is a nonspecific marker of inflammation that is elevated in patients with IE. Normalization of CRP levels in patients with documented IE is a good predictor of a favorable outcome for these individuals.¹²² N-terminal pro-B-type natriuretic peptide along with troponin levels also predict the outcome for patients with IE.¹²³

Complication rates with IE have remained relatively unchanged despite advances in diagnosis and antimicrobial therapy. Complications can generally be related to local extension of infection (eg, valve ring abscess, fistulae, conduction block), destruction of or interference with intracardiac structures (eg, leaflet perforation or valvular obstruction), embolization (eg, stroke, septic pulmonary emboli), bacteremia/sepsis (eg, multisystem organ failure), and immune complex disease (eg, glomerulonephritis).

Heart Failure

Heart failure, the most frequent major complication of IE,¹²⁴ was found to occur in 32% of patients in a recent prospective study.² Its development portends an adverse prognosis with medical therapy alone^1,2 and is an indication for surgical intervention in most instances.^100,125 Reduced left ventricular (LV) systolic function is a powerful predictor of an adverse outcome after surgery.¹²⁶ Heart failure in IE is most often related to acute, severe valvular dysfunction as a result of either leaflet destruction or interference with normal leaflet coaptation. Heart failure may also develop secondary to rupture of infected mitral chordae, obstruction caused by bulky vegetations, development of intracardiac shunts, or prosthetic valve dehiscence.⁶⁶ Heart failure may also develop more gradually, over the intermediate-to-long term, as a function of continued valve incompetence with concomitant worsening of ventricular function after otherwise successful antibiotic treatment.

Heart failure is most commonly associated with aortic valve IE (29%), followed by mitral valve (20%) and tricuspid valve (8%) involvement.¹²⁷ In acute severe aortic regurgitation, the left ventricle operates on the steep portion of its diastolic pressure-volume relationship. The sudden delivery of a large regurgitant volume into an unprepared left ventricle is met with a marked increase in LV diastolic and left atrial pressures. Forward stroke volume falls, in part because of the inability of the left ventricle to dilate acutely. Tachycardia develops, but is usually not enough to maintain cardiac output. Such patients may present with pulmonary edema and shock. Examination findings may be masked by the severity of the heart failure. The pulse pressure is not widened, the first heart sound is soft, and the diastolic murmur is of relatively short duration. The rapid decrease in coronary driving pressure, represented by the aortic-LV pressure gradient, may result in diminished coronary blood flow and myocardial ischemia, even with normal epicardial coronary arteries. Inappropriate bradycardia, which can develop if the infection extends into the conduction system, is often accompanied by AV block (Fig. 67–7). If the patient is receiving a β-blocker, this can lead to catastrophic cardiogenic shock. Patients with acute severe mitral regurgitation may present with pulmonary edema, low cardiac output, and/or rapid atrial fibrillation. These latter patients can usually be stabilized with intensive medical therapy and, in contrast to patients with acute severe aortic regurgitation, surgery can be deferred temporarily. Patients with acute tricuspid regurgitation may show signs of right heart failure; medical management is the rule here rather than the exception. Premorbid heart disease, including antecedent valvular disease, coronary artery disease, cardiomyopathy, and/or arrhythmia, may also increase the likelihood that heart failure will develop, even with lesser degrees of acute valvular dysfunction.

Embolism

Embolization is a frequent complication of IE. The brain and the spleen are the most common sites of embolization in left-sided IE, whereas septic pulmonary emboli are common in right-sided IE.^2,3,4,64 A recent prospective study of 2781 patients from ICE found the incidence of stroke to be 17% and that of embolization other than stroke to be 23%.² Central nervous system (CNS) embolization can present without any neurologic symptoms or findings or with subtle neurologic abnormalities (headache), focal motor or sensory defects caused by branch vessel occlusion, or sudden hemiplegia and obtundation, as seen with a ruptured mycotic aneurysm with resultant intracranial hemorrhage (Fig. 67–8). Up to 90% of CNS emboli lodge in the distribution of the middle cerebral artery and carry a high mortality.¹²⁸ Any patient with suspected or definite IE who develops neurologic symptoms should undergo immediate neurologic imaging and be considered to have CNS embolization until proven otherwise.

