European Heart Journal (2009) 30, 2369–2413 doi:10.

1093/eurheartj/ehp285

ESC GUIDELINES

Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009)
The Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC)
Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and by the International Society of Chemotherapy (ISC) for Infection and Cancer
Authors/Task Force Members: Gilbert Habib (Chairperson) (France)*, Bruno Hoen (France), Pilar Tornos (Spain), Franck Thuny (France), Bernard Prendergast (UK), Isidre Vilacosta (Spain), Philippe Moreillon (Switzerland), Manuel de Jesus Antunes (Portugal), Ulf Thilen (Sweden), John Lekakis (Greece), Maria Lengyel (Hungary), ¨ Ludwig Muller (Austria), Christoph K. Naber (Germany), Petros Nihoyannopoulos (UK), Anton Moritz (Germany), Jose Luis Zamorano (Spain) ESC Committee for Practice Guidelines (CPG): Alec Vahanian (Chairperson) (France), Angelo Auricchio (Switzerland), Jeroen Bax (The Netherlands), Claudio Ceconi (Italy), Veronica Dean (France), Gerasimos Filippatos (Greece), Christian Funck-Brentano (France), Richard Hobbs (UK), Peter Kearney (Ireland), Theresa McDonagh (UK), Keith McGregor (France), Bogdan A. Popescu (Romania), Zeljko Reiner (Croatia), Udo Sechtem (Germany), Per Anton Sirnes (Norway), Michal Tendera (Poland), Panos Vardas (Greece), Petr Widimsky (Czech Republic) Document Reviewers: Alec Vahanian (CPG Review Coordinator) (France), Rio Aguilar (Spain), Maria Grazia Bongiorni (Italy), Michael Borger (Germany), Eric Butchart (UK), Nicolas Danchin (France), Francois Delahaye (France), Raimund Erbel (Germany), Damian Franzen (Germany), Kate Gould (UK), Roger Hall ´ ´ (UK), Christian Hassager (Denmark), Keld Kjeldsen (Denmark), Richard McManus (UK), Jose M. Miro (Spain), ´ ´ Ales Mokracek (Czech Republic), Raphael Rosenhek (Austria), Jose A. San Roman Calvar (Spain), Petar Seferovic (Serbia), Christine Selton-Suty (France), Miguel Sousa Uva (Portugal), Rita Trinchero (Italy), Guy van Camp (Belgium)
The disclosure forms of the authors and reviewers are available on the ESC website www.escardio.org/guidelines

* Corresponding author. Gilbert Habib, Service de Cardiologie, CHU La Timone, Bd Jean Moulin, 13005 Marseille, France. Tel: þ33 4 91 38 63 79, Email: gilbert.habib@free.fr
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC. Disclaimer. The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written. Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient’s guardian or carer. It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

& The European Society of Cardiology 2009. All rights reserved. For permissions please email: journals.permissions@oxfordjournals.org.

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ESC Guidelines

Table of Contents
A. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Justification/scope of the problem . . . . . . . . . . . . . . . . . C. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A changing epidemiology . . . . . . . . . . . . . . . . . . . . . Incidence of infective endocarditis . . . . . . . . . . . . . . . Types of infective endocarditis . . . . . . . . . . . . . . . . . . Microbiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The valve endothelium . . . . . . . . . . . . . . . . . . . . . . . Transient bacteraemia . . . . . . . . . . . . . . . . . . . . . . . Microbial pathogens and host defences . . . . . . . . . . . . E. Preventive measures . . . . . . . . . . . . . . . . . . . . . . . . . . Evidence justifying the use of antibiotic prophylaxis for infective endocarditis in previous ESC recommendations Reasons justifying revision of previous ESC Guidelines . . Principles of the new ESC Guidelines . . . . . . . . . . . . . Limitations and consequences of the new ESC Guidelines F. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . Microbiological diagnosis . . . . . . . . . . . . . . . . . . . . . . Diagnostic criteria and their limitations . . . . . . . . . . . . G. Prognostic assessment at admission . . . . . . . . . . . . . . . . H. Antimicrobial therapy: principles and methods . . . . . . . . . General principles . . . . . . . . . . . . . . . . . . . . . . . . . . Penicillin-susceptible oral streptococci and group D streptococci . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Penicillin-resistant oral streptococci and group D streptococci . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Streptococcus pneumoniae, b-haemolytic streptococci (groups A, B, C, and G) . . . . . . . . . . . . . . . . . . . . . . Nutritionally variant streptococci . . . . . . . . . . . . . . . . Staphylococcus aureus and coagulase-negative staphylococci . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methicillin-resistant and vancomycin-resistant staphylococci . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enterococcus spp. . . . . . . . . . . . . . . . . . . . . . . . . . . . Gram-negative bacteria . . . . . . . . . . . . . . . . . . . . . . . Blood culture-negative infective endocarditis . . . . . . . . Fungi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Empirical therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Outpatient parenteral antibiotic therapy for infective endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I. Complications and indications for surgery in left-sided native valve infective endocarditis . . . . . . . . . . . . . . . . . . . . . . . . Part 1. Indications and optimal timing of surgery . . . . . . . . . Heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncontrolled infection . . . . . . . . . . . . . . . . . . . . . . . Prevention of systemic embolism . . . . . . . . . . . . . . . . Part 2. Principles, methods, and immediate results of surgery . Pre- and peri-operative management . . . . . . . . . . . . . . Surgical approach and techniques . . . . . . . . . . . . . . . . Operative mortality, morbidity, and post-operative complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2371 2372 2372 2372 2373 2373 2373 2374 2374 2374 2374 2375 2375 2375 2376 2378 2378 2378 2379 2380 2382 2383 2383 2383 2384 2384 2384 2384 2386 2387 2387 2387 2387 2388 2388 2389 2391 2391 2391 2392 2393 2394 2394 2394 2394

J. Other complications of infective endocarditis Part 1. Neurological complications, antithrombotic therapy . . Part 2. Other complications (infectious aneurysms, acute renal failure, rheumatic complications, splenic abscess, myocarditis, pericarditis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . K. Outcome after discharge and long-term prognosis . . . . . . Recurrences: relapses and reinfections . . . . . . . . . . . . Heart failure and need for valvular surgery . . . . . . . . . Long-term mortality . . . . . . . . . . . . . . . . . . . . . . . . Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . L. Specific situations Part 1. Prosthetic valve endocarditis . . . . . . . . . . . . . . . . . . Part 2. Infective endocarditis on pacemakers and implantable defibrillators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Part 3. Right-sided infective endocarditis . . . . . . . . . . . . . . . Part 4. Infective endocarditis in congenital heart disease . . . . Part 5. Infective endocarditis in the elderly . . . . . . . . . . . . . Part 6. Infective endocarditis during pregnancy . . . . . . . . . . . M. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations and acronyms
BCNIE CD CDRIE CHD CNS CT ELISA HF IA ICD ICE IE IVDA LDI MBC MIC MRI MRSA MSSA NBTE NVE OPAT PBP PCR PET PMP PPM PVE TEE TTE VISA blood culture-negative infective endocarditis cardiac device cardiac device-related infective endocarditis congenital heart disease coagulase-negative staphylococci computed tomography enzyme-linked immunosorbent assay heart failure infectious aneurysm implantable cardioverter defibrillator International Collaboration on Endocarditis infective endocarditis intravenous drug abuser local device infection minimal bactericidal concentration minimal inhibitory concentration magnetic resonance imaging methicillin-resistant Staphylococcus aureus methicillin-susceptible Staphylococcus aureus non-bacterial thrombotic endocarditis native valve endocarditis outpatient parenteral antibiotic therapy plasma-binding protein polymerase chain reaction positron emission tomography platelet microbicidal protein permanent pacemaker prosthetic valve endocarditis transoesophagal echocardiography transthoracic echocardiography vancomycin-intermediate Staphylococcus aureus

ESC Guidelines

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arise during the writing period must be notified to the ESC. The Task Force report received its entire financial support from the ESC and was developed without any involvement of the pharmaceutical, device, or surgical industry. The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups, or consensus panels. The Committee is also responsible for the endorsement process of these Guidelines and Expert Consensus Documents or statements. Once the document has been finalized and approved by all the experts involved in the Task Force, it is submitted to outside specialists for review. The document is revised, and finally approved by the CPG and subsequently published. After publication, dissemination of the message is of paramount importance. Pocket-sized versions and personal digital assistant (PDA)-downloadable versions are useful at the point of care. Some surveys have shown that the intended users are sometimes unaware of the existence of guidelines, or simply do not translate them into practice. Thus, implementation programmes for new guidelines form an important component of knowledge dissemination. Meetings are organized by the ESC, and directed towards its member National Societies and key opinion leaders in Europe. Implementation meetings can also be undertaken at national levels, once the guidelines have been endorsed by the ESC member societies, and translated into the national language. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations. Thus, the task of writing Guidelines or Expert Consensus documents covers not only the integration of the most recent research, but also the creation of educational tools and implementation programmes for the recommendations. The loop between clinical research, writing of guidelines, and implementing them into clinical

A. Preamble
Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on outcome, as well as the risk/ benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/ knowledge/guidelines/rules). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/ or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk/ benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in Tables 1 and 2. The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that

Table 1

Classes of recommendations

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Table 2

Levels of evidence

practice can then only be completed if surveys and registries are performed to verify that real-life daily practice is in keeping with what is recommended in the guidelines. Such surveys and registries also make it possible to evaluate the impact of implementation of the guidelines on patient outcomes. Guidelines and recommendations should help the physicians to make decisions in their daily practice, However, the ultimate judgement regarding the care of an individual patient must be made by the physician in charge of his/her care.

in clinical decision making. These recommendations were obtained by expert consensus after thorough review of the available literature. An evidence-based scoring system was used, based on a classification of the strength of recommendation and the levels of evidence.

C. Epidemiology
A changing epidemiology
The epidemiological profile of IE has changed substantially over the last few years, especially in industrialized nations.1 Once a disease affecting young adults with previously well-identified (mostly rheumatic) valve disease, IE is now affecting older patients who more often develop IE as the result of health care-associated procedures, either in patients with no previously known valve disease14 or in patients with prosthetic valves.15 A recent systematic review of 15 population-based investigations accounting for 2371 IE cases from seven developed countries (Denmark, France, Italy, The Netherlands, Sweden, the UK, and the USA) showed an increasing incidence of IE associated with a prosthetic valve, an increase in cases with underlying mitral valve prolapse, and a decrease in those with underlying rheumatic heart disease.16 Newer predisposing factors have emerged—valve prostheses, degenerative valve sclerosis, intravenous drug abuse—associated with increased use of invasive procedures at risk for bacteraemia, resulting in health care-associated IE.17 In a pooled analysis of 3784 episodes of IE, it was shown that oral streptococci had fallen into second place to staphylococci as the leading cause of IE.1 However, this apparent temporal shift from predominantly streptococcal to predominantly staphylococcal IE may be partly due to recruitment/referral bias in specialized centres, since this trend is not evident in population-based epidemiological surveys of IE.18 In developing countries, classical patterns persist. In Tunisia, for instance, most cases of IE develop in patients with rheumatic valve disease, streptococci predominate, and up to 50% may be associated with negative blood cultures.19 In other African countries, the persistence of a high burden of rheumatic fever, rheumatic valvular heart diseases, and IE has also been highlighted.20 In addition, significant geographical variations have been shown. The highest increase in the rate of staphylococcal IE has been reported in the USA,21 where chronic haemodialysis, diabetes mellitus, and intravascular devices are the three main factors

B. Justification/scope of the problem
Infective endocarditis (IE) is a peculiar disease for at least three reasons: First, neither the incidence nor the mortality of the disease have decreased in the past 30 years.1 Despite major advances in both diagnostic and therapeutic procedures, this disease still carries a poor prognosis and a high mortality. Secondly, IE is not a uniform disease, but presents in a variety of different forms, varying according to the initial clinical manifestation, the underlying cardiac disease (if any), the microorganism involved, the presence or absence of complications, and underlying patient characteristics. For this reason, IE requires a collaborative approach, involving primary care physicians, cardiologists, surgeons, microbiologists, infectious disease specialists, and frequently others, including neurologists, neurosurgeons, radiologists, and pathologists.2 Thirdly, guidelines are often based on expert opinion because of the low incidence of the disease, the absence of randomized trials, and the limited number of meta-analyses.3,4 Several reasons justify the decision of the ESC to update the previous guidelines published in 2004.3 IE is clearly an evolving disease, with changes in its microbiological profile, a higher incidence of health care-associated cases, elderly patients, and patients with intracardiac devices or prostheses. Conversely, cases related to rheumatic disease have become less frequent in industrialized nations. In addition, several new national and international guidelines or state-of-the-art papers have been published in recent years.3 – 13 Unfortunately, their conclusions are not uniform, particularly in the field of prophylaxis, where conflicting recommendations have been formulated.3,4,6,8 – 13 Clearly, an objective for the next few years will be an attempt to harmonize these recommendations. The main objective of the current Task Force was to provide clear and simple recommendations, assisting health care providers

14. left-sided Table 3 Classification and definitions of infective endocarditis . milleri’ or ‘S. Furthermore. and Gemella morbillorum. the following situations can be identified: community-acquired IE. the male:female ratio is !2:1.28 a.22 In other countries. S.23 Incidence of infective endocarditis The incidence of IE ranges from one country to another within 3–10 episodes/100 000 person-years. In an attempt to avoid overlap. the incidence of IE was very low in young patients but increased dramatically with age—the peak incidence was 14.ESC Guidelines 2373 prosthetic valve IE.21. and device-related IE (the latter including IE developing on pacemaker or defibrillator wires with or without associated valve involvement) (Table 3). associated with the development of Staphylococcus aureus endocarditis. health care-associated IE (nosocomial and non-nosocomial). according to the site of infection and the presence or absence of intracardiac foreign material: left-sided native valve IE. Causative microorganisms are most often staphylococci. S. the main predisposing factor for S. and IE in intravenous drug abusers (IVDAs). streptococci. salivarius. Microorganisms of this group are almost always susceptible to penicillin G. and S. anginosus’ group (S. S. mitis. female patients may have a worse prognosis and undergo valve surgery less frequently than their male counterparts. sanguis. constellatus) must be distinguished since they Types of infective endocarditis IE should be regarded as a set of clinical situations which are sometimes very different from each other. and enterococci. intermedius. In all epidemiological studies of IE.27 Microbiology According to microbiological findings. in these surveys. Of note. the following four categories of IE must be separated. right-sided IE. anginosus. S. although this higher proportion of men is poorly understood. Members of the ‘S. the following categories are proposed: 1. mutans. representing 85% of all IE. Infective endocarditis due to streptococci and enterococci Oral (formerly viridans) streptococci form a mixed group of microorganisms.5 episodes/100 000 person-years in patients between 70 and 80 years of age. aureus IE may be intravenous drug abuse.24 – 26 This may reflect methodological differences between surveys rather than true variation. Infective endocarditis with positive blood cultures This is the most important category. With regard to acquisition. which includes species such as S.

