Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 7

Infective endocarditis JOSE´ M. FERRO* AND ANA CATARINA FONSECA Department of Neurosciences, Servio de Neurologia, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal

DEFINITION Infective endocarditis is a disease of the inner lining of the heart and cardiac valves, the endocardium, caused by a variety of infectious agents, ranging from streptococci to antibiotic-resistant bacteria, including fungi and rickettsia. Endocarditis causes constitutional, cardiac, and multiorgan symptoms and signs. The central nervous system can be affected in the form of meningitis, cerebritis, encephalopathy, seizures, brain abscess, ischemic embolic stroke, mycotic aneurysm, and subarachnoid or intracerebral hemorrhage (Salgado, 1991; Autret et al., 1993; Sila, 2010). The subject of noninfective endocarditis, also called noninfective or nonbacterial thrombotic endocarditis, which is associated with lupus, antiphospholipid syndrome, hypereosinophilic syndrome, and cancer, is not addressed in this chapter.

CLASSIFICATION Infective endocarditis is traditionally divided into acute and subacute-chronic types, according to the temporal profile of onset. Classically, acute endocarditis usually occurs in previously normal valves and is associated with more aggressive agents and nosocomial infections, while the subacute-chronic form occurs in abnormal valves and is due to more common and “benign” bacteria. Infective endocarditis constitutes a group of clinical situations, whose cause and location can vary. The Task Force on the Prevention, Diagnosis and Treatment of Infective Endocarditis of the European Society of Cardiology (Habib et al., 2009) proposed a classification of infective endocarditis into different categories relating to: ● ●

site of infection: left side; right side the presence or absence of intracardiac foreign material: native valve; prosthetic valve; device-related

●

●

mode of acquisition: community-acquired; health care associated – nosocomial or non-nosocomial; intravenous drug abuse-associated microbiologic findings: with positive blood cultures (streptococci, enterococci, staphylococci); with negative blood cultures because of prior antibiotic treatment; frequently associated with negative blood cultures (variant streptococci, fastidious Gramnegative bacilli of the HACEK group (Haemophilus species – Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus — Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species), Brucella and fungi); infective endocarditis associated with constantly negative blood cultures (Coxiella Burnetti, Bartonella, Chlamydia, Tropheryma whipplei).

HISTORICAL ASPECTS Although several physicians had described valvular vegetations, and a few had studied endocarditis, including Laennec, Bouillaud, and Kirkes (Levy, 1985), the three Gulstonian Lectures on “malignant endocarditis” delivered by William Osler to the Royal College of Physicians in 1885, and published in the same year in the British Medical Journal, are considered the hallmark of modern medical thought in infective endocarditis (Osler, 1885). Mostly based on personal observations, Osler described the symptoms and signs of endocarditis, including its cerebral manifestations (cerebral group) (Osler, 1885), its diagnostic problems, and caveats. He elaborated on an attempted classification (simple and malignant endocarditis) and called attention to the prolonged forms of endocarditis. He also pointed to “persons debilitated,” “addicted to drink,” those with a previous attack of rheumatism, and those affected by the prevalent infectious

*Correspondence to: Professor Jose´ M Ferro, Servic¸o de Neurologia, 6th floor, Hospital de Santa Maria, 1649-028 Lisbon, Portugal. Fax: þ351-21-7957474, E-mail: [email protected]

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disorders of the time, such as scarlet fever, pneumonia, and rheumatic fever, as individuals particularly liable to be attacked by “malignant” endocarditis. Later important contributions include those of Libman, who intensively studied the bacteriology and morbid anatomy of endocarditis. He examined the Austrian composer Gustave Mahler, who died of endocarditis at the age of 51. Libman identified “attenuated Streptococcus” in his blood cultures (Levy, 1986).

EPIDEMIOLOGY Fortunately, infective endocarditis is not very frequent. The estimated incidence is 1.7–6.2/100 000/year (Mylonakis and Calderwood, 2001). A survey in France detected 30 cases per million inhabitants in 1 year (Hoen et al., 2002). The incidence has been stable for several decades. The disease is more common in men (2:1) and in the middle aged, although in recent times an increasing number of the elderly have been affected, due to increased survival and more aggressive diagnostic and therapeutic approaches in this age group. In recent years, the proportion of cases associated with rheumatic valvulopathy and dental surgery has decreased, while several other associated diseases and risk factors have emerged. These include intravenous drug abuse, typically associated with acute right-sided endocarditis, prosthetic valves, degenerative valve disease, implanted cardiac devices (Baddour et al., 2010; Zahr et al., 2010), and iatrogenic or nosocomial infections. About half of the patients in whom the diagnosis is made nowadays do not have a known history of an underlying cardiac disease or intervention. In the International Collaboration on Endocarditis-Prospective Cohort Study, infective endocarditis was most often an acute disease, frequently caused by Staphylococcus aureus infection (Murdoch et al., 2009).

PATHOPHYSIOLOGY As a rule, the valve endothelium and the endocardium are resistant to colonization and infection by circulating bacteria. In the absence of valve lesion, it is necessary to have either mechanical disruption of the endothelium or endothelial inflammation in order for valves to become colonized and infected (Que et al., 2005; Beynon et al., 2006; Prendergast, 2006; Habib et al., 2009). Following mechanical disruption of endothelium, there is an exposure of the underlying extracellular matrix proteins and stromal cells which trigger the deposition of fibrin and platelets as part of a physiologic healing process. A small clot of fibrin and platelets is formed over the damaged endothelium. During transient bacteremia, circulating pathogens bind to the formed coagulum. This process attracts and activates monocytes to

