Infective Endocarditis
Summary
This protean disease, whose salient features have been known for centuries, continues to pose major diagnostic and therapeutic challenges. Infective endocarditis predominantly affects cardiac valves and leads to local destruction with subsequent regurgitation. Embolism, especially to the brain, is the most feared extracardiac complication. Diagnosis rests on positive blood cultures and demonstration of vegetations by echocardiography. The rise of aggressive pathogens and the frequency of unfavourable clinical circumstances, such as presence of prosthetic valves or compromised immunocompetence, have resulted in more frequent and earlier surgical therapy. Although endocarditis is no longer uniformly fatal, outcomes are still characterized by high morbidity and mortality. The upcoming European Society of Cardiology recommendations for endocarditis prophylaxis hopefully will further improve disease prevention and management of patients at increased risk.
Definition
Infection of valvular tissue or cardiovascular endothelium by a variety of pathogens constitutes infective endocarditis. Although endocarditis mostly involves the cardiac valves, it may also manifest as endarteritis (e.g. in aortic coarctation) or develop on foreign bodies such as intravenous lines, pacemaker leads, conduits, etc. Former classifications of endocarditis as subacute, acute, or chronic have been discarded. A newer classification based on European Society of Cardiology (ESC) task force recommendations [1] is provided in Table 22.1.
Table 22.1 ESC recommendations on classification and terminology of infective endocarditis [1]
Infective endocarditis may be classified by: |
|---|
Activity |
Active/healed |
Recurrence |
Recurrent, if a relapse occurs within a year of eradication/operation; persistent, if no eradication has occurred |
Confidence of diagnosis |
Definite, if vegetations are demonstrated in the presence of systemic infection (with or without positive blood cultures) |
Suspected, if clinically strongly suggested |
Possible if clinical suspicion is less strong (e.g. differential diagnosis of fever) |
Special circumstances |
Prosthetic endocarditis (early if within 1 year of valve replacement, otherwise late), pacemaker endocarditis, and endocarditis in a patient with intravenous drug abuse |
According to the site of involvement |
Aortic, mitral, tricuspid, pulmonary, right heart, left heart |
According to the causative agent |
E.g. staphylococcal endocarditis |
Epidemiology
The incidence of infective endocarditis in the general population is estimated at 14–31 per million persons and year [2–5]. Subgroups such as immunocompromised persons and addicts of intravenous drugs have a much higher incidence of endocarditis. The incidence increases with age and is higher in men than in women.
Pathology and pathophysiology
The initial necessary condition for the development of infective endocarditis is endocardial or endothelial damage. Such damage may be induced by regurgitant, stenotic, or shunt lesions creating high-velocity blood jets, (micro-)trauma, surgery, foreign bodies, etc. Adherence of platelets to the injured endothelium leads to a small local, initially sterile fibrin-platelet aggregate, the so-called non-bacterial thrombotic endocarditis, which then becomes infected by pathogens circulating in the blood. Conversely, intact endothelium is very resistant to bacterial colonization. Bacteraemia most often originates from the skin and oropharynx. The ability of microorganisms to adhere to the initial thrombus, to colonize it, and to grow, differs widely and depends, among other factors, on their ability to bind to fibronectin, a surface glycoprotein found on many cells, including endothelial cells. If the initial microthrombus is colonized and to the degree in which cellular and humoral host defences are overcome, rapid growth ensues and within days a macroscopically detectable vegetation is formed, which contains staggering amounts of bacteria (in the order of 1010/g), thrombus, and leucocytes, together with tissue debris. The vegetation is the hallmark of infective endocarditis ( Fig. 22.1). It may grow from nearly invisible to several centimetres in length and is most often (though not exclusively) attached on the low-pressure side of the underlying structure, i.e. the atrial side of atrioventricular valves and the low-pressure side of shunt lesions, due to the endothelial damage secondary to high-velocity jets at these sites.
Vegetations may lead to valve incompetence, or, rarely, obstruction. Bacterial invasion may also lead to direct damage of valve structures, such as leaflet defects or tears, chordal rupture, to the development of fistulae between heart cavities, or to perivalvular abscess formation. A rare form of an endocarditic abscess is the so-called pseudoaneurysm of the mitral aortic intervalvular fibrosa [6], which is a ring abscess located in the section of the aortic and mitral valve circumference which are contiguous. These outpouchings may communicate with the left ventricle or left ventricular outflow tract and, after rupture, create a fistula to the left atrium. Tissue invasion may lead to conduction abnormalities such as complete atrioventricular block, and to pericardial effusion.
Prosthetic valves are high-risk lesions for endocarditis. In mechanical valves usually the sewing ring is affected, with a high incidence of periprosthetic leaks and abscesses. In bioprostheses, both the ring and the leaflets themselves can be affected. Intravenous lines and pacemaker leads may develop adherent vegetations and infection may spread to contiguous tissue.
Vegetations are prone to embolization, in particular if they are large and mobile. Clinically, embolism is found in one-third to one-half of cases, but the true incidence is much higher due to often silent embolism. Left heart endocarditis embolizes predominantly to the brain, the spleen, and the kidneys, as well as the limbs. Metastatic abscesses may ensue. Right heart endocarditis embolizes to the lung with consecutive lung abscess or pneumonia. Aortic vegetations prolapsing into the left ventricle may create secondary infection of the anterior mitral leaflet by direct contact during diastole (‘kissing lesions’).