Diagnosis in such cases relies on serological testing. Degenerative valve lesions are detected by echocardiography in up to 50% of asymptomatic patients over 60 years. and fungi. Local inflammation triggers endothelial cells to express integrins of the b1 family (very late antigen). fastidious Gram-negative bacilli of the HACEK group (Haemophilus parainfluenzae. Microbial pathogens and host defences Classical IE pathogens (S. like oral streptococci. Among enterococci. as in rheumatic carditis. microulcers. E. durans. Chlamydia. where they can either persist and escape host defences and antibiotics. staphylococcal prosthetic valve IE is more frequently due to coagulase-negative staphylococci (CNS) with oxacillin resistance. and the deposition of fibrin and platelets as a normal healing process. are the three species that cause IE. trigger local procoagulant activity. Bartonella. Endothelial damage may result from mechanical lesions provoked by turbulent blood flow. bacteraemia does not occur only after invasive procedures. faecium.. fibronectin. or degenerative changes in elderly individuals. Kingella kingae. Transient bacteraemia The role of bacteraemia has been studied in animals with catheterinduced NBTE. adherent bacteria must escape host defences. However. and to a lesser extent E. fibrinogen. S. at least in community-acquired IE. Staphylococcal infective endocarditis Traditionally. b. Following colonization.37 They are equipped with numerous surface determinants that mediate adherence to host matrix molecules present on damaged valves (e.22 Conversely. and K. Cardiobacterium hominis. nutritionally variant ‘defective’ streptococci.) share the ability to adhere to damaged valves. and nurture infected vegetations in which they can survive. Actinobacillus actinomycetemcomitans. aureus trigger their active internalization into valve endothelial cells.29 – 31 especially S.34 Thus. denitrificans). Blood cultures may remain negative for many days after antibiotic discontinuation. recently reclassified into other species (Abiotrophia and Granulicatella). CNS can also cause native valve IE. Infective endocarditis associated with constantly negative blood cultures They are caused by intracellular bacteria such as Coxiella burnetii. or multiply and spread to distant organs. Integrins of the b1 family bind circulating fibronectin to the endothelial surface while S. S. 2. and causative organisms are most often oral streptococci or CNS. aureus and other potential intracellular pathogens. However. platelet proteins) and trigger platelet activation. which frequently has an aggressive clinical course. Such spontaneous bacteraemia is of low grade and short duration [1– 100 colony-forming units (cfu)/ml of blood for . mechanical disruption of the endothelium results in exposure of underlying extracellular matrix proteins. Infective endocarditis frequently associated with negative blood cultures They are usually due to fastidious organisms such as nutritionally variant streptococci. inflammation. the agent of Whipple’s disease. aphrophilus.36 3.35 Of note. Integrins are transmembrane proteins that can connect extracellular determinants to the cellular cytoskeleton. but also as a consequence of chewing and tooth brushing. as recently demonstrated. and were until recently gathered under the name of Streptococcus bovis. This might account for the increased risk of IE in the elderly. Pathophysiology The valve endothelium The normal valve endothelium is resistant to colonization and infection by circulating bacteria. Streptococcus spp. favouring infection by most types of organism. Likewise. Both the magnitude of bacteraemia and the ability of the pathogen to attach to damaged valves are important. Tropheryma whipplei. influenzae. . should also be distinguished since they are often tolerant to penicillin [minimal bactericidal concentration (MBC) much higher than the mimimal inhibitory concentration (MIC)].32 Overall. Endothelial inflammation without valve lesions may also promote IE. but its high incidence may explain why most cases of IE are unrelated to invasive procedures. these account for up to 5% of all IE. and Enterococcus spp.2374 tend to form abscesses and cause haematogenously disseminated infection. They are usually sensitive to penicillin G. the production of tissue factor. Eikenella corrodens. aureus. lugdunensis. cell culture or gene amplification. Brucella. and. H. Gram- 4. Infective endocarditis with negative blood cultures because of prior antibiotic treatment This situation arises in patients who received antibiotics for unexplained fever before any blood cultures were performed and in whom the diagnosis of IE was not considered. aureus was the most frequent cause not only of IE but also of prosthetic valve IE. which are associated with inflammation. native valve staphylococcal IE is due to S. faecalis. Group D streptococci form the ‘Streptococcus bovis/Streptococcus equinus’ complex. Hence.10 min]. aureus and some other IE pathogens carry fibronectin-binding proteins on their surface. promoting IE due to S. often requiring a longer duration of antibiotic treatment. in a recent study of 1779 cases of IE collected prospectively in 16 countries. and microthrombi. Once adherent. electrodes or catheters. and one occurring on physically undamaged endothelium. including commensal species of the human intestinal tract.33 and in a similar proportion of elderly patients with IE. H. In contrast. there are at least two scenarios for primary valve infection: one involving a physically damaged endothelium. usually the diagnosis is eventually considered in the face of relapsing febrile episodes following antibiotic discontinuation. paraphrophilus. which is most often susceptible to oxacillin. ESC Guidelines D. aureus. Such nonbacterial thrombotic endocarditis (NBTE) facilitates bacterial adherence and infection. when activated endothelial cells bind fibronectin they provide an adhesive surface to circulating staphylococci. E. H.g.26.

ranges from 1:14 000 000 for dental procedures in the average population to 1:95 000 in patients with previous IE. no sufficient evidence exists from case –control studies36. no potential index procedure preceding the first clinical appearance of IE can be identified. Recent guideline committees of national cardiovascular societies have re-evaluated the existing scientific evidence in this field. Incidence of bacteraemia after dental procedures and during daily routine activities The reported incidence of transient bacteraemia after dental procedures is highly variable and ranges from 10 to 100%.52 to support the necessity of IE prophylaxis. However. . (2) Prophylaxis should be limited to the highest risk patients (patients with the highest incidence of IE and/or highest risk of adverse outcome from IE). whereas similar bacteria recovered from patients with other types of infection are susceptible.6.44 positive bacteria are resistant to complement. The incidence after other types of medical procedures is even less well established. in patients with poor dental health. bacteraemia can be observed independently of dental procedures. this observation leads to two conclusions: (i) IE prophylaxis can at best only protect a small proportion of patients.52 Finally. case reports.50 and so far there are no data demonstrating that reduced duration or frequency of bacteraemia after any medical procedure leads to a reduced procedure-related risk of IE. escaping PMP-induced killing is a typical characteristic of IE-causing pathogens. non-evidence-based use of antibiotics for all at-risk patients undergoing interventional procedures.46 These estimations demonstrate the huge number of patients that will require treatment to prevent one single case of IE. (3) The indications for antibiotic prophylaxis for IE should be reduced in comparison with previous recommendations. and rates of post-procedural bacteraemia are higher in this group. but to limit prophylaxis to the highest risk patients. However.51.40 Reasons justifying revision of previous ESC Guidelines Within these guidelines. These findings emphasize the importance of good oral hygiene and regular dental review to prevent IE.ESC Guidelines 2375 (a) Increased lifetime risk of IE is not an ideal measure of the extent to which a patient may benefit from antibiotic prophylaxis for distinct procedures. no case of fatal anaphylaxis has been reported in the literature after oral amoxicillin administration for prophylaxis of IE.45.44 2. The main reasons justifying the revision of previous recommendations are the following: 1.49. particularly in patients with predisposing factors. Similarly.47 and (ii) the bacteraemia that causes IE in the majority of patients appears to derive from another source. flossing. Lack of scientific evidence for the efficacy of infective endocarditis prophylaxis Studies reporting on the efficacy of antibiotic prophylaxis to prevent or alter bacteraemia in humans after dental procedures are contradictory. Preventive measures Evidence justifying the use of antibiotic prophylaxis for infective endocarditis in previous ESC recommendations The principle of prophylaxis for IE was developed on the basis of observational studies in the early 20th century. In contrast.48 (d) Widespread and often inappropriate use of antibiotics may result in the emergence of resistant microorganisms. they may be the target of platelet microbicidal proteins (PMPs). studies on isolated aspects of the hypothesis. which are produced by activated platelets and kill microbes by disturbing their plasma membrane. Risks and benefits of prophylaxis The following considerations are critical with respect to the assumption that antibiotic prophylaxis can efficiently prevent IE in patients who are at increased lifetime risk of the disease: 3.26 Even if effectiveness and compliance are assumed to approximate 100%. Even strict adherence to generally accepted recommendations for prophylaxis might have little impact on the total number of patients with IE in the community. the Task Force aimed to avoid extensive. the procedure-related risk. and these results should be interpreted with caution. data from animal experiments. (b) In the majority of patients. transient bacteraemia is reported to occur frequently in the context of daily routine activities such as tooth brushing. In addition. Bacteria recovered from patients with IE are consistently resistant to PMP-induced killing. or chewing. E. they did uniformly and independently draw four conclusions: (1) The existing evidence does not support the extensive use of antibiotic prophylaxis recommended in previous guidelines. (c) Antibiotic administration carries a small risk of anaphylaxis.38 Thus. the extent to which antiobiotic use for IE prophylaxis could be implicated in the general problem of resistance is unknown. or by altering bacterial properties leading to reduced bacterial adherence on the endothelial surface. and contradictory observational studies. A better parameter.53 and assumptions on efficacy are based on non-uniform expert opinion. the concept of antibiotic prophylaxis efficacy itself has never been investigated in a prospective randomized controlled trial. and that prophylactic antibiotics can prevent IE in these patients by minimizing or preventing bacteraemia.42.9 – 11 Although the individual recommendations of these committees differ in some aspects.39 The basic hypothesis is based on the assumption that bacteraemia subsequent to medical procedures can cause IE. However. The recommendations for prophylaxis are based in part on the results of animal studies showing that antibiotics could prevent the development of experimental IE after inoculation of bacteria.43 It therefore appears plausible that a large proportion of IE-causing bacteraemia may derive from these daily routine activities.41 This may be a result of different analytical methods and sampling procedures.

b a . Table 5 Recommendations for prophylaxis of infective endocarditis in highest risk patients according to the type of procedure at risk Class of recommendation.54. – ESC Guidelines to limit its indication to patients with the highest risk of IE (Table 4) undergoing the highest risk procedures (Table 5). Principles of the new ESC Guidelines Although recent guidelines proposed limitation of prophylaxis to patients at increased risk of adverse outcome of IE6 or even complete cessation of antibiotic prophylaxis in any patient groups.55 Table 4 Cardiac conditions at highest risk of infective endocarditis for which prophylaxis is recommended when a high risk procedure is performed a b Class of recommendation. please refer to text. but 1. Patients with the highest risk of infective endocarditis (Table 4) They include three categories of patients: (a) Patients with a prosthetic valve or a prosthetic material used for cardiac valve repair: these patients have a higher risk of IE. *For management when infections are present. Level of evidence.12 the Task Force decided: – to maintain the principle of antibiotic prophylaxis when performing procedures at risk of IE in patients with predisposing cardiac conditions. a higher mortality from IE and more often develop complications of the disease than patients with native valves and an identical pathogen.2376 (4) Good oral hygiene and regular dental review are of particular importance for the prevention of IE. Level of evidence.

although the risk of adverse outcome is high when IE occurs in transplant patients. b. for children. e.57 (c) Patients with congenital heart disease (CHD). Vancomycin should only be administered to patients unable to tolerate b-lactams.60 The ESC Task Force does not recommend prophylaxis in such situations. If the infection is known or suspected to be caused by MRSA. cefazolin or ceftriaxone 1 g i. vancomycin or another suitable agent should be administered. 2.61 particularly when piercing involves the tongue. for children. Prophylaxis is not recommended for any other form of native valve disease (including the most commonly identified conditions. The main targets for antibiotic prophylaxis in these patients are oral streptococci. aureus (MRSA). consultation with an infectious diseases specialist is recommended. e. or vancomycin. particularly for those individuals with CHD who are at increased susceptibility for the acquisition of IE. Dental procedures Procedures at risk involve the manipulation of the gingival or periapical region of teeth or perforation of the oral mucosa (including scaling and root canal procedures). Education of patients at risk of IE is paramount. (b) Patients with previous IE: they also have a greater risk of new IE. ii. the Task Force recommends prophylaxis for the first 6 months after the procedure until endothelialization of the prosthetic material occurs. The impact of increasing resistance of these pathogens for the efficacy of antibiotic prophylaxis is unclear.g. Fluoroquinolones and glycopeptides are not recommended due to their unclear efficacy and the potential induction of resistance. or 50 mg/kg i. and is not recommended in other situations. Gastrointestinal or genitourinary procedures. or other prostheses. ampicillin. it is reasonable that the antibiotic regimen includes an agent active against enterococci. drainage of an abscess. angio-oedema. In addition. Vancomycin or clindamycin may be used in patients unable to tolerate a b-lactam. skin structure. iii. in particular those with complex cyanotic heart disease and those who have post-operative palliative shunts. In the case of an established infection or if antibiotic therapy is indicated to prevent wound infection or sepsis associated with a gastrointestinal or genitourinary tract procedure in patients described in Table 4.62. for adults or 50 mg/kg i. . an anti-staphylococcal penicillin or cephalosporin.6 this is not supported by strong evidence. * Alternatively cephalexin 2 g i. Respiratory tract procedures. Patients listed in Table 4 who undergo an invasive respiratory tract procedure to treat an established infection. mitral valve prolapse. If undertaken. Although AHA guidelines recommend prophylaxis in cardiac transplant recipients who develop cardiac valvulopathy. Other at-risk procedures There is no compelling evidence that bacteraemia resulting from either respiratory tract procedures. Case reports of IE after piercing and tattooing are increasing. amoxicillin.v.v. iv. procedures should be performed under strictly sterile conditions though antibiotic prophylaxis is not recommended. the probability of IE from dental origin is extremely low in these patients. i. Vancomycin or another suitable agent should be administered if the infection is known or suspected to be caused by a methicillin-resistant strain of S. should receive an antibiotic regimen which contains an anti-staphylococcal penicillin or cephalosporin. gastrointestinal or genitorurinary procedures. or urticaria after intake of penicillin and ampicillin. Vancomycin should be given to patients unable to tolerate a b-lactam.ESC Guidelines 2377 cause IE. Currently no data are available on (a) the incidence of IE after such procedures and (b) the efficacy of antibiotics for prevention.g.58.63 although publication bias may overestimate the problem since millions of people are tattooed and pierced around the world and CHD concerns only 1% of the general population. bicuspid aortic valve. These growing social trends are a cause for concern. or musculoskeletal tissue. prophylaxis is not recommended in patients undergoing these procedures. Prophylaxis should only be considered for patients described in Table 4 undergoing any of these procedures. Highest risk procedures (Table 5) a. and calcific aortic stenosis). and piercing and tattooing procedures should be discouraged. Table 6 summarizes the main regimens of antibiotic prophylaxis recommended before dental procedures. e. Body piercing and tattooing. dermatological or musculoskeletal procedures Table 6 Recommended prophylaxis for dental procedures at risk Cephalosporins should not be used in patients with anaphylaxis. conduits.v.g.59 After surgical repair with no residual defects. it is reasonable that the therapeutic regimen contains an agent active against staphylococci and b-haemolytic streptococci. For patients described in Table 4 undergoing surgical procedures involving infected skin (including oral abscesses). Thus.56.v. If infection is caused by a known or suspected strain of resistant enterococcus. higher mortality and incidence of complications than patients with a first episode of IE. Dermatological or musculoskeletal procedures.

