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Robbin's Pathology says that vegetations of IE are more common on the atrial side in AV valves. In Liebmann Sack's Endocarditis, which is a sterile (non bacterial) type of endocarditis, the underside of the valve also has vegetations. Why is it so? If its just colonization of bacteria in IE, how does it matter where?
Does gravity matter in colonisation of bacteria!! ?
With the bacterial IE, it would look like the vegetations tend to colonize the lower pressure sides of the valve structure (REF1). Something that was made clear that distinguishes the IE vegetations frm the Libman-Sacks vegetations was overall motility. Specifically, Libman-Sacks vegetations exhibit no independent motion and are largely sessile, whereas IE vegetations can be motile (REF2). In terms of where they attach I think this makes sense, the more motile vegetations colonize the less turbulent area, and the sessile vegetations seem to hold up in either scenario. Reference 1 also rather usefully points out that IE vegetations may be located anywhere on the valve structure as well, they just tend to be on the low-pressure side.
So being said i would argue that the motility of the organisms is a deciding factor.
Infective endocarditis generally develops when there is a pre-existing valvular lesion. The location where the vegetation in infective endocarditis develops is based on the pressure of the surroundings. Bacteria tend to colonise places where the pressure is low.
'Where the pressure is low', depends upon what kind of a valve deformity is already present.
In mitral regurgitation, blood when pumped from the left ventricle enters the atria due to the patent bicuspid valve. Naturally, the pressure is more on the ventricular side than the atrial side. Hence, the bacteria settle on the top of the leaf. Moreover, the do so at the edges of the leaves. This is because, since the blood has to squeeze through, according to to bernoulli's theorem (Venturi effect). Hence they form on the edges of the atrial side of the valves
In case of an aortic regurgitation, since there is a backflow of blood from the aorta to the ventricles, the vegetations are found on the underside of the aortic valves.
Liebmann Sacks (which is non infective and happens in lupus) is common in the mitral valve though it can happen anywhere. I assume, since bacteria are living cells, the pressure constraint applies to them but not to sterile vegetations like the one in lupus.
I implore you to have a look at this wonderful video which explains it all. Picture credits and reference : Endocarditis by osmosis.org
The earliest description of the vegetative lesions of infective endocarditis (IE) has been attributed to Lazarus Riverius (1589-1655). 1 Later, Giovanni Lancisi (1654-1720) provided a more complete description of these pathologic lesions of the heart in De Subitaneis Mortibus written in 1709. 2 Throughout the eighteenth and early nineteenth centuries there were many descriptions of endocarditis by investigators such as Morgagni and Corvisart, yet it was not until the middle to late 19th century that a link was made among the lesions, the associated inflammation, and the sequelae of the disease. In 1841, Bouillard (1796-1881) made the important connection between the inflamed endocardium, a “typhoid” state, and “gangrenous endocarditis.” This event was followed by the observations of Virchow (1821-1902), in 1847, and Kirkes (1823-1864), in 1852, connecting the dots between the presence of vegetative lesions and embolic events. 1
In his famous 1885 Gulstonian lectures Sir William Osler summarized the knowledge at that time and in addition made several important observations. First he described the acute and fulminating forms of the disease and was able to articulate specific characteristics of a more chronic and insidious form. He then improved the nomenclature of the disease and suggested calling the clinical course of the disease either “simple” or “malignant.” 3,4 In addition, he described the classic presentation of a typical case and noted the diagnostic uncertainty in many cases. Finally, Osler believed that endocarditis would turn out to be a “mycotic” process, describing it as, “in all its forms, an essentially mycotic process the local and constitutional effects being produced by the growth on valves, and the transference to distant parts of microbes, which vary in character with the disease in which it develops.”
The true incidence of IE is difficult to ascertain. In a Swedish urban setting, Hogevik et al 6 found an incidence of 5.9 episodes per 100,000 person-years from 1984 to 1988. During a similar period in a Philadelphia metropolitan study, the total incidence was calculated to be 9.29 episodes per 100,000 person-years. 7 When intravenous drug users were excluded, this incidence fell to 5.02 episodes per 100,000 person-years. In both urban and rural settings in France, the incidence was estimated to be around 2.43 episodes per 100,000 person-years in 1991 8 and increased to 3.1 episodes per 100,000 person-years in 1999 9 with a peak incidence of 14.5 episodes per 100,000 person-years in the elderly. The growing incidence in elderly individuals has been confirmed in the Medicare population in the United States, in which it was 20.4 episodes per 100,000 person-years in 1998 (a 13.7% increase from 1986). 10 In fact, more than half of all cases of IE in the United States and Europe now occur in patients older than 60 years, and the median age of patients has increased steadily during the past 40 years. 11 Health care–associated IE results from health care–associated bacteremias. They include both nosocomial and nonnosocomial infections, have a high mortality rate, and are frequent in patients who are undergoing hemodialysis and/or who have other debilitating diseases. The typical patient nowadays is therefore less likely to be one with poor dentition and rheumatic disease 12 and more likely to be elderly and to have undergone a procedure to implant a device such as a prosthetic valve, pacemaker, and/or defibrillator 5 or to have a major comorbid condition.
Table 25-1 summarizes cardiac conditions and the subsequent estimated incidence of IE per 100,000 patient-years. 13 Sex and age also influence the incidence of IE, with males predominating. Male : female ratios have been noted to range from 3.2 : 1 to 9 : 1. 11,14 Of interest, 50% to 70% of children younger than 2 years in whom IE develops have no apparent underlying heart disease, whereas older children usually have a congenital heart condition. 15 Endocarditis in patients with injection drug use (IDU)—defined as the intravenous injection of recreational drugs such as heroin, cocaine, and amphetamines—also may occur when there is no apparent underlying valvular pathologic lesions. 16 Despite these exceptions, most patients do have identifiable underlying structural heart disease at the time of their endocarditis diagnosis. 17,18 Earlier reports, before 1967, showed that rheumatic heart disease was the most common cardiac abnormality, being present in 39% of patients, 19 whereas later series suggest its presence in only about 6%. 18 Estimates of specific valvular lesion involvement is summarized in Table 25-2.
Modified from Pallasch TJ. Antibiotic prophylaxis: problems in paradise. Dent Clin North Am 200347:665-679.
|PERCENTAGE OF ENDOCARDITIS CASES AFFECTED|
|Native Valve Disease|
|Congenital heart disease:||4-18|
|Cyanotic heart disease||8|
|Tetralogy of Fallot||2|
|Ventricular septal defect||1.5|
|Patent ductus arteriosus||1.5|
|Atrial septal defect, coarctation of aorta||<1|
|Right-sided (including device infection)||5-10|
When valvular disease is considered as a whole, endocarditis still is an uncommon disease process. In the Euro Heart Survey 24 of the incidence of valvular disease in a general population, endocarditis was the major diagnosis in less than 1% of patients who were found to have aortic or mitral stenosis, in only 7.5% of those with aortic regurgitation, and in 3.5% of those who had mitral regurgitation.
Left-sided native valve endocarditis (NVE) remains the most common presentation, accounting for 70% of all cases of IE. Mortality depends on comorbidities but still is at least 15% as a whole. 25 Degenerative mitral valve disease (mitral valve prolapse) is the leading predisposing valve lesion, with the risk particularly high in children and in patients older than 50 years. Patients with degenerative aortic valve disease are also at risk, helping explain the rising age of patients presenting with IE. One review estimated a slightly greater incidence of mitral than aortic involvement, 8% involving both, 4% involving the tricuspid valve, and 3.5% occurring in patients with congenital heart disease. 26 Endocarditis is unusual in patients with isolated pulmonary stenosis, atrial septal defect, mitral stenosis, or hypertrophic cardiomyopathy.
Prosthetic valve endocarditis (PVE) accounts for up to 20% of the patients with endocarditis reported in a recent series from the International Collaboration on Endocarditis-Prospective Cohort Study. 27 Staphylococcus aureus was the most common organism. Having a prosthetic heart valve is the greatest risk for development of IE in every series. It is estimated that IE will develop in 1.4% to 3.1% of all patients with prosthetic valve at 1 year and 3% to 5.7% at 5 years. 28 There are two disparate risk periods for the development of PVE, an early period and a late period, although some writers believe it is more useful to consider early (2 months), middle (2 to 12 months), and late (>12 months) periods as the organisms involved shift gradually rather than abruptly. 28 The early period is generally defined as the first 60 days after heart surgery, and most of the implicated organisms are considered nosocomial. The late period involves organisms more like those involved in NVE. Although there has always been a suggestion that the mechanical valves are more susceptible to IE, by 5 years there appears to be no real difference, and most series do not suggest a difference in the risk by model, position, or type of valve (mechanical or bioprosthetic). 29 Some patient factors have been associated with PVE, including renal dysfunction, young age, prior endocarditis, and perioperative wound infections. 30 Health care–associated prosthetic valve endocarditis is identified in 36.5% of all cases, and most infections (71%) occur in the first year after the valve was implanted. The rate of in-hospital death remains high, at 23%, and its occurrence is associated with older age and the complications related to the surgical intervention. The higher risk of “redo” aortic valve replacement (AVR) for endocarditis is emphasized in a report of 313 patients by Leontyev et al. 31 Perioperative mortality was 24.3% in “redo” AVR for IE compared with 6.8% for redo AVR for reasons other than endocarditis.