Renal involvement in infective endocarditis includes septic renal embolism, immune-complex mediated glomerulonephritis, and interstitial nephritis due to antimicrobial therapy. Renal involvement in infective endocarditis is associated with impaired prognosis [7].
Infective endocarditis leads to a constant, often low-grade bacteraemia. Frank sepsis often ensues, especially with aggressive organisms such as staphylococci. Infective endocarditis is believed to be uniformly fatal if not treated.
Infective endocarditis may also arise in extracardiac locations, mostly the cerebral and thoracic large arteries, and create so-called mycotic aneurysms, which may rupture.
Risk factors
Congenital and acquired valvular heart diseases are strong risk factors for infective endocarditis. It is estimated that approximately one-half of patients with endocarditis have some form of underlying heart disease, most often bicuspid aortic valve, mitral valve prolapse, other degenerative valvular disease, ventricular septal defect, hypertrophic obstructive cardiomyopathy, aortic coarctation, and others. Prosthetic heart valves, both of the mechanical and biological type, are prone to infection, as are other foreign bodies such as central venous lines, pacemaker and ICD leads, intravenous ports, ventriculo-atrial shunts, Dacron patches or conduits (see Table 22.2). Of note, while ventricular septal defects carry a high risk of endocarditis, atrial septal defect of secundum type or patent foramen ovale do not entail an elevated risk. Furthermore, immunosuppression, dialysis, intravenous drug abuse, HIV infection, and long-term intensive care treatment all increase the risk of acquiring infective endocarditis, in particular in the presence of a pre-existent cardiovascular lesion. Whereas previously all patients with risk lesions were considered candidates for endocarditis prophylaxis whenever they underwent procedures inducive of bacteraemia (such as oropharyngeal procedures or surgery, dental procedures, lower digestive tract procedures (in particular with biopsy), and others) ( Tables 22.2 and 22.3), the recent corresponding guidelines by the American Heart Association have completely revised this standpoint, as outlined in ‘Prophylaxis and prevention’, p.831 [8].
Table 22.2 Lesions conferring elevated risk of acquiring infective endocarditis*
Acquired or congenital valvular heart disease, including bicuspid aortic valve and mitral valve prolapse |
Presence of a valvular prosthesis or surgically created conduit |
Previous endocarditis |
Immunosuppression (e.g. after organ transplantation) |
Hypertrophic obstructive cardiomyopathy |
Ventricular septal defect |
Complex, especially cyanotic, congenital heart disease |
Shunt lesions (congenital or surgically constructed) except atrial septal defects of secundum type |
Aortic coarctation |
* However, note that endocarditis prophylaxis is regarded mandatory by recent guidelines in only some of these lesions (see text).
Data from Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. Circulation 1997; 96: 358–66.
Table 22.3 Interventions and procedures potentially associated with bacteraemia
Dental procedures that cause oral bleeding (e.g. dental extraction, removal of tartar) |
Oropharyngeal surgery including tonsillectomy |
Oesophageal dilatation, sclerotherapy of oesophageal varices, and endoscopic retrograde cholangiography with biliary obstruction |
Gall bladder surgery, appendectomy, colectomy |
Genitourinary procedures including catheterization and cystoscopy in the presence of urinary tract infection, transurethral prostate resection |
Abscess surgery |
* However, note that endocarditis prophylaxis is regarded mandatory by recent guidelines in only some of these lesions (see text).
Data from Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. Circulation 1997; 96: 358–66.
Causative pathogens
Almost all known pathogenic bacteria have been implied in cases of infective endocarditis. In practice, however, a limited variety of organisms are significant. Only the most frequent pathogens will therefore be discussed. Remarkably, infective endocarditis is most often a disease produced by Gram-positive bacteria, especially cocci.
Streptococcal disease
These bacteria are still the most frequent cause of infective endocarditis and typically produce the classic protracted or ‘subacute’ course of endocarditis. The origin of streptococci is most often the oropharynx. They are mostly, but not always susceptible to penicillin G. Streptococcus gallolyticus (formerly Streptococcus bovis) endocarditis has been found to be frequently associated with adenoma and adenocarcinoma of the colon, making colonoscopy advisable if Streptococcus gallolyticus bacteraemia is documented [9, 10].
Staphylococci
Staphylococcal endocarditis has increased substantially in frequency and staphylococci are now the second most common, and in some series the most common, aetiologic agents in native valve endocarditis. Staphylococcus aureus, an extremely aggressive and destructive organism, causes 90% of all cases of staphylococcal endocarditis. Staphylococcus epidermidis is the most frequent cause of early prosthetic valve endocarditis. Staphylococci often produce beta-lactamase and are therefore resistant to many, if not all beta-lactam antibiotics, i.e. penicillins and cephalosporins. Vancomycin and teicoplanin remain effective. The origin of staphylococci is most frequently the skin. Hospital-acquired staphylococcal infections via catheters and intravenous lines are also frequent.