produce cytokines and tissue factor. These mediators activate the coagulation cascade, attract and activate more platelets, and induce the production of cytokines, integrin, and tissue factor from endothelial cells, resulting in progressive enlargement of the infected vegetation. Mechanical damage of endothelium can be caused by turbulent blood flow, electrodes, catheters, or other intracardiac devices, inflammation, or degenerative changes. Local valve inflammation triggers the expression of integrins of the b1 family by the endothelial cells. b1 integrins bind circulating fibronectin to the endothelial surface. Some pathogens, such as Staphylococcus aureus, carry fibronectin-binding proteins on their surface. Therefore, when the activated endothelial cells connect with fibronectin, they are providing an adhesive surface to circulating pathogens. Once adhered, the pathogens can activate their internalization into valve endothelial cells where they can persist, multiply, and spread. In response to invasion, endothelial cells produce cytokines and tissue factor activity, resulting in the formation of the vegetation (Moreillon and Que, 2004; Que et al., 2005). Transient bacteremia can occur during invasive procedures, but also after tooth brushing and chewing. The high incidence of these low-grade and short-lived bacteremias can explain cases of infective endocarditis unrelated to invasive procedures (Strom et al., 2000). Valve colonization and infection can cause valvular dysfunction, continuous bacteremia, embolic phenomena, and immune-mediated disease. The neurologic complications result mainly from systemic embolization of septic emboli from the valvular vegetations, causing an ischemic cerebral infarction, which can eventually undergo hemorrhagic transformation. Septic emboli obstructing the lumen or the vasa vasorum also cause a focal vasculitis, leading to a focal cerebritis, which ultimately can develop into a brain abscess or meningoencephalitis. Mycotic aneurysms occur when the inflammation process from the septic emboli penetrates the vessel wall through the muscularis media to the lamina elastica interna. The rupture of infected vessel wall or of mycotic aneurysms can cause subarachnoid or intracerebral hemorrhage.

CLINICAL ASPECTS Systemic, cardiac and multiorgan manifestations Systemic manifestations of infective endocarditis include fever> 38 C (96% of the patients) (Murdoch et al., 2009), often associated with chills, poor appetite, and weight loss. Fever can be absent in patients with previous use of antibiotics and in endocarditis due to less virulent

INFECTIVE ENDOCARDITIS agents. A new regurgitant heart murmur can be found in half (48%) of the subjects and worsening of old murmur in 20%. Other classic clinical manifestations include active vasculitic phenomena such as splinter hemorrhages (red to brownish, linear, and located under the fingernails or toenails) (8%), Roth spots (retinal hemorrhage with a fibrin-white center) (2%), conjunctival hemorrhages (5%) and glomerulonephritis, emboli to the brain (see below), lung or spleen and splenomegaly (11%). Osler’s nodes (tender, subcutaneous, situated on the pulp of the digits or thenar eminence) (3%), Janeway’s lesions (nontender, erythematous, hemorrhagic or pustular lesions, on the palms or soles) (5%), and digital clubbing are less common nowadays (Mylonakis and Calderwood, 2001; Beynon et al., 2006; Murdoch et al., 2009). Clinical presentation varies with the mode of onset and the involved side of the heart. Acute endocarditis typically has high fever, signs of systemic toxicity, systemic emboli, sudden cardiac failure or valvular incompetence. In right-sided endocarditis, pulmonary emboli are common. In subacute endocarditis, a syndrome of fever of unknown cause, enlarged spleen and the classic vasculitic and cutaneous findings described above are more likely to be seen. Atypical presentations are particularly common in elderly, immunocompromised patients (Pe´rez de Isla et al., 2007) and right-sided infective endocarditis.

Neurologic manifestations Between 20% and 40% of patients with infective endocarditis have neurologic complications. Neurologic complications are more frequent in patients with large size valvular vegetations, mitral valve infective endocarditis, and infection due to Staphylococcus aureus (Nadji et al., 2005) or Streptococcus bovis. The risk of embolism is particularly high within the first 2 weeks after diagnosis and decreases in frequency after the beginning of antibiotic therapy (Thuny et al., 2007; Snygg-Martin et al., 2008). A large single-center study showed a trend for increasing frequency of neurologic complications in infective endocarditis, probably associated with an increase in more aggressive nosocomial acquired and Staphylococcus aureus endocarditis (Corral et al., 2007). Patients with infective endocarditis associated with neurologic complications tend to have higher morbidity and mortality than patients without neurologic complications (Heiro et al., 2000). Neurologic manifestations can be the first sign of infective endocarditis. In one study, 46% of patients first presented with a neurologic manifestation (Heiro et al., 2000). The neurologic complications of infective endocarditis can be divided in two main groups: cerebrovascular and infectious. Cerebrovascular complications are the most

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frequent and include ischemic stroke, transient ischemic attack, hemorrhagic stroke and mycotic aneurysms. Infectious complications include meningitis, cerebritis, brain abscesses and discitis. Acute encephalopathy can also occur. There are reports of isolated neurologic symptoms, such as headache, seizures, or trigeminal neuralgia. Less frequent are reports of peripheral neurologic involvement including peripheral neuropathies and spondylodiscitis. Although the majority of the cerebrovascular complications of infective endocarditis are symptomatic, there has been an increase in the report of “silent lesions,” mainly due to the more frequent use of neuroimaging (Snygg-Martin et al., 2008; Cooper et al., 2009). In a prospective study, “silent lesions” were documented in DWI-MRI in 70% of patients with left-sided heart valvular endocarditis (Cooper et al., 2009). There is no information at present on the impact of these lesions on the long-term outcome. One study reported a high frequency of cerebral microbleeds in patients with infective endocarditis: 57% of patients with infectious endocarditis versus 15% in control subjects (Klein et al., 2009). In T2* sequences, these microbleeds were qualitatively and anatomically different from those found in conditions such as cerebral amyloid angiopathy or hypertensive vasculopathy. They were mostly homogeneous, 50%).

MYCOTIC ANEURYSMS When the infective emboli lodge in small distal cerebral arteries and in the vasa vasorum, they begin an intensive inflammation in the media and adventitia, diminishing the integrity of the vessel wall and weakening it, leading to the formation of a pseudoaneurysm. This process can be as short as a day, but may last more than 1 week under antibiotic treatment (Kannoth and Thomas, 2009).

Fig. 7.2. Multiple brain infarcts of different size in a patient with endocarditis.

Mycotic aneurysms are reported as a complication of infective endocarditis in 2–4% of patients (Peters et al., 2006). However, most mycotic aneurysms are clinically silent and the true prevalence of this complication may be underreported. These aneurysms are more commonly found in the anterior circulation, in the middle cerebral artery territory, mainly on its distal branches, in up to 70% of cases (Fig. 7.3). They have a fusiform and irregular morphology, no neck (Chapot et al., 2002; Kannoth et al., 2007), and are multiple in up to 25% of patients (Chun et al., 2001).