the Task Force strongly recommends prospective evaluation in the wake of these new guidelines to evaluate whether reduced use of prophylaxis is associated with a change in the incidence of IE.2378 v. They represent up to 30% of all cases of IE and are characterized by an increasing incidence and a severe prognosis. Thus. Ethically. and these views should be respected. As Table 7 Clinical presentation of infective endocarditis *NB: Fever may be absent in the elderly. .66 Finally. Cardiac or vascular surgery.67 The clinical history of IE is highly variable according to the causative microorganism. rheumatological and autoimmune disease. Procedures causing health care-associated IE. often associated with systemic symptoms of chills. rapidly progressive infection. repeated if the procedure is prolonged. poor appetite. In patients undergoing implantation of a prosthetic valve or intravascular prosthetic or other foreign material. unless the latter procedure is urgent. the presence or absence of pre-existing cardiac disease. aseptic measures during the insertion and manipulation of venous catheters and during any invasive procedures are mandatory to reduce the rate of this infection. Up to 90% of patients present with fever. Following informed review and discussion. It is strongly recommended that potential sources of dental sepsis are eliminated at least 2 weeks before implantation of a prosthetic valve or other intracardiac or intravascular foreign material. Aseptic measures are mandatory during venous catheters manipulation and during any invasive procedures in order to reduce the rate of health care-associated IE F. IE should be suspected in a variety of very different clinical situations (Table 7).64 Although routine antimicrobial prophylaxis administered before most invasive procedures is not recommended. peri-operative antibiotic prophylaxis should be considered due to the increased risk and adverse outcome of an infection. aureus. and the mode of presentation. Heart Limitations and consequences of the new ESC Guidelines The Task Force understands that these updated recommendations dramatically change long-established practice for physicians. many may wish to continue with routine prophylaxis. The early involvement of a cardiologist and an infectious disease specialist to guide management is highly recommended. these practitioners need to discuss the potential benefit and harm of antibiotic prophylaxis with their patients before a final decision is made.1 year after surgery) prosthetic valve infections are CNS and S. In summary. It may present as an acute. the current recommendations are not based on appropriate evidence. dentists. The most frequent microorganisms underlying early (. Prophylaxis should be started immediately before the procedure. and their patients.65 though unnecessarily so since adherence to recognized guidelines affords robust legal protection. and terminated 48 h afterwards. and weight loss. ESC Guidelines neither the previous guidelines nor the current proposed modifications are based on strong evidence. Diagnosis Clinical features The diverse nature and evolving epidemiological profile of IE ensure it remains a diagnostic challenge. vi. or malignancy. but also as a subacute or chronic disease with low grade fever and non-specific symptoms which may thwart or confuse initial assessment. but reflect an expert consensus of opinion. in the immunocompromised patient and in IE involving less virulent or atypical organisms. after antibiotic pre-treatment. the Task Force proposes limitation of antibiotic prophylaxis to patients with the highest risk of IE undergoing the highest risk dental procedures. Patients may therefore present to a variety of specialists who may consider a range of alternative diagnoses including chronic infection. thus representing an important health problem. Practitioners may also have a reasonable fear of litigation should prophylaxis be withdrawn. cardiologists. Good oral hygiene and regular dental review have a very important role in reducing the risk of IE.

69 in whom fever is less frequent than in younger individuals.7 Atypical presentation is common in elderly or immunocompromised patients. and follow-up (Table 8) of IE is clearly recognized. these lack specificity and have not been integrated into current diagnostic criteria. and appropriate application in the context of simple clinical criteria improves diagnostic yield71 (Figure 1). management. Echocardiography Transthoracic and transoesophageal echocardiography (TTE/TEE) are now ubiquitous and their fundamental importance in diagnosis. b a murmurs are found in up to 85% of patients. although peripheral stigmata of IE are increasingly uncommon elsewhere. *TEE is not mandatory in isolated right-sided native valve IE with good quality TTE examination and unequivocal echocardiographic findings. anaemia. and glomerulonephritis remain common. An exception is the patient with S. However. TTE ¼ transthoracic echocardiography. and microscopic haematuria. The utility of both modes of investigation is diminished when applied indiscriminately.70 Echocardiography must be performed rapidly. . the diagnostic suspicion may be strengthened by laboratory signs of infection. Level of evidence. lung or spleen occur in 30% of patients and are often the presenting feature. as soon as IE is suspected.3 However. such as elevated C-reactive protein or sedimentation rate. Classic textbook signs may still be seen in the developing world. however.68 In a febrile patient. Roth spots. vascular and immunological phenomena such as splinter haemorrhages. TTE ¼ transthoracic echocardiography. as patients generally present at an early stage of the disease. IE ¼ infective endocarditis.ESC Guidelines 2379 Table 8 Role of echocardiography in infective endocarditis Class of recommendation. TEE ¼ transoesophageal echocardiography. TEE ¼ transoesophageal echocardiography. leukocytosis. aureus Figure 1 Indications for echocardiography in suspected infective endocarditis. and emboli to the brain. A high index of suspicion and low threshold for investigation to exclude IE are therefore essential in these and other high-risk groups.

abscess.77 Microbiological diagnosis 1. each containing 10 mL of blood obtained from a peripheral vein using meticulous sterile technique. When cultures remain negative at 5 days.76 while the roles of three-dimensional echocardiography and other alternative modes of imaging [computed tomography (CT). or even earlier in case of S. Appearances resembling vegetations may be seen in degenerative or myxomatous valve disease. especially for potentially ‘contaminants’ such as CNS or corynebacteria. degenerative calcified lesions. Identification of vegetations may be difficult in the presence of preexisting severe lesions (mitral valve prolapse. if vegetations are very small (. and (2) virtually all blood cultures (or a majority of them) are positive. subculture onto chocolate agar plates may .75 However. and its devastating effects once intracardiac infection is established.79. diagnosis may be particularly challenging in IE affecting intracardiac devices. The use of harmonic imaging has improved study quality. and new dehiscence of a prosthetic valve (see Table 9 for anatomical and echocardiographic definitions).72 Three echocardiographic findings are major criteria in the diagnosis of IE: vegetation.2380 ESC Guidelines Table 9 Anatomic and echocardiographic definitions bacteraemia where routine echocardiography is justified in view of the frequency of IE in this setting and of the virulence of this organism. typically staphylococcal) and misleading findings. small abscesses may be difficult to identify. cultures should be incubated in both aerobic and anaerobic atmospheres to detect organisms such as Bacteroides or Clostridium species. although surveys of contemporary practice reveal frequent violations of this rule. with little additional information derived after the second or third assessment. and radionuclide scanning] have yet to be evaluated in IE.13. Additional echocardiographic study is seldom helpful. a single positive blood culture shoud be regarded cautiously for establishing the diagnosis of IE. particularly for the assessment of the perivalvular extent of abscesses and pseudoaneurysms.2 mm). and rheumatoid disease. positron emission tomography (PET). and in association with small intracardiac tumours (typically fibroelastomata). The need for culture prior to antibiotic administration is self-evident. not yet present (or already embolized). repeat TTE/TEE must be performed 7–10 days later if the clinical level of suspicion is still high. Although IE caused by anaerobes is uncommon.78 Sampling from central venous catheters should be avoided in view of the high risk of contaminants (false positives. Other advances in imaging technology have had minimal impact in routine clinical practice. As a result. systemic lupus (inflammatory Libman –Sacks lesions). Three sets (including at least one aerobic and one anaerobic). Similarly. Multislice CT has recently been shown to give good results in the evaluation of IE-associated valvular abnormalities. is virtually always sufficient to identify the usual microorganisms—the diagnostic yield of repeated sampling thereafter is low. prosthetic valves).73 However. follow-up echocardiography to monitor complications and response to treatment is mandatory (Table 8). which has two implications: (1) there is no rationale for delaying blood sampling to coincide with peaks of fever. Blood cultures Positive blood cultures remain the cornerstones of diagnosis and provide live bacteria for susceptibility testing. valvular thrombus. chordal rupture. and in the presence of a prosthetic device (especially in the mitral position). even with use of TEE. particularly at the earliest stage of disease. aureus infection. as compared with TEE. bacteraemia is almost constant. in the post-operative period. The sensitivity of TTE ranges from 40 to 63% and that of TEE from 90 to 100%.74 In cases with an initially negative examination. advanced malignancy (marantic endocarditis).80 In IE. primary antiphospholipid syndrome. and in non-vegetant IE. magnetic resonance imaging (MRI).

5– 31% of all cases of IE.83 These organisms may be particularly common in IE affecting patients with prosthetic valves. and alternative techniques (or an alternative diagnosis) should be considered at this stage. underlying the need for withdrawing antibiotics and repeat blood Figure 2 Microbiological diagnosis in culture-positive and culture-negative infective endocarditis. renal failure.ESC Guidelines 2381 cultures in this situation. and immunocompromised states (Table 10). Histological/immunological techniques Pathological examination of resected valvular tissue or embolic fragments remains the gold standard for the diagnosis of IE and may also guide antimicrobial treatment if the causative agent can be identified allow identification of a fastidious organism. IE ¼ infective endocarditis. pacemakers. indwelling venous lines. 3. An increasingly common scenario is infection by fastidious organisms with limited proliferation under conventional culture conditions. consider antibiotic withdrawal and repeat blood cultures. Early consultation with an infectious disease specialist is recommended. . 2. Prolonged culture is associated with rising likelihood of contamination. Table 10 Investigation of rare causes of culture-negative infective endocarditis PCR ¼ polymerase chain reaction.82 BCNIE arises most commonly as a consequence of prior antibiotic administration. with profound impact on clinical outcome. often delaying diagnosis and the initiation of treatment. PCR ¼ polymerase chain reaction. or requiring specialized tools for identification (see Section C).81 A proposed scheme for the identification of microorganisms in culture-positive and culture-negative IE is provided in Figure 2. Culture-negative infective endocarditis and atypical organisms Blood-culture negative IE (BCNIE) occurs in 2. *If the organism remains unidentified and the patient is stable.

increasing prevalence of staphylococcal infection. and ELISA detection of Legionella species has been described using this technique. Electron microscopy has high sensitivity and may help to characterize new microorganisms. Incorporation of these methods into accepted diagnostic criteria awaits prospective validation.86 Although there are several advantages.93. and recent data demonstrate similar utility for staphylococci. but results still require careful specialist interpretation. Fowler VG. positive PCR can persist for months after successful eradication of infection.92 based upon clinical.84 Immunological analysis of urine may allow detection of microorganism degradation products. Indeed. and widespread use of TEE. Recent amendments recognize the role of Q-fever (a worldwide zoonosis caused by Coxiella burnetii). Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis.87. and microbiological findings provide high sensitivity and specificity (80% overall) for the diagnosis of IE.94 . 4. Bashore T. Corey GR. 94) Adapted from Li JS. risk of contamination.88 Improvements (including the availability of real-time PCR and a wider range of comparator gene sequences)89 and availability of other emerging technologies90 will address many of these deficiencies.30:633 –638. false negatives due to the presence of PCR inhibitors in clinical samples.85 The technique has been validated using valve tissue from patients undergoing surgery for IE. Nettles R. and persistent positivity despite clinical remission. Molecular biology techniques The polymerase chain reaction (PCR) allows rapid and reliable detection of fastidious and non-culturable agents in patients with IE.2382 ESC Guidelines Table 11 Modified Duke criteria for the diagnosis of infective endocarditis (adapted from Li et al. echocardiographic. PCR of excised valve tissue or embolic material should be performed in patients with negative blood cultures who undergo valve surgery or embolectomy. Diagnostic criteria and their limitations The Duke criteria. inherent limitations include the lack of reliable application to whole blood samples. Coxiella burnetii and Bartonella species may be easily detected by serological testing using indirect immunofluorescence or enzyme-linked immunosorbent assay (ELISA). Although PCR positivity has been proposed as a major diagnostic criterion for IE. including extreme sensitivity.91 the technique seems unlikely to supersede blood cultures as a prime diagnostic tool. Sexton DJ. Ryan T. inability to provide information concerning bacterial sensitivity to antimicrobial agents. and the resultant so-called modified Duke criteria are now recommended for diagnostic classification (Table 11). Jr. but is time consuming and expensive. Mick N.. by means of special stains or immunohistological techniques. The presence of a positive PCR at the time of pathological examination of the excised valve is not synonymous with treatment failure unless valve cultures are positive. Clin Infect Dis 2000.