Q fever endocarditis
Q fever, a zoonosis caused by the intracellular rickettsia Coxiella burnetii, is endemic worldwide but particularly frequent in France. Its natural sources are cattle, sheep, goats, and others. An estimated 10% of cases affect the heart. Coxiella burnetii does not grow on culture media. Diagnosis is by serology or polymerase chain reaction (PCR). Doxycycline in combination with rifampicin is the recommended antibiotic therapy.
Enterococci
Enterococcus faecalis is the most frequent pathogen of this group, typically originating in the gastrointestinal tract. Antibiotic resistance in these organisms is variable, although they are usually susceptible to the combination of a beta-lactam antibiotic and an aminoglycoside as gentamicin.
Symptoms and signs
Clinical signs
Fever, chills, malaise, night sweats, arthralgias, and weight loss are unspecific systemic symptoms of infectious endocarditis, in particular the more protracted forms formerly designated as ‘subacute’. It should be noted that in the elderly these symptoms, including temperature elevation, may be mitigated or absent. In immunosuppressed patients, clinical signs of generalized infection may also be inapparent. Haemofiltration may suppress temperature elevation. However, endocarditis without at least a minor degree of temperature elevation is very rare. A warm dry skin, tachycardia, and spleen enlargement (in particular in protracted endocarditis) are additional physical signs of systemic inflammation.
The classical specific physical signs of endocarditis are largely signs of destructive (valvular regurgitation murmurs and heart failure) or embolic (although in part immunologically mediated) complications of endocarditis and thus signal advanced disease.
Cardiac signs include:
♦ In mitral endocarditis: a new or greatly increased typical holosystolic murmur of mitral regurgitation, best heard over the apex and radiating to the left axilla, associated with dyspnoea, pulmonary congestion, or oedema, and other signs of left heart backward failure;
♦ In aortic endocarditis: a new typical diastolic murmur of aortic regurgitation, best heard over the left sternal border, low diastolic blood pressure, associated with dyspnoea, pulmonary congestion, or oedema, and other signs of left heart backward failure;
♦ In tricuspid endocarditis: a new typical soft parasternal systolic murmur of tricuspid regurgitation increasing with inspiration, together with jugular vein distention, a prominent systolic jugular vein pulse, and liver enlargement.
Systemic embolism from left heart (or arterial) endocarditis is often the first clinical sign of endocarditis, and may manifest as
♦ Neurologic impairment, ranging from transient symptoms to fatal massive stroke. Intracranial haemorrhage in infective endocarditis occurs in 5% of patients, may be due to secondary bleeding into an infarcted zone or to rupture of a mycotic aneurysm of a cerebral artery ( Fig. 22.2). Meningitis may develop due to a septic cerebral abscess. Neurologic complications in infective endocarditis are ominous and predict dramatically increased mortality.
♦ Limb, abdominal (kidney, spleen), or even coronary ischaemia (rare).
All of these sites may develop septic abscesses. Right heart endocarditis in the majority of cases leads to—sometimes clinically silent—septic pulmonary embolism and may present with signs of pneumonia and pleuritis. For typical cutaneous signs of endocarditis see Table 22.4 and Fig. 22.3. Fundoscopy may reveal retinal haemorrhage with a pale centre (Roth spots; see Fig. 22.4). It cannot be overemphasized that, in spite of the wealth of time-honoured clinical signs and symptoms of infective endocarditis, this is a notoriously difficult disease to diagnose. This holds particularly true for the early stages, before destructive or embolic events have occurred. It may also explain why in a large multicentre registry [11], average time from onset of symptoms to hospital admission was 29 days!
Table 22.4 Cutaneous signs of infective endocarditis (mediated by microembolism, haemorrhage, or immunologic responses) (see Fig. 22.3)
Petechiae (extremities, conjunctivae, buccal mucosa); |
Splinter haemorrhages (subungual) |
Osler nodes (small, tender, purple, subcutaneous nodules on the palmar side of the digits) |
Janeway lesions (erythematous non-tender macular lesions on palms and soles) |
Laboratory signs
There is no specific laboratory marker of infective endocarditis. Laboratory abnormalities include leucocytosis with granulocytosis with a left shift (or even leucopoenia, especially in overt sepsis), elevated sedimentation rate, elevated C-reactive protein and gamma globulin levels. Anaemia of infection with low serum iron levels is a cardinal sign of endocarditis. Circulating immune complexes and occasionally a positive rheumatoid factor are detectable. Importantly, urinalysis is very frequently pathologic even without manifest septic embolism to the kidney. Haematuria (often only microscopic) and proteinuria, and particularly red blood cell casts are present. However, the most important laboratory test is unquestionably the blood culture.
Infective endocarditis usually leads to a continuous bacteraemia, such that (in the absence of pre-treatment with antibiotics) blood cultures are very sensitive to detect the disease and may be drawn at any time independent from the time course of fever. It has been reported that one of the first two separate blood cultures was positive in 98% of patients with infective bacterial endocarditis in patients not receiving antibiotics [12]. For proper technique, see Table 22.5. However, if the patient is already treated with antibiotics the diagnostic yield decreases drastically. Furthermore, some pathogens are fastidious or don’t grow at all on usual culture media, necessitating a close cooperation with the microbiologist in such cases. Table 22.6 provides a list of difficult-to-identify pathogens and techniques to identify them.