Right-sided endocarditis is seen in about 5% to 10% of IE surveys 16,25 and has a better prognosis than left-sided disease, though the mortality remains high in patients with human immunodeficiency virus (HIV). 32 Right-sided endocarditis typically occurs in patients with illicit IDU (including patients with HIV) and those with structural abnormalities of the right heart due to congenital heart disease, pacemaker or defibrillator implantation, or central venous catheters. The most significant risk factor for right-sided IE is certainly IDU however, left-sided disease may be more common in some groups of addicts. In one series, left-sided involvement occurred in 57% of patients with IDU compared with 40% with right-sided disease. 33 The most common infecting organism in patients with IDU is S. aureus , where it has been reported as the offending organism in up to 82%. 34
Prognosis in patients with IDU and IE is generally better than that in overall patients with IE who do not have a history of IDU, because of the lower risk of IE on the right side. 32 The patients with IDU and IE generally are also much younger than other IE populations. Of importance, the presence of HIV infection does not appear to alter the diagnostic use of the Duke criteria or the course of the disease, 35 although patients with a very low CD4 + count (<200 cells/mm 3 ) are at greater risk. 9
The expanded use of cardiovascular electronic devices has resulted in infections not only on the device leads themselves but also on the tricuspid leaflet. A pocket infection appears to predispose to this form of IE. 36 A study from the Medicare database indicates that although the device implantation rate rose 42% in the 1990s, the IE infection rate rose 124%. 36 One estimate of the rate of these device-related infections suggests it is about 0.55 cases per 1,000 implants. 37 Removal of the device is almost always required for cure. 38,39
|EPIDEMIOLOGIC FEATURE||COMMON MICROORGANISM(S)|
|Injection drug usage||Staphylococcus aureus , coagulase-negative staphylococci, β-hemolytic streptococci, fungi, aerobic gram-negative bacilli (including Pseudomonas ), polymicrobial|
|Indwelling medical devices||S. aureus , coagulase-negative staphylococci, β-hemolytic streptococci, fungi, aerobic gram-negative bacilli, Corynebacterium spp.|
|Poor dental health||Viridans group streptococci, HACEK group ( Haemophilus , Actinobacillus, Cardiobacterium, Eikenella , and Kingella ), nutritionally deficient streptococci, Abiotrophia defectiva , Granulicatella spp., Gemella spp.|
|Diabetes mellitus||S. aureus , β-hemolytic streptococci, Streptococcus pneumoniae|
|Acquired immunodeficiency syndrome||Salmonella spp., S. pneumoniae , S. aureus|
|Chronic skin infections, burns||S. aureus , β-hemolytic streptococci, aerobic gram-negative bacilli, fungi|
|Genitourinary infections or manipulation, including pregnancy, abortion, and delivery||Enterococcus spp., group B streptococci, Listeria monocytogenes , aerobic gram-negative bacilli, Neisseria gonorrhoeae|
|Alcoholic cirrhosis||Bartonella spp., Aeromonas spp., Listeria spp., S. pneumoniae , β-hemolytic streptococci|
|Gastrointestinal lesions||Streptococcus bovis , Enterococcus spp., Clostridium septicum|
|Solid organ transplantation||S. aureus , Aspergillus fumigatus , Candida spp., Enterococcus spp.|
|Homelessness, body lice||Bartonella spp.|
|Pneumonia, meningitis||S. pneumoniae|
|Contact with containerized milk or infected farm animals||Brucella spp., Pasteurella spp., Coxiella burnetii, Erysipelothrix spp.|
|Dog/cat exposure||Bartonella spp., Pasteurella spp., C. septicum|
Modified from Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications. Circulation 2005111:e394-e434.
IDU is clearly a risk factor for IE, and those who use cocaine may have the greatest risk. 40 A prior history of endocarditis is an important predisposing factor in recurrent IE in patients with IDU. Recurrent endocarditis occurred in 4.5% of one large cohort of nonaddicts who survived their initial episode. 41
Pacemaker-associated infections have increased with the increased use of electrophysiologic (EP) devices. A report from the Multicenter Electrophysiologic Device Infection Cohort (MEDIC) registry 42 from 2009 through 2011 found that early (<6 months after implantation) device infections were generally related to pocket infections and that later IE was the result of other bacteremias. Staphylococci (coagulase-negative, methicillin-resistant, and methicillin-sensitive) were the most common organisms involved. As mentioned, effective treatment almost always requires removal of leads.
Patients undergoing hemodialysis are the largest subgroup with health care–related IE. 43,44 Predisposing factors in this population include intravascular access, calcific valvular disease, and impairment of the immune system. Of patients with health care–associated IE who are not undergoing dialysis, most have underlying predisposing conditions, including diabetes, cancer, and immunosuppressive therapy use. Identifiable underlying cardiac predisposition to IE occurs in less than 50% of this group. 5 Most invasive organisms originate from the skin or urinary tract, and the presence of intravenous lines or other invasive procedures is frequently evident. 45 Staphylococcus is the predominant offender.
A number of cases of IE have been reported in patients with HIV infection. 49,50 Some valves have been infected with unusual organisms such as Salmonella and Listeria . 50 It has been reported that HIV infection is an independent risk factor for IE in injection drug users, 51 although this finding has not been confirmed in other studies. 50
The clinical examination, the organism involved and its response to therapy, and the echocardiographic information can establish the prognosis and guide decision making in the treatment of IE. A number of studies have examined other factors in an effort to understand prognosis in patients with IE. Chu et al 52 examined 267 consecutive patients with acute IE to determine factors early in the course of the disease that were independently associated with mortality. After controlling data for severity of illness with Acute Physiology and Chronic Health Evaluation (APACHE) II scoring, they found that the independent predictors of early mortality were the presence of diabetes mellitus (odds ratio [OR], 2.48 95% confidence interval [CI], 1.24-4.96), S. aureus infection (OR, 2.06 95% CI, 1.01-4.20), and an embolic event (OR, 2.79 95% CI, 1.15-6.80). In a similar fashion, Hasbun et al 53 found that five baseline features were independently associated with mortality and developed a scoring system that included the following: mental status, lethargy or disorientation (4 points) Charlson comorbidity scale, 2 or greater (3 points) HF, moderate to severe (3 points) microbiology, S. aureus (6 points), other non-viridans infection (8 points) and therapy, medical therapy only (5 points). On the basis of this point system, patients with a score of 6 points or less only had 6% mortality at 6 months, whereas patients with a score of more than 15 points had 63% mortality. In other studies, the need for hemodialysis has also been found to portend a poor outcome, 43,54 as has the presence of poor ventricular function. 55 Another study identified patients with an altered mental state, those with mobile vegetations, and those undergoing hemodialysis as the cohort with the highest risk. 56
Newer guidelines for endocarditis prophylaxis have created a great deal of controversy. In a population-based case-control study from Philadelphia, pulmonary, cardiac, gastrointestinal, and genitourinary procedures or surgery did not emerge as risk factors for the development of community-acquired endocarditis, and dental flossing reduced the risk only modestly. 57 One review emphasized that despite the known association of endocarditis with poor dental hygiene and a visit to the dentist’s office, the actual risk of endocarditis from a dental procedure (such as a tooth extraction) is exceedingly low 13 ( Table 25-4). In fact the event rate is so low, even in supposedly high-risk patients, that a trial designed to demonstrate an increased risk of IE from a dental procedure would require a prohibitively large number of patients and is likely not feasible.
|General population||1 per 14 million procedures|
|Mitral valve prolapse||1 per 1.1 million|
|Congenital heart disease||1 per 475,000|
|Rheumatic heart disease||1 per 142,000|
|Prosthetic valve||1 per 114,000|
|Prior endocarditis||1 per 95,000|
Modified from Pallasch TJ. Antibiotic prophylaxis: problems in paradise. Dent Clin North Am 200347:665-679.
