Peter Zimbwa and Steven M. Gordon
Over the last three decades, the overall incidence of infective endocarditis (IE) and the associated mortality have remained constant, between 1.7 and 6.2 per 100,000 people per year, and between 10% and 30%, respectively.1–4 The clinical spectrum of IE has, however, undergone dramatic changes. These changes are noted in:
The at-risk population
The underlying susceptible cardiac lesions
The etiologic pathogens
The clinical presentation
The diagnostic evaluation
The antimicrobial agents
The recommendations for prophylaxis
In industrialized countries, the population at risk for IE has become older, parallel to an ageing population. The attendant degenerative valve lesions such as calcific aortic stenosis and myxomatous mitral regurgitation (MR) have superseded rheumatic heart disease as the primary risk factors for IE. In developing countries where antibiotic use is not as widespread, however, rheumatic heart disease remains the key risk factor for IE. Invasive medical interventions, particularly with intravascular catheters, hemodialysis, and cardiac implantable electronic devices, have led to the emergence and prominence of health care–associated (nosocomial) IE. There has also been growth in those at risk in industrialized countries among injection drug users (IDU), and patients with prosthetic valves. The etiologic pathogens have remained largely unchanged, with viridans streptococci and staphylococci species accounting for the majority of cases. However, their relative contributions and antibiotic sensitivities have changed, mirroring the risk factors. For instance, the majority of cases in the 1960s and 1970s were caused by viridans streptococci, and 15% of cases were due to staphylococci. More recently, staphylococci have surpassed streptococci as the most common cause of IE accounting for 31% of the cases, whereas viridans streptococci were identified in 17%.2 In most urban areas, IDU may account for the majority of IE that is most commonly caused by Staphylococcus aureus.3,11 Such patients tend to be younger and present more acutely with fever and sepsis syndromes rather than as the classic Oslerian subacute and chronic presentation of fever of unknown origin, with regurgitant valvulitis, splinter hemorrhages (Fig. 35.1), Osler nodes (Fig. 35.2), Janeway lesions (Fig. 35.3), or Roth spots.
FIGURE 35.1 Splinter hemorrhages.
FIGURE 35.2 Osler nodes
FIGURE 35.3 Janeway lesions.
The International Collaboration on Endocarditis–Prospective Cohort Study (ICE-PCS), Murdoch and coinvestigators2 prospectively collected data on 2,781 patients with definite IE by the modified Duke criteria at 58 hospitals in 25 countries from June 1, 2000, through September 1, 2005. The median age of the cohort was 57.9 years, and 72.1% had native valve endocarditis (NVE). Most patients (77%) presented early (within 30 days) with few of the classic features of IE. Recent health care exposure was found in 25% of patients. S. aureus was the most common pathogen (31.2%). Left-sided IE was more common (mitral valve 41.1%, aortic valve 37.6%). Common complications included stroke (16.9%), embolization other than stroke (22.6%), heart failure (32.3%), and intracardiac abscess (14.4%). Surgical therapy was common (48.2%), and in-hospital mortality was high (17.7%). Increased risk of in-hospital death was associated with prosthetic valves (PV), older age, pulmonary edema, S. aureus, coagulase-negative staphylococcal infection, mitral valve vegetation, and paravalvular complications. Viridans streptococcal infection and surgery were associated with a decreased risk.
DEFINITIONS
IE is defined as a microbial infection of the endocardium. Acute and subacute endocarditis are further subdivisions based on the tempo and severity of the infection1 with subacute presentation usually defined as >2 months of symptoms before diagnosis. Prosthetic valve endocarditis within 12 months after valve surgery is defined as early and is often caused by drug-resistant, surgery-related pathogens, such as methicillin-resistant Staphylococcus aureus(MRSA).1 Infections that are acquired after this period, presumably after endothelialization of the valve prosthesis, are defined as late. Late PV is more likely caused by the same set of pathogens that cause NVE, such as oral streptococci, and the HACEK group (Haemophilus species, Aggregatibacter (formerly Act-inobacillus) actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species).1 Hospital-acquired IE has been defined as either IE with onset of symptoms >72 hours after hospitalization or IE occurring from 4 to 8 weeks after discharge from the hospital if an invasive procedure was performed during hospitalization.5
EPIDEMIOLOGY
IE is uncommon. The incidence of community-acquired NVE has remained between 1.7 and 6.2 per 100,000 person-years over the last three decades. The associated mortality has also remained unchanged (between 10% and 30%) over the same period.1–4 While three decades ago, IE was mainly a complication of rheumatic heart disease in children and young adults, in the industrialized world, IE is now mainly seen in much older adults rendered vulnerable by new risk factors including degenerative heart valve disease, valve prostheses, hemodialysis, intravascular catheters, cardiac implantable electronic devices, and IDU.1–4
Left-sided IE is more frequent than right-sided IE, accounting for over two-thirds of NVE.2,6 Prosthetic valve endocarditis of the left side has the worst prognosis, associated with mortality that can exceed 40%.5–7 The cumulative risk for PV increases with duration of the prosthesis, reported to be approximately 1% at 1 year and 2% to 3% at 5 years.8,9 Right-sided IE commonly occurs in the setting of IDU, indwelling central venous catheter, cardiac implantable electronic devices, congenital heart disease (CHD), and human immunodeficiency virus (HIV) infection.10,11 The incidence of IE associated with IDU is 150 to 2,000 per 100,000 person-years with in-hospital mortality <10%.1 Although its prognosis is generally better than that of left-sided IE, in patients with acquired immunodeficiency syndrome (AIDS), mortality of right heart endocarditis can reach 50%.12,13
Hospital-acquired IE constitutes 9% to 29% of all cases and has increased in frequency in recent years owing to greater use of invasive procedures.14,15 MRSA, coagulase-negative staphylococci, and gram-negative bacilli tend to predominate as causative agents, with mortality rates as high as 40% to 60%. Fowler et al.16 recruited 324 patients with S. aureus bacteremia caused by an infected intravascular device to define patient and bacterial characteristics associated with the development of hematogenous complications (including endocarditis). On multivariable analysis, symptom duration, hemodialysis dependence, presence of a long-term intravascular catheter, or a noncatheter device, and infection with MRSA placed the patients at a higher risk of developing hematogenous complications.