Emboli may also end in other organ systems, including the liver, spleen, kidneys, and lungs. Metastatic sites of infection may appear in the spine and/or paraspinous space and may be the cause of prolonged fever or bacteremia despite appropriate antimicrobial therapy. Septic pulmonary emboli are present in the majority of cases of right-sided IE related to intravenous drug use.^129,130 Rarely coronary embolism can cause myocardial infarction. Although coronary embolization is relatively rare, it has long been appreciated that patients with IE can develop scattered areas of myocardial microinfarction in the absence of epicardial vessel occlusion. Such areas have been attributed to microembolization, hypoperfusion, and immunologic phenomena with microembolization the most likely culprit.¹³⁰ Janeway and Osler lesions are vascular phenomena indicative of embolization of vegetative material⁶³ (see Fig. 67–5D).

Given the varied incidence of systemic embolization among patients with IE, the ability to assess patients for embolic risk is important and may help identify patients who might benefit from an earlier surgical intervention. However, the prediction of individual patient risk for embolization has proven difficult. Embolization risk appears to decrease precipitously after 2 weeks of appropriate antibiotic therapy, from 13 to 1.2 embolic events per 1000 patient-days in a Mayo Clinic report¹³¹ and from 4.8 to 1.7 embolic events per 1000 patient-days in a more recent report from the ICE group.¹³² A prior embolic event has generally not been a predictor for recurrent embolization. An exception to this observation was noted in the report from Vilacosta and colleagues.¹³³ In many series, the risk of embolization appears to be higher with mitral than with aortic valve endocarditis (approximately 25% vs 10%, respectively), particularly with anterior mitral valve leaflet involvement.^134,135,136 A number of echocardiographic studies have demonstrated a trend toward higher embolic rates with left-sided vegetations that are > 1 cm in diameter,^137,138 and more recent work suggests that vegetation size > 1.5 cm is a predictor of IE-related mortality.¹³⁹ Increasing or unchanged vegetation size during antimicrobial therapy, as seen on serial TEE studies, may be associated with higher embolic rates.¹⁴⁰ It has been suggested that there exists an interaction between vegetation size and the presence of patient-specific antiphospholipid antibodies.^116,117,139 The risk of embolization may also be related to microbial-specific features and is consistently higher with Staphylococcus aureus, S lugdunensis, certain streptococcal strains, H influenzae, and fungi.

Mycotic Aneurysms

Mycotic aneurysms (MAs) represent a small, but extremely dangerous, subset of embolic complications. They occur most frequently in the intracranial arteries and have a particular predilection for the middle cerebral artery and its branches (see Fig. 67–8).¹⁴⁰ MAs result from septic embolization to the arterial vasa-vasorum, with subsequent spread of infection and weakening of the vessel wall. MAs tend to develop at arterial branch points, which are a common site of embolic impaction. The overall mortality among IE patients with intracranial MAs is 60% and approaches 80% if rupture occurs.¹⁴¹ The presenting symptoms of intracranial MAs are highly variable and can range from a localized headache (as seen with a small sentinel bleed) to dense neurologic deficits resulting from sudden intracranial hemorrhage.¹⁴² Routine screening of patients with definite IE for the presence of intracranial MAs is not currently recommended, and neurologic imaging is reserved for symptomatic patients. In such patients, a contrast-enhanced computed tomography (CT) scan is highly sensitive for the detection of intracranial hemorrhage and may thus indirectly identify the location of an MA.⁶⁶ CT angiography and magnetic resonance angiography are evolving techniques for the detection of intracranial MAs, although their sensitivity for small aneurysms remains inferior to that of invasive four-vessel cerebral angiography.¹⁴² Although many intracranial MAs often heal with medical therapy,¹⁴³ a subset may rupture unpredictably. There are no good predictors of whether an asymptomatic intracranial aneurysm will rupture, although enlargement on antibiotic therapy is usually an indication for invasive intervention.¹⁴³ Given the complex risks of prophylactic neurosurgical intervention, decisions concerning medical versus surgical therapy must be individualized.⁶⁶ Percutaneous neuroradiologic intervention is preferred when anatomically appropriate.¹⁴⁴ MAs may develop in other arteries (eg, splenic, mesenteric) and remain clinically silent or rupture spontaneously. These MAs are sometimes detected incidentally during abdominal imaging obtained for another indication.