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Spondylodiscitis (vertebral osteomyelitis) can result from septic emboli of vertebral arteries, vertebral septic necrosis or immunocomplex deposition. It was reported in 2.6% of patients in a pooled analysis of six retrospective reviews (Cone et al., 2008). Presentation ranges from low back pain or myalgia to frank septic arthritis. The lumbar region is more frequently involved, followed by the thoracic and cervical regions. More than one vertebra is involved in 10% of cases. Vertebral osteomyelitis caused by streptococci or enterococci should raise the suspicion of an infectious endocarditis. In a retrospective analysis of 136 cases of endocarditis, 26% of patients with streptococcal or enterecoccocal spondylodiscitis had an infective endocarditis (Mulleman et al., 2006). Fig. 7.3. Intra-arterial cerebral angiography: mycotic aneurysm in distal branch of the middle cerebral artery. Notice also the “string of beads” pattern in the distal cortical arteries, typical of associated septic and autoimmune vasculitis.

In a retrospective study, mycotic aneurysms tended to present predominantly with focal signs or intracerebral hemorrhages, in contrast to berry aneurysms, which tended to present as subarachnoid hemorrhage (Kannoth et al., 2007). There are some case reports of mycotic aneurysms presenting as subdural hematomas. Patients with mycotic aneurysms are usually younger than patients with nonmycotic aneurysms and present more frequently with fever (Kannoth et al., 2007). Mycotic aneurysms may disappear, enlarge, or develop de novo during antibiotic therapy (Ahmadi et al., 1993). The mortality rate in patients with infective endocarditis and ruptured intracranial aneurysm is high, and varies between 40% and 80% (Wajnberg et al., 2008).

Central nervous system infection The dissemination of infected embolic material into cerebral or meningeal vessels may lead to meningitis or brain abscesses. Meningitis is reported as a complication of infective endocarditis in up to 3.5% of patients. The most common agent is Staphylococcus aureus. Typically an aseptic pattern in the cerebrospinal fluid with a slight mononuclear pleocytosis can be found. This aseptic pattern can be due to parameningeal inflammation, antibiotic pretreatment, or low cerebrospinal fluid bacterial burden. Brain abscesses are relatively rare, accounting for 1–4% of neurologic complications (Salgado, 1991). These abscesses are usually multiple with no, or limited, meningeal enhancement (Azuma et al., 2009). Pyogenic ventriculitis (Yavasoglu et al., 2005; Kiyan et al., 2007) and intramedullary abscess of the spinal cord (Ferna´ndezRuiz et al., 2009) were also reported.

Other neurologic manifestations ACUTE ENCEPHALOPATHY Acute encephalopathy is thought to result from multifocal brain ischemia related to multiple small emboli. Corral et al., (2007) found, in a retrospective review of infective endocarditis patients, that most of the cases of diffuse encephalopathy were associated with toxic or metabolic changes. A thorough search for metabolic or toxic causes in infective endocarditis patients with diffuse encephalopathy should be carried out before establishing that infective endocarditis is the direct cause of acute encephalopathy (Corral et al., 2007).

MONONEUROPATHY AND POLYNEUROPATHY Seven cases of embolic mononeuropathy in infective endocarditis were reported. The nerves involved were ulnar, peroneal, facial, median, sciatic, and maxillary (Tsai et al., 2008). The peripheral nerve lesion is thought to be caused by embolic occlusion of the vasa nervorum with ischemic changes in the nerve (Jones et al., 1969). Bacterial endocarditis has been associated with Guillain–Barre´ syndrome. These cases were due to infection with Coxiella burnetii, Streptococcus viridans and Staphylococcus aureus (Baravelli et al., 2007).

DIAGNOSIS The diagnosis of infective endocarditis requires a high suspicion rate and pattern recognition in an appropriate clinical context. It also requires the judicious integration of clinical symptoms and signs, including those of central nervous system (CNS) involvement, with the results of ancillary procedures, namely laboratory, echocardiography and neuroimaging studies.

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Laboratory Anemia, leukocytosis, high erythrocyte sedimentation rate (61%), high C-reactive protein level (62%), elevated rheumatoid factor (5%), and abnormal urinalysis, including hematuria (26%), are present in most, but not all, patients. However, these laboratory changes are not specific.

Electrocardiography Electrocardiography should be performed on admission and repeated during the course of the disease, as it may show new conduction defects, namely atrioventricular, fascicular, and bundle-branch block, which suggest perivalvular aortic invasion. These patients may need cardiac monitoring until they are stable.

Echocardiography Echocardiography has an important role in the demonstration of heart involvement in infective endocarditis. Echocardiography should be performed as early as possible. Three echocardiographic findings can be considered typical for the diagnosis of endocarditis: mobile, echodense masses attached to valvular leaflets (Fig. 7.4) or mural endocardium, or on implanted material; periannular abscesses or new dehiscence of a valvular prosthesis; new valvular regurgitation (Baddour et al., 2005). The sensitivity of transthoracic echocardiography (40–63%) is lower than that of transesophageal echocardiography (90–100%). On the other hand, transesophageal echocardiography is less often immediately available and may be difficult to perform in unstable patients.

Fig. 7.4. A 46-year-old woman with bitemporal headache of sudden onset and a right parietal and a left occipital hematoma on brain CT. Transesophageal echocardiogram: 3 mm mobile vegetation adherent to the aortic valve.

The European Society of Cardiology Guidelines recommend the use of transthoracic echocardiography as the first-line imaging modality in suspected infective endocarditis (Habib et al., 2009). Transesophageal echocardiography is recommended in patients with high clinical suspicion of infective endocarditis and normal transthoracic echocardiography. Echocardiography (one or both modalities) should be repeated within 7–10 days if the initial examination was negative but the clinical suspicion of infective endocarditis remains high. Echocardiography is also recommended for the follow-up under medical therapy, intraoperatively if surgery is performed, and following completion of therapy (Habib et al., 2009). North American guidelines prefer transesophageal echocardiography as the early modality, transthoracic echocardiography being used when transesophageal echocardiography is not immediately available (Baddour et al., 2005). With increasing demand for echocardiography to exclude endocarditis in low-risk patients, it is important to fine-tune the selection of suspected patients who most benefit from this diagnostic technique. In one study, the absence of: (1) a history of valve replacement or intravenous drug use; (2) signs of embolic phenomena; (3) central venous access; (4) positive blood cultures indicates a near zero possibility of endocarditis (Greaves et al., 2003).