As part of the rationale eliminating most scenarios requiring endocarditis prophylaxis, both the American Heart Association (AHA) 58 and the British Cardiac Society 59 have now published guidelines suggesting its use only in patients who not only have the greatest risk for endocarditis but who also would suffer the most from the consequences of the disease. The two lists of such patients differ slightly. The AHA/American College of Cardiology (ACC) Adult Congenital Heart Disease guidelines also weighed in by suggesting that endocarditis prophylaxis be extended to coverage of the high-risk group during vaginal delivery. 60
The United Kingdom National Institute for Health and Clinical Excellence (NICE) working group has now taken the final step in this evolving process and suggests eliminating all prophylaxis before any procedure. 61 The NICE guidelines acknowledge that certain conditions predisposing to endocarditis—acquired valvular heart disease, valve replacement, structural congenital disease (including surgically corrected or palliated structural conditions, fully repaired ventricular septal defect or patent ductus arteriosus, and closure devices), previous endocarditis, and hypertrophic cardiomyopathy—may increase the risk of IE should bacteremia occur. On the basis of their review of all available data, the NICE guidelines working group recommends eliminating antibiotic prophylaxis for all dental or nondental procedures. They also note no preventive advantage of chlorhexidine mouthwash. Although there remain questions as to the value of eliminating endocarditis prophylaxis entirely, 62 most physicians have gradually accepted the current endocarditis prophylaxis guidelines with some trepidation. 63–66 A comparison of the various recommendations from these guideline committees is summarized in Table 25-5.
The normal heart valve is a three-layer histologic structure of endothelium, spongiosa, and ventricularis. Its endothelium is in continuity with the endothelium over the arterial, atrial, and ventricular walls. The endothelial lining is resistant to infection by bacteria and fungi except for a few highly virulent organisms. Events that result in endocarditis constitute a complex interaction between the host and the invading microorganisms and involve the vascular endothelium, the host immune system, hemostatic mechanisms, cardiac anatomic characteristics, surface properties, enzyme and toxin production by the microorganisms, and peripheral events that have caused the bacteremia. 28 Endothelial damage is the inciting event, followed by a platelet-fibrin deposition that provides a milieu for bacterial colonization. The role of endothelial damage as the inciting event is supported by the observation that the most likely areas of vegetation formation are similar to those where blood flow injury is most likely to occur: on the ventricular side of the semilunar valves and the atrial side of atrioventricular valves. 67 Jet lesions from insufficient valves may also damage endothelium, and vegetations may form on such sites of injury, for example, the mitral chordae in aortic regurgitation, the atrial wall (McCallum patch) in mitral regurgitation, and the septal leaflet of the tricuspid valve in a ventricular septal defect. Figure 25-1 illustrates the classic locations of endocardial and valvular lesions as well as the vegetation formation.
For example S. aureus possesses clumping factor A (or fibrinogen-binding protein A) and fibronectin-binding protein A, both of which are known to be involved in valve colonization and invasion. The clumping factor appears to mediate the primary attachment of the bacteria to the NBTE lesion, and this step is followed by internalization of the organism, which is promoted by fibronectin-binding protein. Eventually proinflammatory and procoagulant responses occur. 70 Once safely inside the cells, the bacteria can survive, protected from antibiotics and host defense. 71 This process may explain why certain organisms, such as staphylococcal species and streptococci, which have the ability to bind to platelets and incite the clotting mechanism, may be more virulent than those organisms that are more readily shed into the bloodstream. The fact that S. aureus may also induce endothelial cells to produce a clotting tissue factor could, at least partially, explain why S. aureus adheres to relatively normal valve tissue. Particulate material that may be injected by intravenous drug users may also promote S. aureus adherence by stimulating adhesive binding molecules on normal heart valves. 72 This concept has been postulated to explain the distinct predilection for tricuspid valve involvement in intravenous drug users. 73 A potential therapeutic approach to prevent this binding was attempted by use of the St. Jude Silzon prosthetic valve ring, a silver-coated polyester ring (St. Jude Medical, Inc., St. Paul, Minnesota). Unfortunately, concerns regarding increased paravalvular regurgitation and emboli led to the product’s early withdrawal from clinical trials. 74
Enterococcus faecalis and other enterococcal species are also equipped with collagen adhesions 75 and aggregation substances 75 and are capable of biofilm production. 76 The clinical importance of biofilm production by these organisms has been strongly implicated in their antibiotic resistance and provides a potential therapeutic target for attacking the infections. 76
Some writers have postulated that local inflammation from degenerative lesions might have a direct role in endothelial infection. 5 Inflammatory mechanisms could potentially play a role in the pathogenesis of certain fastidious infections involving pathogens, such as Coxiella burnetii (Q fever), Chlamydia spp., Legionella spp., and Bartonella spp. 77
In up to 30% of patients, a preexisting cardiac abnormality may not be evident. 68 Several organisms appear capable of infecting apparently normal valves, including S. aureus , some streptococci, Salmonella, Rickettsia, Borrelia , and Candida spp. In addition to the mechanisms already described, it has even been postulated that some endothelial cells may contain metabolically latent organisms that eventually damage the endothelium. 78
The role of transient bacteremia in vegetation formation is indisputable. 79 Transient bacteremia is unavoidable, however, and occurs even during such mundane activities as chewing food and toothbrushing. Toothbrushing twice a day for a year has been found to result in a 154,000 times greater risk of bacteremia than would result from a single tooth extraction, the dental procedure associated with the highest bacteremia. 80 Taken overall, the cumulative exposure from such routine activities may be as high as 5.6 million times greater than that derived from a single tooth extraction. 80 Data such as these have led to the skepticism regarding the value of endocarditis prophylaxis during dental procedures.
Host defenses against infection likely also play an important but poorly defined role. Perhaps surprisingly, IE is not more pre valent in immunocompromised patients, with the possible exception of those with HIV disease. 81 Endocarditis involving gram-positive organisms is much more common than gram-negative, in part because of differences in the organism itself, but possibly also related to host defenses. For instance, the C5b-C9 membrane-attack complex of complement has a much greater killing effect on the membranes of gram-negative than of gram-positive organisms. 5 Platelet microbicidal proteins may also play some role, 82 especially because platelet deposition is so important in in vegetation formation.
The role of viruses as causative agents in IE remains unproven. A 2011 report revealing coxsackievirus cultured from an infected intracardiac patch raises the issue anew. 83 Burch et al 84 have suggested the possibility for many years, though later reviews of culture-negative endocarditis have not provided much evidence for viral etiologies. 85
The prevalences of the clinical features observed in patients with IE are summarized in Table 25-6. Many of these features were espoused by Osler in the Gulstonian lectures 4,87 but are rarely seen in an era when diagnostic testing is better and there is antimicrobial therapy. Most patients continue to have an initial indolent course from 2 weeks to many months with vague symptoms. Symptoms include fever, chills, anorexia, weight loss, night sweats, and malaise.
A murmur is apparent in 80% to 85% of patients, 28 although auscultation is a dying art in cardiology and a murmur may not always be recognized by health care providers even when present. The murmur of acute and fulminant aortic regurgitation may be particularly difficult to hear because there is little diastolic gradient. Whereas tricuspid regurgitation should be evident from examination of the jugular venous pulse, the murmur is often quite soft when right ventricular systolic pressure is normal.
Musculoskeletal aches and pains are common in IE and often occur early in the course. 91 Any joint can be involved, but back and shoulder pains are most frequently cited. 92 Septic emboli may result in osteomyelitis or bone abscess formation (especially in the spine). Musculoskeletal pain must be taken seriously if it persists during the course of therapy.
Neurologic symptoms are common, being seen in as many as 30% to 50% of patients with IE. Symptoms appear to be more common in patients with IDU and those with staphylococcal IE. 93 Embolic stroke is the most common and serious manifestation. Intracranial hemorrhage may occur from a ruptured arterial vessel, a ruptured mycotic aneurysm, or bleeding into a thrombotic stroke distribution. 94 In addition, neurologic symptoms may be related to cerebritis or meningitis or to toxic or immune-mediated injury. Brain abscess is rare, but microabscesses from virulent organisms, such as S. aureus , occur with some frequency. 95 Meningitis may be a major feature in IE due to Streptococcus pneumoniae .