Table 22.5 Properly obtaining blood cultures in suspected endocarditis
Three separate sets from three different venepunctures over 24 hours, at least 1 hour apart |
If possible before antibiotic therapy or after cessation of antibiotic therapy (3–7 days, depending on previous therapy duration) |
Each set contains one aerobic and one anaerobic flask, to each of which 5–(preferably)10mL blood are added |
Rapid processing or storage at appropriate temperature (check with laboratory); notify laboratory of the clinical suspicion of infective endocarditis |
Table 22.6 Culture-negative endocarditis: difficult-to-identify pathogens and tests to detect them
Coxiella burnetii (Q fever): serology or PCR |
Bartonella spp.: acridine orange staining of blood cultures, extended subculturing, serology, PCR |
Brucella spp.: serology, PCR |
Legionella spp.: serology, PCR |
Fungi other than Candida spp.: lysis-centrifugation and culturing on special fungal media |
‘HACEK’ pathogens (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella spp.): prolonged culturing |
PCR, polymerase chain reaction.
Pathogens can, and should, also be cultured or identified by PCR from excised material, e.g. valves or emboli, especially if blood cultures remain negative, to guide appropriate antibiotic therapy, in particular after surgery. This technique may also identify specific pathogenic strains and thus elucidate their source [13–15].
Diagnosis
The definitive diagnosis of endocarditis rests on two pillars: the positive blood culture and evidence of vegetations, usually by echocardiography. Table 22.7 lays out the accepted criteria for the diagnosis of infective endocarditis, the so-called Duke criteria [16]. These criteria are helpful for epidemiology and standardization of diagnosis but may not be sufficient to make management decisions or to confirm or reject the diagnosis in unclear cases. Echocardiography is the imaging technique of choice and its findings are pivotal for patient management. Transoesophageal echocardiography has a well-documented superior sensitivity to transthoracic echo to diagnose endocarditic vegetations, destructive complications, and abscesses [17–21]. Whenever there is a strong clinical suspicion of endocarditis and the transthoracic echo is inconclusive or negative, transoesophageal echocardiography should be performed. Conversely, a negative transoesophageal echo argues strongly against infective endocarditis. However, if the clinical suspicion is substantial (e.g. positive blood cultures of a typical pathogen), transoesophageal echocardiography should be repeated after a few days, in particular in the presence of underlying heart disease, e.g. a prosthetic heart valve. It has been shown that repeat negative transoesophageal echocardiography carries a very high negative predictive value for infective endocarditis and may be the clinical ‘gold standard’ for excluding infective endocarditis [22]. Because of the increasing frequency of 1) antibiotic pre-treatment, leading to false negative blood cultures, and 2) prosthetic valve endocarditis, with its attendant difficulty of visualization of vegetations, it has been proposed to modify the Duke criteria to include patients with clear vegetations on echo and systemic inflammatory signs, but negative blood cultures, if they have had antibiotic pre-treatment, and to require a repeat negative transoesophageal echo study to exclude endocarditis in patients with prosthetic valves. Furthermore, Q fever endocarditis should be routinely ruled out serologically, since blood cultures remain negative in this disease [23].
Table 22.7 The ‘Duke criteria’ [16] for the diagnosis of infective endocarditis
‘Definite’ diagnosis—established by: |
|---|
Pathology (histologic evidence of active endocarditis in an endocarditic lesion or identification of microorganisms in a vegetation or abscess), or |
Clinically: |
two major |
or |
one major + three minor |
or |
five minor criteria |
Major criteria: |
Positive blood culture (>one) of typical pathogens |
Vegetation, abscess, or prosthesis dehiscence on echo |
New valvular regurgitation |
Minor criteria: |
Predisposition (predisposing heart disease or intravenous drug use), fever ≥38°C, embolic events, immunologic/embolic signs (conjunctival haemorrhages, Janeway lesions*, Osler nodes*, Roth spots, glomerulonephritis, rheumatoid factor), serology consistent with endocarditis, positive blood culture which is not typical for infective endocarditis |
Possible diagnosis |
|---|
Neither definite nor rejected |
Rejected diagnosis |
|---|
Firm alternative diagnosis for symptoms suggestive of endocarditis, resolution of symptoms after <4 days of antibiotic treatment, no pathologic evidence of endocarditis during surgery or autopsy. |
Echocardiographic signs of infective endocarditis
Conceptually, these can be divided into additional structures due to the disease (vegetation, abscess, pseudoaneurysm) and defects (regurgitant lesions, perforations, fistulae). The hallmark of endocarditis on echo is the identification of a vegetation, appearing as a mobile, irregular mass with jagged edges attached to a valvular structure ( Figs. 22.5–22.8; 22.1 and 22.2). Size may vary from few millimetres to several centimetres. Vegetations typically arise from the low-pressure side of a valve leaflet (e.g. the atrial side of the mitral valve) and are highly mobile. They may prolapse through the valve with the blood flow. Their echodensity is relatively low (similar to myocardium) in the early stages and increases over time. Highly echogenic, ‘fibrous’ or ‘calcified’ vegetations usually indicate that the vegetation is old, with lower embolic risk. If vegetations are large, in rare cases obstruction may occur.