Identification of the pathogenic agent The identification of the microorganism causing the endocarditis is crucial for planning a rational treatment. Before starting antibiotics, three sets of blood samples of 10 mL should be collected aseptically from a peripheral vein for both aerobic and anaerobic cultures (for anaerobic species such as Bacteroides and Clostridium). Cultures are positive in 85–90% of the patients. If cultures are negative after 5 days, cultures in chocolate agar plates may allow the identification of fastidious agents. Negative blood cultures are particularly likely in patients who were on, or started antibiotics before the diagnosis and in endocarditis caused by agents such as Coxiella burnetti, Brucella, Chlamydia, Legionella, Bartonella, Mycoplasma, Tropheryma whipplei, the HACEK group, and fungi. These organisms are particularly common in patients with prosthetic valves, intracardiac or intravenous devices, and in immunocompromised subjects. In cases with negative cultures, the agent may be identified using prolonged incubation, special culture techniques, serologic tests, and molecular biology techniques. Polymerase chain reaction (PCR) is a reliable and sensitive technique to identify fastidious and nonculturable agents. It must, however, be kept in mind that PCR has been validated in tissue from valve surgery and its application to whole blood samples may not be reliable. Positive PCR may persist for months after successful

INFECTIVE ENDOCARDITIS treatment of the infection. Accessible emboli (e.g., cutaneous) and resected valvular tissue should also be examined pathologically and cultured (Prendergast, 2004; Habib et al., 2009; Parize and Mainardi, 2011). In the International Collaboration on EndocarditisProspective Cohort Study (Murdoch et al., 2009), Staphylococcus aureus was the most frequent pathogen (31%), followed by Streptococcus viridans (17%), coagulasenegative staphylococcus (11%), enterococcus (10%), Streptococcus bovis (6%), other streptococcus (6%), HACEK group (2%), fungus (2%), and other agents in 4%. Cultures were negative in 10% of the patients.

Diagnostic criteria An attempt to define diagnostic criteria which could be simultaneously sensitive and specific for the diagnosis of infective endocarditis led to the establishment of the Duke criteria in 1994 (Durack et al., 1994). These criteria were originally developed to define cases of infective endocarditis for clinical trials and epidemiologic studies. The modified Duke criteria use clinical, microbiologic, echocardiography, and pathologic criteria to establish the diagnosis of infective endocarditis according to three categories: definitive, possible, and rejected (Table 7.1) (Li et al., 2000). The diagnosis of infective endocarditis, according to the criteria, relies on the presence of bacteremia and the demonstration of heart involvement. The specificity of the original Duke criteria is high (0.99), with a negative predictive value of 0.92. The sensitivity of the new criteria is lowered in culture-negative patients and in centers with limited access to echocardiography and polymerase chain reaction. Taking into account the heterogeneous presentation of this disease, both the European Society of Cardiology and the American Heart Association Guidelines suggest that although the Duke criteria are useful for the diagnosis of infective endocarditis and should be used as a primary diagnostic schema, they should not replace clinical judgment (Baddour et al., 2005; Habib et al., 2009).

Diagnosis of the neurologic complications In the presence of neurologic symptoms, early brain imaging with computed tomography (CT) can identify hemorrhagic strokes, early ischemic changes, and established infarcts, and rounded annular, single or multiple hypodense lesions, with variable, asymmetric contrast enhancement suggestive of brain abscess (Fig. 7.5). Magnetic resonance imaging (MRI) is more sensitive than CT, for the identification of small and asymptomatic emboli, microbleeds, for the early detection of acute infarcts (using DWI sequences), and for the diagnosis of brain abscess, cerebritis, and other intracranial infections. Characteristic are bull’s-eye-like lesions, which are

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hyperintense lesions with a central hypointense area on T2 or T2* sequences, representing inflammatory areas surrounding bleeding/aneurysm (Bertonini et al., 1989). MRI can also show reversible T2 prolongation and restricted diffusion in the corpus callosum (Takanashi et al., 2006). In a recent single center study of 130 patients, MRI performed within 7 days after admission identified cerebral lesions in 82% of patients with endocarditis, including many without neurologic manifestations. MRI findings influenced management in 28%, often leading to modifications of the therapeutic plans (18%), including surgical plan modification (14%) (Duval et al., 2010). Lumbar puncture is often performed in the diagnostic work-up of patients with fever and neurologic symptoms, before the diagnosis of endocarditis is established. After endocarditis is identified, lumbar puncture is recommended only in patients with suspected meningitis, or if headache and signs of meningeal irritation persist after fever and bacteremia remit with antibiotics (Salgado et al., 1989). Cerebrospinal blood cultures are positive in only 15–25% of the patients (Sila, 2010). Intra-arterial digital angiography remains the gold standard for the diagnosis of mycotic aneurysm (Fig. 7.3). CT and MR angiography are being increasingly used to screen for mycotic aneurysms, to perform noninvasive follow-up, and to access cure and recurrence of mycotic aneurysms after antibiotic, endovascular, or surgical treatment. At present, CT and MR angiography should be considered screening techniques. They have a comparable sensitivity and specificity (90–95%), but they are much less accurate in the detection of aneurysms smaller than 5 mm (Huston et al., 1994; White et al., 2001). CT angiography can be performed more rapidly than MR angiography, but it has the risk of a substantial volume load, which may produce acute heart failure. Both the American (Baddour et al., 2005) and the European guidelines (Habib et al., 2009) recommend MR or CT angiography to identify and monitor mycotic aneurysms. Intra-arterial angiography is reserved for cases where the suspicion of mycotic aneurysm remains, despite negative MR or CT angiography. Transcranial Doppler can be a promising tool for the prediction of the risk of neurologic complications in patients with infective endocarditis. In one study, neurologic complications occurred in 83% of patients with positive cerebral microembolic signs and in 33% of patients lacking such microembolic signs (Lepur and Barsic, 2009).

