Chapter 38. Infectious Endocarditis

Endocarditis, inflammation of the endocardial surface of the heart, can have numerous etiologies including mechanical irritation, neoplastic, autoimmune, or infectious diseases.1–4 This chapter will focus on the infectious causes that are typically bacteria, mycobacteria, and fungi. Although the cardiac valves are most commonly involved, the mural endocardium, septal defects, chordae tendineae, and even intracardiac medical equipment (pacemaker/defibrillator leads or septal occluder devices) can also be sites of infection.1–6 Infectious endocarditis (IE) has an incidence of 3.6/100,000 per year and accounts for 1/1,000 hospital admissions in the United States. There is a 2:1 male to female ratio with current overall in-patient mortality between 11% and 26%, although this figure may be drastically different for the various subsets of IE patients.1,3,7

The first published description of the valvular cardiac lesions due to IE was over 300 years ago by Lazarus Riverius, while about 200 years ago Jean Baptiste Boulaud defined the anatomy of the endocardium; 150 years ago, the association of preexisting rheumatic valvular damage and bicuspid aortic valves with IE was noted by Sir James Paget.8,9 In 1905 when blood cultures came into clinical practice, the antemortem diagnostic rate for IE was approximately 50%.9 IE has had numerous classification schemes over the last century starting with Sir William Osler who divided IE into “simple” and “malignant” categories based on the length of time from symptom onset to death along with the associated complications. These categories evolved into the following IE classification in the preantibiotic era: (1) acute (onset of symptoms to death <6 weeks, caused by a highly virulent organism capable of infecting a normal heart); (2) subacute (onset of symptoms to death 6 weeks to 3 months, caused by a less virulent organism that infects hearts with preexisting endocardial damage); (3) chronic (>3 months from symptom onset to death, caused by an indolent microbe capable of infecting only abnormal hearts or immunosuppressed patients).9,10 Current classifications include diagnostic status (definite or probable), anatomic site (right- or left-sided cardiac valves), valve type (native or prosthetic), microbe (bacterial or fungal species), and patient population (intravenous [IV] drug abusers [IVDA], elderly, nosocomial infection). Prosthetic valve IE is further divided into early (<2 months after surgery), intermediate (2 months to 1 year), and late (>1 year after surgery) cases; the early cases are typically nosocomial while the intermediate and late cases are community acquired.10–12 Another classification that reflects the early description by Osler is simple (infection limited to valve cusps and leaflets) or advanced (deep tissue infection including perivalvular structures, cardiac abscess or pseudoaneurysm formation, and systemic infectious emboli). These various categories of IE differ in incidence, presentation, microbial etiology, and outcome.1,3,10,13

The disease process of IE and vegetation formation requires multiple steps (see Figure 38-1) starting with endothelial damage from high-velocity jets of blood due to congenital or acquired cardiac abnormalities, or mechanical damage from intracardiac devices or blood-borne debris.1,10 Platelets and fibrin then form a sterile thrombus at the site of endothelial damage; certain disease states, such as malignancy, uremia, and autoimmune diseases, can form sterile cardiac vegetations without overt endothelial damage. The initially sterile site is seeded by transient bacteremia and then matures with additional fibrin deposition and bacterial proliferation. The vegetation has no vasculature, so it is relatively protected from activated phagocytes or antibiotic penetration.10,11

In developing countries, rheumatic heart disease is still the main risk for IE; as treatment of streptococcal pharyngitis improved in the United States and Europe, there has been less cardiac sequelae, so in these areas congenital (bicuspid aortic valve, hypertrophic obstructive cardiomyopthy, mitral valve prolapse with regurgitation) and degenerative cardiac diseases (aortic valve calcification) are the leading risk factors for IE. Other recognized risks include diabetes mellitus, hemodialysis, immunosuppression, and previous IE. Approximately 50% of cases have no known prior valve abnormality but likely had microscopic valvular lesions that were vulnerable to highly virulent organisms such as Staphylococcus aureus or Streptococcus pneumoniae.2,3,7