Typically, endocarditis causes valvular regurgitation by several mechanisms: defects in the valvular tissue, rupture of chordae, and interposition of vegetations between the leaflet tips. Valvular regurgitation due to endocarditis is very frequent and often severe and dramatic (W 22.3). All typical echocardiographic signs of acute severe mitral or aortic regurgitation may be present. Endocarditis may progress to invasion of the tissue with central necrotization, i.e. abscess formation. This is typical of aortic and prosthetic endocarditis and aggressive pathogens such as staphylococci. On echocardiography, abscesses are perivalvular zones of abnormal tissue thickening, sometimes with central echolucency and possible flow in and out of an abscess cavity ( Figs. 22.9 and 22.10; 22.6, 22.7, 22.8). They are recognized better and much more frequently by transoesophageal echocardiography [19]; recognition is important because formation of an abscess not rarely predicts failure of conservative antibiotic treatment. A special form of abscess is the mitral valve pseudoaneurysm ( Fig. 22.11), a localized outpouching of a mitral leaflet or the intervalvular fibrous tissue between aortic and mitral valve, often with a perforation and regurgitation [6].
Other imaging modalities, such as magnetic resonance imaging, multidetector computed tomography (CT), or
Problems in the diagnosis of infective endocarditis
The widespread use of antibiotics in the presence of signs of systemic inflammation, e.g. fever, often without a clear diagnosis of the type of infection, greatly impairs the sensitivity of blood cultures. In one large registry [11], at least 23% of patients were treated with antibiotics before blood cultures were obtained, and without recognizing endocarditis as the underlying disease. Thus, one is often left with a clinical picture compatible with infective endocarditis, but negative blood cultures. This situation would not qualify as ‘definite endocarditis’ applying the Duke criteria strictly, and a corresponding modification of the Duke criteria has been advocated, as outlined earlier [23]. There is now consensus that if in the presence of systemic inflammatory signs clear-cut echocardiographic evidence of fresh vegetations or abscess can be obtained, these patients should be managed as having acute infective endocarditis. However, the situation remains problematic if morphologic evidence is less clear, e.g. in the presence of degenerative valvular changes, in prosthetic valves, or pacemaker leads without unequivocal vegetations, or if old endocarditic changes are present. In these cases, often the course of the disease and changes in valve appearance over time have to be awaited in order to make a clear diagnostic decision.
Prosthetic valve endocarditis
Infective endocarditis in a patient with a prosthetic valve is conceptually classified into early endocarditis, which is perceived as nosocomial disease originating in the surgical valve replacement, occurring up to 1 year after surgery, and late (usually community-acquired) prosthetic valve endocarditis. The risk is highest in the first weeks and months after surgery, and mortality in early prosthetic endocarditis has been reported to be extremely high. While the absolute number of patients with prosthetic valves is increasing, the relative incidence of prosthetic endocarditis has declined in recent years and is now well under 0.5% per year for late prosthetic endocarditis [24]. Early prosthetic endocarditis is characterized by preponderance of Staphylococcus epidermidis as a causative agent, while the pathogens of late endocarditis are similar to native valve endocarditis. Prosthetic endocarditis tends to be more severe than native valve endocarditis, is difficult to diagnose due to echocardiographic imaging problems with prostheses (W 22.4 and 22.5), and almost always necessitates repeat surgery [25, 26]. In staphylococcal prosthetic valve endocarditis, mortality has been reported to be 75% (!) with medical treatment and still 25% with surgical treatment [27]. In mechanical prostheses, the disease is almost exclusively located along the sewing ring of the prosthesis, creating paravalvular leaks, fistulae, and abscesses, while in bioprostheses both the ring and the leaflets may be colonized by bacteria. Transoesophageal examination is extremely useful and should always be performed.
Infective endocarditis in addicts of intravenous drugs
Several features set this type of infective endocarditis apart from the general picture. Infections are often mixed, involving Staphylococcus aureus in >50%, and predominantly affect the tricuspid valve (because of the venous entry site of the infection). The majority of patients are HIV infected or otherwise immunocompromised, but mostly have no underlying heart disease. The prognosis of tricuspid endocarditis of intravenous drug addicts is relatively good under conservative treatment, but recurrence is common due to patients’ lifestyles.
Therapy
Antibiotic treatment is mandatory and should be instituted immediately by intravenous route after a sufficient number of blood cultures have been taken (see Table 22.5) and the diagnosis is clear or probable. Susceptibility testing should always be obtained if a pathogen is identified. Vancomycin and aminoglycoside therapy may be optimized by drug serum level determinations. Table 22.8 lists typical antibiotic regimens for different clinical situations and causative agents. Duration of therapy is somewhat arbitrary and should be guided by the course of the disease, but 4 weeks of intravenous therapy are a usually considered the minimum. Response to treatment is best monitored by clinical status, in particular course of fever, and by C-reactive protein. C-reactive protein and leucocyte count should fall rapidly and may remain slightly, but not markedly, elevated if the patient responds to therapy [1]. Echo follow-up examinations are important for later comparisons and detection of complications.