PROGNOSIS In-hospital mortality of patients with infective endocarditis ranges between 10% and 25% (Mansur et al., 1996;

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Table 7.1 Modified Duke criteria for the diagnosis of infective endocarditis Definition of terms used in the proposed modified Duke criteria for the diagnosis of infective endocarditis (IE) Definite infective endocarditis Pathologic criteria (1) Microorganisms demonstrated by culture or histologic examination of vegetation, vegetation that has embolized, or an intracardiac abscess specimen; or (2) Pathologic lesions; vegetation or intracardiac abscess confirmed by histologic examination showing active endocarditis Clinical criteria (1) 2 major criteria; or (2) 1 major criterion and 3 minor criteria; or (3) 5 minor criteria Possible infective endocarditis (1) 1 major criterion and 1 minor criterion; or (2) 3 minor criteria Rejected (1) Firm alternate diagnosis explaining evidence of infective endocarditis; or (2) Resolution of infective endocarditis syndrome with antibiotic therapy for < 4 days; or (3) No pathologic evidence of infective endocarditis at surgery or autopsy, with antibiotic therapy for 4 separate cultures of blood (with first and last sample drawn at least 1 h apart) Single positive blood culture for Coxiella burnetii or antiphase I IgG antibody titer 11:800 ● Evidence of endocardial involvement ● Echocardiogram positive for IE (TEE recommended in patients with prosthetic valves, rated at least “possible IE” by clinical criteria, or complicated IE (paravalvular abscess); TTE as first test in other patients), defined as follows: Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or abscess; or new partial dehiscence of prosthetic valve ● New valvular regurgitation (worsening or changing of pre-existing murmur not sufficient) Minor criteria

● Predisposition, predisposing heart condition or injection drug use ● Fever, temperature > 37 C ● Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival

hemorrhages, and Janeway’s lesions ● Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factora ● Microbiologic evidence: positive blood culture but does not meet a major criterion as noted above or serologic evidence of active

infection with organism consistent with IE TEE, transesophageal echocardiography; TTE, transthoracic echocardiography. a Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis (Li et al., 2000).

Netzer et al., 2002; Wallace et al., 2002; Hasbun et al., 2003; Chu et al., 2004; Delahaye et al., 2007; San Roman et al., 2007; Thuny et al., 2005; Murdoch et al., 2009). Acute prognosis is influenced by: (1) patient characteristics: older age, prosthetic valve, insulin-dependent diabetes, comorbidities; (2) cardiac complications: heart failure, periannular complications;

(3) noncardiac complications: renal failure, septic shock; (4) stroke; (5) microorganisms: Staphylococcus aureus, fungi, Gram-negative bacilli; (6) echocardiographic features: perianullar complications, severe left-sided regurgitation, low left ventricular ejection fraction, pulmonary hypertension, large vegetations, severe prosthetic dysfunction, premature mitral valve closure, or

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Fig. 7.5. A 74-year-old hypertensive woman found unconscious at home. Coma and tetraparesis. Aortic valve vegetation on transesophageal echocardiography. Brain CT: left temporo-occipito-parietal hematoma (left) and ischemic infarct in the distal territory of the right anterior cerebral artery (right).

other signs of elevated diastolic pressure (Habib et al., 2009). Patients with heart failure, periannular complications, and Staphylococcus aureus infections have the highest risk of death, which reaches 79% when all these three risk factors are present simultaneously (San Roman et al., 2007). In the International Collaboration on Endocarditis-Prospective Cohort Study of 2781 patients, the predictors of in-hospital mortality (17.7%) were prosthetic valve involvement, increasing age, pulmonary edema, Staphylococcus aureus infection, coagulasenegative staphylococcal infection, mitral valve vegetation, and paravalvular complications (Murdoch et al., 2009).

PREVENTION Until recently, there was consensus that infective endocarditis was preventable by using antibiotics in patients with cardiac diseases at risk of endocarditis during procedures associated with transient bacteraemia, such as dental, gastrointestinal, urogenital, and obstetrics procedures. This dominant view has been challenged by the lack of randomized controlled trials demonstrating the efficacy of antibiotic treatment (Oliver et al., 2008) and by the observation that comparable transient bacteremia also occurs during everyday life, e.g., during tooth brushing. Currently no antibiotic prophylaxis is recommended by the National Institute for Health and Clinical Excellence Guidelines (National Institute for Health and Clinical Excellence, Short Clinical Guidelines Technical Team, 2008). The ACC/AHA (American College of Cardiology/American Heart Association) downgraded from class I to class IIa (reasonable practice) their recommendation to use prophylactic antibiotics in high-risk patients undergoing dental procedures (Nishimura et al., 2008). The guidelines of the European Society of

Cardiology (Habib et al., 2009) only recommend antibiotic prophylaxis for dental procedures and for patients at highest risk of infective endocarditis (prosthetic valve, previous endocarditis, and some patients with congenital heart disease). Maintaining good oral hygiene and avoiding piercing and tattoos is advised.

TREATMENT The treatment of endocarditis includes general measures, antimicrobial therapy and treatment of complications, namely systemic, cardiac, and neurologic. The essential aspect of the treatment of infective endocarditis is the eradication of the systemic and cardiac infection by the application of appropriate antimicrobial therapy and, if necessary, by cardiac surgery, which removes infected tissue and material, and drains abscesses.

Antimicrobial therapy A full presentation of the antimicrobial treatments more appropriate for each specific agent is beyond the scope of this chapter. The interested reader is referred to the American Heart Association (Baddour et al., 2005) and the European Society of Cardiology (Habib et al., 2009) Guidelines. Antimicrobial treatment should last longer (minimum 6 weeks) for prosthetic than for native valve endocarditis (2–6 weeks). Otherwise, the antimicrobial regimens are rather similar. Table 7.2 summarizes the antimicrobial treatment of infective endocarditis following the 2009 European Society of Cardiology Guidelines. The reader is advised to check for periodic updates of these treatment regimens. The proposed antibiotic regimen for initial empiric treatment of infective endocarditis, while waiting for