RISK FACTORS
Important risk factors for IE include:
Degenerative valvular heart disease
Prosthetic heart valves
Increased exposure to nosocomial bacteremia
Poor dental hygiene
Long-term hemodialysis
Injection drug use
HIV infection
PATHOGENESIS
Four main mechanisms are responsible for the initiation and localization of infection of the endocardium:
1. A previously damaged cardiac valve or a situation in which a jet effect is produced by blood flowing from a region of high pressure to one of low pressure
2. A sterile platelet fibrin thrombus
3. A pathogen in the bloodstream
4. High titer of agglutinating antibody for the infecting organism
Damaged endocardium results in exposure of the underlying extracellular matrix proteins, which engenders thrombosis with production of tissue factor, and the deposition of fibrin and platelets.17 Pathogens then adhere to the damaged endothelium and set up infection via adhesins which include proteins and polysaccharides collectively known as Microbial Surface Component Reacting with Adhesive Matrix Molecules (MSCRAMMs).18 In experimental IE using animal models, both the magnitude of bacterial inoculum and the adhesive properties of bacteria were important in determining the likelihood of subsequent infection.19 Inoculating animals with bacterial bolus injections between 105 and 107 colony-forming units (CFU)/mL induced IE.20 Veloso et al.21 tested whether IE could also be induced by injecting the same absolute number of bacteria but at a very low level. They found that such low-grade continuous infusion (over >10 hours) was as infective as high-grade bolus infusion, confirming that perhaps the most critical factor for IE induction is total bacterial burden, rather than peak bacterial concentration. Transient, recurrent, low-grade, and short duration (1 to 100 CFU/mL for <10 minutes) bacteremia occurs during chewing and brushing teeth.22 Such “normal” cumulative exposure exceeds a single tooth extraction by the order of 105.23,24 This likely explains why most cases of IE occur without antecedent dental procedures and why health care-associated IE arises from recurrent health care–related bacteremia,25,26 a point for consideration in IE prophylaxis.
MICROBIOLOGY
In recent times, staphylococci, particularly S. aureus, have overtaken viridans streptococci as the most common cause of IE.1,2 In the future, we foresee a further shift in IE being caused by S. aureus.Coagulase-negative staphylococci are the most common pathogens in early PV1 Staphylococcus lugdunensis, a coagulase-negative organism, tends to cause a particularly virulent form of IE with high rates of perivalvular extension and metastatic seeding.1 The most common streptococci isolated from patients with IE are Streptococcus sanguis, Streptococcus bovis, Streptococcus mutans, and Streptococcus mitis.1Endocarditis by group D streptococci, mainly Streptococcus gallolyticus, previously known as S. bovis, is prevalent among the elderly and is associated with preexisting colonic lesions.1 Polymicrobial IE is encountered most often in the setting of IDU and is uncommon.1
The HACEK group are gram-negative aerobic organisms associated with the so-called “culture-negative” IE and are now readily identified by blood culture systems. Culture-negative IE accounts for around 10% of most reported series of IE.2 The most common cause of culture-negative endocarditis is prior administration of antibiotics. To overcome this problem, special blood culture media containing charcoal have been devised to inhibit the effects of antibiotics.27 When blood cultures from patients with IE remain negative at 48 to 72 hours, the laboratory should be alerted for prolonged incubation or for plating of subcultures on enriched media. A list of organisms that cause culture-negative endocarditis is provided in Table 35.1. A comparison of microorganisms identified in published series of blood culture-negative IE shows that the most common etiologies are Bartonella species, Coxiella burnetti,and Tropheryma whipplei.28
TABLE
35.1 Organisms Causing Culture-Negative Endocarditis
PCR, polymerase chain reaction; HACEK organisms Haemophilus species (H. parainfluenzae, H. aphrophilus, and H. paraphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae; PAS, periodic acid–Schiff; BCYE, buffered charcoal yeast extract.
Reproduced from Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345(18):1318–1330, with permission from the Massachusetts Medical Society.
Bartonella species are fastidious gram-negative coccobacilli that are mainly transmitted by arthropod vectors. Bartonella henselae infections occur following exposure to cats or cat fleas and are associated with various diseases including cat-scratch disease, meningoencephalitis, bacillary angiomatosis, peliosis hepatitis as well as a subacute IE. Among the 24 known Bartonella species, most cases of IE are caused by B. henselae or Bartonella quintana and account for approximately 1% to 3% of IE cases and 9% to 10% of culture-negative IE.
C. burnetii is the cause of Q fever and is a common cause of IE in parts of the world where sheep, cattle, and goats are birthed.29 Coxiella tends to infect prosthetic valves or previously damaged aortic and mitral valves and causes small subendothelial vegetations that are often missed by echocardiography. The organism resides in the acidic phagolysosome, where antibiotic activity may be inhibited.
Tropheryma whipplei is a rod-shaped bacterium that is identified as PAS-positive microorganism inside the macrophages.30 It is the causative pathogen for Whipple disease characterized by chronic enteritis with malabsorption, arthritis, lymphadenopathy, uveitis, encephalitis, and dementia. It can also cause culture-negative endocarditis. Diagnosis is best achieved by polymerase chain reaction (PCR).