The diagnosis of IE hinges on clinical suspicion and the demonstration of continuous bacteremia. It was not until the late 1970s that Pelletier and Petersdorf 97 developed a case definition based on a 30-year experience of caring for patients with IE in Seattle. Although this definition was highly specific, it lacked sufficient sensitivity. In 1981, von Reyn et al 98 published an analysis that provided four diagnostic categories for cases of suspected IE (rejected, possible, probable, and definite), and the effort improved both the sensitivity and the specificity of the previous case definition. The definition did not incorporate imaging information, however.
In 1994, Durack et al 99 from Duke University Medical Center incorporated echocardiography into the criteria for the first time, giving rise to what have come to be known as the Duke criteria. These criteria have been validated subsequently by many other studies, 100–102 including the latest modifications ( Table 25-7). 103,104 There are now three diagnostic categories. Definite endocarditis is considered to be present if there is pathologic evidence (surgical pathologic histology or culture or vegetation histology or culture) or if there is clinical evidence as demonstrated by the presence of two major criteria or one major criterion and three minor criteria or five minor criteria. Possible endocarditis is defined as having one major criterion and one minor criterion or three minor criteria. Rejected diagnosis is defined as having a firm alternative diagnosis or sustained resolution of the evidence for endocarditis after 4 or fewer days of antibiotic therapy or no pathologic evidence of endocarditis at surgery or autopsy after 4 or fewer days of therapy.
DETECTION OF VEGETATIONS
There is no better technique for non-invasive visualisation of vegetations than echocardiography (fig 1). Overall the detection rate for vegetations by transthoracic echocardiography (TTE) in patients with a clinical suspicion of endocarditis averages around 50%. 4 The diagnostic yield of the technique in the detection of vegetations is influenced by several factors: image quality echogenicity and vegetation size vegetation location presence of previous valvar disease or valvar prosthesis experience and skill of the examiner and pre-test probability of endocarditis.
Large vegetations (arrows) in the mitral valve secondary to fungal endocarditis. LA: left atrium LV: left ventricle.
Native valve endocarditis
The use of harmonic imaging has improved study quality, but not the sensitivity in the visualisation of vegetations. 4, 5 Vegetation size also affects TTE sensitivity 6 since only 25% of vegetations < 5 mm and 70% of those between 6–10 mm are identified. 7 Underlying valve disease may influence the diagnostic accuracy of TTE when a myxomatous mitral valve or sclerotic or calcified valves are present. These limitations have been overcome by TOE owing to its better resolution and multiple study planes. Many studies have compared the sensitivity and specificity of TTE and TOE in the diagnosis of vegetations (table 1). In the majority of these studies TTE sensitivity ranges between 40–63% and that of TOE between 90–100%. 4, 6– 8
Studies comparing the sensitivity and specificity of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE) in the diagnosis of vegetations
A negative TOE has an important clinical impact on the diagnosis of endocarditis with a high negative predictive value ranging from 86–97%. In patients with native heart valves a negative TOE virtually rules out the diagnosis of infective endocarditis. However, in the study of Sochowski and colleagues 9 five out of 65 patients (7.6%) with an initially negative TOE were finally diagnosed with endocarditis: in three of the patients a TOE performed 1–2 weeks after the initial examination showed the presence of vegetations. This study underlines the importance of recognising the phase of the disease in which the study is performed, since vegetations may not be large enough to be visualised when endocarditis is suspected very early on.
In common with other diagnostic techniques, specificity of echocardiography is related to the clinical indication and the type of population studied. The technique does not permit differentiation between septic vegetations and other aseptic vegetations present in other situations such as Libman-Sacks endocarditis in systemic lupus erythematosus, and antiphospholipid syndrome or marantic endocarditis. Vegetations persisting after effective treatment must not be interpreted as a clinical recurrence of the disease unless supported by clinical features and bacteriologic evidence. Specificity is influenced mainly by the presence of valvar thickening or calcifications and also by rupture mitral chordae tendinae or Lambl’s nodules which can be confused with vegetation images. 4, 8
The usefulness of TOE in patients with suspected endocarditis on a native valve is related to the results of the TTE. TOE is useful when TTE is negative or inconclusive.
Prosthetic valve endocarditis
Vegetations on prosthetic valves are more difficult to detect by TTE than those involving native valves, and therefore TOE should always be used if the diagnosis of prosthetic endocarditis is suspected (fig 2). The sewing ring and support structures of mechanical and bioprosthetic valves are strongly echogenic and may prevent vegetation detection within the valve apparatus or its shadow. The vegetative growth appears as thickening and irregularity of the normally smooth contour of the sewing ring. Both thrombus and pannus have a similar appearance and cannot be distinguished from vegetative material. It is also important to recognise strands to avoid false positive diagnoses. Strands are commonly observed by TOE on prosthetic valves, particularly in the early postoperative months, especially in mitral prostheses. 10
Aortic periannular abscess (arrows) in a prosthetic valve endocarditis. LA: left atrium RA: right atrium RV: right ventricle.
In large series of prosthetic endocarditis TOE has shown an 86–94% sensitivity and 88–100% specificity for vegetation diagnosis, while TTE sensitivity was only 36–69%. 11 Bioprosthetic valve leaflets may become infected with secondary destruction of leaflet tissue. The distinction between wear-and-tear degeneration of tissue valves and endocarditis is often difficult. TOE also led to an improved diagnostic accuracy in the diagnosis of endocarditis on bioprosthetic valves 8
Right sided endocarditis and pacemaker lead infections
TTE allows an easy and correct diagnosis of tricuspid vegetations, probably because the majority of patients with tricuspid endocarditis are young intravenous drug abusers with large vegetations. The vegetations are located in the atrial side of the tricuspid valve, in the way of the regurgitant jet. San Roman and colleagues 12 showed that TOE did not increase the accuracy of TTE in the detection of vegetations in tricuspid endocarditis. However, despite the low number of cases described, TOE appears to be more sensitive than TTE in the diagnosis of pulmonary valve endocarditis.
Infection or endocarditis on a pacemaker lead are difficult to diagnose by TTE since pacemaker leads produce reverberations and artefacts that may mask or make difficult the recognition of vegetations close to these structures. In addition when vegetations were visualised it was difficult to determine whether tricuspid valve endocarditis, lead infection, or both were present. TOE was clearly superior to TTE in this clinical setting (sensitivity 23% v 94%).
Rare Disease Database
Infective endocarditis (IE) is an infection of the inner lining of the heart muscle (endocardium) caused by bacteria, fungi, or germs that enter through the bloodstream. IE occurs most frequently in patients with abnormal (leaky or narrow) heart valves, artificial (prosthetic) heart valve or in people who have a pacemaker lead. Any structural heart disease can predispose a person to developing IE. In the past, rheumatic fever was the main precursor to IE and still remains a common predisposition in developing countries. The presenting symptoms are a low-grade persistent fever without an obvious cause, fatigue and shortness of breath on exertion. Patients also may have joint and muscle pain and their health care provider may hear a new or changing murmur.
The endocardium covers the heart valves, and it is these valves which are primarily affected by infective endocarditis. If the infection remains untreated, multiplying bacteria may eventually destroy the valves and result in heart failure. Bacteria may also form small clots (emboli) which move through the blood and block small arteries. These clots may lodge in various parts of the body including the brain and cause serious damage.
The prevalence of cases of IE has risen in the United States due to the increase in the number of elderly patients receiving invasive surgeries as well as the rise in the number of individuals using IV drugs. Other risk factors include congenital heart disease, prior episode of IE and mitral valve prolapse with leaky valve. Therefore, early diagnosis is key to improve clinical outcomes and survival. Antibiotics are essential for treatment and are most effective if the disease is caught early. However, in many cases heart surgery also is needed.
Endocarditis was first described by William Osler in 1885. Developments in medical science and research in microbiology have contributed to a better understanding of the disease. The most common risk factors for infective endocarditis are previous heart damage, recent heart surgery or poor dental hygiene.
Signs & Symptoms
Infective endocarditis is an infection of the valves and/or lining of the heart. The presenting symptoms are a low-grade persistent fever without an obvious cause and fatigue and shortness of breath on exertion. Patients also may have joint pain (arthralgia) and muscle pain (myalgia) and their health care provider may hear a new or changing murmur. In addition, the following signs and symptoms occur:
- Heart murmur not previously present or a changed heart murmur
- Presents in 80% of endocarditis patients
Infection on the heart valve results in destruction of the leaflet tissue, leaking of the valve and heart failure. Extension of infection into tissue next to valve may result in an abscess with rupture between different chambers of the heart. Clots (emboli) resulting from infective endocarditis may produce serious damage. Symptoms depend upon the location of the clot. In 20-40% of individuals with infective endocarditis, clots lodge in the brain and may cause weakness on one side of the body, loss of vision or stroke. Clots may also cause abdominal pain, flank pain, or arterial insufficiency in an extremity. An eye doctor might see bleeding in the back of the eye (Roth spots). Damage from clots may be temporary or permanent.