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Table 7.2 Summary of antimicrobial regimens for infective endocarditis, following the European Society of Cardiology guidelines (Habib et al., 2009) Drug Oral and D group streptococci, sensitive to penicillin Penicillin G, or Amoxicillin, or Ceftriaxone Oral and D group streptococci, relatively resistant to penicillin Penicillin G, or Amoxicillin, plus Gentamicin Staphyloccocci, native valves Flucloxacillin, plus Gentamicin Staphyloccocci, native valves, methicillin-resistant Vancomycin, plus Gentamicin Staphyloccocci, prosthetic valves Flucloxacillin, plus Gentamicin, plus Rifampin Staphyloccocci, prosthetic valves, methicillin-resistant Vancomycin, plus Gentamicin, plus Rifampin Enteroccocci Amoxicillin, plus Gentamicin Gram-negative bacteria, HACEK species Ceftriaxone Brucella Doxycycline, plus Cotrimoxazole, plus Rifampin Coxiella burnetii Doxycycline, plus Ofloxacin Bartonella Ceftriaxone, plus Gentamicin Legionella Erythromycin, plus Rifampin

Dosage

Duration (weeks)

12–18 million U/day, IV, every 4 hours 100–200 mg/kg/day, IV, every 4 or 6 hours 2 g/day IV or IM, 1 dose

4 4 4

24 million U/day, IV, every 4 hours 200 mg/kg/day, IV, every 4 or 6 hours 3 mg/kg/day, IV or IM, 1 dose

4 4 2

12 g/day, IV, every 4 or 6 hours 3 mg/kg/day, IV or IM, 2 or 3 doses

4–6 3–5 days

30 mg/kg/day, IV, every 12 hours 3 mg/kg/day, IV or IM, 2 or 3 doses

4–6 3–5 days

12 g/day, IV, every 4 or 6 hours 3 mg/kg/day, IV or IM, 2 or 3 doses 1200 mg/day, IV or orally, 2 doses

6 2 6

30 mg/kg/day, IV, every 12 hours 3 mg/kg/day, IV or IM, 2 or 3 doses 1200 mg/day, IV or orally, 2 doses

6 2 6

200 mg/kg/day, IV, every 4 or 6 hours 3 mg/kg/day, IV or IM, 2 or 3 doses

4–6 4–6

2 g/day IV or IM, 1 dose

4

200 mg, orally, every 24 hours 960 mg, orally, every 12 hours 300–600 mg, orally, 2 doses

 12  12  12

200 mg, orally, every 24 hours 400 mg, oral, every 24 hours

 18 months  18 months

2 g/day IV or IM, 1 dose 3 mg/kg/day, IV or IM, 2 or 3 doses

6 3

3 g/24 hours, IV, followed by orally 300–1200 mg, orally, every 24 hours

2þ4 6

IV, intravenous; IM, intramuscular; HACEK, Haemophilus species (Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species.

the identification of the agent or when the pathogen cannot be identified, in patients with native and prosthetic valves, more than 12 months after surgery, consists of amoxicillin þ clavulanate, 12 g/day, intravenously, every 6 hours, plus gentamicin, 3 mg/kg/day, intravenously or intramuscularly, in 2 or 3 doses, for 4–6 weeks.

Role of cardiac surgery In most tertiary centers, half of the patients with infective endocarditis undergo cardiac surgery for the treatment of complications (Tornos et al., 2005). In recent years there has been a trend toward a more aggressive attitude, i.e., toward early surgery in the management

INFECTIVE ENDOCARDITIS of heart failure, abscess, and uncontrolled infection in the context of infective endocarditis (Habib, 2009; Shang et al., 2009). However, the subject is still a matter of intense debate, in particular the indication for cardiac surgery for the prevention of embolism and the timing of surgery after cerebral embolism (Habib, 2009; Prendergast and Tornos, 2010; Thuny and Habib, 2010). The 2009 European Society of Cardiology Guidelines (Habib et al., 2009) and the American Heart Association Guidelines (Baddour et al., 2005) provide recommendations for surgery and their timing. Briefly, in the 2009 European Society of Cardiology Guidelines, surgery should be performed as an emergency when in aortic or mitral endocarditis there is acute heart failure with severe acute regurgitation or valve obstruction, or with fistula in a cardiac chamber or pericardium, manifesting as refractory pulmonary edema or cardiogenic shock, due to aortic or mitral endocarditis. Urgent indications include: (1) persisting heart failure, due to severe acute regurgitation or valve obstruction; (2) uncontrolled infection, owing to local complications such as abscess, fistula, false aneurysm or enlarging vegetation, to persistent (>7 days) fever or positive cultures, or to infection caused by fungi or multiresistant organisms; (3) prevention of embolism. Preventing systemic embolization, which goes mainly to the brain and spleen, is difficult, because most of the emboli occur before admission or are the cause of hospitalization (Di Salvo et al., 2001). The risk of embolization is highest in the first 2 weeks of antibiotic treatment. Size and mobility of vegetations are the most important predictors of a new embolic event. Variables associated with an increased risk of embolism are listed in Table 7.3 (Rohmann et al., 1991; Sanfilippo et al., 1991; Rohmann et al., 1992; Erbel et al., 1995; Tischler and Vaitkus, 1997; Cabell et al., 2001; Di Salvo et al., 2001; Pergola et al., 2001; Vilacosta et al., 2002; Durante Mangoni et al., 2003; Mugge et al., 2003; Thuny et al., 2005; Fabri et al., 2006; Dickerman et al., 2007; Hsu and Lin, 2007; Tleyjeh et al., 2007). For the prevention of embolism, surgery is recommended on an urgent basis in the following scenarios: (1) aortic or mitral infective endocarditis with large (>10 mm) vegetations (i) following one or more embolic episodes despite appropriate antibiotic therapy, (ii) and with other predictors of complicated course (heart failure, persistent infection, abscess); (2) isolated large (>15 mm) vegetation. The American guidelines consider as possible indications for surgery: anterior mitral leaflet vegetation, in particular if larger than 10 mm (Fig. 7.6), persisting vegetation after systemic embolization, and increase in vegetation size, despite appropriate antimicrobial therapy. However, the authors of the guidelines stress that decision making regarding the role of surgical

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Table 7.3 Risk factors for embolism in infective endocarditis Initial phase: first days up to 2 weeks Older age Previous embolism Vegetation Location: mitral valve, anterior leaflet Mobile Size: large (>10 mm) and very large (>15 mm) Increasing size despite antibiotic treatment Microorganism Staphylococci Streptococcus bovis Candida Biologic markers C-reactive protein

Fig. 7.6. A 48-year-old man with fever, acute onset of leftsided weakness and a right middle cerebral artery infarct on CT. Transesophageal echocardiogram: large (15  9 mm), mobile vegetation in the anterior leaflet of the mitral valve. The patient underwent heart surgery.

intervention is difficult and complex and must be individualized. The benefit of surgery appears to be greatest in the first week of antibiotic therapy, when the risk of embolism peaks (Habib et al., 2009). A recent small (76 patients) randomized controlled trial compared early surgery versus conventional treatment in patients with left-sided infective endocarditis, severe valve disease, and large vegetations, and concluded that early surgery significantly reduced the risk of death and embolic events (Kang et al., 2012).