Brucellae are zoonotic infections.31 Humans are infected through the ingestion of contaminated meat or unpasteurized milk, the inhalation of infectious aerosols, or direct contact with infected tissues. This is mainly a disease of farmers, abattoir workers, veterinarians, and shepherds. Because vegetations are large and valve destruction commonly occurs, most patients require a combination of antimicrobial therapy and valve replacement. Legionella IE often presents as a febrile illness present over many months.32 Most patients have prosthetic valves. Embolic events are unusual with this organism. Pseudomonas aeruginosa is a rare cause of IE and occurs in the setting of IDU.2
Fungal IE is usually caused by Candida species but may also include other species such as Aspergillus and Histoplasmosis capsulatum.33 It usually manifests as bulky vegetations, perivalvular extension of infection, metastatic seeding, and embolization to large blood vessels. Predisposing factors for fungal IE are IDU, prolonged antibiotic therapy, immunosuppression, intravenous catheters, cardiac implantable electronic devices, prior or concomitant bacterial endocarditis, and disseminated fungal infection. The rate of recovery of filamentous fungi such as Aspergillus is <30% even with the lysis centrifugation system.
The Important Role of Staphlococcus aureus Bacteremia
The issue of IE in patients with prosthetic valves and S. aureus bacteremia has been recently addressed in two studies. Fowler et al.16 found that 42 of 324 (13%) patients with S. aureus bacteremia caused by intravascular device infection developed a hematogenous complication. Of these 42 patients, 31 (74%) had IE. In a prospective study by El-Ahdab et al.,34 approximately 50% of patients with prosthetic valves who developed S. aureus bacteremia had definite endocarditis. The mortality rate was high (60%) in those patients who were managed medically. The authors recommend that all such patients undergo transesophageal echocardiography (TEE) whenever possible.
CLINICAL FEATURES
IE is a systemic disease with protean manifestations. In 1885, William Osler presented the first comprehensive description of endocarditis during three Gulstonian Lectures at the Royal College of Physicians in the United Kingdom. Emanuel Libman later associated the valvular lesions with bacteremia in 1906.1 In patients presenting with classic features such as bacteremia or fungemia, active valvulitis, peripheral emboli, and immunologic vascular phenomena, the diagnosis of IE is straightforward. Fever is the most common symptom and sign; however, it may be absent in patients with congestive heart failure (CHF), severe debility, chronic renal or liver failure, previous use of antimicrobial drugs, or IE caused by less virulent organisms. Other common symptoms of subacute IE include anorexia, weight loss, malaise, and night sweats. Musculoskeletal complaints are an early symptom in subacute IE, ranging from low-back pain and myalgias to frank septic arthritis. A chronic wasting disease similar to that seen in HIV or cancer may develop in a proportion of patients with subacute IE. Pulmonary findings such as pneumonia may be the dominant feature in isolated right-sided IE. The onset of nosocomial IE is usually acute, and signs of endocarditis are infrequent.
The presentation of IE often includes extracardiac manifestations or findings that are associated with intracardiac extension of infection. Most patients with IE have a heart murmur (most commonly preexisting). A murmur or other evidence of valvular disease, especially aortic regurgitation (AR) or MR, may be a common sign in subacute IE. Patients may have petechiae on the skin, conjunctivae, or oral mucosa, as well as splenomegaly and other peripheral manifestations.
Skin lesions often provide a clue to IE diagnosis. Splinter hemorrhages (see Fig. 35.1) are 1 to 2 mm subungual brown streaks and are of greater significance when seen in the proximal nail bed rather than distal splinters that are usually related to trauma, such as that incurred while gardening. Osler nodes (see Fig. 35.2) are red, painful, indurated lesions between 2 and 15 mm, found on the palms and soles. Janeway lesions (see Fig. 35.3) are red, painless macules that appear on the palms and soles. Roth spots are boat-shaped retinal hemorrhages with a pale center. Embolization of small vegetations to the distal extremities may result in “blue toe syndrome,” which resolves in most cases without sequelae. Acute IE presents as severe sepsis with high fevers, lethargy, rapid cardiac deterioration, and shock. In acute AR, signs such as a widened pulse pressure are not usually present. In acute MR, a fourth heart sound may develop rather than the typical third heart sound seen in chronic MR. A rapid destruction of left-sided valves occurs leading to heart failure and circulatory collapse. Heart failure may result from valvular destruction, myocardial abscess, myocardial ischemia from vegetation embolization of the coronary circulation, arrhythmia such as atrial fibrillation, and sepsis.
Metastatic infection and vegetation embolization in IE can occur in virtually any organ, resulting in an acutely ischemic limb, a splenic infarct causing referred left shoulder pain from diaphragmatic irritation, a kidney infarct causing flank pain, etc. Brain complications of IE include cerebral vascular accident (CVA) from vegetation embolization or ruptured cerebral mycotic aneurysm (MA) that usually presents with intracranial hemorrhage. Anyone with a fever and a stroke should have blood cultures and be evaluated for possible IE. Symptoms and signs of cerebral involvement may be subtle however, including lethargy, confusion, and frank psychosis. Renal failure may occur from severe sepsis, embolization, immune complex deposition with acute post infectious glomerulonephritis, or may arise from therapy with antibiotics such as gentamicin. Prosthetic valve endocarditis may be manifested as an indolent illness with low-grade fever or it can be an acute febrile and toxic illness. The high frequency of invasive infection in PV results in higher rates of new or changing murmurs and of CHF. Unexplained fever in a patient with a prosthetic valve should prompt careful evaluation for PV35
DIAGNOSIS
A substantial proportion of patients with IE do not present with the classic Oslerian manifestations because of the acute nature of their illness. The diagnosis of IE requires a high index of suspicion, as well as the assimilation of clinical, laboratory, electrocardiographic, and echocardiographic data. Nonspecific laboratory abnormalities may be present, including anemia, leukocytosis, and elevated erythrocyte sedimentation rate and C-reactive protein level, and abnormal urinalysis with hematuria, proteinuria, or red cell casts. New electrocardiographic abnormalities may arise including AV or bundle-branch block, particularly in the setting of aortic-valve endocarditis with perivalvular invasion and aortic root abscess formation. Such patients need close cardiac monitoring.