While streptococcal species are still the leading infectious agents for IE worldwide, their incidence has been declining with better oral hygiene and dental care plus appropriate antibiotic prophylaxis. On the other hand, S. aureus IE has been increasing in incidence and is the leading cause in intensive care unit (ICU) cases and in IVDA. In non-IVDA native valve endocarditis (NVE), streptococcal species (viridans, mutans, mitis, sanguis) typically from the mouth and nasopharynx account for 17–36% of cases; Streptococcus bovis accounts for 6% and is associated with gastrointestinal (GI) lesions in the elderly. S. aureus accounts for up to 30% of the cases in this category, with the skin as the major source, but in half of the cases there is no obvious portal of entry so that nasal carriage is also a source. Enterococcus species cause 8–11% of the NVE in non-IVDA patients, who are mostly older with GI/genitourinary (GU) lesions or recent procedures. The Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella (HACEK) group only accounts for 3% of cases in this population; although gram-negative bacilli (GNB) are leading causes of sepsis, their lack of avid adherence to endothelium diminishes the risk of IE during bacteremia. S. pneumoniae causes a small number of cases of NVE in a subset of non-IVDA patients with diabetes mellitus, malignancy, chronic obstructive pulmonary disease (COPD), or alcoholism; the lungs are the source, and meningitis is associated in 40–60% of patients. Fungal or polymicrobial IE is uncommon in NVE who are not IVDA.1,2,7,14

In the IVDA population, there is a 2–5% per year risk of IE; it is higher with cocaine than heroin due to the shorter duration of cocaine that requires more frequent injections but not heating of the drug, which may decrease the bacterial counts with heroin “cooking.” S. aureus is the number one microbe in this group, with the majority being methicillin-sensitive. Fungus, predominantly Candida and Aspergillus species, accounts for about 10% of IE cases in drug abusers. Pseudomonas aeruginosa can also be responsible for IE when unboiled tap or toilet water is used to rinse drug paraphernalia or to dissolve drugs for injection. Polymicrobial IE is unique to this population where it accounts for 2–5% of cases. Human immunodeficiency virus (HIV) infection is an independent risk factor for IE in the IVDA and is associated with increased mortality as the CD4 cell count is decreased below 200 cells/mm3. It should be noted that IE is usually not considered a complication of acquired immune deficiency syndrome (AIDS) and is quite rare in non-IVDA patients with HIV infection. When this patient type develops IE, atypical organisms such as Salmonella are often responsible.15–17

The typical presentation of fever and cardiac murmur with skin and conjunctival lesions may not necessarily be present, and in cases of very acute IE due to aggressive organisms, the classic cutaneous and retinal immunologic findings will be absent. Although 85% of patients with IE have a murmur, they may not have a murmur at initial presentation but only develop it during the course of their illness. Obvious signs of bacterial emboli (see Figure 38-2A and B) are indicative of IE on physical examination when present in approximately 50% of cases.1,5

At least one complication occurs in 57% of cases, with 26% having two and 14% having three or more complications. Complications of IE are divided into the two categories of cardiac and extracardiac, with the overwhelming majority of complications occurring early in the course of illness. Cardiac complications are secondary to local destruction and emboli and include valve cusps and leaflets, chordae tendineae, atrioventricular (AV) nodal and His–Purkinje conductive tissue, myocardium (abscess, septal or free wall perforation, aneurysm), pericardium (purulent pericarditis or hemopericardium leading to tamponade), and coronary arteries (due to emboli). Congestive heart failure (CHF) is the most common complication of IE, occurring due to valvular regurgitation; myocardial failure is not a typical feature. Extracardiac complications include systemic embolization and organ failure. The emboli may be sterile and cause ischemia or infarction at the target organ or they may be septic and form an abscess; alternatively, a bland infarct may be seeded by ongoing bacteremia and lead to an abscess. The most frequent sites of embolization are the brain, spleen, kidneys, skin, liver, and mesenteric and iliac arteries. A mycotic aneurysm may result at any arterial site of emboli.1,10,18