Table 22.8 Antibiotic therapy of infective endocarditis
I Native valve endocarditis due to penicillin-sensitive streptococci |
|---|
Penicillin G IV 3–6 million units every 6 hours for 4 weeks |
+ gentamicin IV 1mg/kg every 8 hours over 2 weeks |
II Empirical therapy of culture-negative native valve endocarditis |
|---|
Vancomycin IV 15mg/kg every 12 hours over 4–6 weeks |
+ gentamicin IV 1mg/kg every 8 hours over 2 weeks; some recommendations add IV ampicillin or amoxycillin to this regimen |
Empirical therapy of culture-negative prosthetic valve endocarditis: |
As in I + rifampicin PO 300–450mg every 8 hours over 4–6 weeks |
III Staphylococcal native valve endocarditis |
|---|
If methicillin-susceptible: |
Oxacillin IV 2–3g every 6 hours over 4 weeks |
+ gentamicin IV 1mg/kg every 8 hours over 3–5 days |
If methicillin-resistant: |
Vancomycin IV 15mg/kg every 12 hours over 6 weeks |
IV Staphylococcal prosthetic valve endocarditis |
|---|
If methicillin-susceptible: |
Oxacillin IV 2–3g every 6 hours over 6 weeks |
+ gentamicin IV 1mg/kg every 8 hours over 2 weeks |
+ rifampicin IV 300mg every 8 hours, over 6 weeks |
If methicillin-resistant: |
Vancomycin IV 15mg/kg every 12 hours over 6 weeks |
+ gentamicin IV 1mg/kg every 8 hours over 6 weeks |
+ rifampicin IV 300mg every 8 hours over 6 weeks |
IV, intravenous
Note that in prosthetic valve endocarditis, surgery is recommended. Vancomycin may be replaced by teicoplanin.
Modified with permission from the ESC recommendations where further regimens for special clinical situations may be looked up: Horstkotte D, Follath F, Gutschik E, et al. Guidelines on prevention, diagnosis and treatment of infective endocarditis executive summary; the task force on infective endocarditis of the European society of cardiology. Eur Heart J 2004; 25: 267–76.
Indications, timing, and type of surgery
Traditionally, infective endocarditis has been seen as a disease amenable to antibiotic therapy, which in case of complications necessitated surgery. The typical complications were heart failure due to severe acute regurgitation or sepsis, and systemic embolism. This view was supported by the frequency of streptococcal endocarditis of native valves with its relatively protracted, subacute course; indeed, this led to the term ‘endocarditis lenta’, or slow endocarditis. This type of endocarditis responds relatively well to penicillin therapy. Unfortunately, today the physician often confronts more aggressive infections, in particular staphylococcal endocarditis, and often the disease arises in immunocompromised patients or patients with implanted devices, such as prosthetic valves, pacemaker electrodes, central venous lines, port access lines, etc. Moreover, the focus of attention has shifted to prevent, rather than treat, catastrophic complications such as embolism and valvular destruction. Thus, in referral centres nowadays surgery is used earlier and much more frequently than previously [28–32]. Table 22.9 lists accepted indications for surgery in infective endocarditis. Although the decision must always be individualized, indications for surgery include heart failure from valvular dysfunction, a high risk of embolism (large mobile vegetations), presence of an abscess, and treatment-resistant sepsis. Prosthetic valve endocarditis is usually an indication for surgery, especially in the presence of prosthetic malfunction and in the first year after valve replacement, but sometimes late bioprosthetic endocarditis can be managed conservatively. The most difficult problem in the decision to proceed to surgery revolves around preventing embolism or recurrence of embolism. While it is generally accepted that large (usually defined as >10mm) mobile vegetations pose a grave embolic threat and should therefore be removed surgically as soon as possible [33–36], there are conflicting data on how to treat smaller vegetations. Particularly difficult clinical decisions have to be made after a cerebral embolic event. Several retrospective analyses have suggested that immediate operation on cardiopulmonary bypass with its profound anticoagulation entails a substantial risk of haemorrhagic transformation of an embolic insult and subsequent aggravation of neurological damage [37]. Traditionally, therefore, an interval of 2–3 weeks after a cerebral embolism has been recommended before surgery. However, recently there has been some support for early operation (within 72 hours) after an embolic insult if no haemorrhage is detectable on cerebral CT [1, 38]. Because of the critical importance of cerebral embolism in the decision for surgery, it is advisable to obtain a preoperative cerebral CT in all patients undergoing surgery for endocarditis. If concomitant coronary artery disease is suspected, coronary angiography may be performed, but should not delay surgery for endocarditis; in the presence of mobile aortic vegetations, coronary angiography should be withheld. Non-invasive coronary angiography by multidetector CT has become an acceptable alternative in these patients. Surgically, it is usually necessary to replace the valve if disease is extensive or destruction has occurred. Operation may become even more extensive if surrounding tissue is affected, e.g. in the case of aortic abscess. In some cases, valve repair or vegectomy (removal of vegetations leaving the valve intact) suffices [38, 40, 41]. Valve replacement may be done with any kind of prosthetic valves, although some authors have found homografts to be particularly successful [42].