Bacteria that cause infective endocarditis reach the heart through the bloodstream. Normally, heart valves are highly resistant to the attachment of bacteria and resulting infection. Damage to the heart valves and inner lining of the heart is the main risk factor for infective endocarditis because it leaves the tissue susceptible to bacterial overgrowth. As the microorganisms quickly move past the damaged valve lining, those strains that can most strongly adhere to the surface are bacteria that have the best chance of producing infective endocarditis. Clumps of bacteria and cells called vegetations form on the heart valves affecting proper function of the heart. If left untreated, this vegetation may cause the valve to leak or may result in an abscess next to the valve or in the heart muscles leading to tissue damage and blockage of the normal electrical conduction pathways. In addition, the vegetation may break loose and cause damage to the brain (stroke), kidneys or lungs.
Risk factors that contribute to the onset of Infective Endocarditis include:
- Intravenous drug use with a needle contaminated with bacteria or fungi
- Presence of an artificial (prosthetic) heart valve or other valve repair material
- Presence of a cardiac pacemaker lead
- Previous infective endocarditis
- Mitral valve prolapse with valve leakage
- An aortic valve with only 2 (instead of the normal 3 valve leaflets). This condition, called a bicuspid aortic valve, is present in about 1% of people.
- Narrowing (stenosis) of the aortic valve due to age-related calcification
- Other abnormal valves caused by rheumatic fever and degenerative conditions
- Congenital heart disease, especially if repaired with artificial material.
People who are on immunosuppressive medication (such as after heart transplantation) also are at higher risk. In patients with risk factors, any dental procedure (including routine dental cleaning) risks the spread of bacteria which is prevented by treatment with antibiotics just before dental procedures in people at highest risk. Infections elsewhere in the body and chronic indwelling catheters (such as for chemotherapy) also increase the risk of infective endocarditis.
Approximately 80% of infective endocarditis cases are caused by the bacteria streptococci and staphylococci. The third most common bacteria causing this disease is enterococci, and, like staphylococci, is commonly associated with healthcare-associated infective endocarditis. While very rare, infections due to gram-negative and fungal pathogens are often acquired in healthcare settings.
The mouth is a major portal for bacteria to enter the body, specifically streptococcal bacteremia. Historically, prophylactic treatment with antibiotics was used for all patients at high risk for developing IE when undergoing surgical, dental or other invasive procedures. The American Heart Association recommended penicillin prophylaxis in 1955 for patients with congenital heart disease and rheumatic heart disease prior to undergoing any dental procedures. Emerging resistance to antibiotics due to overuse and lack of research to support the use of prophylaxis led the USA and Europe to restrict the use of antibiotics by 2009. The United Kingdom went on to abandon the use of antibiotic prophylaxis entirely. The USA reserves this treatment for those with prosthetic heart valves, prior IE, congenital heart disease and cardiac transplant recipients.
Infective endocarditis appears to be approximately twice as common in men as women. In the past, disease onset occurred at an average age of 35 years of age. However, with more patients having artificial heart valves and pacemakers, the average age at onset has increased to over 50 years. Infective endocarditis has an incidence rate of 3-10 cases in every 100,000 people. No race or ethnicity is more affected than others. Prognosis of infective endocarditis remains poor despite advances in diagnosis and therapies. Mortality rates are approximately 25% even with the best therapies available.
Infective endocarditis most commonly affects people who:
- Have had previous cardiac valve surgery
- Have artificial heart valves and cardiac devices such as pacemakers
- Previous infective endocarditis
- Mitral valve prolapse with valve leakage
- A congenital bicuspid aortic valve.
- Rheumatic fever causing abnormal valve function (mainly in developing countries)
- Certain congenital defects-those defects such as atrial septal defect or patent ductus arteriosus that are repaired do not increase the risk of developing IE.
- Use intravenous drugs
- Have HIV
- Have frequent contact with healthcare facilities/personnel
- Have certain dental procedures
For those with heart valve replacements, the risk of infection is highest within the first year after the procedure takes place. Those who have had this type of procedure remain at higher risk for infective endocarditis for the rest of their life compared to those who have not had these procedures.
Acute bacterial endocarditis is usually caused by staphylococcus aureus bacteria and occasionally by the bacterial strains brucella and listeria. This form of infective endocarditis, compared to other forms, is more likely to affect normal heart valves.
Subacute bacterial endocarditis is usually caused by streptococcal bacteria. This form of the disease usually develops on damaged valves after dental surgery involving infected gums, reproductive or urinary (genitourinary tract) surgery or operations on the gastrointestinal tract. A history of a preceding dental, genital or urologic procedure is common. Symptoms usually begin within two weeks following the procedure, but diagnosis is often delayed because symptoms are subtle and patients may not seek care immediately and because diagnosis can be difficult, especially early in the disease course. A previous history of heart disease is present in most individuals with subacute bacterial endocarditis.
In developing countries, heart damage caused by rheumatic heart disease is the leading predisposing condition for infective endocarditis however in developed countries, rheumatic heart disease is implicated in less than 5% of infective endocarditis cases.
Prosthetic valvular endocarditis (PVE) develops in 2% to 3% of individuals in the year following artificial (prosthetic) valve placement or tissue valve replacement, occasionally resulting from organisms accidentally implanted during surgery. The number of reported cases of prosthetic valvular endocarditis is highest with artificial aortic valve replacement. These infections frequently result from contamination during an operation. Approximately 30% of the reported cases are caused by staphylococcus.
The key step in the diagnosis of endocarditis is obtaining blood cultures before antibiotics are started. People with risk factors for endocarditis, particularly those with prosthetic valves and pacemakers, should know the symptoms of endocarditis and should insist on blood culture when they have an unexplained fever. Diagnosis of infective endocarditis can be done based on pathology or by meeting certain clinical diagnostic criteria. These criteria are known as the Duke Clinical Criteria and a patient must show either: 2 major, 1 major and 3 minor, or 5 minor criteria to be diagnosed with infective endocarditis. These include
Major Clinical Criteria
- Blood culture
- Normally positive if patient has IE
- If negative, further testing i.e. serological testing
- In Infective endocarditis, clumps of infection called vegetation invade the lining of the heart and valves causing inflammation that disrupts normal function. Echocardiography is used to visualize this.
- Two types of echocardiography are used to diagnose IE: transthoracic echocardiogram (TTE) and transesophageal echocardiography (TEE). TTE is performed by holding a device (transducer) against the patient’s chest while TEE involves inserting a small transducer attached to a tube into the patient’s mouth and extending it into the esophagus to get a more detailed view of the heart structures and function. TEE is a more invasive procedure but provides more accurate view of valves.
- Positive for the bacteria Coxiella burnetii or 1 IgG antibody titer ≥1:800
Minor Clinical Criteria
- Predisposing condition
- Intravenous drug use
- Cardiac condition
- Arterial embolism- sudden interruption of blood flow to organ or body part due to clot (embolus)
- Septic pulmonary emboli-blood clots in the lungs containing bacteria
- Mycotic aneurysm- dilation of an artery due to infection damaging vessel wall
- Intracranial hemorrhage- brain bleed
- Conjunctival hemorrhages- rupture of blood vessels in the eye
- Janeway’s lesions-nodules on palms of hands and soles of feet
Cardiac CT scan (computed tomography), an imaging test, may be indicated in the event the results of TTE and TEE are inconclusive and clinical presentation is consistent with IE.
Without prompt, appropriate treatment, infective endocarditis results in serious heart damage or death. Mortality rate within the first 30 days of infection has been reported to be
20% but survival without antibiotic therapy is unlikely. Therefore, early diagnosis and aggressive therapy are critical for successful treatment. Therapeutic measures typically include intravenous infusion of high doses of appropriate antibiotic drugs. Antibiotic therapy is needed for at least six or eight weeks and is provided intravenously for at least 2 weeks and often for the entire treatment duration. The specific drugs or drug combinations used may depend upon the bacterium responsible for the infection and other factors (e.g., bacterial strain resistance to certain antibiotics). The specific antibiotics uses in each patient are selected based on the blood culture results and determining which antibiotics kill the specific bacteria isolated in each patient. Often more than one antibiotic is given together to increase effectiveness. The type of antibiotic needed will be determined in consultation with infectious disease specialists.