96. when infection affects a prosthetic valve or pacemaker lead. these patients should be followed up closely and referred to tertiary care centres with surgical facilities.102 – 104 Nowadays. and when IE affects the right heart95 (particularly in IVDAs). Antimicrobial therapy: principles and methods General principles Successful treatment of IE relies on microbe eradication by antimicrobial drugs.ESC Guidelines 2383 assessed according to these variables. e. when blood cultures are negative. it should be kept in mind that these modifications await formal validation and that the original criteria were initially developed to define cases of IE for epidemiological studies and clinical trials. Host defences are of little help.107 Predictably. both in animal experiments and in humans. depressed left ventricular function. The Duke criteria are useful for the classification of IE but do not replace clinical judgement.108. G.14.96 When three of these factors are present. periannular complications.14. Surgery contributes by removing infected material and draining abscesses.96 Therefore.106 In those patients who need urgent surgery. prognostic assessment at admission can be performed using simple clinical. microbiological. A high degree of co-morbidity. The risk of patients with left-sided IE has been formally H. persistent infection and renal failure are predictors of mortality.68. Quick identification of patients at highest risk of death may offer the opportunity to change the course of the disease and improve prognosis.109 Table 12 Predictors of poor outcome in patients with IE .g. patients with an indication for surgery who cannot proceed due to prohibitive surgical risk have the worst prognosis. However. Prognosis in IE is influenced by four main factors: patient characteristics. aureus infection are at highest risk of death and need for surgery in the active phase of the disease. echocardiography and blood cultures are the cornerstone of diagnosis of IE. the risk reaches 79%. the infecting organism. In summary. but both TTE and TEE should ultimately be performed in the majority of cases of suspected or definite IE. It will also allow identification of patients with the worst immediate outcome who will benefit from closer follow-up and a more aggressive treatment strategy (eg. 50% of patients undergo surgery during hospitalization. especially in settings where sensitivity of the modified criteria is diminished.97 – 99.105. This explains why bactericidal regimens are more effective than bacteriostatic therapy.6 to 26%. Prognostic assessment at admission The in-hospital mortality rate of patients with IE varies from 9. the presence or absence of cardiac and non-cardiac complications. and should be used to choose the best therapeutic option.96 – 102 but differs considerably from patient to patient. and echocardiographic findings (Table 12). insulin-dependent diabetes. and/or S. urgent surgery). Clear deficiencies remain and clinical judgement remains essential.100.97 Patients with heart failure (HF). and echocardiographic parameters.15 In summary. and the presence of stroke are also predictors of poor in-hospital outcome. TTE must be performed first.

not for PVE. antibiotic therapy for penicillin-resistant and penicillin-susceptible oral streptococci is qualitatively similar (Table 13).113.126 Group A streptococci are uniformly susceptible to b-lactams. Ceftriaxone alone or combined with gentamicin or netilmicin given once a day is particularly convenient for outpatient therapy. Fifty patients (83%) were cured and 10 (17%) died. and G) IE due to S.118. Little experience exists with highly resistant isolates (MIC . anginosus. combined with an aminoglycoside for at least the first 2 weeks.129 Seven patients had large vegetations (. Bactericidal drug combinations are preferred to monotherapy against tolerant organisms. C.124 which requires special consideration in cases with penicillin resistance. Drug treatment of PVE should last longer (at least 6 weeks) than that of native valve endocarditis (NVE) (2–6 weeks). 47/60 (78%) patients were treated with penicillin G or ceftriaxone mostly combined with aminoglycosides. the duration of treatment is based on the first day of effective antibiotic therapy. milleri produce abscesses and thus may require adjunctive surgery.110 – 112 Cure rate is expected to be .7. Group B. B.125 IE due to group A. Some bacteria carry mutations rendering them tolerant during both active growth and stationary (dormant) phases. but is otherwise similar. which has not been formally investigated. oralis. C. C.128 possibly due to delayed diagnosis and treatment. especially the elderly. and some with either clindamycin or aminoglycosides alone. except for staphylococcal PVE where the regimen should include rifampin whenever the strain is susceptible. However. In non-complicated cases. some guidelines consider a MIC . One major hindrance to drug-induced killing is bacterial antibiotic tolerance. Recent large strain collections report .127 Antibiotic treatment is similar to that of oral streptococci (Table 13). In cases with meningitis. but to patients’ underlying conditions. In both NVE and PVE. B. and G streptococci and S. Treatment guidelines for penicillin-resistant streptococcal IE rely on retrospective series. milleri group (S. Antibiotic recommendations include penicillin G. Penicillin-resistant oral streptococci and group D streptococci Penicillin-resistant oral streptococci are classified as relatively resistant (MIC 0.30% of relatively and fully . However. and justify the need for prolonged therapy (6 weeks) to sterilize infected heart valves fully.1 mg/L) is similar to that of oral streptococci (Table 13).g.e. shortterm 2-week therapy can be administered by combining penicillin or ceftriaxone with gentamicin or netilmicin. Loading is critical because the drug is highly bound to serum proteins (!98%) and penetrates slowly into vegetations.2384 Aminoglycosides synergize with cell wall inhibitors (i.g.). i. intermedius)—is relatively rare.109a the choice of antibiotic being based on the susceptibility of the latest recovered bacterial isolate. whereas other serogroups may display resistance. and S. penicillin must be avoided because it poorly penetrates the cerebrospinal fluid. or G streptococci—including the S. They are present in vegetations and biofilms. In NVE needing valve replacement by a prosthesis during antibiotic therapy. Penicillin-susceptible oral streptococci and group D streptococci Recommended regimens against susceptible streptococci (penicillin MIC 0. pneumoniae has become rare since the introduction of antibiotics.10 mm) and underwent surgery. but now occurs in other adults. except for the use of short-term 2-week therapy.114 The latter two studies demonstrated that gentamicin and netilmicin can be given once daily in patients with IE due to susceptible streptococci and normal renal function.g. . e.4 mg/L)—vancomycin might be preferred in such circumstances. oral streptococci) and eradicate problematic organisms (e.2 mg/L). One recent study reported on eight cases of successful treatment with penicillin G or ceftriaxone plus gentamicin. Enterococcus spp.116 However. and should be replaced with ceftriaxone or cefotaxime alone or in combination with vancomycin. After surgery.e. except that short-term therapy is not recommended.122 Treatment outcome was similar in PVE and NVE.126 Mortality of Group B PVE is very high and cardiac surgery is recommended. Treatment of penicillin-susceptible strains (MIC 0. a new full course of treatment should only start if valve cultures are positive. they are still susceptible to growth inhibition by the drug. Teicoplanin has been proposed as an alternative3 and requires loading doses (6 mg/kg/12 h for 3 days) followed by 6–10 mg/kg/day. Tolerant microbes are not resistant. Streptococcus pneumoniae. in prosthetic valve endocarditis (PVE).113 – 115 Patients allergic to b-lactams should receive vancomycin.3. S. not on the day of surgery. It is associated with meningitis in up to 30% of cases.110 Such resistant streptococci are increasing. Compiling four of them. only limited retrospective studies have assessed its efficacy in streptococcal117 and enterococcal118 IE.1 mg/L) without meningitis.3.95%. b-lactams and glycopeptides) for bactericidal activity and are useful to shorten the duration of therapy (e. but escape drug-induced killing and may resume growth after treatment discontinuation. IE due to group B streptococci was once associated with the peripartum period. in penicillin-resistant cases aminoglycoside treatment may be prolonged to 3 –4 weeks and short-term therapy regimens are not recommended. The same holds true for penicillinresistant strains (MIC . b-haemolytic streptococci (groups A. which is associated with higher rates of complications and treatment failure (up to 40%). ESC Guidelines resistant S. Slow-growing and dormant microbes display phenotypic tolerance towards most antimicrobials (except rifampin to some extent).7.125 –2 mg/L) and fully-resistant (MIC . Nutritionally variant streptococci They produce IE with a protracted course.120 – 123 Most penicillin MICs were !1 mg/L. constellatus. Death was not related to resistance.0.121 Hence.5 mg/L as fully resistant.99% of group D streptococci remain penicillin susceptible. mitis and S. ceftriaxone or vancomycin for 6 weeks. the post-operative antibiotic regimen should be that recommended for NVE.119 Conversely.125 mg/L) are summarized in Table 13.

112 i Serum vancomycin concentrations should achieve 10 –15 mg/L at pre-dose (trough) level and 30 –45 mg/L at post-dose level (peak. pre-dose (trough) concentrations should be .1 mg/L and post-dose (peak. e Preferred for outpatient therapy. d Or ampicillin. b a .ESC Guidelines 2385 Table 13 Antibiotic treatment of infective endocarditis due to oral streptococci and group D streptococcia See text for other streptococcal species. h Renal function and serum gentamicin concentrations should be monitored once a week. 1 h after injection) serum concentrations should be 10 –12 mg/L. same dosages as amoxicillin. g Only if non complicated native valve IE. c 6-week therapy in PVE. Preferred in patients . 1 h after infusion is completed). When given in a single daily dose.65 years or with impaired renal function. f Paediatric doses should not exceed adult doses.

2386 ESC Guidelines Staphylococcus aureus and coagulase-negative staphylococci Staphylococcus aureus is usually responsible for acute and destructive IE. capitis).130. to minimize the risk of resistant mutant selection. Serum vancomycin concentrations should achieve 25 –30 mg/L at pre-dose (trough) levels. Of note. Paediatric doses should not exceed adult doses. pre-dose (trough) concentrations should be . Rifampin is believed to play a special role in prosthetic device infection because it helps eradicate bacteria attached to foreign material.131 Table 14 summarizes treatment recommendations for methicillinsusceptible and methicillin-resistant S. Renal function and serum gentamicin concentrations should be monitored once/week (twice/week in patients with renal failure). The clinical benefit of gentamicin addition has not been formally demonstrated. lugdunensis and some cases of S. When given in three divided doses.112 b c a . 1 h after injection) concentrations should be between 3– 4 mg/L. whereas CNS produce more protracted valve infections (except S. e Although the clinical benefit of gentamicin has not been demonstrated. d Rifampin increases the hepatic metabolism of warfarin and other drugs. the benefit of additional Table 14 Antibiotic treatment of infective endocarditis due to Staphylococcus spp.1 mg/L and post-dose (peak. aureus and CNS in both native and prosthetic valve IE.135 Rifampin should always be used in combination with another effective antistaphylococcal drug. Its use is associated with increased toxicity and is therefore optional. it remains recommended for PVE.

They are usually resistant to multiple antibiotics.45%)134 and often requires early valve replacement. Non-HACEK species The International Collaboration on Endocarditis (ICE) reported non-HACEK Gram-negative bacteria in 49/2761 (1.148 which synergize by inhibiting complementary PBPs. aureus (VISA) (MIC 4 – 16 mg/L) and hetero-VISA (MIC 2 mg/L. Enterococcus spp. One study reported success with shortcourse administration of aminoglycosides (2 – 3 weeks) in 74 (81%) of 91 episodes of enterococcal IE. or 1000 mg/day orally) is a less well validated option.132.143 b-lactams plus oxazolidinones. other third-generation cephalosporins.150 2. Other differences in comparison with NVE include the overall duration of therapy.140 However. Otherwise. Secondly. standard MIC tests may be difficult to interpret. and are associated with IE treatment failures. Prolonged courses of gentamicin require regular monitoring of serum drug levels and renal and vestibular function. Ampicillin (or amoxicillin) might be preferred Blood culture-negative infective endocarditis The main causes of BCNIE are summarized in Section F.ESC Guidelines 2387 since MICs are 2 – 4 times lower.136 Although the level of evidence is poor. faecalis and E. Again. and tigecycline. Use of the latter is based on its success in treatment of infected orthopaedic prostheses135 (in combination with quinolones) and in the prevention of re-infection of vascular prostheses. faecalis is the combination of ampicillin and ceftriaxone. and eradication requires prolonged administration (up to 6 weeks) of synergistic bactericidal combinations of cell wall inhibitors with aminoglycosides (Table 15). However. sometimes with additional quinolones or cotrimoxazole. In vitro bactericidal tests and monitoring of serum antibiotic concentrations may be helpful. aminoglycoside in S. vancomycin-intermediate S. Conversely. including aminoglycosides.v. First. although treatment may be associated with microbial resistance.138 Moreover.8%) of IE cases.146 Fully penicillin-susceptible strains (penicillin MIC 8 mg/L) are treated with penicillin G or ampicillin (or amoxicillin) combined with gentamicin. they are susceptible to ceftriaxone.149. Enterococcal IE is primarily caused by Enterococcus faecalis (90% of cases) and. intravenous ampicillin (12 g/day i. Streptomycin may remain active in such cases and is a useful alternative.v. A further recently described option against gentamicin-resistant E. enterococci are highly tolerant to antibiotic-induced killing.v.152 Treatment options are summarized in Table 16.141 Other choices include newer b-lactams with relatively good PBP2A affinity. and drug interactions.139. and the addition of rifampin. Importantly.) was recently approved for S.153 . Varying results have been reported with quinupristin–dalfopristin. by Enterococcus faecium or other species. Because of their rarity and severity. High-level gentamicin resistance is frequent in both E. HACEK-related species HACEK Gram-negative bacilli are fastidious organisms needing specialized investigations (see also Section C). quinupristin – dalfopristin with or without b-lactams. definitive studies are missing. Because they grow slowly.142.145 Such cases warrant collaborative management with an infectious diseases specialist. Ciprofloxacin (2 Â 400 mg/day i. and quinolones—the standard treatment is ceftriaxone 2 g/day for 4 weeks. more rarely. and vancomycin. but with subpopulations growing at higher concentrations) have emerged worldwide. and ampicillin is therefore no longer the first-line option.151 Recommended treatment is early surgery plus long-term (!6 weeks) therapy with bactericidal combinations of b-lactams and aminoglycosides.139 Observational studies suggest that daptomycin might also be considered in leftsided IE and may overcome methicillin and vancomycin resistance. Since dual resistance is rare. they may be resistant to multiple drugs. faecium. some highly vancomycinresistant S. but these regimens are invalid for left-sided IE. aureus IE is not formally demonstrated. which confers cross-resistance to most b-lactams. in four or six doses) plus gentamicin (3 mg/kg/ day divided in two or three doses) for 4 weeks is an option. Short-term (2 week) and oral treatment have been proposed for uncomplicated rightsided IE (see also Section L). If they do not produce b-lactamase. adding rifampin in the treatment of staphylococcal PVE is standard practice.500 mg/L is associated with loss of bactericidal synergism with cell wall inhibitors. linezolid.137 Methicillin-resistant and vancomycin-resistant staphylococci MRSA produce low-affinity plasma-binding protein (PBP) 2A. Some HACEK group bacilli produce b-lactamases. Gram-negative bacteria 1. leaving only vancomycin to treat severe infections.133 It is optional for the first 3 – 5 days of therapy in NVE. aureus have been isolated from infected patients in recent years. hepatotoxicity. b-lactam might be used against vancomycin-resistant strains and vice versa. and recommended for the first 2 weeks in PVE. b-Lactam and vancomycin resistance are mainly observed in E. prolonged additional use of aminoglycosides. They pose two major problems. Staphylococcus aureus PVE carries a very high risk of mortality (. these conditions should be managed with the input of an infectious diseases specialist. daptomycin needs to be administered in appropriate doses to avoid further resistance.147 This option might be considered in cases where prolonged treatment is limited by toxicity. and aminoglycosides should not be used in such conditions. requiring new approaches to treatment. b-lactams (via PBP5 modification and sometimes b-lactamases). New lipopeptide daptomycin (6 mg/kg/day i.144 and b-lactams plus vancomycin. faecium. these situations require the expertise of an infectious diseases specialist. daptomycin.146 An aminoglycoside MIC . more prolonged courses of b-lactams or vancomycin should be considered. aureus bacteraemia and right-sided IE.