The Duke Criteria
The variability of illness in IE mandates a diagnostic strategy that is both sensitive and specific. In 1981, Von Reyn et al.36 proposed very stringent Beth Israel criteria to aid in the diagnosis of IE. In 1994, a group at Duke University proposed standardized criteria for assessing patients with suspected IE.37 These criteria integrated factors predisposing patients to the development of IE, the blood-culture isolate and persistence of bacteremia, and echocardiographic findings with other clinical and laboratory information. In a review of the individual value of each component of the Duke criteria, the major microbiologic criteria had the highest relative importance. This further stresses the importance of obtaining adequate blood cultures in a patient suspected of having IE, preferably prior to the administration of antibiotics.
The Duke criteria classify patients into three categories: definite cases identified either clinically or pathologically, possible cases, and rejected cases. Numerous studies have validated the usefulness of the Duke criteria.38–43Misclassification of culture-negative cases, the increasing role of TEE, the relative risk of endocarditis in S. aureus bacteremia, and the overly broad categorization of cases as “possible” were problems with the original criteria. A modified version of the Duke criteria has recently been proposed.44 (Table 35.2).
TABLE
35.2 Modified Duke Criteria
Cases are defined clinically as definite if they fulfill two major criteria, one major criterion plus three minor criteria, or five minor criteria; they are defined as possible if they fulfill one major and one minor criterion, or three minor criteria. HACEK, Haemophilus species (H. parainfluenzae, H. aphriphilus, and H. paraphrophilus), A. actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.
Reproduced from Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345(18):1318–1330, with permission from the Massachusetts Medical Society.
Blood Cultures
Blood cultures are excellent traditional tools, not only for diagnosis, but also for the determination of antibiotic susceptibility to guide therapy. According to Towns and Reller,27 best practice guidelines for blood cultures include:
Obtaining blood cultures before starting antimicrobials whenever possible
Exercising strict aseptic technique and optimal skin preparation when collecting blood cultures
In acute presentations, obtaining at least two or preferably three sets of blood cultures rapidly within 5 to 10 minutes of each other prior to starting antibiotic therapy
In subacute presentations, obtaining three separate sets of blood cultures spaced 30 minutes apart
Obtaining 20 mL of blood for each sample drawn (for adults)
Role of PCR Amplification in Clinical Specimens
The diagnosis of IE is straightforward in a patient with typical signs and symptoms and a positive blood culture with a characteristic microorganism. It can be more difficult when blood cultures are sterile, either because of prior antimicrobial therapy or because of the fastidious nature of the pathogen. More recently, a range of microorganisms including T. whipplei, C. burnetii, B. henselae, and B. quintana have been identified using a broad-range PCR in valvular specimens. Using universal primers, species-specific genetic sequences can be identified directly from tissue samples. This technique is culture independent, and almost all bacteria can be detected in a single reaction. Species-specific PCR primers are also available for many bacterial genera, including T. whipplei, Chlamydia, Brucella, Legionella, mycobacteria, and Mycoplasma.
In a recent study by Greub et al.45 culture, histologic examination, and broad-range PCR were performed on valve samples taken from 127 patients with definite and possible IE (determined prior to valve surgery according to modified Duke criteria) and from 118 patients without IE. The sensitivity of PCR was 61%, that of histology 63%, and that of valve culture 13%. The specificity of both PCR and histology was 100%.
Echocardiography
Echocardiography is key in the management of IE. It is used for the diagnosis of IE and the detection of cardiac complications in order to inform the need and timing of surgical intervention. Intraoperative echocardiography is used to guide the surgeon. Transthoracic echocardiography (TTE) is rapid and noninvasive. It has excellent specificity for vegetations (98%).46 However, TTE may produce suboptimal images in up to 20% of adult patients because of obesity, chronic obstructive pulmonary disease, or chest-wall deformities; the overall sensitivity for vegetations may be <60% to 70%.46 Additionally, TTE cannot exclude several important aspects of IE, including infection on prosthetic valves, periannular abscess, leaflet perforation, and fistulae.46
TEE utilizes a probe juxtaposed to the heart with less interference from interposed tissues. It also utilizes higher ultrasonic frequencies. This produces images with higher spatial resolution. It is however more costly and invasive, with small but finite risk, the worst being esophageal perforation. TEE increases the sensitivity for detecting vegetations to 75% to 95% while maintaining specificity of 85% to 98%.46,47–49 It is particularly useful in patients with prosthetic valves and for the evaluation of myocardial invasion.50 TEE is more sensitive (76% to 100%) and more specific (94%) than TTE for defining perivalvular extension of IE and the presence of a myocardial abscess.51–53 It is more sensitive than TTE for identifying valve perforations.54 A TEE with spectral and color-flow Doppler techniques can also demonstrate fistulas, pseudoaneurysms, or abscess cavities. A negative TEE has a negative predictive value for IE of over 92%.46 Recent guidelines suggest that among patients with suspected IE, TTE should be used in the evaluation of those with native valves who are good candidates for imaging.55,56 In fact, the appropriate use of echocardiography depends on the probability of IE. If this probability is low, a negative TTE is a cost-effective and clinically satisfactory way to rule out IE.57 For patients with intermediate probability of IE endocarditic, initial use of TEE is more cost-effective and diagnostically efficient than initial use of TTE, which, if negative, is followed by TEE.57 Intermediate probability patients include those with unexplained bacteremia and gram-positive cocci, those with catheter-associated S. aureus bacteremia, and those admitted with fever or bacteremia in the setting of recent IDU. The category of low prior probability includes patients with gram-negative bacteremia with a clear noncardiac source and patients with a firm alternate diagnosis or those in whom the “endocarditis” syndrome resolved within 4 days.
There has been controversy whether vegetation size as measured by echocardiography is a prognostic indicator for embolism or even an indication for surgery. Di Salvo et al.58 in a study of 178 patients with IE reported that those with vegetations >1 cm or those with “highly mobile” vegetations may need to be considered for early surgery irrespective of their response to antimicrobials, the presence of valve destruction, or heart failure. On the other hand, De Castro et al.59 reported no relationship between vegetation size and the risk of embolization in a study involving 57 patients. Echocardiographic features that suggest potential need for surgical intervention are shown in Table 35.3.