Periannular Extension of Infection

Extension or spread of infection beyond the valve annulus is a potentially very dangerous development that usually presages the need for surgical therapy. Findings such as persistent fever and bacteremia despite antibiotic therapy, heart failure, or new conduction block should raise an immediate suspicion for this complication. Although a relatively insensitive sign, the development of new AV block on a 12-lead ECG in the setting of aortic valve IE has a high positive predictive value for the presence of perivalvular abscess formation.¹⁴⁵ Periannular extension may occur in 10% to 40% of all native valve IE and complicates aortic valve IE more commonly than either mitral or tricuspid valve IE. Periannular extension is more common with PVE (occurring in > 50% of patients),¹⁴⁵ as the interface between the prosthetic sewing ring and native annular tissue is often the initial site of infection (Fig. 67–9).¹⁴⁶ Perivalvular extension sets the stage for abscess formation, perforation, fistula development, and hemodynamic deterioration. The aortic annular segment adjacent to the membranous septum and the atrioventricular node is particularly vulnerable to abscess formation and may explain the occurrence of conduction block seen in some patients with aortic valve IE (see Fig. 67–7).^145,147 Patients with suspected periannular extension of infection and intracardiac abscess formation should undergo prompt TEE, which is both sensitive and specific for detection of this complication.^147,148,149 Surgical therapy is directed toward complete eradication of the infection and correction of the anatomical abnormalities. Valve replacement with reconstruction or replacement of the supporting annular structures is usually required.

Renal Dysfunction

Renal dysfunction is a common complication of IE and is often multifactorial in nature given the high incidence of pre-existing renal disease, acute immune complex disease, drug-induced nephrotoxicity, and hemodynamic perturbations. A recent necropsy and biopsy study of 62 patients with IE revealed that localized renal infarction (often caused by septic emboli) was present in 31%, acute glomerulonephritis in 26%, acute interstitial nephritis (likely antibiotic related) in 10%, and renal cortical necrosis in 10%.¹⁵⁰ Glomerulonephritis, as suggested by the appearance of red cell casts in the urine, is caused by immune complex deposition and complement activation. Similar examples of immune complex disease include nonseptic arthritis, and palpable purpuric skin lesions with findings of leukocytoclastic vasculitis on biopsy (see Figs. 67–4 and 67–5).

General Principles

Rapid institution of appropriate parenteral antibiotic therapy is the single most important initial intervention in the treatment of suspected or proven IE. Given the rising rate of antimicrobial resistance among causative organisms,⁵⁸ therapy is predicated on the identification of the responsible pathogen and delineation of its antibiotic sensitivities. An infectious disease specialist should supervise the dose, duration, and method of delivery of antimicrobial therapy during and after hospitalization. Serum antibiotic levels should be monitored where appropriate and renal and hepatic function assayed when indicated. A recent American Heart Association Scientific Statement⁵⁸ has addressed antimicrobial therapy for IE, and specific recommendations are provided in Tables 67–8, 67–9, 67–10, 67–11, 67–12, 67–13, 67–14.