b-lactams. C) (monitor haematological toxicity).500 mg/L): if susceptible to streptomycin. and vancomycin: suggested alternatives are (i) linezolid 2 Â 600 mg/day i. A).156 Suppressive treatment with oral azoles is often maintained long term and sometimes for life. replace gentamicin with streptomycin 15 mg/kg/day in two equally divided doses (I. b b-Lactam resistance: (i) if due to b-lactamase production. antibiotics. and Bartonella spp. Empirical therapy Treatment of IE should be started promptly. NVE and late PVE regimens should cover staphylococci. especially for antibiotic resistance and specific genuine culture-negative pathogens (Table 16).2388 ESC Guidelines Table 15 Antibiotic treatment of infective endocarditis due to Enterococcus spp.5 mg/kg/day for !8 weeks (IIa. Monitor serum vancomycin concentrations as indicated in Table 13. if so. Suggested regimens are summarized in Table 17.154 Most cases are treated with various forms of amphotericin B with or without azoles. HACEK species. late PVE) and (iii) knowledge of local epidemiology. f Paediatric doses should not exceed adult doses. C). the latter resulting in BCNIE. The combination of ampicillin with ceftriaxone was recently suggested for gentamicin-resistant E.v. C). (ii) if due to PBP5 alteration. predominate.155. or orally for !8 weeks (IIa. Fungi Fungi are most frequently observed in PVE and in IE affecting IVDAs and immunocompromised patients. (iii) b-lactam combinations including imipenem plus ampicillin or ceftriaxone plus ampicillin for !8 weeks (IIb. use vancomycin-based regimens. Candida and Aspergillus spp. C). a High level resistance to gentamicin (MIC . replace ampicillin with ampicillin –sulbactam or amoxicillin with amoxicillin –clavulanate (I. streptococci. Otherwise. when surgery was performed (early vs.3 months symptoms and in PVE. use more prolonged course of b-lactam therapy.157 The initial choice of empirical treatment depends on several considerations: (i) whether the patient has received prior antibiotic therapy or not (ii) whether the infection affects a native valve or a prosthesis (and. and treatment necessitates dual antifungal administration and valve replacement. g In b-lactam allergic patients. d 6-week therapy recommended for patients with . (ii) quinupristin–dafopristin 3 Â 7. although recent case reports describe successful therapy with the new echinocandin caspofungin. c Multiresistance to aminoglycosides. Mortality is very high (. Early PVE regimens should cover methicillin-resistant staphylococci and ideally non-HACEK Gramnegative pathogens. faecalis 148 (IIa. Three sets of blood cultures should be drawn at 30 min intervals before initiation of .50%). e Monitor serum levels of aminoglycosides and renal function as indicated in Table 13. B).

paramedic and social support. c Doxycycline plus hydroxychloroquine (with monitoring of serum hydroxychloroquine levels) is superior to doxycycline alone and to doxycycline þ fluoroquinolone.160. and a second continuation phase (beyond 2 weeks therapy) where OPAT may be feasible.159 Logistic issues are critical and require patient and staff education to enforce compliance. it should be used to consolidate antimicrobial therapy once critical infection-related complications are under control (e. If problems arise. the patient should be directed towards informed medical staff familiar with the case and not an anonymous emergency department.383.g. and stroke). vancomycin.1 year) cotrimoxazole therapy. d Several therapeutic regimens were reported. and Chlamydia spp. and quinolones.161 . Table 18 summarizes the salient questions to address when considering OPAT for IE.. The presented durations are based on selected case reports.158 For IE. during which OPAT has a restricted indication.ESC Guidelines 2389 Table 16 Antibiotic treatment of blood culture-negative infective endocarditis Adapted from Brouqui and Raoult. monitoring of efficacy and adverse effects. Successes have been reported with long-term (. doxycycline.. Legionella spp. Under these conditions. Two different phases may be separated during the course of antibiotic therapy—a first critical phase (the first 2 weeks of therapy).153 a Due to the lack of large series. g-Interferon plays a protective role in intracellular infections and has been proposed as adjuvant therapy in Whipple’s disease. including aminopenicillins and cephalosporins combined with aminoglycosides. acute heart failure. and easy access to medical advice. b Addition of streptomycin (15 mg/kg/24 h in two doses) for the first few weeks is optional. perivalvular abscesses. optimal duration of treatment of IE due to these pathogens is unknown.385. septic emboli. OPAT performs equally well independently of the pathogen and clinical context.250 000 patients/year in the USA. Dosages are as for streptococcal and enterococcal IE (Tables 13 and 15).384 e Newer fluoroquinolones are more potent than ciprofloxacin against intracellular pathogens such as Mycoplasma spp.386 Outpatient parenteral antibiotic therapy for infective endocarditis Outpatient parenteral antibiotic therapy (OPAT) is used in . f Treatment of Whipple IE remains highly empirical.

Table 18 Criteria which determine suitability of outpatient parenteral antibiotic therapy (OPAT) for infective endocarditis Adapted from Andrews and von Reyn.2390 ESC Guidelines Table 17 Proposed antibiotic regimens for initial empirical treatment of infective endocarditis. (before or without pathogen identification) a.b Monitoring of gentamicin and vancomycin dosages is as in Table 13 and Table 14.159 .

Indications and optimal timing of surgery Surgical treatment is used in approximately half of patients with IE because of severe complications. Age per se is not a contraindication to surgery. surgical therapy during the active phase of the disease is associated with significant risk. intracardiac Table 19 Indications and timing of surgery in left-sided native valve infective endocarditis Class of recommendation.7. uncontrolled infection.98.165 In some cases. Level of evidence.165. *Emergency surgery: surgery performed within 24 h. Each case must be individualized and all factors associated with increased risk identified at the time of diagnosis. I. surgery can be postponed to allow 1 or 2 weeks of antibiotic treatment under careful clinical and echocardiographic observation before an elective surgical procedure is performed.e. the need for surgery will be determined by a combination of several high-risk features. surgery needs to be performed on an emergency (within 24 h) or urgent (within a few days) basis. irrespective of the duration of antibiotic treatment.167 The three main indications for early surgery in IE are HF. elective surgery: after at least 1 or 2 weeks of antibiotic therapy.162 – 165 On the other hand. i. b a .79 HF is observed in 50 –60% of cases overall and is more often present when IE affects the aortic (29%) rather than the mitral (20%) valve. are to avoid progressive HF and irreversible structural damage caused by severe infection and to prevent systemic embolism. Surgery is justified in patients with high-risk features which make the possibility of cure with antibiotic treatment unlikely and who do not have co-morbid conditions or complications which make the prospect of recovery remote. In other cases. Complications and indications for surgery in left-sided native valve infective endocarditis Part 1. and prevention of embolic events (Table 19).79 Reasons to consider early surgery in the active phase.7 HF can be caused by severe aortic or mitral insufficiency. Frequently.166 Early consultation with a cardiac surgeon is recommended in order to determine the best therapeutic approach. Identification Heart failure 1. urgent surgery: within a few days. # Surgery may be preferred if procedure preserving the native valve is feasible. Heart failure in infective endocarditis HF is the most frequent complication of IE and represents the most frequent indication for surgery in IE.ESC Guidelines 2391 of patients requiring early surgery is frequently difficult. while the patient is still receiving antibiotic treatment.

particularly in aortic IE. and assessment and monitoring of left ventricular systolic function and left and right heart filling pressures. Surgery must be performed on an emergency basis. or by valve obstruction caused by vegetations. aureus being the most commonly associated organism (46%). Perivalvular extension in infective endocarditis Perivalvular extension of IE is the most frequent cause of uncontrolled infection and is associated with poor prognosis and high likelihood of need for surgery. and two-thirds of these cases occur during the active phase of the disease.178.3 Management of persisting fever includes replacement of intravenous lines. Unless severe co-morbidity exists. more rarely.181 Pseudoaneurysms and fistulae are severe complications of IE and frequently associated with very severe valvular and perivalvular damage.7–10 days). 2. ESC Guidelines the presence of HF indicates early surgery in patients with NVE. intracardiac fistulae.3. In addition to clinical findings. It must be performed on an urgent basis when HF is less severe.176 In summary. locally uncontrolled infection. resistant organisms. particularly those in a mitral location when there is co-existent annular calcification.178 Perivalvular abscess is more common in aortic IE (10–40% in native valve IE)3.177. Chamber size is usually normal.68. Valve perforation.98. leaflet rupture (flail leaflet).174. blood cultures and echocardiography. and aneurysms are best assessed using TEE. TEE is the technique of choice for the diagnosis and follow-up of all perivalvular complications.50%179 – 183 (see Section F). even using TEE. and locally uncontrolled infection. or interference of the vegetation mass with leaflet closure. embolic complications or extracardiac site of infection. Uncontrolled infection Uncontrolled infection is the second most frequent cause for surgery79 and encompasses persisting infection (. and adverse reaction to antibiotics. hospital mortality remains high (41%). and infection with CNS.2392 fistulae. 1. the most important risk factors for perivalvular complications were prosthetic valve. starting with aortic root wall thickening and extending to the development of fistulae. regurgitant flow velocities are frequently low with a short deceleration time since pressures in the left atrium (mitral regurgitation) or left ventricle (aortic regurgitation) equalize rapidly.7.184 In one study. Surgery is also indicated in patients with severe acute aortic or mitral regurgitation without clinical HF but with echocardiographic signs of elevated left ventricular enddiastolic pressure (premature closure of the mitral valve). when patients are in persistent pulmonary oedema or cardiogenic shock despite medical therapy.172 Brain natriuretic peptide (NT-proBNP) has potential use in the diagnosis and monitoring of HF in IE. measurement of pulmonary artery pressure. Resultant aneurysm formation on the atrial aspect of the mitral leaflet may later lead to mitral perforation. Perivalvular complications include abscess formation. and cardiogenic shock.170 The suspicion of valve obstruction is raised by an elevated transvalvular gradient on TTE. third degree atrioventricular block. irrespective of the status of infection. perivalvular abscesses are usually located posteriorly or laterally. In IE with acute regurgitation.177. Usually. and research for intracardiac or extracardiac focus of infection.107.183 Serial echocardiographic studies have shown that abscess formation is a dynamic process. pseudoaneurysms. and fistulae (Table 9). An ECG should therefore be performed frequently during follow-up.171. In patients with well tolerated severe valvular insufficiency and no other reasons for surgery.7 In mitral IE. medical management with antibiotics is recommended under strict clinical and echocardiographic observation.186 – 188 Other complications due to major extension of infection are less frequent and may include ventricular septal defect.7 Moderate-to-severe HF is the most important predictor of in-hospital and 6-month mortality. or. including inadequate antibiotic therapy. when a large vegetation partially obstructs the valve orifice. Echocardiography is also of more general value for haemodynamic assessment of valvular dysfunction.185 – 188 The frequency of fistula formation in IE has been reported to be 1. Persisting infection Persisting fever is a frequent problem observed during treatment of IE. depending on tolerance of the valve lesion and according to the recommendations of the ESC Guidelines on the Management of Valvular Heart Disease.182 In aortic IE. small abscesses can be missed. temperature normalizes within 5– 10 days under specific antibiotic therapy. Clinical presentation of HF may include severe dyspnoea. Surgery should be subsequently considered after healing of IE.188 Despite high rates of surgery in this population (87%).173 HF may progress from mild to severe during treatment. However. leaflet perforation. pulmonary oedema. by valve obstruction.6%.179 – 181 and very frequent in PVE (56–100%). high left atrial pressure.169. aortic location. The most characteristic lesion leading to HF in NVE is valve destruction causing acute regurgitation. Indeed. or moderate or severe pulmonary hypertension. secondary mitral lesions. perivalvular extension is frequently discovered on a systematic TEE.92 which may occur as a result of mitral chordal rupture.165 Surgery is indicated in patients with HF caused by severe aortic or mitral insufficiency. Persisting fever may be related to several reasons.189 Perivalvular extension should be suspected in cases with persistent unexplained fever or new atrioventricular block. TTE is of crucial importance for initial evaluation and follow-up.175 2. while the sensitivity of TTE is . Indications and timing of surgery in the presence of heart failure in infective endocarditis (Table 19) The presence of HF indicates surgery in the majority of patients with IE7 and is the principal indication for urgent surgery. repeat laboratory measurements. perivalvular extension occurs most frequently in the mitral –aortic intervalvular fibrosa. A special situation is secondary infection168 of the anterior mitral leaflet associated with primary aortic IE with aortic regurgitation. infection due to resistant organisms.74 . infected lines. HF is the most frequent and severe complication of IE. S. and acute coronary syndrome.