Table 22.9 Indications for surgery in infective endocarditis
Congestive heart failure due to valvular regurgitation |
Untreatable sepsis, ineffective antibiotic therapy (e.g. in fungi) |
Large (>10mm maximal diameter) mobile vegetation or recurrent embolism |
Endocarditic abscess or other evidence of local tissue invasion, e.g. fistula |
Involvement of a valve prosthesis (especially within 12 months after valve replacement or in the presence of prosthetic malfunction), or other foreign body |
Anticoagulation
It has been hypothesized that anticoagulatory or anti-aggregatory drugs might be beneficial in reducing the growth of vegetations [43]. However, there is no clinical evidence for such measures, and anticoagulation may even be hazardous in view of the potential for haemorrhagic complications after cerebral embolization. Thus, anticoagulation or aspirin in the setting of infective endocarditis is not recommended, unless there is a compelling independent reason for anticoagulation (e.g. a mechanical prosthetic valve) [44].
Prognosis
In spite of antibiotic and surgical therapy, infective endocarditis is not a easily treatable disease. Mortality in large series ranges between 15–20% [5, 11]. Mortality is highest in staphylococcal and fungal endocarditis, and in (especially early) prosthetic endocarditis. The disease also entails a tremendous morbidity from neurologic events and from valvular damage. It is estimated that approximately 30–50% of patients with endocarditis undergo early heart surgery [5, 11], and many sustain a permanent neurologic damage.
Prophylaxis and prevention
The concept of antibiotic prophylaxis is to abolish or mitigate bacteraemia arising predictably from certain procedures in patients who are considered at risk for infective endocarditis by administering one or two properly timed doses of antibiotics. In 2007, the American Heart Association (AHA) has issued new recommendations that were innovative, clear, simple, and associated with a major departure from previous guidelines used for many years [8]. Initial steps into a similar direction had been suggested by the French recommendations in 2002 [45, 46] and by the British Society for Antimicrobial Chemotherapy recommendations in 2006 [47]. The AHA recommendations may be summarized in the following three points:
♦ Endocarditis prophylaxis is only recommended in high-risk patients. Importantly, high-risk patients here are defined not primarily on the basis of an increased risk to develop endocarditis, but rather on the risk of a particularly severe morbid outcome in case they really develop endocarditis. This group includes patients with 1) prosthetic cardiac valve; 2) previous infective endocarditis; 3) complex congenital heart disease; and 4) valuvulopathy following cardiac transplantation (details given in Table 22.10).
♦ Endocarditis prophylaxis prior to dental procedures is only recommended if they involve manipulations in gingival tissue or the periapical region of the teeth or perforation of the oral mucosa. Nevertheless, oral hygiene is considered of critical importance to reduce the risk of endocarditis. Prophylaxis is reasonable for patients who undergo an invasive procedure of the respiratory tract that involves incision or biopsy, such as tonsillectomy or adenoidectomy.
♦ Endocarditis prophylaxis is no longer recommended prior to gastrointestinal or genitourinary procedures.
Table 22.10 Cardiac conditions associated with the highest risk of adverse outcomes from endocarditis for which prophylaxis with dental procedures is reasonable
Prosthetic cardiac valve or prosthetic material used for cardiac valve repair |
Previous infective endocarditis |
Congenital heart disease (CHD) |
Unrepaired cyanotic CHD, including palliative shunts and conduits |
Complex repaired congenital heart defect with prosthetic material or device, either placed by surgery or by catheter intervention, during the first 6 months after the procedure* |
Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization) |
Cardiac transplant recipients who develop cardiac valvulopathy |
* Endothelialization of prosthetic material occurs within 6 months after the procedure.
Modified from Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116: 1736–54. Source: American Heart Association.
Primary reasons leading the committee to revise earlier recommendations [48] and issue the 2007 version of the AHA guidelines for infective endocarditis prophylaxis were [8]:
♦ Infective endocarditis is much more likely to result from frequent exposure to bacteraemias associated with daily activities (e.g. tooth brushing) than from bacteraemia caused by a single dental, gastrointestinal, or genitourinary tract procedure.
♦ Prophylaxis may prevent only an exceedingly small number of cases of infective endocarditis, if any, in individuals who undergo a dental, gastrointestinal, or genitourinary tract procedure.
♦ The risk of antibiotic-associated adverse events exceeds the benefit, if any, from prophylactic antibiotic therapy.
♦ Maintenance of optimal oral health and hygiene may reduce the incidence of bacteraemia from daily activities and is more important than prophylactic antibiotics for a dental procedure to reduce the risk of endocarditis.
Furthermore, over the years AHA guidelines (as well as those of other nations) on endocarditis prophylaxis had become overly complicated, hampering their application by physicians and patients. And finally, previous guidelines and recommendations were based primarily on expert opinion and a few case–control and descriptive studies. There has not been a single controlled, randomized study that evaluated the concept of preventing infective endocarditis by antimicrobial prophylaxis administered prior to dental, gastrointestinal, or genitourinary tract procedures. Based on currently used evidence criteria for guidelines and recommendations, previous endocarditis prophylaxis recommendations would belong to Class IIb (i.e. usefulness/efficacy is less well-established by evidence/opinion) with a Level of Evidence C (only consensus opinion of experts, case studies, or standard of care) [8].