TABLE
35.3 Echocardiographic Features that Suggest Potential HBMl Need for Surgical Intervention
see text for more complete discussion of indications for surgery based on vegetation characterizations.
aSurgery may be required because of risk of embolization.
bSurgery may be required because of heart failure or failure of medical therapy.
cEchocardiography should not be the primary modality used to detect or monitor heart block.
From Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications. Circulation. 2005;111:e394–e434, with permission.
COMPLICATIONS
Certain conditions place patients at increased risk for complications from IE. These are summarized in Table 35.4. Complications of IE may be classified as
TABLE
35.4 Clinical Situations Constituting High Risk for Complications for IE
Reproduced from Bayer AS, Bolger AF, Taubert KA, et al. Diagnosis and management of infective endocarditis and its complications. Circulation. 1998;98(25):2936–2948, with permission.
Cardiac including CHF, paravalvular extension
Neurologic including stroke
Systemic emboli including splenic abscess
MAs, intracranial and extracranial
CHF may develop acutely as a result of valve perforation, rupture of mitral chordae, mechanical blockage of valve orifice by bulky vegetation, fistulization of cardiac chambers, coronary vegetation embolization, or arrhythmia.1 It may occur in a more gradual fashion as result of worsening valvular insufficiency. Heart failure as a result of IE is associated with a grave prognosis and delaying surgery to the point of total ventricular decompensation increases operative mortality. In addition, poor surgical outcomes are portended by renal insufficiency and advanced age.59 Aortic valve infection is more commonly associated with CHF than mitral valve infection. The left ventricle alone bears the brunt of the volume overload in the case of acute aortic insufficiency (AI) as opposed to acute MR where the left atrium and the pulmonary vascular bed accommodate the regurgitant volume. Hence, new-onset, moderate to severe AI due to IE usually requires surgery. The indications for surgery in right-sided IE are less clear-cut. Tricuspid and pulmonary regurgitation are well tolerated as long as there is no preexisting pulmonary vascular resistance. Extension of infection beyond the valve annulus is associated with higher mortality, more frequent CHF, and the need for surgery. This complication occurs in 10% to 40% of all NVE,59 and in 56% to 100% of all PV60 In native aortic valve IE, the extension tends to happen at the weakest portion of the annulus, which resides near the membranous septum and AV node. This is why abscesses and heart block are more frequent in this location.48 Clinical parameters or the size of the vegetation do not predict the possibility of periannular extension. Development of new AV block has a 77% positive predictive value for abscess formation, but the sensitivity is only 42%.60 Urgent surgery is usually indicated for this condition and involves drainage of abscess cavities, excision of necrotic tissue, and closure of fistulous tracts in addition to valve replacement.61
Neurologic complications develop in up to 40% of all patients with IE,1 and over half of those requiring admission to intensive care units. Sonneville et al.62 reported that among 198 patients with definite left-sided IE, 108 (55%) experienced at least 1 neurologic complication. These may include embolic stroke with or without hemorrhage, ruptured intracranial MA, transient ischemic attack, meningitis, and encephalopathy.1,62 Factors independently associated with neurologic complications were S. aureus IE, mitral valve IE, and nonneurologic emboli.62 The majority of emboli lodge in the middle cerebral artery (MCA) distribution.48 The management of a patient with neurologic complications in the acute phase of IE is controversial. Any patient with IE and neurologic symptoms should have preoperative imaging (CT or MRI of the head). Four vessel cerebral angiograms may also be indicated if MA is suspected (usually after rupture causing CNS hemorrhage). A ruptured MA should be clipped, resected, or embolized prior to cardiac surgery for IE.63 In patients with a hemorrhagic infarct, the current recommendation is to wait for 2 to 3 weeks between the neurologic event and cardiac surgery because of the risk of intracranial bleeding during anticoagulation with cardiopulmonary bypass, or post cardiac surgery indications.63,64
Systemic embolization most commonly involves the spleen, kidney, liver, and the iliac or mesenteric arteries.1 Splenic abscess is a rare complication of IE and develops as a result of bacteremic seeding of a bland infarct caused by a splenic artery embolus, or by direct seeding of the splenic tissue by an infected vegetation.48 It occurs in 5% of all splenic infarctions, with viridans streptococci and S. aureus being the major causes. The diagnosis must be suspected in any patient with IE and flank, back or abdominal tenderness in the left upper quadrant or left shoulder (from diaphragmatic irritation).48 Abdominal CT and MRI are the most sensitive modalities to diagnose this complication, and definitive treatment is splenectomy with antibiotics before valve surgery, unless valve replacement is more urgent.48
MAs may be intra- or extracranial. They are uncommon complications of IE and result from septic embolization of vegetations first to the vasa vasorum, then into the intima, and finally through the outer layer of the vessel wall. The commonest sites are the branching points of arteries and occur, in decreasing order, in intracranial arteries, visceral arteries, and arteries of the lower and upper extremities. Intracranial MA occurs in 1.2% to 5% of patients with IE and carry a high mortality rate of 60%. The bifurcations of the distal MCA are the most commonly involved arteries. Symptoms may include severe headache, altered mental status, hemianopia, or cranial neuropathies. Sudden hemorrhage may occur in the absence of other premonitory symptoms.1,48 Routine screening for intracranial MA is not recommended in the absence of neurologic symptoms or signs. Contrast-enhanced CT, MRI, and MRA are all useful techniques to diagnose intracranial MA, but the current gold standard is 4-vessel cerebral angiography. Decisions concerning the medical versus surgical treatment of intracranial MA need to be tailored according to the individual patient. A single intracranial MA distal to the first bifurcation of a major intracranial artery should be monitored closely with serial angiograms and must be excised if it enlarges or bleeds. In the case of multiple aneurysms, close monitoring is required with angiograms or CTs and if more than one aneurysm enlarges, prompt surgical excision is required.48 A less invasive alternative to surgery, especially in distally or peripherally located aneurysms is coil embolization.65 Extracranial MA are often asymptomatic. However, the appearance of a new, painful, pulsatile mass with IE should prompt the diagnosis of extracranial MAs. Hematuria and hypertension should suggest the rupture of a renal artery MA. Massive bloody diarrhea should suggest the rupture of an intrab-dominal MA into the bowel. Hematemesis, hematobilia, and jaundice should suggest rupture of a hepatic artery MA. Mortality in patients with IE is high and revascularization should be established through extra-anatomic routes via uninfected tissue planes. Long-term, suppressive antibiotic therapy will probably be required as patients are at high risk of recurrence of infection especially in the interposed vascular grafts in previously infected areas.