vertebral. while pulmonary embolism is frequent in native right-sided and pacemaker lead IE. when embolic risk peaks. and the duration of antibiotic therapy. uncontrolled infection is most frequently related to perivalvular extension or ‘difficult-to-treat’ organisms. persistent infection despite appropriate antibiotic therapy. The value of early surgery in this situation has never been proven.68 Surgery undertaken for the prevention of embolism must be performed very early. the presence of locally uncontrolled infection indicates early surgery in patients with NVE.193 In summary.68. small abscesses or false aneurysms can be treated conservatively under close clinical and echocardiographic follow-up.195. when there are no other reasons for surgery and fever is easily controlled with antibiotics. the decision to operate early for prevention of embolism must take into account the presence of previous embolic events. cerebral.212 the addition of antiplatelet therapy did not reduce the risk of embolism in the only published randomized study. Indications and timing of surgery to prevent embolism in infective endocarditis (Table 19) Avoiding embolic events is difficult since the majority occur before admission. including the size and mobility of vegetations.68.79 but was rarely the only reason.68.15 mm) and mobile vegetations.196.192. aureus. the presence of a large vegetation favours earlier surgery. surgery is indicated if a favourable early response to antibiotics is not achieved.191 Persistent fever is also usually present. For this reason.210 although some risk persists indefinitely whilst vegetations remain present.186. In these situations. Unless severe co-morbidity exists.200 – 205 although prediction remains difficult in the individual patient.165 The overall benefits of surgery should be weighed against the operative risk and must consider the clinical status and co-morbidity of the patient. and can be diagnosed by non-invasive imaging.8/1000 patient days in the first week of therapy. e. contrast media should be used with caution in patients with renal failure or haemodynamic instability because of the risk of worsening renal impairment in combination with antibiotic nephrotoxicity. Embolic events in infective endocarditis Embolic events are a frequent and life-threatening complication of IE related to the migration of cardiac vegetations. In NVE caused by S.154. according to the probability of conservative surgery.190.200 It must be re-emphasized that the risk of new embolism is highest during the first days following initiation of antibiotic therapy and rapidly decreases thereafter.204.213 The exact role of early surgery in preventing embolic events remains controversial. and other predictors of a complicated course (HF. In the Euro Heart Survey. particularly if the vegetation is located on the mitral valve. embolic events may be totally silent in 20% of patients with IE. surgery is indicated in patients with large vegetations (.194 Conversely. Infection by microorganisms infrequently cured by antimicrobial therapy Surgery is indicated in fungal IE.199 and biological markers.68 In the absence of embolism. abscess formation.195 The best means to reduce the risk of an embolic event is the prompt institution of appropriate antibiotic therapy. systematic abdominal and cerebral CT scan may be helpful.155 Surgery is indicated in IE due to multiresistant organisms.134. especially those affecting the splenic or cerebral circulation.g. especially in staphylococcal IE affecting the mitral valve.7–10 days) despite an appropriate antibiotic regimen and when extracardiac abscesses (splenic.200.10 mm). antibiotics alone are insufficient to eradicate the infection. falling to 1. Prevention of systemic embolism 1.ESC Guidelines 2393 2.203 and this risk is even higher in patients with very large (.10 mm) following one or more clinical or silent embolic events despite appropriate antibiotic therapy. or renal) and other causes of fever have been excluded. Surgery is indicated in patients with large vegetations (.10 mm are at higher risk of embolism. Predicting the risk of embolism Echocardiography plays a key role in predicting embolic events.199 – 203 the increasing or decreasing size of the vegetation under antibiotic therapy.209 Among these. . Overall embolic risk is very high in IE.200 Streptococcus bovis. Thus. the size and mobility of the vegetations are the most potent independent predictors of a new embolic event. Surgery may be considered in patients with very large (.7/1000 patient days in the second week and further thereafter.211. Indications and timing of surgery in the presence of uncontrolled infection in infective endocarditis (Table 19) Persistent infection In some cases of IE. vegetation size was one of the reasons for surgery in 54% of patients with NVE and in 25% of those with PVE.200. Several factors are associated with increased risk of embolism.). and also in the rare infections caused by Gramnegative bacteria.200 multivalvular IE. the size and mobility of the vegetation. However. 3. the risk of new events (occurring after initiation of antibiotic therapy) is only 6–21%. Surgery is indicated when fever and positive blood cultures persist for several days (. Signs of locally uncontrolled infection These include increasing vegetation size.68.195 Whilst promising.195 – 203 However.196. The main indications and timing of surgery to prevent embolism in NVE are given in Table 19. abscess).200 A recent study from the ICE group204 demonstrated that the incidence of stroke in patients receiving appropriate antimicrobial therapy was 4.207 particular microorganisms (staphylococci.195 Thus. the likelihood of conservative surgery.68 Patients with vegetations length . with embolic events occurring in 20 –50% of patients. particularly beyond 2 weeks.208 Candida spp. Stroke is a severe complication and is associated with increased morbidity and mortality. the benefits of surgery to prevent embolism are greatest during the first week of antibiotic therapy.199 – 207 the location of the vegetation on the mitral valve. MRSA or vancomycin-resistant enterococci. Rarely.15 mm) isolated vegetations on the aortic or mitral valve.16. other complications of IE. and surgery is recommended as soon as possible. false aneurysms or the creation of fistulae. previous embolism. although this decision is more difficult and must be very carefully individualized. The brain and spleen are the most frequent sites of embolism in left-sided IE. during the first few days following initiation 3.195.

in post-menopausal women.219 – 221 The use of mitral valve homografts and pulmonary autografts (Ross procedure) has been suggested. Extracardiac infection If a primary focus of infection likely to be responsible for IE has been identified. high-resolution CT may be used to rule out significant coronary artery disease.224. the Task Force does not favour any specific valve substitute but recommends a tailored approach for each individual patient and clinical situation. and immediate results of surgery Pre.237 Immediate post-operative complications are relatively common. Risk is increased with large (>10 mm) vegetations and particularly high with very mobile and larger (>15 mm) vegetations. mechanical prostheses and xenografts compare favourably.40 years. and in patients with at least one cardiovascular risk factor or a history of coronary artery disease. a prosthetic valve then being secured to the reconstructed/reinforced annulus. and duration of antibiotic therapy. falling to 6 –21% after initiation of antibiotic therapy. operative mortality in IE lies between 5 and 15%.224. it must be eradicated prior to cardiac surgical intervention. pneumonia.229 In experienced hands. to guide surgery. valve repair is favoured whenever possible. as the risk of embolism is highest at this time.231 A monoblock aorto-mitral homograft has been suggested as a surgical option for extensive bivalvular IE. Currently. but larger cavities should be allowed to drain into the pericardium or the circulation. In mitral valve IE. re-exploration of the chest for bleeding or tamponade. complicating 20 –50% of cases of IE.218 Residual mitral regurgitation should be assessed using intra-operative TEE.216 Perforations in a single valve cusp or leaflet may be repaired with an autologous glutaraldehyde-treated or bovine pericardial patch. the degree of left ventricular dysfunction.233 Operative mortality. including repair or replacement of the affected valve(s). The risk of embolism is the highest during the first 2 weeks of antibiotic therapy and is clearly related to the size and mobility of the vegetation. if necessary. Governing factors include size and mobility of the vegetation. The cause of death is often multifactorial. but the main reasons are multiorgan failure.2394 of antibiotic therapy (urgent surgery).234 – 239 When surgery must be performed within the first week of antimicrobial therapy. HF. the extent of destruction of cardiac structures. mortality should be similar to routine valve surgery. successful valve repair can be achieved by experienced teams in up to 80% of patients. Exceptions arise when there are large aortic vegetations which may be dislodged during catheterization.217 Therefore. Mitral subannular. and the patient’s haemodynamic condition at the time of surgery. coagulopathy. and help in early post-operative follow-up. However. type of microorganism. embolism is very frequent in IE.and peri-operative management 1. with improved durability. Mechanical and biological prostheses have similar operative mortality.226 – 228 Homografts or stentless xenografts may be preferred in PVE or in cases where there is extensive aortic root destruction with aorto-ventricular discontinuity. respectively. stroke.227. Where infection is confined to the valve cusps or leaflets. or when emergency surgery is necessary. The decision to operate on early to prevent embolism is always difficult and specific for the individual patient. In these situations.215. and atrioventricular block following radical resection of an aortic root abscess with need for pacemaker implantation. The choice of technique depends on the vertical extension of the lesion/tissue defect.104 Surgical approach and techniques The two primary objectives of surgery are total removal of infected tissues and reconstruction of cardiac morphology. low cardiac output syndrome. Intra-operative echocardiography Intra-operative TEE is most useful to determine the exact location and extent of infection.230. In complex cases with locally uncontrolled infection.222. total excision of infected and devitalized tissue should be followed by valve replacement and repair of associated defects to secure valve fixation.239 In less complex cases. replacement of the aortic valve using a mechanical or biological prosthesis is the technique of choice. morbidity.225 However. assess the result. although such excellent results may not be matched in non-specialist centres. a recent study showed that in-hospital mortality is 15%.235. annular. intractable sepsis.68. previous embolism.237 A pre-operative ECG demonstrating left bundle branch block predicts the need for a post-operative permanent pacemaker. Principles. and stroke.223 but their application is limited by poor availability and difficulty of the surgical technique. In aortic IE. with risks of recurrence and non-infective post-operative valvular dysfunction of 12 and 7%. ESC Guidelines Part 2. the Ross procedure may be used in children or adolescents to facilitate growth and in young adults for extended durability. any method to repair or replace the valve may be used. Coronary angiography Coronary angiography is recommended according to the ESC Guidelines on the Management of Valvular Heart Disease176 in men . methods.176 2. unless valve surgery is urgent.232 Cardiac transplantation may be considered in extreme cases where repeated operative procedures have failed to eradicate persistent or recurrent PVE. particularly when IE affects the mitral or tricuspid valve.225. or supraannular tissue defects are preferably repaired with autologous or bovine pericardium. The use of cryopreserved or sterilized homografts has been suggested to reduce the risk of persistent or recurrent infection. Among the most frequent are severe coagulopathy requiring treatment with clotting factors. Small abscesses can be closed directly. acute renal failure requiring haemodialysis. and post-operative complications Peri-operative mortality and morbidity vary according to the type of infective agent.200 In summary. 3. The use of foreign .214 material should be kept to a minimum. where disease is limited to the valve structures alone allowing complete excision of infected tissue.

241 The clinical spectrum of these complications is wide. toxic encephalopathy.98. including ischaemic or haemorrhagic stroke. Table 20 and Figure 3 J. or persistent high embolic risk should not be delayed Figure 3 Therapeutic strategy for patients with infective endocarditis and neurological complications. neurological prognosis is worse and surgery must be postponed for at least 1 month.194. in cases with intracranial haemorrhage. Table 20 Management of neurological complications Class of recommendation. cardiac surgery is not contraindicated unless the neurological prognosis is judged to poor (Figure 3).246. silent cerebral embolism.194. symptomatic or asymptomatic infectious aneurysm. Other complications of infective endocarditis Part 1. A neurologist/neurosurgeon should always be involved in the management of these patients.242 If urgent cardiac surgery is needed.242 – 246 If cerebral haemorrhage has been excluded by cranial CT and neurological damage is not severe (i. Neurological complications. coma). meningitis.e.194. brain abscess.240. CT ¼ computed tomography.194 Rapid diagnosis and initiation of appropriate antibiotics are of major importance to prevent a first or recurrent neurological complication. antithrombotic therapy Neurological complications Neurological events develop in 20–40% of all patients with IE and are mainly the consequence of vegetation embolism.247 Conversely.ESC Guidelines 2395 and can be performed with a relatively low neurological risk (3– 6%) and good probability of complete neurological recovery. surgery indicated for HF. transient ischaemic attack. Level of evidence. most patients still have at least one indication for cardiac surgery. Evidence regarding the optimal time interval between stroke and cardiac surgery is conflicting because of lack of controlled studies.240 They are associated with an excess mortality. uncontrolled infection. particularly in the case of stroke. Staphylococcus aureus causes higher overall rates of neurological complications. After an ischaemic stroke. After a neurological event. MR ¼ magnetic resonance. and seizure.194 and surgery is recommended without delay if an indication remains. close cooperation with the neurosurgical team is mandatory. b a .194 The risk of post-operative neurological deterioration is low after a silent cerebral embolism or transient ischaemic attack. abscess.

In summary. or . or ruptured IAs. notably related to aminoglycosides.255 Clinical presentation is highly variable256 (focal neurological deficit.259 serial imaging is required. confusion.212. Since many unruptured IAs may resolve during antibiotic treatment. To prevent this complication. headache. Although initial experimental studies showed a beneficial impact of aspirin therapy on the risk of an embolic event in S. but no predictors of this complication have been identified to date. neurological events develop in 20 –40% of all patients with IE and are mainly the consequence of embolism. antibiotic Part 2.252 Besides. and even high dose penicillin B Nephrotoxicity of contrast agents used for imaging purposes. or after cardiac surgery B Antibiotic toxicity (acute interstitial nephritis).261 Causes are often multifactorial:262 B Immune complex and vasculitic glomerulonephritis B Renal infarction B Haemodynamic impairment in cases with HF or severe sepsis.257. Haemodialysis may be required in some patients.aureus IE. conventional angiography remains the gold standard and should be performed when non-invasive techniques are negative and suspicion remains. neurosurgery or endovascular therapy is indicated. summarize the recommended management of neurological complications in IE. most patients still have an indication for surgery which is generally not contraindicated. and the experience of the medical team. No randomized trials exist to guide management.249 – 251 no strong evidence exists on its beneficial effect in clinical practice because of conflicting data.248 The recommendations for the management of the anticoagulant therapy are based on low level of evidence (Table 21). Other complications (infectious aneurysms. splenic abscess. rheumatic complications.213.258 However. and the reported frequency of 2 –4% is probably an underestimate since some IAs are clinically silent. Ruptured IAs have a very poor prognosis. myocarditis.253. there is a risk of intracranial haemorrhage which seems to be highest in patients with S. vancomycin (synergistic toxicity with aminoglycosides). and therapy must be tailored to the individual patient.255. Acute renal failure Acute renal failure is a common complication of IE which occurs in 30% of patients and predicts poor prognosis. Antithrombotic therapy There is no indication for the initiation of antithrombotic drugs (thrombolytic drugs.2396 ESC Guidelines Table 21 Management of antithrombotic therapy in infective endocarditis a b Class of recommendation. Stroke is associated with excess mortality.260 The choice between these options will depend on the presence and size of the haematoma. After a first neurological event. aureus PVE and those with a previous neurological event. pericarditis) Infectious aneurysms Infectious (mycotic) aneurysms (IAs) result from septic arterial embolism to the intraluminal space or vasa vasorum. enlarging.252 from subsequent spread of infection through the intimal vessels. In cases with large. some studies showed a non-significant increase of major bleeding episodes. Level of evidence. seizures) and imaging should be performed to detect intracranial IAs in any case of IE with neurological symptoms.213.263 but acute renal failure is often reversible.254 An intracranial location is most frequent. anticoagulant or antiplatelet therapy) during the active phase of IE. acute renal failure. Rapid diagnosis and initiation of appropriate antibiotics are of major importance to prevent a first or recurrent neurological complication. In patients already taking oral anticoagulants. CT and magnetic resonance angiography both reliably diagnose IAs with high sensitivity and specificity.