Choice of Antibiotics

The lesions of IE are extremely difficult to eradicate because the infection exists in a sequestered area of impaired host defense. Thus, IE requires weeks of parenteral antibiotic therapy, preferably with a drug that has bactericidal activity against the offending organism. Combination antimicrobial therapy may provide more rapid bactericidal effect, and in certain circumstances, acts synergistically to accelerate sterilization of the blood.^139,151 All patients should have surveillance blood cultures obtained 2 to 3 days after the initiation of antibiotic therapy to ensure efficacy. Most patients will require long-term venous access via a peripherally inserted central catheter or Hickman line for a 4- to 6-week course of antibiotics. Patients should remain in an inpatient setting during the initial phase of treatment when complications are most likely to occur, after which appropriate patients can be considered for outpatient parenteral antibiotic therapy.^140,152

Empiric Antibiotic Therapy

Initial empiric antibiotic therapy (ie, before blood culture results are available) should cover Staphylococcus aureus and the many species of streptococci that can cause IE, with consideration of E faecalis in certain circumstances. Thus, a combination of a β-lactamase–resistant penicillin (nafcillin), or vancomycin for penicillin-allergic patients, and gentamicin is often used. The tempo of infection can be a valuable clue to the identity of the causative organism; Staphylococcus aureus endocarditis often presents with an acute, fulminant course with high-grade bacteremia. Other risk factors for Staphylococcus aureus IE include chronic hospitalization, indwelling central venous catheters or prosthetic devices, surgical wounds, and intravenous drug use. Vancomycin should be used if the patient is at significant risk for MRSA infection. Oral rifampin is added to nafcillin and gentamicin for staphylococcal infections of prosthetic materials (see Table 67–12). The duration of gentamicin therapy will vary as a function of the offending organism, but is usually 2 weeks or less.

Despite their theoretical benefit, there are no human studies that support the use of either antiplatelet or antithrombin agents to prevent embolic complications or hasten antibiotic cure.¹⁵³ Moreover, small uncontrolled studies suggest that antithrombin therapy actually increases the risk of intracranial hemorrhage after CNS embolization.^154,155 For patients who require anticoagulation for either chronic atrial fibrillation or a mechanical heart valve, warfarin should be discontinued on admission and unfractionated intravenous heparin substituted. Because of their extended therapeutic effect and attenuated response to protamine reversal, low-molecular-weight heparins should be avoided when anticoagulation is needed in hospitalized patients with IE. Warfarin should not be resumed until (1) it is clear that the patient has not had a CNS complication and (2) all invasive procedures are completed. For patients with mechanical valves, there is a small risk of thromboembolism when anticoagulation is withheld for a short period of time. Thus, even when anticoagulation is indicated, it should be administered with caution because the acute phase of IE is a period of high hemorrhagic risk. If neurologic symptoms develop, anticoagulant therapy should be stopped until CNS imaging can be performed. A CNS or major visceral bleed may necessitate the discontinuation of all forms of anticoagulation for a longer period of time, depending on the clinical course and the risk-benefit analysis regarding the timing of re-exposure. In the event of a CNS bleed, neurosurgical and interventional neuroradiologic consultation should be sought, especially because major intracranial hemorrhage is often caused by rupture of an MA. CNS hemorrhage will delay the performance of cardiac surgery (if indicated) for up to 1 month in most circumstances. If cardiac surgery is eventually performed, a tissue valve is preferable in order to avoid the need for postoperative anticoagulation.¹⁵⁶

The decision for surgical intervention in the treatment of IE can be extremely challenging, and there are no randomized clinical trials to guide practice. The most recent American College of Cardiology/American Heart Association guidelines for surgery in IE are summarized in Tables 67–15 and 67–16.¹⁰⁰ Perioperative morbidity and mortality vary according to the type of infection, the extent of destruction of cardiac structures, the degree of LV dysfunction, and hemodynamic status of the patient at the time of surgery.^31,100 Operative mortality in IE ranges between 5% and 15%.^{157,158,159,160,161,162,163,164,165,166}