TREATMENT
Certain principles are important when considering treatment of IE.65 The regimen must be bactericidal. Prolonged therapy is often necessary. Vancomycin is less rapidly bactericidal than semisynthetic penicillins and first-generation cephalosporins. IE is one of the situations where skin testing should be performed on patients with a questionable history of immediate hypersensitivity reactions to penicillin. The American Heart Association46 and European Society of Cardiology56 have published guidelines for the treatment of adults with IE due to streptococci, enterococci, staphylococci, and HACEK microorganisms. These are summarized in Table 35.5.
TABLE
35.5 Therapy of NVE Caused by Highly Penicillin-Susceptible Viridans Group Streptococci and S.bovis
MIC 0.12 µg/mL.
aDosages recommended are for patients with normal renal function.
bPediatric dose should not exceed that of a normal adult.
cOther potentially nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs) should be used with caution in patients receiving gentamicin therapy.
dSee reference 280 in full statement.
eData for once-daily dosing of aminoglycosides for children exist, but no data for treatment of IE exist.
fVancomycin dosages should be infused during course of at least 1 h to reduce risk of histamine-release “red man” syndrome. From Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications. Circulation.2005;111:e394–e434, with permission.
Caveats for the Common Causes of IE
Minimum inhibitory concentrations (MIC) should be determined for streptococci against penicillin as treatment is dependent on the values obtained.1 A 2-week regimen65 may be appropriate in certain situations such as those cases of uncomplicated IE caused by highly penicillin-susceptible viridans streptococci, S. bovis in those patients at low risk for complications from gentamicin therapy. For patients allergic to beta-lactams, vancomycin is an effective alternative. Enterococcus faecium and E. fecalis46,56 are the two major enterococcal causes of IE. These organisms are relatively resistant to penicillin, expanded spectrum penicillins, and vancomycin. They are also uniformly resistant to cephalosporins and relatively resistant to aminoglycosides. The combination of penicillin, vancomycin, or ampicillin with aminoglycosides is necessary to exhibit a synergistic bactericidal effect on these isolates and standard therapy should continue for 4 weeks. All enterococcal isolates causing IE must be screened for antimicrobial susceptibility against penicillin, ampicillin, vancomycin, gentamicin, and streptomycin. Optimal therapy has not been determined for isolates with high level resistance to both gentamicin and streptomycin. For organisms with intrinsic high-level resistance to penicillin (MIC >16 μg/mL), vancomycin is the preferred agent for combination. Vancomycin may enhance the nephrotoxic potential of amoniglycosides. Serum levels of aminoglycosides should be carefully monitored during therapy of enterococcal endocarditis. Peak levels of gentamicin should not exceed 3 and trough levels should not exceed 1. Note that these levels are not as high as those when aminoglycosides are used in the synergistic treatment of gram-negative systemic infections.
Daptomycin has proven in vitro activity against MRSA, methicillin resistant Staphylococcal epidermidis (MRSE), glycopeptide-intermediate S. aureus, and Vancomycin-resistant enterococcus (VRE) faecium in an in vitro pharmacodynamic model with simulated endocardial vegetations.66 For methicillin-susceptible staphylococci NVE,67 nafcillin or oxacillin must be used with a brief 3 to 5 day course of gentamicin. Though the aminoglycoside offered no significant mortality or morbidity benefit, it shortened the duration of positive blood cultures in a multicenter collaborative study while harmful side effects were reduced. For methicillin-susceptible staphylococcal IE in prosthetic valves, nafcillin or oxacillin with rifampin for 6 weeks plus gentamicin for the first 2 weeks is recommended. For methicillin-resistant staphylococcal native valve IE, vancomycin, usually with gentamicin added for the first 3 to 5 days of therapy is the standard. For methicillin-resistant staphylococcal IE on prosthetic valves, combination therapy is advocated with vancomycin and rifampin for 6 weeks plus gentamicin for the first 2 weeks.68 The benefit of rifampin69 in MRSA endocarditis has been derived from the ability of this drug to sterilize “foreign body infection” in experimental animal model. Coagulase-negative staphylococci are now the commonest cause of PV, particularly in the first 12 months following surgery. The organisms are usually methicillin resistant, and treatment should be the combination described. If the organism is resistant to gentamicin, an aminoglycoside to which susceptibility is demonstrated should be chosen. If the isolate is resistant to all aminoglycosides, this component should be omitted from the regimen. In the situation of right-sided native valve IE70,71 caused by methicillin-susceptible S. aureus in IDUs, limited data suggest that a 2-week course of nafcillin or oxacillin with gentamicin may be sufficient. This regimen may not be suitable in IDUs with left-sided IE, metastatic IE such as lung abscess, underlying HIV, or vegetations >1 to 2 cm.
HACEK organisms72 should be considered ampicillin resistant and monotherapy with this drug is no longer recommended. Limited data suggest that a third generation cephalosporin such as ceftriaxone or cefotaxime sodium should be used for 4 weeks in native valve and for 6 weeks in PV Aztreonam, trimethoprim/sulfameth-oxazole, or the fluoroquinolones are the recommended alternative agents for patients with HACEK IE unable to tolerate cephalosporins.