In many affected individuals, antibiotics alone are not sufficient to control the infection, because the antibiotics cannot reach the infected valve material or abscess. In patients with a prosthetic heart valve or other implanted material, surgery is almost always needed to remove the infected artificial material and repair the heart. Surgery also is needed if there is an abscess with blockage of the heart electrical signal, rupture between chambers of the heart, or persistent infection even with antibiotic therapy. In patients with an infected pacemaker or lead, the entire pacemaker system usually needs to be removed to control the infection. Surgery may also be recommended if there is heart failure due to severe valve leakage or if vegetation is large to prevent stroke. In many cases, heart surgery may be recommended urgently, during the same hospitalization. In other patients, surgery may be done at a later date, after completing antibiotic treatment.
In 2015, The European Society of Cardiology developed guidelines for the treatment of infective endocarditis. These guidelines provide clear, simple recommendations for health care providers in diagnosis and treatment of IE: https://academic.oup.com/eurheartj/article/36/44/3075/2293384#108779576
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Baddour L, Wilson W, Bayer A, Fowler V, Tleyjeh I. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications. Circulation. 2019132(15). https://www.ahajournals.org/doi/10.1161/CIR.0000000000000296.
Vincent L, Otto C. Infective Endocarditis: Update on Epidemiology, Outcomes, and Management. Curr Cardiol Rep. 201820(10). doi:10.1007/s11886-018-1043-2. https://www.ncbi.nlm.nih.gov/pubmed/30117004
Bai AD, Steinberg M, Showler A, et al. Diagnostic accuracy of transthoracic echocardiography for infective endocarditis. inical Investigation Infective Endocarditis.| 201730 (7) 639-646.E8
Holland TL, Baddour LM, Bayer AS, Hoen B, Miro JM, Fowler VG Jr. Infective endocarditis. Nat Rev Dis Primers. 20162:16059. https://www.ncbi.nlm.nih.gov/pubmed/27582414
Gilbert Habib, Patrizio Lancellotti, Manuel J Antunes, et al. 2015 ESC guidelines for the management of infective endocarditis: The task Force for the management of infective endocarditis of the European Society of Cardiology (ESC). 2015 36(44)3075-3128. https://academic.oup.com/eurheartj/article/36/44/3075/2293384
Topan A, Carstina D, Slavcovici A, Rancea R, Capalneanu R, Lupse M. Assesment of the Duke criteria for the diagnosis of infective endocarditis after twenty-years. An analysis of 241 cases. Clujul Med. 201588(3):321‐326. doi:10.15386/cjmed-469
Infective endocarditis. Genetic and Rare Diseases Information Center (GARD). Last updated: 6/3/2011. https://rarediseases.info.nih.gov/diseases/6337/infective-endocarditis/cases/29688. Accessed May 5, 2020.
Endocarditis | Cleveland Clinic. Cleveland Clinic. Last reviewed: 04/29/2019. https://my.clevelandclinic.org/health/diseases/16957-endocarditis Accessed May 5, 2020.
Infective Endocarditis. American Heart Association .https://www.heart.org/en/health-topics/infective-endocarditis Accessed May 5, 2020.
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In the modern era, management of IE typically requires a multidisciplinary team including, at a minimum, an infectious disease specialist, a cardiologist and a cardiac surgeon 133 . All patients should receive antimicrobial therapy and a subset may benefit from cardiovascular surgical intervention.
General principles of antimicrobial therapy
The primary purpose of antimicrobial therapy is to eradicate infection. Several characteristics of infected vegetations pose particular challenges in this regard 55 , including high bacterial density (also called the ‘inoculum effect’) 134 , slow rates of bacterial growth in biofilms and low microorganism metabolic activity 135 . As a result, extended courses of parenteral therapy with bactericidal (or fungicidal) agents are typically required.
Duration of therapy
The duration of therapy must be sufficient to completely eradicate microorganisms within cardiac vegetations. Due to poor penetration of antibiotics into these vegetations and the slowly bactericidal properties of some of the commonly used drugs (such as vancomycin), extended courses of antibiotics are usually required. When bactericidal activity is rapid, shorter courses may be feasible. For example, combination therapy with penicillin or ceftriaxone and an aminoglycoside is synergistic for VGS-associated IE, enabling effective courses as short as two weeks for susceptible strains 101 . Right-sided vegetations tend to have lower bacterial densities and may also be amenable to shorter course therapy.
Duration of antimicrobial therapy is generally calculated from the first day on which blood cultures are negative. Blood cultures should be obtained every 24 hours until it is demonstrated that the bloodstream infection has cleared 101,102 . If operative valve tissue cultures are positive, an entire antimicrobial course should be considered following cardiovascular surgery.
Selection of the appropriate antimicrobial agent
Therapy should be targeted to the organism identified in blood cultures or serological studies. While awaiting microbiological results, an empiric regimen may be selected based upon epidemiologic and patient demographic features. Because most IE cases are caused by Gram-positive bacteria, vancomycin is often an appropriate empiric choice. However, other empiric agents may also be appropriate based on local microbiology and susceptibility patterns. Detailed recommendations for antimicrobial treatment of specific pathogens are comprehensively addressed in recent treatment guidelines 101,102,136 . Key points are summarized in Table 3 .
Pathogen-specific therapy of infective endocarditis
Pathogen Regimen(s) Comments Penicillin-susceptible (MIC 𢙀.12 mcg per ml) viridans streptococci and S. bovis Penicillin Adverse effects include hypersensitivity and seizures Ceftriaxone Generally well tolerated, once daily administration may enable outpatient therapy Penicillin (or ceftriaxone) + gentamicin Addition of an aminoglycoside enables a shorter treatment duration (2 weeks vs 4 weeks) at the expense of potential aminoglycoside adverse effects (renal, vestibular and cochlear toxicity) Vancomycin Use should be limited to those with true penicillin allergy Penicillin-intermediate (MIC Ϡ.12 and 𢙀.5 mcg per ml) viridans streptococci Penicillin (or ceftriaxone) + gentamicin 4 weeks of therapy recommended Vancomycin For penicillin-allergic patients or to avoid gentamicin Enterococci and penicillin-resistant (MIC Ϡ.5 mcg per ml) viridans streptococci Penicillin (or ampicillin) + gentamicin Extended therapy (6 weeks) recommended for prosthetic valves and prolonged duration of symptoms prior to diagnosis Ampicillin + ceftriaxone Favoured in patients with renal insufficiency or high-level aminoglycoside resistance Vancomycin + gentamicin Nephrotoxic regimen role of gentamicin is uncertain Daptomycin For vancomycin-resistant and penicillin-resistant enterococci may combine with β-lactam Linezolid May be used for vancomycin- and penicillin-resistant enterococci, although adverse events including bone marrow suppression and neuropathy are of concern with extended treatment courses Staphylococci Nafcillin For MSSA adverse effects include rash, interstitial nephritis Cefazolin For MSSA better tolerated than nafcillin Vancomycin For MRSA Nafcillin + gentamicin 2 week regimen for IV drug users with uncomplicated right-sided IE* Nafcillin + gentamicin + rifampin For prosthetic valve IE substitute vancomycin for nafcillin in patients with MRSA Daptomycin FDA-approved for right-sided S. aureus IE observational data supports use in left-sided IE as well may combine with β-lactam HACEK strains Ceftriaxone Effective for β-lactamase producing strains Ampicillin/sulbactam For β-lactamase producing strains Ciprofloxacin For patients intolerant of β-lactam therapy Enterobacteriaceae Extended-spectrum penicillin or cephalosporin + aminoglycoside (or fluoroquinolone) Rare cause of IE and may require a tailored approach depending on the pathogen Pseudomonas aeruginosa An anti-pseudomonal β-lactam (such as ticarcillin, piperacillin, ceftazidime, cefepime or imipenem) + tobramycin (or fluoroquinolone) Typically requires prolonged therapy and valve surgery Fungi Parenteral antifungal agent (most commonly an amphotericin product) Long-term suppressive therapy with an oral antifungal agent is often required
FDA, Food and Drug Administration HACEK, Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens and Kingella species IE, infective endocarditis IV, intravenous MIC, Minimum inhibitory concentration MRSA, methicillin-resistant S. aureus MSSA, methicillin-susceptible S. aureus.
Considerations for prosthetic valves and implantable cardiac devices
For native valve infective endocarditis (NVIE), treatment duration ranges from 2 weeks to 6 weeks, whereas a treatment duration of 6 weeks is usually used for prosthetic valve infective endocarditis (PVIE). The antibiotics for NVIE and PVIE are typically the same, with the exception of staphylococcal PVIE, for which the addition of rifampin and gentamicin is recommended.