Current recommendations of the AHA for chemoprophylaxis of infective endocarditis in adults are listed in Table 22.11.
Table 22.11 Regimens for prophylaxis against endocarditis recommended by the AHA for adults
Situation | Agent | Single dose for adults 30–60min before procedure |
|---|---|---|
Standard oral | Amoxicillin | 2g |
Unable to take oral medication | Amoxicillin or cefazolin or ceftriaxone | 2g IM or IV 1g IM or IV |
Allergic to penicillins or ampicillin—oral | or clindamycin or azithromycin or clarithromycin | 2g 600mg 500mg |
Allergic to penicillins or ampicillin, and unable to take oral medication | Cefazolin or ceftriaxone† or clindamycin | 1g IM or IV 600mg IM or IV |
IM, intramuscular; IV, intravenous.
* Or other first- or second-generation oral cephalosporin in equivalent adult dosage.
† Cephalosporins should not be used in an individual with a history of anaphylaxis, angio-oedema, or urticaria with penicillins or ampicillin
Modified from Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116: 1736–54. Source: American Heart Association.
The AHA guidelines for prevention of infective endocarditis have caused considerable concern among physicians and dentists. There is uncertainty if patients might be exposed to a larger risk of acquiring endocarditis by discarding previously accepted rules for endocarditis prophylaxis that also included patients at intermediate risk (e.g. patients with mitral valve proplapse and mitral insufficiency, with aortic regurgitation, etc.) and various non-dental procedures (e.g. genitourinary and gastrointestinal interventions). The ESC guidelines for prevention of infective endocarditis are currently under revision and will be published in 2009.
Personal perspective
Despite the substantial advances made in the past in diagnosis (e.g. transoesophageal echocardiography, PCR) and treatment (early surgery, new and better antibiotics) of infective endocarditis, its toll remains depressingly high. The wide spectrum of clinical symptoms, from fever of unexplained origin to stroke and to congestive heart failure implies that very often the physician first confronting the patient is not a cardiologist, and therefore the entire medical community must be better prepared to recognize the disease. To keep infective endocarditis in mind as a differential diagnosis in cases with unexplained fever or infection is the most important step in the diagnostic work-up of the disease. Furthermore, much would be gained if antibiotic therapy in unclear cases of serious infection was not instituted before blood cultures are drawn.
While improvements in diagnostic imaging and in therapy are likely to be rather incremental in the near future (e.g. three-dimensional ultrasound or even intracardiac imaging for better assessment of prostheses), the ability to rapidly detect and identify pathogens may improve dramatically by the use of molecular methods (e.g. PCR). In addition, recommendations for endocarditis prophylaxis are currently undergoing major changes, and it can be speculated that recent and upcoming guidelines will further simplify and improve the preventive management of patients who run a particularly high morbidity and mortality risk if they develop endocarditis after exposure to bacteraemia-associated interventions.
Finally, infective endocarditis will continue to be a field where a multidisciplinary approach with intensive, repeated, and close interaction between cardiologists, cardiac surgeons, and microbiologists is of the utmost importance for the patient’s sake.
Further reading
Horstkotte D, Follath F, Gutschik E, et al. Guidelines on prevention, diagnosis and treatment of infective endocarditis executive summary; The Task Force on Infective Endocarditis of the European Society of Cardiology. Eur Heart J 2004; 25: 267–76.
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Moreillon P, Que YA. Infective endocarditis. Lancet 2004; 363: 139–49.
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Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med 2001; 345: 1318–30.
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Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group (erratum appears in Circulation 2007; 116: e376–e377). Circulation 2007; 116: 1736–54.
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Additional online material
22.1
Large, mobile vegetation on the mitral valve. The vegetation is in the left ventricle during diastole and prolapses into the left atrium in systole.22.2
A close-up of 22.1.22.3
Bicuspid aortic valve and mitral valve endocarditis, with perforation of aortic leaflet. Streptococcal endocarditis with destruction of the aortic valve, which shows severe prolapse and a defect. There is also an endocarditic lesion on the anterior mitral leaflet. Transoesophageal long-axis view. The patient had severe acute aortic regurgitation.22.4
Staphylococcal endocarditis of aortic bioprosthesis: transoesophageal short-axis view.22.5
Same case as 22.4. Staphylococcal endocarditis of aortic bioprosthesis: transoesophageal long-axis view.22.6
Enterococcal endocarditis of mechanical aortic valve prosthesis in the presence of a valved conduit. Vegetation on the ventricular side of prosthesis and large abscess surrounding the conduit.22.7
Para-aortic abscess cavity in the presence of an aortic valve prosthesis. Left, transoesophageal colour Doppler long-axis view of the aortic valve. During systole, the cavity fills with turbulent flow.22.8
Two-dimensional image of 22.722.9
Vegetation attached to the atrial side of the tricuspid valve; staphylococcal endocarditis.22.10
Close up of 22.9.22.11
Surgically confirmed staphylococcal vegetation on the atrial side of a mechanical mitral bileaflet prosthesis.Transesophageal view.22.12
Close-up of 22.11