Treatment of endocarditis associated with cardiovascular implantable electronic devices A comprehensive presentation of endocarditis associated with cardiovascular implantable electronic devices is

86 J.M. FERRO AND A.C. FONSECA beyond the scope of this chapter. The interested reader is demonstrated a benefit of intravenous aspirin in experreferred to the recent American Heart Association imental endocarditis (Kupferwasser et al., 1999, 2003). scientific statement (Baddour et al., 2010) on this topic. Several observational studies indicated that patients on Briefly, if there is valve vegetation, treatment should folchronic antiplatelet treatment at the time of endocardilow the current recommendations for the treatment of tis diagnosis had reduced complications, valve replaceendocarditis. If there is lead vegetation the patients should ment surgery, and mortality (Eisen et al., 2009). be treated with antibiotics for 2–6 weeks, depending on Chronic antiplatelet treatment decreased the risk of the presence of complications (4–6 weeks) and on the embolism in one study (Anavekar et al., 2007), but agent (4 weeks if the agent is Staphylococcus aureus). not in others (Chan et al., 2008; Pepin et al., 2009) Complete device and lead removal is recommended for and increased the risk of bleeding (Chan et al., 2008). all patients with definite endocarditis associated with carUnfortunately, a randomized clinical trail comparing diovascular implantable electronic devices. aspirin 325 mg with placebo in 115 endocarditis patients failed to show any benefit of aspirin in the prevention of cerebral embolism: 28% of the patients on aspirin Treatment of the neurologic complications suffered an event comparing with 20% on placebo Neurologic complications should be managed according (OR 1.62; 95% CI 0.68–3.86). There was a trend toward to their respective treatment guidelines or consensus more bleeding in the aspirin group (OR 1.92; 95% CI 0.76–4.86). Aspirin had no effect on vegetation size. (e.g., antibiotic and neurosurgery for brain abscess). In this trial, aspirin was initiated 34 days after symptom However, such guidelines were in general written without considering the context of particular conditions, onset (Chan et al., 2003). Based on the available evisuch as endocarditis. Notoriously, some aspects of dence, routine antiplatelet therapy is not indicated in management of cerebrovascular complications are cominfective endocarditis (Baddour et al., 2005; Salem plex and controversial and deserve some discussion. et al., 2008; Habib et al., 2009). Nevertheless the European guidelines recommend that, if there is a previous indication and the patient is on antiplatelet therapy, Thrombolysis in acute stroke associated interruption of this therapy is only recommended in with endocarditis the presence of major bleeding (Habib et al., 2009). Endocarditis is listed among the contraindications for Concerning anticoagulants, the evidence is based only treatment with intravenous rtPA in acute ischemic stroke on observational studies. There is no indication to (European Agency for the Evaluation of Medicinal start anticoagulants after the diagnosis of infective Products, 2002). In practice, the majority of patients with endocarditis, even if a cardioembolic ischemic stroke the diagnosis of endocarditis and a hyperacute ischemic has occurred. In fact there is no support for the use of stroke will have other contraindications for rtPA. A few anticoagulants in this indication since they do not cases have been reported where intravenous rtPA was prevent embolization from the vegetations (Paschalis given within 3 hours of stroke onset in patients who were et al., 1990) and they increase the risk of intracerebral found later to harbor cardiac vegetation and were then bleeding. Bleeding can be due to hemorrhagic diagnosed with endocarditis. Outcomes were contradictransformation of ischemic infarcts, rupture of vessels tory. Two patients, including a 12-year-old child, were with walls damaged by septic or immune-mediated successfully treated without hemorrhagic complications vasculitis or rupture of a mycotic aneurysm. Anticoagu(Junna et al., 2007; Tan et al., 2009). In contrast, a case lant therapy is associated with increased mortality in series of three patients treated with rtPA reported that particular in Staphyloccocus aureus endocarditis all developed multifocal intracranial hemorrhages. (Roder et al., 1997; Tornos et al., 1999; Heiro et al., None had mycotic aneurysms (Bhuva et al., 2010). This 2000; Baddour et al., 2005), although this was not conlimited evidence suggests that thrombolysis in ischemic firmed in a recent series (Rasmussen et al., 2009). On stroke associated with infective endocarditis carries a the other hand, patients with mechanical valves will have high risk of intracranial bleeding. We found no cases the highest risk of cerebral embolism if anticoagulation reporting on the use of intra-arterial thrombolysis in this is stopped. indication. Current recommendations concerning the use of anticoagulation in infective endocarditis are therefore based on low quality and controversial information. Antithrombotic treatment The European Society of Cardiology Guidelines indicate A mechanistic approach would suggest that antiplatelet that: (1) there is no indication to start antithrombotic drugs and anticoagulants could decrease the risk of drugs; (2) in previously anticoagulated patients: (i) in embolism in endocarditis. An animal study also ischemic stroke without intracerebral hemorrhage, oral