With right-sided IE, pulmonary emboli may occur leading to septic emboli (see Figure 38-3), empyema, and right heart dysfunction. Organ failure during the course of IE is most commonly due to hemodynamic deterioration and hypoperfusion, again from valvular CHF. The exception is acute renal failure, which may be multifactorial due to acute tubular necrosis from ischemia or drugs (aminoglycosides, vancomycin, IV contrast), glomerulonephritis, or renal infarcts from emboli (see Figure 38-4). Embolization risk is highest for large vegetations (>1 cm diameter) particularly if involving the anterior leaflet of the mitral valve.2,7

With left-sided IE, CHF due to severe valvular incompetence is the most common serious complication. It occurs more frequently with aortic than mitral valve infection since the left ventricle is less tolerant of the sudden volume overload of acute regurgitation than is the left atrium. Central nervous system (CNS) complications occur in 20–40% of left-sided IE cases; they occur early and are the first sign of IE in 47% of patients, but the risk of further complications drops drastically after initiation of appropriate antibiotics. CNS complications are due to emboli to the cerebral arteries (the middle cerebral artery in >90% of episodes) leading to ischemia or infarction secondary to vessel occlusion. The resulting transient ischemic attack (TIA)/cerebrovascular accident (CVA) is the most common CNS complication of IE representing 40–50% all CNS events. Brain abscess due to septic emboli (see Figure 38-5) only accounts for 5% of CNS events while meningitis accounts for 5–40%. Intracranial hemorrhage represents 10% of CNS complications of IE and can be caused by rupture of a mycotic aneurysm, septic erosion of a vessel without aneurysm (known as acute necrotizing arteritis), or hemorrhagic transformation of a recent ischemic stroke.1,18

IE patients may require admission to an ICU due to septic shock, cardiogenic shock, respiratory failure, pulmonary edema from acute valve dysfunction, acute renal failure requiring renal replacement therapy, acute CNS events (stroke, intracranial hemorrhage, encephalitis), or symptomatic bradycardia/heart block requiring cardiac pacing (see Figure 38-6). While simple IE cases can be treated by an in-patient physician, these complicated cases necessitate a multidisciplinary approach by the coordinated care of intensivists, infectious disease specialists, neurologists, cardiologists, and cardiac surgeons.19,20

Drug Users

The incidence of IE in IVDA is 1.5–20/1,000 addicts, with 80% involving the right heart as compared with only 9% right heart infection in non-IVDA native valve IE patients. This high proportion of right-sided disease in drug users is thought to result from microscopic endocardial damage due to impurities in illicit drug preparations and repeated bacteremia from unsterile injections. The most frequent underlying cardiac abnormality that predisposes IVDA patients to IE is a previous episode of IE. Right-sided IE is also associated with cardiac pacing and implanted defibrillators, where the vegetations are usually confined to the leads but there is tricuspid valve involvement in 10% of cases.7,15,17

Prosthetic Valve

Prosthetic valve endocarditis (PVE) accounts for up to one quarter of all IE cases, and the percentage has been increasing as more valve replacements are performed. The risk of IE for patients with prosthetic valves is 1% at 1 year and 2–3% at 5 years. The early risk is higher with mechanical valves than for biologic valves, but the risk appears to become equivalent later in the postoperative dates. PVE of mechanical valves typically has involvement of the cusps, sewing ring, and valve annulus, while with biologic valves the infection is mostly limited to the cusps.2,5,7