Infections of cardiac implantable electronic devices (such as pacemakers and defibrillators) may occur with or without associated valvular IE 137 . Regardless of whether infection appears to involve the device lead alone (which is sometimes termed ‘lead endocarditis’), the valve alone, or both, complete device and lead removal is recommended 138 . There are limited clinical data to inform the optimal duration of antibiotic therapy for cardiac device infections at least 4𠄶 weeks, using the same antibiotics as for valvular IE, are recommended for lead endocarditis 138 .
The critical distinction in selecting antibiotic therapy for S. aureus𠄺ssociated IE is whether the isolate is methicillin-resistant (MRSA) or methicillin-susceptible (MSSA). Antistaphylococcal β-lactam antibiotics are recommended whenever possible for MSSA𠄺ssociated IE, as data from observational studies suggest worse outcomes for patients with MSSA bloodstream infections who are treated with vancomycin 105,139 . Whether it is necessary to use a β-lactam antibiotic as empiric therapy is unclear small retrospective studies have suggested a potential benefit 140 . A more recent cohort study among patients with MSSA bacteraemia suggested that β-lactams are superior for definitive therapy once MSSA has been identified, but not for empiric treatment 139 . Providers might avoid prescribing β-lactams to patients with reported penicillin allergies. However, among patients with a reported penicillin allergy, most do not have a true allergy when skin testing is performed 141 and skin testing appeared cost-effective in decision analyses for treating MSSA bactaeremia 142 and IE 143 .
For MRSA IE, vancomycin has historically been the antibiotic of choice and it remains a first-line therapy in treatment guidelines 101,102,136,144 . Recent reports have raised the concern that after decades of use, the vancomycin minimum inhibitory concentration (MIC) for S. aureus might be rising 145 . Increased vancomycin MICs, even among isolates still classified as susceptible, might be associated with worse outcomes in MRSA bacteraemia, although meta-analyses have reached different conclusions 146,147 . In a prospective cohort of 93 patients with left-sided MSSA IE who were treated with cloxacillin, high vancomycin MIC (𢙑.5 mg per L) was associated with increased mortality, even though these patients did not receive vancomycin 148 . In light of this finding, it seems that a higher vancomycin MIC may be a surrogate marker for host-specific or pathogen-specific factors that lead to worse outcomes. Clinicians may consider use of an alternative antibiotic for MRSA IE with a vancomycin MIC of 𢙑.5 mg per L, but data are lacking to support a mortality benefit for alternative approaches. Ultimately, the patient’s clinical response should determine the continued use of vancomycin, independent of the MIC 144 .
Daptomycin is FDA-approved for treatment of adults with S. aureus bactaeremia and right-sided IE and is an alternative to vancomycin for MRSA IE 101 . The FDA-approved dose for IE is 6 mg per kg per day, but many authorities use higher doses (such as 8 mg per kg per day) due to concerns for treatment-emergent resistance, which occurred in approximately 5% (7 of 120 daptomycin-treated patients) in the Phase III clinical trial comparing daptomycin to standard therapy for S. aureus bacteraemia and IE 149 . Daptomycin seems to be safe and effective at these higher doses 150 .
Gentamicin is not recommended for staphylococcal NVIE 101 because it is associated with nephrotoxicity and does not have robust data to support clinical benefit 153 . Similarly, rifampin is also not recommended as an adjunct therapy for NVIE 101 because it has been associated with adverse effects 154 and prolonged bacteraemia 155 and should be avoided in staphylococcal NVIE unless there is another indication for its use, such as concurrent osteoarticular infection. For staphylococcal PVIE, weak evidence supports the use of both gentamicin and rifampin 156 . A large trial examining the role of adjunctive rifampin for S. aureus bacteraemia has recently completed enrollment 157 .
Observational data have been reported for other antibiotic combinations. For example, ceftaroline is a cephalosporin antibiotic active against MRSA and has been used as salvage therapy for IE alone or in combination with other anti-staphylococcal antibiotics 158,159 . Other combinations have displayed in vitro synergy and have limited human data in MRSA bacteraemia, such as vancomycin or daptomycin paired with other β-lactams or with trimethoprim-sulfamethoxazole, daptomycin plus fosfomycin, or fosfomycin combined with β-lactams 160,161 .
Recommended treatment regimens for coagulase-negative staphylococci are the same as those for S. aureus 101,102 .
Standard treatment for streptococcal IE is a β-lactam antibiotic (such as penicillin, amoxicillin or ceftriaxone) for 4 weeks. The addition of an aminoglycoside may enable a shorter 2-week course of therapy when administered once daily in combination with ceftriaxone for streptococcal NVIE 101,162 . For streptococcal isolates with an increased penicillin or ceftriaxone MIC, gentamicin should be added 101 .
From the early days of the antibiotic era, clinicians noted that penicillin worked less well for enterococci than for streptococci and combination therapy with an aminoglycoside was therefore recommended 163 . Although this has remained the standard approach, increasing rates of aminoglycoside resistance and the toxicity associated with this class of antibiotics have spurred efforts to find alternative therapeutic options.
Recent data suggest that the combination of ampicillin and ceftriaxone may be effective for IE due to ampicillin-susceptible E. faecalis, particularly in patients with aminoglycoside resistance, or in whom there is concern for nephrotoxicity with an aminoglycoside 164,165 . Vancomycin-resistant enterococcal IE is fortunately rare, but has been successfully treated with linezolid 166 and daptomycin 152 If daptomycin is used, high dose therapy may be considered 101 .
HACEK group organisms (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) were historically treated with ampicillin. However, β-lactamase producing strains are increasingly problematic and susceptibility testing may fail to identify these strains 167 . Therefore, HACEK organisms should be considered ampicillin-resistant and ceftriaxone is preferred. A duration of 4 weeks of therapy is generally sufficient for these organisms 101 .
IE due to non-HACEK Gram-negative bacilli is rare 18 . Consequently, optimal management strategies are not defined. Cardiac surgery combined with prolonged antibiotic therapy is considered a reasonable strategy in many cases 101 .
Fungal IE is also rare but outcomes are poor. Valve surgery is often employed but this approach is not clearly associated with improved outcomes 168 . Following initial parenteral therapy with an amphotericin-based regimen or an echinocandin, indefinite azole therapy is recommended, particularly if valve surgery is not performed 169,170 .
Culture-negative IE cases are particularly challenging to manage. Although sterile blood cultures are most commonly due to patient receipt of antibiotics prior to obtaining blood cultures, they may also arise from inadequate microbiological techniques, infection with fastidious organisms or noninfectious causes of valvular vegetations such as marantic or Libman-Sacks IE. Choosing an antibiotic regimen in these cases requires balancing the need for empiric therapy for all the likely pathogens with the potential adverse effects of using multiple antibiotics. Investigation for ‘true’ culture-negative IE (that is, for uncommon pathogens that do not grow in routine blood cultures) may yield an aetiology in these cases.
The rate of early valve replacement or repair has increased over time 4 in keeping with the prevailing opinion that surgery is a key component of the management of many complicated IE cases. The evidence base for this practice, however, is decidedly mixed. A single randomized trial demonstrated a significant reduction in the composite outcome of in-hospital deaths and embolic events with early surgery 171 . While clearly transformational, study generalizability was nonetheless questioned. Study subjects were younger, healthier and infected with less virulent pathogens (for example, VGS) than contemporary IE patients encountered in general practice 172 . For most patients with IE, recommendations for surgery are based on observational studies and expert opinion.
The principal consensus indications for valve surgery are heart failure, uncontrolled infection and prevention of embolic events in patients at high risk. Uncontrolled infection may be related to paravalvular complications, such as abscess, an enlarging vegetation or dehiscence of a prosthetic valve. In addition, uncontrolled infection may be manifested by ongoing systemic illness with persistent fevers and positive blood cultures despite appropriate antibiotic therapy. As larger left-sided vegetations are more likely to lead to embolic events, IE with a vegetation of 㸐 mm in length is a relative indication for surgical intervention.
The timing of cardiac surgery for patients with IE and neurovascular complications remains controversial. A large prospective cohort study of 857 patients with IE complicated by ischemic stroke without haemorrhagic conversion found that no patient benefit was gained from delaying surgery 173 . By contrast, patients with embolic stroke complicated by haemorrhagic conversion sustained higher mortality when surgery was performed within 4 weeks of the haemorrhagic event compared with later surgery (75% versus 40%, respectively) 174 . On the basis of these observational data, the AHA currently recommends that valve surgery may be considered in patients with IE who also have stroke or subclinical cerebral emboli without delay if intracranial haemorrhage has been excluded by imaging studies and neurological damage is not severe (such as coma). In patients with major ischemic stroke or intracranial haemorrhage, AHA guidelines currently state that delaying valve surgery for at least 4 weeks is reasonable 101 .