Caveats for the Uncommon Causes of IE
C. burnetii73 IE is usually treated with a combination of doxycycline and rifampin, trimethoprim-sulfamethoxazole, or fluoroquinolones. The optimal duration of therapy is unknown. Valve replacement is only indicated for CHF, PV, or uncontrolled infection. Many experts recommend long-term and possibly indefinite therapy in this setting. Yet others have suggested a minimum of 3 years of therapy once phase I IgG antibody titers drop to <1:4,000 and phase I IgA antibody is undetectable. Few patients with Brucella31 IE have been cured with antimicrobial therapy alone. Most require valve replacement in addition to the following: doxycycline plus either streptomycin or gentamicin OR doxycycline plus either trimethoprim/sulfamethoxazole or rifampin. Again, the optimal duration of therapy is unknown, but authorities recommend this regimen for 8 weeks to 10 months following valve replacement. In Legionella32IE, cure has been obtained by prolonged parenteral therapy with either doxycycline or erythromycin followed by an oral course for a prolonged period. The total duration of therapy is usually 6 to 17 months. Pseudomonas aeruginosa74 IE of the right side usually requires the combination of high doses of an antipseudomonal penicillin (piperacillin) and an aminoglycoside (tobramycin). Left-sided Pseudomonas IE rarely responds to medical therapy alone and surgery is considered mandatory. In fungal IE59 caused by Aspergillus or Candida species, Amphotericin B has poor penetration into vegetations. Most vegetations are bulky and metastatic complications, including periannular extension and embolization to large blood vessels are frequent. Virtually all complicated cases of Candida IE need surgery, and mortality is 90% to 100% in Aspergillus IE without surgery.
INDICATIONS FOR SURGERY IN INFECTIVE ENDOCARDITIS
Surgery is frequently required in patients with IE particularly when complicated by perivalvular and myocardial abscess and valvular dysfunction. The decision regarding surgery in the treatment of IE is multidisciplinary with input from an experienced cardiothoracic cardiac surgeon, a cardiologist, and an infectious disease clinician. It should be individualized per patient. Surgical therapy in IE has contributed to the overall decrease in mortality, especially in patients with CHF, complicated perivalvular extension, and in PV46,56,59,63,64 The general preoperative condition of the patient, chronic hemodialysis, ongoing antibiotic treatment, timing of surgery, surgical techniques, postoperative care, and follow-up are important influences of outcome. Preoperative New York Heart Association (NYHA) class, age, and preoperative renal failure are the variables that foretell operative mortality in logistic regression analysis. The following table summarizes the indications for surgical intervention in IE (Table 35.6).
TABLE
35.6 Indications for Surgery in Patients with IE
A, strong evidence or general agreement that cardiac surgery is useful and effective; AR, aortic regurgitation; B, inconclusive or conflicting evidence or a divergence of opinion about the usefulness/efficacy of cardiac surgery, but weight of evidence/opinion of the majority is in favor; C, inconclusive or conflicting evidence or a divergence of opinion; lack of clear consensus on the basis of evidence/opinion of the majority. MR, mitral regurgitation; NYHA, New York Heart Association classification.
Reprinted from Olaison L, Pettersson G. Current best practices and guidelines. Indications for surgical intervention in infective endocarditis. Cardiol Clin. 2003;21(2):235–251, with permission from Elsevier.
PROPHYLAXIS
IE is a disease characterized by high morbidity and mortality that should be prevented whenever possible. In the absence of controlled prospective studies and therefore based largely on expert opinion, the American Heart Association75 and the European Society of Cardiology56 recently revised their guidelines for IE prophylaxis. The absence of epidemiologic correlations between dental or other procedures and ensuing IE led them to recommend prophylaxis only to those patients at highest risk by virtue of their underlying cardiac conditions, when undergoing procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa (Table 35.7). Prophylaxis is no longer recommended for patients who undergo a genitourinary or gastrointestinal tract procedure.
TABLE
35.7 Cardiac Conditions Associated with the Highest Risk of Adverse Outcome from Endocarditis for which Prophylaxis with Dental Procedures is Reasonable
Note that antibiotic prophylaxis is not recommended for procedures on the genitourinary or gastrointestinal tracts, if indication for prophylaxis implicates only endocarditis prevention. (Adapted from Habib G, Hoen B, Tornos P, et al. ESC Committee for Practice Guidelines. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J. 2009;30(19):2369–2413, and Nishimura RA, Carabello BA, Faxon DP, et al. ACC/AHA 2008 Guideline update on valvular heart disease: focused update on infective endocarditis: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;52(8):676–685.)
CONCLUSIONS
IE remains an important disease characterized by high morbidity and mortality. Over the last three decades, the overall incidence of IE and the associated mortality have remained constant. Dramatic changes have however occurred in the at-risk population, underlying susceptible cardiac lesions, etiologic pathogens, diagnostic evaluation, clinical presentation, antimicrobial agents, and recommendations for prophylaxis. It is a complex systemic disease that requires close multispecialty collaboration in order to effect its successful management. Even with advanced diagnostic and management strategies in the 21st century, it still is a life-threatening disease.
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QUESTIONS AND ANSWERS
Questions
1. All of the following are true statements except:
a. By definition, “early” prosthetic valve endocarditis refers to the development of infection within 60 days of surgery.
b. Aztreonam is not an acceptable alternative for the treatment of HACEK endocarditis.
c. Gram-negative bacilli are important pathogens causing hospital-acquired endocarditis.
d. Endocarditis with Streptococcus bovis should prompt a search for a colonic neoplasm.
e. Surgery is often necessary in infective endocarditis (IE) with Brucella organisms.
2. Which of the following is true?
a. Mitral valve prolapse without mitral regurgitation (MR) is a risk factor for the development of IE.
b. Mechanical valves are at higher risk than bio-prosthetic valves for IE during the first 90 days following surgery. 7
c. MSSA is the most common causative agent of health care-acquired endocarditis in the United States.
d. Hemodialysis patients are at higher risk for Staphylococcus aureus bacteremia and health care-associated IE.
e. Rheumatic valvulitis is still the most common predisposing factor for IE in the elderly in developed nations.