Nosocomial Endocarditis

A relatively new category of endocarditis is nosocomial IE (NIE) defined as occurring greater than 48 hours after hospital admission or within 4–8 weeks of an invasive procedure performed in the hospital, which includes early prosthetic valve infections. The incidence of NIE is estimated to be 0.8 per 10,000 hospital admissions, and it accounts for 14–25% of all IE cases. Considered a subset of NIE is ICU-acquired IE that has an estimated incidence of 5 per 1,000 ICU admissions. Elderly (age >65) patients more often develop NIE than do younger (age <65) patients and have twice the in-patient mortality; their risk factors are diabetes mellitus, and GI or GU cancers. The source of infection is a central venous catheter in 9–48% of cases, a peripheral venous catheter in 6–22% of cases, a pulmonary artery catheter in 2–9% of cases, and GU tract surgery or instrumentation in 20–30% of cases. S. aureus is the most prevalent microbe causing 52–57% of cases (an intravascular device is the source in 91% of these patients); 13–25% of hospitalized patients experiencing staphylococcal bacteremia will develop IE. Coagulase-negative Staphylococcus causes 40% of cases (associated with prosthetic valves in 89%), Enterococcus species causes 5–30% of cases, and GNB cases are rare except for P. aeruginosa in hemodialysis patients. This organism has the capability to adhere to endocardium unlike most GNB that are often responsible for bacteremia and sepsis but not IE due to low adherence factors. Although fungal NIE is still relatively rare (less than 10% of all IE cases), its incidence is increasing; the hallmarks of fungal IE are bulky vegetations with emboli to major arteries.10,13,14

Previous diagnostic criteria for IE, such as the Von Reyn criteria, have been replaced by the more sensitive and specific Duke criteria that include echocardiographic data that previously were not included. Recent updates to the Duke criteria have made evidence of S. aureus bacteremia a major criterion. For suspected cases of IE, at least three sets of blood cultures should be done at individual venipuncture sites during the first 24 hours after presentation; there should be at least 1 hour between first and last sets being drawn. This protocol is intended to reduce the chance of identifying contaminated samples while enhancing the ability to detect persistent bacteremia, the hallmark of IE. Only 5–7% of patients not recently on antibiotics have negative blood culture results. In these patients, antibiotic binding resins can be used to enhance the culture yield as well as polymerase chain reaction (PCR) testing can be done on vegetation or embolic samples, since PCR will yield positive results even after several weeks of antibiotic treatment.1,2,21

Transthoracic echocardiography (TTE) has a sensitivity of 46–65% for detecting left heart vegetations as compared with 90–93% for transesophageal echocardiography (TEE); the sensitivity for detecting left heart regurgitation is also 58–63% for TTE and 88–98% for TEE, but the two modalities are equal for detecting right heart IE. The risk of a false-negative study TTE is increased by obesity, COPD, prosthetic valves, and vegetation size <5 mm. TTE is often of limited utility in the ICU due to restrictions on patient positioning, surgical wounds interfering with optimal ultrasound probe contact, and mechanical ventilation resulting in poor image resolution. Based on these data, it is considered reasonable for low-risk suitable patients to have a TTE as an initial study but to use TEE for high-risk or complicated patients including any suspected PVE. Although there are pathognomonic echocardiographic findings, such as leaflet perforation, periannular or myocardial abscess, or new prosthetic valve dehiscence, neither mode can reliably differentiate the classic sonographic finding of IE, an oscillating intracardiac mass representing a vegetation (see Figure 38-7), from other noninfective lesions such as tumors, thrombus marantic endocarditis, or myxomatous valvular degeneration. Other diagnostic tests that are considered helpful in IE are a chest radiograph, an electrocardiogram, and a urinalysis.22–24

The treatment for IE is based on the principal of sustained antimicrobial activity with high serum concentrations in order to eradicate dormant microbes in vegetations and distant emboli. Prolonged IV bactericidal antibiotic regimens are the standard treatment. Blood cultures should be drawn every 24–48 hours after initiation of therapy until cultures are negative; this result marks the beginning of the time course of the regimen. Initial antibiotic regimens are described for the distinct patient population and should be adjusted based on microbe sensitivity and minimum inhibitory concentration. An initial choice of a cell wall active drug (β-lactam or vancomycin) plus an aminoglycoside will give synergistic coverage against Staphylococcus, Streptococcus, and Enterococcus species that account for over 80% of all IE; this strategy has been shown to reduce the duration of bacteremia but not to change clinical outcomes.2,4