INFECTIVE ENDOCARDITIS 87 anticoagulants should be replaced by unfractionated The timing for cardiac surgery after a central neuroheparin for 2 weeks, with close monitoring of activated logic complication is controversial, and the evidence suppartial thromboplastin time (APTT); (ii) in intracranial porting the recommendations is of limited quality and hemorrhage, all anticoagulation should be interrupted; based on observational studies (Eishi et al., 1995; (iii) in intracranial hemorrhage and a mechanical valve, Gillinov et al., 1996; Jault et al., 1997; Piper et al., 2001; unfractionated heparin, with close monitoring of APTT, Angswurm et al., 2004; Ruttman et al., 2006). When should be reinitiated as soon as possible; (iv) in the needed, cardiac surgery can be performed without delay absence of stroke, in Staphyloccocus aureus endoafter a silent cerebral embolism or TIA lesion. Conversely, carditis oral anticoagulants may be replaced by unfracsurgery must be postponed for at least 1 month following tionated heparin for 2 weeks, with close monitoring intracranial hemorrhage. After ischemic stroke, unless the of APTT (Habib et al., 2009). The American College clinical deficit is very severe, surgery should not be delayed of Chest Physicians Guidelines (Salem et al., 2008) (Habib et al., 2009). If a patient harbors a ruptured mycotic are more conservative regarding the indication for aneurysm, the aneurysm should be treated before cardiac continuing antithrombotic drugs in previously surgery. If unruptured, the aneurysm should not preclude anticoagulated patients. They state that if a patient is or delay cardiac surgery (Kannoth and Thomas, 2009). on vitamin K antagonists at the time of the diagnosis of endocarditis, they should be discontinued at the time Treatment of mycotic aneurysms of the initial presentation and unfractionated heparin substituted, until it is clear that invasive procedures will Unruptured mycotic aneurysms up to 10 mm may be not be required and the patient has stabilized without cured and disappear after antibiotic treatment signs of CNS involvement. It is suggested that the vita(Ahmadi et al., 1993). The risk of rupture and death is min K antagonist be reinstated only when the patient is lower in unruptured (30%) than in ruptured aneurysm deemed stable without contraindications or neurologic (80%) (Bohmfalk et al., 1978; Wilson et al., 1982). In one study (Bingham, 1977), aneurysms resolved in complications. 52% of patients, decreased in size in 29%, but enlarged in 19%. In 10% a new aneurysm was found in follow-up angiography. From the analysis of published case series, Cardiac surgery after a neurologic it is evident that the mortality in more recent series is low complication in both medically and surgical/endovascular treated Patients with infective endocarditis who suffer a neuropatients (Peters et al., 2006). The majority of patients logic event may still need cardiac surgery (Thuny et al., with unruptured aneurysms never required surgery or 2007). In fact, the neurologic complication itself can be endovascular treatment, while the majority of patients an indication for surgery (e.g., recurrent embolism with ruptured mycotic aneurysms needed neurosurgery despite appropriate antimicrobial treatment). Neuroor endovascular treatment (Corr et al., 1995). Contrary to logic complications are not a contraindication for the noninfectious aneurysms, it is difficult to predict which surgical treatment of heart failure, paravalvular infecmycotic aneurysms have the highest risk of rupture. The tious complications, uncontrolled systemic infection, morphologic features, size, and location of mycotic and persistent high-risk embolic vegetation (see above), aneurysms are poor predictors of rupture. The recomunless an intracranial hemorrhage is shown on brain mendation for the management of unruptured mycotic imaging or the CNS damage is clinically very severe aneurysms is antibiotic treatment and noninvasive (e.g., coma, devastating neurologic deficit). follow-up by CT or MR angiography. It is not known Cardiac surgery requiring cardiopulmonary bypass how frequently the imaging follow-up should be percan cause or aggravate cerebral damage by a variety of formed (Kannoth and Thomas, 2009). Our own “edumechanisms, including macro- and microembolization cated guess” is to do the angiographic follow-up on a and hypoperfusion. Cardiopulmonary bypass requires weekly basis, if the neurologic condition is stable. If heparinization, which can induce de novo cerebral bleedthe aneurysm is large (>10 mm), enlarges, does not ing or hemorrhagic transformation of a pre-existent resolve, or ruptures, surgical or endovascular treatment ischemic infarct or infectious lesion. Cardiopulmonary should be performed, as for ruptured aneurysms bypass also induces a systemic inflammatory response, (Baddour et al., 2005; Peters et al., 2006; Habib et al., which may aggravate cerebral edema (Sila, 2010). The 2009; Kannoth and Thomas, 2009; Ducruet et al., 2010). operative risk is increased in patients with neurologic For a ruptured aneurysm, endovascular or neurosurcomplications, except in patients with silent lesions or gical therapy is indicated. Current consensus and recomtransient ischemic attacks (TIAs), whose surgical risk mendations are again based only on case series and case is low (Thuny et al., 2007). control studies. Neurosurgical intervention is emergent

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if there is intracerebral bleeding causing mass effect or hydrocephalus. Endovascular occlusion of the aneurysm with cyanocrylate or coils is an effective and safe alternative to surgery (Chapot et al., 2002; Dhomne et al., 2008). Management algorithms based on expert opinion suggest that neurosurgery (often using microvascular techniques) should be the first option if there is mass effect from the aneurysm or the surrounding hematoma, for aneurysms located in arteries supplying eloquent neural territories, and in distal aneurysms, if they are located in an accessible location. The remaining mycotic aneurysms can be treated by endovascular intervention, if such expertise is available. Any of the treatment modalities can be used as a rescue alternative if the other fails to exclude the aneurysm (Baddour et al., 2005; Peters et al., 2006; Habib et al., 2009; Kannoth and Thomas, 2009; Ducruet et al., 2010). Although new aneurysms can develop after appropriate antimicrobial treatment, there were no instances of subarachnoid hemorrhage among 121 patients discharged after a full course of antibiotics (Salgado et al., 1987).

Treatment of intracranial infections Antimicrobial treatment of meningitis and cerebritis should be that of the endocarditis, depending on the type of agent identified. For brain abscess, ceftriaxone plus metronidazole is the usual empiric combination. Neurosurgery is rarely indicated because brain abscesses are usually small and multiple (Salgado, 1991) and can be cured by antibiotic treatment. Neurosurgery can be indicated in enlarging abscesses and in abscesses associated with a deteriorating neurologic condition, despite antimicrobial treatment.

CONCLUSIONS Despite important improvements in the diagnostic technologies for heart and brain imaging, infective endocarditis remains a formidable diagnostic and therapeutic challenge. Its contemporary management requires the cooperation of cardiologists, cardiac surgeons, neurologists, neurosurgeons, neuroradiologists, intensivists, and specialists in infectious diseases. Most of the current recommendation and guidelines are based on low-quality evidence. The lack of robust information in such a serious and potentially lethal disease stresses the need for large, multidisciplinary registries and randomized controlled trials.

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