3. All of the following are correctly matched associations except:
a. Brucella—abattoir workers
b. Coxiella—sheep farmers
c. Pseudomonas IE—injection drug users (IDU)
d. Fungal IE—prolonged antibiotic exposure
e. HACEK IE—veterinarians
4. The cutoff minimum inhibitory concentrations (MIC) for a penicillin-susceptible Streptococcus viridans is:
a. ≤0.5 μg/mL
b. ≤0.05 μg/mL
c. ≤0.01 μg/mL
d. ≥1 μg/mL
e. ≤0.12 μg/mL
5. Regarding the complications of IE, all of the following are true except:
a. Four-vessel cerebral angiography is the current gold standard for diagnosing intracranial mycotic aneurysms (MAs).
b. Mitral valve infection is a more common cause of congestive heart failure (CHF) in IE than aortic valve infection.
c. The definitive treatment of a splenic abscess resulting from embolization in IE is splenectomy.
d. Transthoracic echocardiogram is inferior to transesophageal echocardiogram in detecting paravalvular extension of IE.
e. Extracranial MAs are more common in the visceral arteries than in the upper-extremity arteries.
6. Wich of the following is associated with a lower complication rate in a patient with endocarditis?
a. Streptocoocus viridans infection
b. Perivalvular abscess
c. Methicillin resistant Staphylococcal aureus (MSSA) infection
d. Older age
e. Pulmonary edema
7. Which of the following is not considered an indication for surgical intervention in endocarditis?
a. Persistent bacteremia and increasing size of vegetation despite appropriate bactericidal antibiotic therapy
b. Mitral valve vegetation of 4 mm in a patient with moderate MR who remains culture negative on appropriate antibiotic therapy
c. Aortic valve endocarditis with an episode of congestive failure with severe aortic regurgitation (AR)
d. Mobile vegetation on the mitral valve that is 10 mm long in a patient with a recent episode of homonymous hemianopsia
e. Mobile mitral vegetation of >15 mm in length despite a 2 week course of appropriate antibiotic therapy
8. Which of the following is considered an appropriate indication for antibiotic prophylaxis against endocarditis?
a. Patient with severe aortic stenosis undergoing a dental extraction
b. Atrial septal defect patient undergoing colonoscopy
c. Patient with prosthetic mitral valve undergoing dental cleaning
d. Patient with mitral valve prolapse and moderate MR undergoing cystoscopy
e. Patient with mitral valve repair with a prosthetic ring and mild residual MR undergoing transurethral resection of prostate
9. Which of the following causes of endocarditis usually require serologic testing for definitive diagnosis rather than blood cultures?
a. Coxiella burnetti
b. Streptococcus viridans
c. Streptococcus bovis
d. Psedomonas aeruginosa
e. HACEK organisms
10. Which of the following statements about endocarditis in the current era is true?
a. It typically presents with a subacute course over months before presentation.
b. Enterococcus is the most common organism implicated.
c. Surgery is required in <20% of cases.
d. Right-sided valve lesions now predominate.
e. Heart failure is the most likely cardiac complication.
Answers
1. Answer A: Early-onset prosthetic valve endocarditis is usually attributed to pathogens from perioperative contamination (health care-associated), and therefore within 60 days from implant of the valve. Aztreonam (gram-negative organism only) will not be active against HACEK organisms. Staphylococcus aureus is the most common health care-associated cause of IE (not gram-negative organisms). Brucella IE almost always requires surgery for cure.
2. Answer D: Staphylococcus aureus is recognized as the most common health care-associated pathogen causing IE. Patients receiving hemodialysis with indwelling vascular catheters are at particular risk for S. aureus bacteremia and subsequent endocarditis.76 Mitral valve prolapse without regurgitation is not a high-risk condition for IE. Methicillin-resistant S. aureus is more common than methicillin-susceptible S. aureus as a cause of nosocomial IE in the United States. There is no significant difference in the incidence of PV for mechanical valves and bioprosthetic valves during the first 90 days following surgery. Rheumatic valvulitis is not the most common predisposing factor for IE in the developed world.
3. Answer E: HACEK organisms are not particularly associated with veterinarians. Brucella is a zoonosis and associated with abattoir workers. Similarly, C. burnetii (agent of Q fever) is associated with parturient sheep. Pseudomonas has been associated with injected drug users (contamination with processing), and nosocomial fungal IE can follow prolonged antibiotic use (risk factor for fungemia).
4. Answer E: The NCCLS cutoff for S. viridans penicillin susceptibility is 0.12 mg/mL.
5. Answer B: Mitral valve IE is not more often associated with complications of CHF than aortic valve IE. MRA is not as sensitive as four-vessel angiogram for detection of MAs.
6. Answer A: All of the other factors increase the risk of a complicated course and mortality in IE.
7. Answer B: Moderate MR with moderate size vegetation does not mandate surgical intervention. All of the other scenarios are considered indications for surgical intervention.
8. Answer C: The revised guidelines now recommend antibiotic prophylaxis only in high-risk instances such as with prosthetic valves, uncorrected complex congenital heart disease (CHD), or a history of previous endocarditis. Prophylaxis is no longer recommended for genitourinary or gastrointestinal procedures.
9. Answer A: Coxiella burnetti, the pathogen responsible for Q fever endocarditis requires serologic testing for diagnosis in most instances as most laboratories are not set up to grow it in culture. The other organisms usually grow in blood culture though delayed culture is common with HACEK organisms.
10. Answer E: The presentation now is less classical and subacute and occurs within 30 days of onset typically. Staphylococcus aureus is the most common infecting organism and surgery may be required in up to 50% of cases. Left-sided valve lesions predominate and heart failure is the most common cardiac complication.