For NVE, the primary indication for surgery in the active phase of infection is the development of clinical heart failure from either acute valve regurgitation or, less commonly, stenosis (Fig. 67–10). Evidence of elevated LV end-diastolic or left atrial pressures by either invasive (catheter) or noninvasive (echocardiographic/Doppler) assessment may also prompt surgery. Valve surgery is indicated for treatment of fungal or other highly resistant organisms and for treatment of intracardiac abscess, perforation, fistulous tracts, and false aneurysms. Surgery is reasonable for patients with recurrent emboli and persistent vegetations and for patients with persistent bacteremia despite several days (5-7 days) of appropriate antibiotic therapy in the absence of a metastatic focus of infection. Surgery to prevent embolization can be considered for treatment of large (> 1.0 cm), mobile vegetations, particularly in high-volume cardiac surgical centers with expertise in primary valve repair. This latter issue remains controversial, although improvements in repair techniques and surgical outcomes would seem to warrant this recommendation. Most echocardiographic studies have shown a relationship between vegetation size and the risk of embolization, particularly for lesions affecting the anterior mitral valve leaflet. In these studies, embolization risk increases significantly for vegetation size greater than 1.0 cm.^{137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161} Because embolization risk appears to decrease precipitously after institution of appropriate antibiotic therapy,¹³¹ prophylactic surgery to prevent embolization should be performed early in the course of the infection. Before undertaking such surgery, the members of an experienced medical/surgical team should concur that the likelihood of successful repair is high. In many instances, repair constitutes vegetectomy and pericardial patch repair of the underlying defect. Leaflet resection, placement of an annular ring, or both may be required, as dictated by the intraoperative findings.

It has been extensively documented in many recent trials that early valve surgery for patients with IE results in decreased early and late mortality. This is particularly true for patients with any complication such as heart failure, heart block, large vegetation size, recurrent embolization, perivalvular extension of infection, infection with a resistant organism, and other signs or symptoms of clinical instability^{160,161,162,163,164,165,166,167} (see Table 67–15).

Indications for surgery in patients with PVE are similar to those for patients with native valve IE. Heart failure, a poorly responsive microorganism, perivalvular extension, or an unstable prosthesis are class I indications for surgery. Prosthetic valve dehiscence is defined as a rocking motion of the valve with excursion of 15 degrees or more in at least one plane. As noted, perivalvular abscess formation is more common with PVE than with NVE because the infection typically involves the interface between the sewing ring and surrounding tissue (see Fig. 67–9).¹⁴⁵ Early surgery may be considered for selected patients with PVE without perivalvular extension or heart failure. For example, Staphylococcus aureus PVE is rarely eradicated with antibiotics alone, and retrospective analyses suggest that combined medical and surgical therapy is more effective than medical therapy alone.^96,166 Relapse of PVE after appropriate antibiotic therapy should lead to a careful search for perivalvular extension or for metastatic foci of infection.^3,4 Some patients with relapsed PVE may respond to a second course of antimicrobial therapy, but the majority will require surgery for cure. Despite the frequent need for surgery, medical cure with antibiotic therapy should be initially attempted for uncomplicated PVE caused by first infection with a sensitive organism (eg, enterococci, streptococci).