8% of patients with pyogenic spondylodiscitis and was more common in cases of streptococcal infection and predisposing heart conditions.57. Treatment consists of appropriate antibiotic regimens. whereas later events suggest reinfection.275 For these purposes. HF.269 Myocarditis. Patients with previous IE are at risk of reinfection.267 MRI or CT of the spine should be performed in IE patients with back pain.270. Table 22 Factors associated with an increased rate of relapse . suboptimal choice of initial antibiotics. echocardiography may be performed in patients with a definite diagnosis of pyogenic spondylodiscitis and underlying cardiac conditions predisposing to endocarditis. IE was diagnosed in 30.272.5%.235 – 237.7 and 22. or ultrasound. myalgia. there is often uncertainty as to whether the repeat infection is a relapse of the initial infection or a new infection (reinfection).56 In contrast. Following in-hospital treatment.3. Recurrences: relapses and reinfections The risk of recurrence amongst survivors of IE varies between 2. the timing of the second episode of IE may be used to distinguish relapse from reinfection. Percutaneous drainage is an alternative for high-risk surgical candidates. there are two types of recurrence: relapse and reinfection. In these cases. Prolonged antibiotic therapy is generally required in definite spondylodiscitis. Regional myocardial infarction may be caused by coronary embolism or compression. an episode of IE caused by the same species within 6 months of the initial episode represents relapse. Relapses are most often due to insufficient duration of original treatment.268.ESC Guidelines 2397 doses should be adjusted for creatinine clearance with careful monitoring of serum levels (aminoglycosides and vancomycin). relapse should be treated for a further 4 –6 weeks depending on the causative microorganism and its susceptibility (remembering that resistance may develop in the meantime). and these patients should be evaluated by abdominal CT. and a persistent focus of infection (e. Splenectomy may be considered for splenic rupture or large abscesses which respond poorly to antibiotics alone. although variable.264 – 266 In one study. with dramatic and often fatal consequences. ruptured pseudoaneurysms or fistulae may communicate with the pericardium. pericarditis Cardiac failure may also be due to myocarditis which is frequently associated with abscess formation. When the duration of therapy has been insufficient or the choice of antibiotic incorrect. the rate of recurrence in non-IVDAs was 1.3 Myocardial involvement is best assessed using TTE. Conversely.274 and prophylactic measures should be very strict. storage of endocarditis isolates for at least 1 year is recommended.3. aureus infection. Imaging with nephrotoxic contrast agents should be avoided in those with haemodynamic impairment or previous renal insufficiency. Reinfection is more Splenic abscess Although splenic emboli are common. back pain) are frequent during IE. or bacteraemia often as a result of S. splenic abscess is rare. need for valve surgery.56 When the same species is isolated during a subsequent episode of IE. Ventricular arrhythmias may indicate myocardial involvement and imply a poor prognosis.105. Persistent or recurrent fever and bacteraemia suggest the diagnosis. the time between episodes is usually shorter for relapse than for reinfection—in broad terms.56 When these techniques or the identity of both isolates are unavailable.273 Rheumatic complications Musculoskeletal symptoms (arthralgia.56 Factors associated with an increased rate of relapse are listed in Table 22. K.272 Although not systematically differentiated in the literature. Peripheral arthritis occurs in 14% and spondylodiscitis in 3–15% of cases.3 Pericarditis may be associated with an abscess. the main complications include recurrence of infection. Outcome after discharge and long-term prognosis Late complications occurring after the initial infection contribute to the poor prognosis of IE.271 Rarely.g. and death. MRI. periprosthetic abscess). The term ‘relapse’ refers to a repeat episode of IE caused by the same microorganism as the previous episode. Purulent pericarditis is rare and may necessitate surgical drainage. and rheumatic complications may be the first manifestations of the disease. ‘reinfection’ is primarily used to describe infection with a different microorganism. and should be performed before valvular surgery unless the latter is urgent. molecular methods including strain-typing techniques should be employed.273 – 275 In a recent large series with mean 5-year follow-up.3% per patient-year. myocarditis.56. Thus.

To monitor the development of secondary HF.274 Information concerning longer follow-up is scarce. particularly in the early post-operative period. more probably due to community-acquired infections. Clinical presentation is frequently atypical. particularly during the first year of follow-up. IE was the cause of the late mortality in only 6. and fistulae. as compared with NVE. which can be diagnosed by fluoroscopy and/or TEE. and 12 months during the first year following completion of treatment.225. recommendations for surgery follow conventional guidelines.79 and in 20% of 2670 patients with definite IE in the ICE Prospective Cohort Study. As in NVE. Streptococcus bovis.1. in which fever and inflammatory syndromes are common in the absence of IE.284 However.3.236.272. 6. In cases with perioperative contamination. The consequence of PVE is usually new prosthetic regurgitation. C-reactive protein) and TTE at 1. this is an artificial distinction.3 Patients with reinfection are at higher risk of death and need for valve replacement.188. Similarly. both are more frequently negative in PVE. resistant microorganisms. Specific situations Part 1. After discharge.282 In late PVE. There is no evidence base to guide the optimal monitoring of these patients. co-morbidity. suggesting that long-term mortality is related to the underlying conditions rather than IE itself.1. leading to vegetations.237 Aortic valve and root replacement with a prosthetic conduit yields results comparable with those of homograft root replacement. In PVE. and poor prognosis.2398 frequent in IVDAs (especially in the year after the initial episode). What is important is not the time from the surgical procedure to the onset of IE. and enterococci being the most frequent organisms. patients with IE must be informed of the risk of recurrence and educated about how to diagnose and prevent a new episode of IE.277 in patients undergoing chronic dialysis.14 in 26% of cases inthe Euro Heart Survey. with staphylococci.273 Following the in-hospital phase.5% of patients who died. Staphylococci.278 ESC Guidelines L.272.285 Although TEE is mandatory in suspected PVE (Figure 1).2% per patientyear.176 As a consequence of increasing rates of operation during the active phase of the infection.235.3. chills. the infection usually involves the junction between the sewing ring and the annulus. an initial clinical evaluation and baseline TTE should be performed at the completion of antimicrobial therapy and repeated serially.273 In a recent series. A survival at 15 –20 years of 50% has been reported.273. including the procurement of blood cultures before empirical use of antibiotics. However. Less frequently. determination of the optimal therapeutic strategy. Preventive measures should be applied in these patients who are a high risk group (see Section E). blood cultures are more frequently negative in PVE. cusp rupture. In summary. Prosthetic valve endocarditis PVE is the most severe form of IE and occurs in 1– 6% of patients with valve prostheses279—an incidence of 0.106 PVE is still associated with difficulties in diagnosis.57. persistent focus of infection. and perforation.105. relapse and reinfection are rare following IE. A negative echocardiogram is frequently observed in PVE2 and does not exclude the diagnosis.57.281. A recent large prospective multicentre international registry found that 37% of PVE were associated with nosocomial infection or non-nosocomial health care-associated infections in outpatients with extensive health care contact.101.253.106.235. They should be aware that recurrence can occur in IE and that new onset of fever. diagnosis of PVE is mainly based on the results of echocardiography and blood cultures. and HF. or intravenous drug abuse. particularly when surgery has not been performed. but whether IE is acquired peri-operatively or not and which microorganism is involved.272 Follow-up Patients should be educated about the signs and symptoms of IE after discharge. ranging from 3 to 7% in the most recent series.273 Definition and pathophysiology Early PVE is defined as occurring within 1 year of surgery.273 and in those with multiple risk factors for IE. large vegetations may cause prosthetic valve obstruction. the need for late valve surgery is low. leading to perivalvular abscess. pseudoaneurysms. principal factors which determine long-term mortality are age.106 The pathogenesis of PVE differs according to both the type of contamination and the type of prosthetic valve. and late PVE beyond 1 year. but the Task Force recommend clinical evaluation. 3. or other signs of infection mandate immediate evaluation. fungi. dehiscence. and Gram-negative bacilli are the main causes of early PVE. After completion of treatment.236.276 in PVE.3 –1. the same and other mechanisms may exist. but may be caused by inadequate initial antibiotic therapy. For example. oral streptococci. while the microbiology of late PVE mirrors that of NVE.280 – 284 It accounts for 10 –30% of all cases of IE280 and affects mechanical and bioprosthetic valves equally.236.275 The type of valve implanted has no effect on the risk of recurrent IE. blood samples (white cell count. even when infection is healed. because of significant differences between the microbiological profiles observed before and after this time point. Diagnosis Diagnosis is more difficult in PVE than in NVE. infection is frequently located on the leaflets of the prosthesis.275. its diagnostic value is lower than in NVE. staphylococcal and fungal infections are more frequent and streptococcal infection less frequent than in NVE.235. in late bioprosthetic PVE. Heart failure and need for valvular surgery Progressive HF can occur as a consequence of valve destruction. PVE was observed in 16% of cases in the French Survey. Long-term mortality Long-term survival is 60 –90% at 10 years. .

it was performed in only 50% of patients with PVE in the Euro Heart Survey. or persistent fever.287 Prognosis and treatment A very high in-hospital mortality rate of 20 –40% has been reported in PVE.279. Radical debridement in these cases means removal of all foreign material. An exception is S. which requires a more prolonged antibiotic regimen (particularly aminoglycosides) and frequent use of rifampin (see Section H). a surgical strategy is recommended for PVE in high-risk subgroups identified by prognostic assessment. the best therapeutic option is still debated.286. including the original prosthesis. stroke. prognostic assessment is of crucial importance in PVE.283.280 As in NVE. The need for surgery should be considered in all cases of early PVE. patients who are initially treated medically require close follow-up. The Duke criteria have been shown to be helpful for the diagnosis of NVE. Alternatively. and any calcium remaining from previous surgery. urgent surgery: within a few days. complicated PVE and staphylococcal infection are the most powerful markers.288. Among these. patients with uncomplicated nonstaphylococcal and non-fungal late PVE can be managed conservatively. Homografts. early PVE. HF.283 Although no evidence-based data exist.92.291 Conversely. Similar data have been reported by others. and homograft or xenograft root replacement is indicated for any abnormality of the aortic root that distorts the aortic sinuses. and intracardiac abscess.294. stentless xenografts. By definition. Although surgical treatment is frequently necessary in PVE. with a sensitivity of 70 –80%.134.263. early surgery is frequently needed in early staphylococcal PVE134. because of their lower sensitivity in this setting. and these patients need aggressive management. since it allows identification of high-risk subgroups of patients in whom an aggressive strategy may be necessary. Similarly. Antimicrobial therapy for PVE is similar to that for NVE.283.13. or autografts may be Table 23 Indications and timing of surgery in prosthetic valve infective endocarditis (PVE) Class of recommendation.e. PVE complicated by HF.79 similar to patients with NVE. because of the risk of late events. most cases referred for surgery represent uncontrolled PVE and are treated accordingly. elective surgery: after at least 1 or 2 weeks of antibiotic therapy. *Emergency surgery is surgery performed within 24 h. since most are caused by staphylococci or other aggressive organisms. Table 23 summarizes the main indications and proposed timing of surgery in PVE. a valved Dacron conduit278 can be used.285 but are less useful in PVE. staphylococcal infection.290 or PVE caused by fungi or other highly resistant organisms.288 – 290 including age. b a .106. severe prosthetic dysfunction. i. Several factors have been associated with poor prognosis in PVE.ESC Guidelines 2399 considered in aortic PVE. Level of evidence. abscess.291 – 295 Although surgery is generally considered the best option when PVE causes severe prosthetic dysfunction or HF.295 However. aureus PVE. Surgery for PVE follows the general principles outlined for NVE.