Valve surgery was traditionally recommended for difficult-to-treat pathogens such as Pseudomonas aeruginosa, fungal organisms and β-lactam resistant staphylococci. However, these pathogen-specific recommendations for surgery have been recently called into question in favour of an individualized decision-making approach based upon hemodynamic and structural indications 168,175 .
Other adjunctive therapies
Patients with PVIE who are receiving oral anticoagulants may be at an increased risk of death from cerebral haemorrhage 176 . Antiplatelet therapies are not currently recommended for IE. A single randomized trial examined the role of 325 mg of aspirin daily for patients with IE. The incidence of embolic events was similar in between aspirin- and placebo-treated patients, and there was a non-significant increase in the rate of cerebral bleeding episodes 177 . There are several limitations to this study, however, that include dose of aspirin used and delayed initiation of aspirin. For patients with another indication for antiplatelet therapy, it may be reasonable to continue the antiplatelet agent unless bleeding complications develop. Similarly, it is not recommended to initiate anticoagulant therapy such as warfarin for the purpose of treating IE. In patients with IE who have another indication for anticoagulation therapy, such as a mechanical valve, data are contradictory on whether to continue anticoagulation during acute therapy 176,178 and bridging therapy with heparin products has not been studied.
Management of metastatic foci
Metastatic foci of infection frequently complicate IE. As with any infection, recognition of these foci of infection is important so that targeted interventions, such as drainage of abscesses or removal of infected prosthetic material, may be undertaken. This is of critical importance in patients who require valve surgery because a persistent source of infection may serve as a source from which a recently placed prosthetic valve or annuloplasty ring becomes infected 101,102 . Some metastatic foci, such as vertebral osteomyelitis, may require additional antibiotic therapy beyond what is typically indicated for IE 179 . There is currently insufficient evidence to recommend specific imaging strategies to look for metastatic foci in all patients with IE.
Care at completion of therapy
Most patients with IE in the modern era are cured and attention can eventually turn to a follow-up plan. Elements of follow-up may include an echocardiogram at the completion of antimicrobial therapy to establish a new baseline for subsequent comparison, referral to a drug cessation program for patients who are IDUs and a thorough dental evaluation. A comprehensive search for the initial portal of pathogen entry may be undertaken so that this can be addressed to minimize repeat episodes of IE. In a prospective single centre experience, a systematic search revealed the likely source in 74% of 318 patients 180 . Routine blood cultures at completion of antibiotic therapy are not recommended given a very low rate of positivity in patients with no signs of active infection. Patients should also be monitored for complications of IE, including relapse, incident heart failure and complications of antibiotic therapy, such as audiologic toxicity from aminoglycosides or incident Clostridium difficile infection.
The findings of this study suggest that Libman-Sacks endocarditis and associated acute CVD often resolve or significantly improve with conventional anti-inflammatory and antithrombotic therapy. These results argue for a multidisciplinary approach and an initial trial of medical therapy for Libman-Sacks endocarditis with close clinical follow-up and reimaging before considering high-risk valve surgery. However, a larger randomized cross-sectional and longitudinal study of antiplatelet versus anticoagulant therapy combined with standard anti-inflammatory therapy is needed to confirm these findings.
Suggested Further Readings
Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis. Circulation 2005111:3167. Find this resource:
Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 199496:200–9. (Classic Article.) Find this resource:
Hermans PE. The clinical manifestations of infective endocarditis. Mayo Clinic proceedings 198257:15–21. (Classic Article.) Find this resource:
Hoen B, Duval X. Infective endocarditis. N Engl J Med 2013368:1425–33. Find this resource:
Lamas CC, Fournier P-E, Zappa M, et al. Diagnosis of blood culture-negative endocarditis and clinical comparison between blood culture-negative and blood culture-positive cases. Infection 201644:459–66. (p. 304) Find this resource:
Can we diagnose Infective endocarditis without vegetation ?
Vegetation Negative Infective-Endocarditis
S Venkatesan, G Gnanavelu, G Karthikeyan, V Jaganathan, R Alagesan,
M Annamalai, S Shanmugasundaram, S Geetha, A Balaguru, G Anuradha
Madras Medical College, Chennai
The definitive diagnosis of infective endocartitis (IE) remains a contentious clinical issue. Many diagnostic criteria have been advanced. However, none has withstood the test of time. Currently Duke’s criteria is considered as de facto standard. Documentation of vegetation within the cardiac chambers and positivity of blood culture is the sine qua non of IE and evidently they constitute the major criteria. Ironically, according to Duke’s criteria, IE could still be diagnosed in the absence of vegetation, provided it fulfils other major criteria of culture positivity. In this context, we report our analysis of patients with IE without vegetation. Out of 24 patients admitted between 2004-2005 in our hospital with the diagnosis of IE, 4 patients failed to show vegetations. All had rheumatic heart disease (RHD) and presented with prolonged fever. All had severe eccentric mitral regurigitation (MR). One had severe aortic regurgitation (AR) also. One had flail posterior mitral leaflet (PML). All had blood culture positive – 3 for staphylococcus auerus 1 for pseudomonas. None had vegetations on the first echocardiographic examination. Transesophageal echcardiography (TEE) also failed to detect a vegetation or abscess. The diagnosis of IE was made on the basis of Duke’s criteria (1 major and 3 minor features). Treatment was started based on culture positivity and sensitivity. All patients underwent serial echocardiography every week for 6 weeks. New mobile vegetation was detected in 1 patient in anterior mitral leaflet (AML) measuring 12 mm after 2 weeks. Three patients never showed any evidence of vegetation. One patient developed cerebral vasculitis and another renal insufficiency during the course of treatment. Two patients stabilized with medical management. One expired and other had refractory cardiac failure and was referred for emergency surgery. The mechanism of absence of vegetation in IE could be varied. Simple temporal dissociation between appearance of vegetation and the clinical syndrome should be the first possibility. Further, vigorous antimicrobial treatment might have prevented the formation of vegetation. But, as we have seen in few patients, it never appeared. This was possibly due to layered vegetation like that of a thrombus on the surface of the valve or adjacent myocardium. The process of vegetation formation need not be endoluminal, it can burrough into the tissue plane intramurally without projecting into the cavity. Spontaneous rupture of chordae secondary to inflammation without any vegetation is another possibility.
We conclude , even though vegetations are considered sine quo non of IE in many clinical situations, IE occurs without vegetation. The mechanisms could be varied.
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Cardiac infections demonstrate heterogeneity and variability in their clinical presentations due to their diverse causes, overlap of the anatomic regions (endocardium, myocardium, pericardium) predominantly involved, and the broad spectrum of imaging findings. Understanding the mechanisms of infection and immune system evasion or immune dysregulation that may ensue after initial microbial infection is helpful in image interpretation. For the medical imager, as for the clinician, a high index of suspicion based on the patient’s clinical history is key to early accurate diagnosis of cardiac infections.
Echocardiography is usually adequate for initial evaluation and management of cardiac infections. However, in complex endocardial infections and viral or parasitic myocarditis, cardiac CT angiography and cardiac MR imaging have become the imaging modalities of choice due to their advantages in cross-sectional imaging, tissue characterization, functional imaging, and intervention planning (Table 2) (2–6,11–13,19–25). Cardiac MR imaging adds prognostic value in viral and parasitic IM as well as to understanding of disease pathogenesis, such as in Chagas cardiomyopathy (11). Both cardiac CT angiography and cardiac MR imaging are helpful in delineation of critical complications that can change treatment, such as abscess formation, pseudoaneurysm, valve destruction or dysfunction leading to acute heart failure, and the chronic complications of IP (2–6,11–13,19–25).
Table 2: CT and MR Imaging in Cardiac Infections
Given the increase in global travel and migration, familiarity by radiologists with the spectrum of cardiac infections and their imaging manifestations is becoming essential. Previously regionalized diseases may now be encountered with increasing frequency in otherwise nonendemic areas (2,8,11).
Disclosures of Conflicts of Interest.—S.M. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: royalties from Elsevier. Other financial activities: disclosed no relevant relationships.
Recipient of a Certificate of Merit award for an education exhibit at the 2014 RSNA Annual Meeting.
Watch the video: Infective Endocarditis, Animation (September 2022).