The timing of surgery after CNS embolization in either NVE or PVE is problematic because of the risk of hemorrhagic transformation. The clinical spectrum of neurologic complications in IE is wide and includes ischemic or hemorrhagic stroke, transient ischemic attack, silent cerebral embolism, symptomatic or asymptomatic MA, brain abscess, meningitis, toxic encephalopathy, and seizure.^134,135,162 Furthermore, there is a high prevalence of asymptomatic findings on head CT in patients with IE.¹⁶² It should be re-emphasized that rapid diagnosis and initiation of appropriate antibiotic therapy are of major importance to prevent a first or recurrent neurologic complication. After a neurologic event, many patients will still have at least one indication for which surgery should be considered.¹⁶² One prospective study found that the risk of postoperative neurologic deterioration is low after silent cerebral embolism or a transient ischemic attack, and surgery for such cases is recommended without delay if an indication remains.^3,4,162 After an ischemic stroke, cardiac surgery is not absolutely contraindicated unless the neurologic prognosis is deemed to be poor. There is conflicting evidence regarding the optimal time interval between stroke and cardiac surgery.^{3,4,156,162,163,164,165,166,167,168,169,170,171,172,173} If cerebral hemorrhage has been excluded by head CT imaging and neurologic damage is not severe (eg, coma or severe neurological dysfunction), and surgery is indicated for heart failure, uncontrolled infection, or abscess, the intervention should not be delayed and can be performed with relatively low neurologic risk (3%-6%) with a reasonable probability of a favorable neurologic outcome.^165,166 Conversely, in cases with intracerebral hemorrhage, the neurologic prognosis is worse, and surgery is usually postponed for at least 1 month.¹⁶³ In all cases of IE with neurologic complications, early neurologic and neurosurgical consultation is advisable. Before contemplating cardiac surgery in a patient with neurologic complications, MAs may require attention with extirpation by either percutaneous or surgical techniques.^153,166,167 Recent guidelines from the European Society of Cardiology provide recommendations for management of neurologic complications and the timing of surgery (Table 67–17 and Fig. 67–11).⁴

Patients with IE are an extremely heterogeneous group, with varying comorbidities, causative organisms, and complications. Accurate prognostic classification may help inform individual treatment decisions. Chu and colleagues⁷⁸ analyzed 267 consecutive cases of definite IE with an overall mortality of approximately 20% and found the following factors to be independently predictive of death: diabetes mellitus, Staphylococcus aureus as the causative organism, an embolic event, and increased Acute Physiology and Chronic Health Evaluation (APACHE) II score. Data obtained from ICE have supported the finding that diabetes mellitus is independently associated with higher mortality in IE.¹⁷⁴ Hasbun and colleagues¹ derived an externally validated prognostic classi­fication system for adults presenting with complicated left-sided NVE. The 6-month mortality was approximately 25%. Five clinical features were associated with 6-month mortality: increased Charlson comorbidity score, abnormal mental status, moderate-to-severe heart failure, causative organism other than viridans streptococci, and medical therapy without valve surgery. Using these prognostic features, the authors derived a weighted integer scoring system that classified patients into four groups with progressively increasing 6-month death risk, ranging from 5% to 59%.

In a separate analysis, Fowler and colleagues²⁶ analyzed 300 patients with definite IE caused by Staphylococcus aureus unrelated to intravenous drug use who were enrolled in the ICE Prospective Cohort Study. They found the following factors to be independently associated with in-hospital death: advanced age, stroke, and persistent bacteremia. Another study of Staphylococcus aureus NVE from the ICE-merged database found advanced age, heart failure, periannular abscess formation, and absence of surgical therapy to be associated with higher mortality.¹⁷⁵ Thuny and colleagues¹¹⁷ performed TEE in 384 consecutive patients with IE. Embolism occurred in 34.1% of patients before and 7.3% of patients after initiation of antibiotics. In addition to age, female sex, serum creatinine > 2.0 mg/dL, moderate or severe heart failure, and infection with Staphylococcus aureus, vegetation length > 1.5 cm was an independent predictor of 1-year mortality. Total mortality at 1 year was 20.6%. Most recently, the ICE Prospective Cohort Study of 2781 cases of IE found the following characteristics to be associated with an increased risk of in-hospital death: PVE, increasing age, pulmonary edema, Staphylococcus aureus infection, CoNS infection, mitral valve vegetation, and paravalvular complication.² Lopez et al¹⁷⁶ found that persistently positive blood cultures after the initiation of antibiotic therapy were an independent risk factor for in-hospital mortality in patients with left-sided native valve IE. Also of interest was the nationwide population study from Taiwan by Yang et al¹⁷⁷ that demonstrated that patients with IE who were concomitantly taking a statin agent had a reduced risk of in-hospital and subsequent mortality. One observational study demonstrated that the implementation of a standardized diagnostic and therapeutic protocol was associated with an improvement in outcomes.¹⁷⁸ Although the decision to undertake early surgery for the treatment of IE must be made on an individual basis, these data provide a useful approach for aggressive medical and surgical intervention in high-risk patient groups.¹⁷⁹