Streptococcus viridans IE cases typically respond clinically to antibiotic treatment more quickly than does IE due to S. aureus or Enterococcus. For IE due to les virulent organisms, fever often resolves after 2–5 days of appropriate antibiotics. Persistent fever beyond the first week of treatment often indicates complicated disease, while recurrence of fever in weeks 3–4 is more often due to drug hypersensitivity, particularly with high β-lactams, but emboli may still occur. All patients should receive their first 2 weeks of therapy as in-patients to monitor for complications during this highest-risk period. Stable patients without complication may be considered for outpatient IV therapy to complete their regimen after this time. There is no benefit of additional oral antibiotics after completing a full IV course. Follow-up cultures should be done to ensure treatment success without relapse that most commonly occurs within 2 months of the conclusion of the antibiotic regimen. The relapse, or treatment failure rate, is <2% for S. viridans, 8–20% for Enterococcus, and 11% for S. aureus. There is no proven benefit at preventing emboli by giving aspirin or heparin, but since these agents increase the risk of intracranial hemorrhage, they should be avoided. Anticoagulation can be used judiciously for a prosthetic valve patient, but it should be held for 2 weeks if an embolic CNS event occurs.2,4,11

Although there have not been any controlled studies, it does appear that combined medical and surgical treatment yields a better outcome than medical treatment alone for complicated left-sided IE, particularly if S. aureus is the cause. More than 25% of all IE patients receive cardiac surgery during their acute illness and 20–40% receive it later. Despite the goal of sterilizing the tissue of the surgical field prior to procedure, there is little correlation between length of preoperative antibiotics and outcome. It may be a more productive goal of performing valve surgery early so as to prevent the possible complications that may occur and thereby increase the operative risks. The strongest indications for surgical treatment are CHF due to acute valvular dysfunction or prosthesis dehiscence, prosthetic valve obstruction, periannular or myocardial abscess, mycotic aneurysm, fungal IE, or S. aureus PVE. Combined medical and surgical therapy lowers the mortality rate of NVE patients with moderate–severe CHF to 11–35% as compared with 56–86% with medical therapy alone. Persistent bacteremia after 1 week on appropriate antibiotics or ongoing systemic emboli is also considered indications for surgical treatment. Unstable septic shock or severe uncorrected coagulopathy is a contraindication for valve surgery. Operative mortality is significantly higher if pulmonary edema or cardiogenic shock due to valvular dysfunction has developed. If the patient has had an ischemic CNS embolic event, surgery can be done early (within 72 hours) in efforts to prevent further emboli or surgery should be delayed 2–3 weeks to decrease the risk of hemorrhagic transformation due to heparin exposure; it is recommended to delay surgery for a minimum of 4 weeks after an intracranial hemorrhage. These recommendations to postpone surgery are only valid if CHF or cardiogenic shock has not developed. Tricuspid valvulectomy without replacement is highly effective treatment for IE but invariably leads to severe and permanent right ventricular dysfunction. The postoperative antibiotic regimen should complete a full course or be at least 7–15 days if the valve cultures are negative; if the valve cultures are positive, then a full antibiotic course should be given starting at the date of surgery.25–30

While the overall in-patient mortality is 16% for all IE cases, there is quite a range in mortality depending on the disease category. The mortality is 26% for complicated left-sided NVE, 44% for PVE, 45–54% for IE patients requiring ICU admission, and highest at 68% for NIE; the lowest risk mortality at <10% is in IVDA with isolated right-sided disease. Factors indicating a poor prognosis are CHF, septic shock, CNS events, acute renal failure, immunocompromise, higher Acute Physiology and Chronic Health Evaluation (APACHE) II score, and S. aureus as the infectious agent.2,4,5,20

New recommendations for IE prophylaxis have limited treatment to the highest-risk groups (see Table 38-1): prosthetic valves, previous IE, valvulopathy after cardiac transplant, complex cyanotic congenital heart disease, and surgical systemic–pulmonary shunts. It also limited the procedures requiring prophylaxis to gingival or periapical dental work or incision through infected skin or soft tissue.31