The use of antibiotic prophylaxis before dental, endoscopic, or surgical procedures for the prevention of IE has changed significantly over the years since the publication of the revised 2007 American Heart Association Guidelines.⁹² The rationale for the revisions is based on four principles including the recognition that previous recommendations lacked a robust evidence base. Accordingly, the emphasis has shifted from providing antibiotic prophylaxis to patients at high risk for the lifetime acquisition of IE to providing antibiotic prophylaxis to patients at highest risk for the development of an adverse outcome from IE. High-risk patient groups are listed in Table 67–18.¹⁸⁰ The specific procedures for which antibiotic prophylaxis is recommended in the absence of an intercurrent infection are listed in Table 67–19. With regard to IE prevention, there is general agreement between the American Heart Association Guidelines⁹² and those more recently released by the European Society of Cardiology.³⁰ Recommended antibiotic regimens are listed in Table 67–20.

The revised guidelines have narrowed the procedures for which antibiotic prophylaxis is recommended. In particular, antibiotic prophylaxis solely to prevent IE is no longer recommended for GI/genitourinary tract procedures (including diagnostic esophagogastroduodenoscopy or colonoscopy), as no published data demonstrate a conclusive link between these procedures and the development of IE.¹⁶⁰ Antibiotic prophylaxis for high-risk patients is currently recommended only for the procedures listed in Table 67–19. In the unique scenario in which a high-risk patient requires elective urinary tract manipulation (eg, cystoscopy) and has an established enterococcal urinary tract infection or colonization, antibiotic therapy to eradicate enterococci from the urine before the procedure may be reasonable. If the urinary tract procedure is not elective, it is reasonable that the empiric or specific antimicrobial regimen administered to the patient contain an active antienterococcal agent.⁹² All patients who undergo heart valve replacement or who receive an intravascular graft or intracardiac device should receive periprocedural prophylaxis with an antistaphylococcal agent. Antibiotic prophylaxis for IE prevention before dental procedures is not recommended for patients who have undergone coronary artery bypass grafting, percutaneous coronary intervention (with or without a stent), or implantation of a pacemaker/ICD.

Prophylactic antibiotics for IE prevention should be administered in a single dose before the procedure. If the dosage is inadvertently not administered before the procedure, it may be given up to 2 hours after the procedure.⁹² Prophylactic antibiotic recommendations for dental procedures are directed against viridans group streptococci and are listed in Table 67–20. Prophylaxis for respiratory procedures is identical. Amoxicillin is the first choice for oral therapy because it is well absorbed in the GI tract and provides high and sustained serum concentrations. For patients who are allergic to penicillins or amoxicillin, a first-generation cephalosporin is recommended.⁹² There are a few special circumstances in which different microbial coverage is recommended. For high-risk patients with established genitourinary tract colonization or infection with enterococci, it is reasonable that antienterococcal prophylaxis be administered before cystoscopy.⁹² In centers with high prevalence of methicillin-resistant staphylococci, prophylaxis before valve replacement surgery or cardiac device implantation with vancomycin is reasonable, but has not been shown to be superior to prophylaxis with a cephalosporin.⁹² Prophylaxis should be initiated immediately preoperatively, repeated during prolonged procedures to maintain serum concentrations intraoperatively, and continued for no more than 48 hours postoperatively to minimize emergence of resistant organisms.⁹²

It is recognized that patients and providers may find that these revised guideline recommendations depart too radically from previously accepted standards. Many remain uncomfortable with their execution in patients with mitral valve prolapse with severe mitral regurgitation, hypertrophic obstructive cardiomyopathy, and bicuspid aortic valve disease. Accordingly, individual judgment respectful of patient preference is advised.

We would like to thank Dr. Saptarsi M. Haldar and Dr. Patrick T. O’Gara, who contributed to the previous version of this chapter in the 13th edition.