296 The rising number of patients with an implanted CD explains the increasing frequency of IE in these patients. Infective endocarditis on pacemakers and implantable defibrillators Infection of cardiac devices (CDs). CDRIE must be suspected in the presence of unexplained fever in a patient with a CD. Clinical presentation is frequently misleading. if treated without surgery. surgery requires good exposure under . and early PVE are associated with worse prognosis. both TTE and TEE may be falsely negative in CDRIE. Septic pulmonary embolism is a very frequent complication of CDRIE. S. Attempts to treat these patients with antibiotic alone have been proposed in the case of negative TEE.313 However. Diagnosis is more difficult than in NVE.297 The consequence may be formation of vegetations. including permanent pacemakers (PPMs) and implantable cardioverter defibrillators (ICDs). quantification of tricuspid regurgitation. with predominant respiratory or rheumatological symptoms. However. Complicated PVE. However.299 Both diagnosis and therapeutic strategy are particularly difficult in these patients.300 CDRIE is defined as an infection extending to the electrode leads.305. Antibiotic prophylaxis is protective in this indication. ESC Guidelines implantation. and a normal echographic examination does not rule out CDRIE.312 CD extraction can be performed percutaneously without need for surgical intervention in the majority of patients.296.302 It has recently been proposed that positive lead cultures can be used as a sign of CDRIE only in the absence of pocket infection or when the leads were removed using a remote incision from the pocket or surgical extraction.302 The main mechanism of CDRIE is contamination by local bacteriological flora at the time of device implantation. Duration of therapy should be 4–6 weeks in most cases.305 to include local signs of infection and pulmonary embolism as major criteria. CD removal is recommended in all cases of proven CDRIE and should also be considered when CRDIE is only suspected.309 Blood cultures are positive in 77% of cases of CDRIE. Fever is frequently blunted. cardiac valve leaflets. As in other forms of IE. differentiating LDI and CDRIE is frequently difficult. In one study. percutaneous extraction may be more difficult when the CD has been implanted for several years. tenderness.296.296. or when severe tricuspid valve IE is associated. A distinction should be made between local device infection (LDI) and cardiac device-related IE (CDRIE). aureus being predominant in the acute forms of PPM infection. Pulmonary embolism as a result of vegetation displacement during extraction occurs frequently.314 when percutaneous extraction is technically impossible.3 on the electrode lead.305 Finally. in the case of occult infection without any other apparent source than the device. Preliminary experience with intracardiac echocardiography has recently been reported.297.302 Staphylococci are the most frequent pathogens.2400 In summary. and follow-up after lead extraction. sizing of vegetations. However. fluctuance.302. these episodes are frequently asymptomatic. Definition and pathophysiology of cardiac device infections. However. which can be found anywhere from the subclavian vein to the superior vena cava. Echocardiography plays a key role in CDRIE and is helpful for the diagnosis of both lead vegetation and tricuspid involvement. warmth.311 However. Modifications of Duke criteria have been proposed.305 Some authors recommend surgery to be performed in patients with very large vegetations.9 per 1000 device-years and a higher probability of infection after ICD as compared with PPM. staphylococcal PVE. including fever within 24 h before implantation.301 culture of intravascular lead segments was positive in 72% of 50 patients with manifestations strictly limited to the implantation site. particularly when vegetations are large.305 – 308 and is cost-effective. non-staphylococcal late PVE can be managed conservatively with close follow-up. Patients with non-complicated. erosion.305 as well as local signs of infection. on the tricuspid valve. Part 2. it is recommended to perform both in suspected CDRIE.297 A recent populationbased study found an incidence of CD infection of 1. or purulent drainage.298 Overall incidence lies between that of NVE in the general population and that of PVE. use of temporary pacing before Treatment (Table 24) In the majority of patients.310 Antimicrobial therapy for PPM infections should be individualized and based on culture and susceptibility results if possible.302 For this reason. PVE represents 20% of all cases of IE with increasing incidence. wound dehiscence. Several factors have been associated with CD infections. is a severe disease associated with high mortality. or endocardial surface. and percutaneous extraction remains the recommended method even in cases of large vegetations. lung CT and lung scintigraphy are both useful to detect pulmonary septic embolism. The reported incidence of PPM infection varies widely among studies. echocardiography and blood cultures are the cornerstone of diagnosis. the infection can spread along the electrode to the endocardium and the electrode tip.302. but also on the mural endocardium of the right atrium and right ventricle. in the case of definite CDRIE. and early reimplantation. CDRIE must be treated by prolonged antibiotic therapy associated with device removal.305 The Duke criteria are difficult to apply in these patients because of lower sensitivity. particularly in elderly patients. the possibility of intra-operative contamination of the lead tip cannot be excluded in these patients.304 Diagnosis CDRIE is one of the most difficult forms of IE to diagnose.302. Although TEE has superior sensitivity and specificity to TTE. including erythema. medical therapy alone has been associated with high mortality and risk of recurrence.313 since overall risks are even higher with surgical extraction. Other possible mechanisms of CDRIE include haematogenous seeding from a distant focus of infection. LDI is defined as an infection limited to the pocket of the CD and is clinically suspected in the presence of local signs of inflammation at the generator pocket.302. and must be managed aggressively.303 Then. When performed.

In the majority of patients. but some recent data show an increasing number of hospitalizations for intravenous drug abuse-related IE. and this decision must be adapted to the individual patient. this situation is most frequently observed in IVDAs. right ventricular free wall. If immediate reimplantation is necessary. reimplantation can be postponed for a few days or weeks. and must be suspected in the presence of frequently misleading symptoms. Right-sided infective endocarditis Epidemiology Right-sided IE accounts for 5 –10% of cases of IE. Part 3.322 Damage to the right-sided valves from injected particulate matter associated with poor injection hygiene. Prognosis is poor. extracorporeal circulation to allow complete removal of all foreign material. with reduced infectious risk. central venous catheter. mortality associated with surgical removal is high315 in these frequently elderly patients with associated co-morbidities.14. particularly in elderly patients.310. and abnormalities of immune function are some of the pathophysiological hypotheses underlying right-sided IE in IVDAs.ESC Guidelines 2401 Table 24 Cardiac device-related infective endocarditis (CDRIE): treatment and prevention a b Class of recommendation.320. However.304 If reimplantation is performed.320 Although it may occur in patients with a PPM. epicardial implantation is a possible alternative.318 In summary. There is no clear recommendation concerning the optimal timing and site of reimplantation. particularly those with advanced immunosuppression. Level of evidence. Excision of all infected contact lesions at the level of the tricuspid valve. contaminated drug solutions. and distal superior vena cava is essential. device extraction may be considered. pulmonary and eustachian valve infection may also be observed.300. antibiotic prophylaxis is usually recommended before implantation.306. or CHD. The exact incidence of IE in IVDAs is unknown. and left-sided IE is not . a new transvenous system is usually implanted on the contralateral side. reassessment may lead to the conclusion that reimplantation is unnecessary in a number of patients.317 Although there are no large controlled studies on this topic.323 Whilst the tricuspid valve is the usual site of infection in IVDAs. Temporary pacing is not recommended because it has been shown to be a risk factor for subsequent CD infection. not least because of its frequent occurrence in elderly patients with associated co-morbidity. In other patients. Immediate reimplantation should be avoided owing to the risk of new infection. CDRIE must be treated by prolonged antibiotic therapy and device removal.321 This disease occurs more frequently in IVDAs who are HIV seropositive.316 In patients with NVE or PVE and an apparently non-infected PPM. ICD. Finally. right atrium.319. CDRIE is one of the most difficult forms of IE to diagnose.

356 and (3) if valve replacement is Prognosis and treatment Prognosis of right-sided NVE is relatively good.340. therapy in IVDAs does not differ from that in non-addicts. TEE is more sensitive in the detection of pulmonary vegetations332 and abscesses (particularly those adjacent to the membranous septum).351 2. a CD4 count of .335.343. ESC Guidelines Diagnosis and complications The usual manifestations of right-sided IE are persistent fever. depending on the local prevalence of MRSA.352. therapy has to be adjusted.345 (c) therapy with antibiotics other than penicillinase-resistant penicillins.334 Once the causative organisms have been isolated. aureus and 3 Good response to treatment and .345 Indications for surgery and the peri-operative approach in IVDAS are the same as for non-addicts but should be more conservative overall since IVDAS have a much higher incidence of recurrent IE. and associated left-sided involvement. antibiotic treatment should include cover against streptococci and enterococci. and the location of cardiac involvement. 20 mm vegetation and 3 Absence of severe immunosuppression (.336.342.g. fungi.i. (b) IE caused by organisms which are difficult to eradicate (e.347 (d) IVDA with severe immunosuppression (CD4 count .339 More conventionally. Surgery Surgical treatment should generally be avoided in right-sided native IE. but should be considered in the following situations (Table 25): (a) right HF secondary to severe tricuspid regurgitation with poor response to diuretic therapy. but can be caused by the increase of pulmonary pressures or severe right-sided valvular regurgitation or obstruction. the choice of initial empiric antimicrobial therapy depends on the suspected microorganism. with clear data demonstrating that penicillinase-resistant penicillin regimens are superior to glycopeptide-containing regimens.337 If the patient is a pentazocine addict.341 There are also consistent data showing that a 2-week treatment may be sufficient341 – 343 and that the addition of an aminoglycoside may be unnecessary. streptococci. Antimicrobial therapy On admission. Candida spp. other Gramnegative organisms. aureus. 3 Absence of metastatic sites of infection or empyema and 3 Absence of cardiac and extracardiac complications and 3 Absence of associated prosthetic valve or left-sided valve infection and 3 .200 cells/mL has a high prognostic value. When systemic emboli occur. glycopeptides should not be used in a 2-week treatment.20 mm which persist after recurrent pulmonary emboli with or without concomitant right HF. Pulmonary septic emboli may be complicated by pulmonary infarction.20 mm.) provided that the strain is fully susceptible to both drugs and patient adherence is monitored carefully. aeruginosa) despite adequate antimicrobial therapy.200 cells/mL) with or without AIDS. S.320.324 – 326 Staphylococcus aureus is the dominant organism (60– 90%). the type of drug and solvent used by the addict.329 – 331 However. paradoxical embolism or associated left-sided IE should be considered.352 (c) Tricuspid valve vegetations . which may manifest with chest pain. poor penetration into vegetations.g.344. albicans) should be considered and antifungal treatment added.355 Current strategies for surgery of tricuspid valve IE should be based on the following three principles: (1) debridement of the infected area or ‘vegetectomy’.333 – 335 Vegetation length . aureus must always be covered.344 (b) right-sided IE complicated by right HF. (2) valve repair whenever possible.d. and purulent pulmonary effusion.327. persistent fungi).g.333.341 Two-week treatment with oxacillin (or cloxacillin) with or without gentamicin is possible if all the following criteria are fulfilled: 3 Methicillin-susceptible S. an antipseudomonas agent should be added. and polymicrobial infections also occur less frequently.328 Right HF is rare.334 In right-sided NVE. and increased drug clearance in IVDAs. e. the standard therapy for IE due to MSSA is appropriate.338 If an IVDA uses brown heroin dissolved in lemon juice.20 mm and fungal aetiology were the main predictors of death in a recent large retrospective cohort of right-sided IE in IVDAs.333.349 (e) associated left-sided IE. aureus IE in IVDAs may also be successfully treated with oral ciprofloxacin (750 mg b. P. or haemoptysis.335 In HIV-infected patients. (not C.i. Cardiac surgery in HIV-infected IVDAS with IE does not worsen the prognosis of either the IE or the HIV.350 For organisms other than MSSA. with an in-hospital mortality rate .322 1.96 h) to antibiotic therapy.354.d. septic metastatic foci outside the lungs (including empyema).2402 unusual in this group.343. S.) plus rifampicin (300 mg b. cough. and multiple septic pulmonary emboli. avoiding artificial material. a 2-week course of antimicrobial therapy is unsuitable. pneumothorax. In IVDAs. Because of limited bactericidal activity. or extracardiac complications. enterococci. The standard 4–6 week regimen must be used in the following situations: (a) slow clinical or microbiological response (.353 usually due to continued drug abuse. Right-sided S. Treatment will include either penicillinase-resistant penicillins or vancomycin. in IVDAs with underlying valve lesions and/or left-sided involvement. acute respiratory failure.348.10%. vegetations . acute renal failure.346. TTE usually allows assessment of tricuspid involvement because of the anterior location of this valve and usual large vegetations. particularly in IVDAs or venous catheter-related infection.344. bacteraemia. Although the full implications of HIV infection for the medical and surgical therapy of IE in IVDAS are not yet fully known. abscess.200 CD4 cells/mm3) with or without AIDS.327 and Pseudomonas aeruginosa. or bacteraemia for at least 7 days (e.

The reported incidence of IE in CHD is 15 –140 times higher than that in the general population (the highest estimate originating from a highly specialized unit). dental. CHD often consists of multiple cardiac lesions. unavoidable. if unavailable. and when there is a high risk of devastating septic embolism. Prognosis is better than in other forms of IE.58. such as secundum atrial septal defect and pulmonary valve disease. The superiority of TEE over TTE has not been systematically studied in this setting. a xenograft valve) is preferred. and selection bias associated with studies from highly specialized centres hampers universal application.368 The importance of good oral. probably due to selection bias.357 Valvectomy without prosthetic replacement has been advocated. Preventive measures and patient education are of particular importance in this population.370 However. Despite relatively low in-hospital mortality. However. after multiple pulmonary emboli. and skin hygiene has already been emphasized. right-sided IE has a high risk of recurrence in IVDAs and a conservative approach to surgery is recommended in this group.366 The principal symptoms. Treatment of IE in CHD follows general principles. However. a negative study does not exclude the diagnosis.362.361. In summary. IE in CHD carries a mortality of 4–10%. e. but may be associated with severe post-operative right HF. closure of a patent ductus arteriosus) with the sole purpose of eliminating the risk of IE. Level of evidence. right-sided IE is more frequent in CHD than in acquired cardiac disease.62. . the procedure may increase the overall risk of IE. carry a low risk of IE. and basis for diagnosis do not differ from IE in general. at least involving the tongue and mucous membranes.366 This better prognosis in comparison with acquired heart disease may reflect the higher proportion of right heart IE.g. between 2 and 18%.58. There are no scientific data justifying cardiac surgery or percutaneous interventions (e. there is also an educational problem. use of a pulmonary homograft (or. complications.ESC Guidelines 2403 Table 25 Indications for surgical treatment of right-sided infective endocarditis a b Class of recommendation.364. Surgical repair of CHD often reduces the risk of IE.371 Cardiac repair as a secondary preventive measure to reduce the risk of recurrent IE has been described but not systematically studied.362. complex anatomy and the presence of artificial material may reduce the rate of detection of vegetations and other features of IE.359. Cardiac surgery is appropriate when medical therapy fails. However. Infective endocarditis in congenital heart disease The population of children and adults with CHD is expanding. IE in CHD is rare and more frequently affects the right heart.360 Pulmonary valve replacement is best avoided—if judged necessary. Primary prevention is vital. each contributing to the total risk of IE. Complex anatomy makes echocardiographic assessment difficult. in other cases when artificial valve substitutes are implanted. thus favouring the addition of TEE.362 The reported proportion of CHD in patients with IE varies. and awareness of the risk of IE and need for preventive measures are not satisfactorily spread in the population with CHD. our knowledge of IE in this setting is limited since systematic studies are few and often retrospective. right-sided IE is most frequently observed in IVDAs and CHD. with a mortality rate <10%. and this is the major substrate for IE in younger patients. and antibiotic prophylaxis is indicated in high-risk groups as defined in Section E. For example.367 The distribution of causative organisms does not differ from the pattern found in acquired heart disease. In summary.58.362. provided there is no residual lesion. However.366 Some simple lesions. Part 4. particularly in patients with elevated pulmonary arterial pressure. but the valve should be subsequently replaced once cure of infection has been achieved. streptococci and staphylococci being the most common strains.369 Cosmetic piercing.363 – 365 with a consistent minor male dominance. It may be performed in extreme cases. excision of the tricuspid valve with prosthetic valve replacement. TTE is of major value in these patients.362 However. Diagnostic features include respiratory symptoms and fever. when serious haemodynamic complications arise. the incidence of IE is considerably higher in patients with a ventricular septal defect when there is associated aortic regurgitation.358 Cryopreserved mitral homografts have been used for management of persistent tricuspid endocarditis.g. However. should be discouraged in this group. particularly in the adult group.

Baltimore RS. Oto A. Priori SG. Al-Nawas B. Taubert KA. The Organizing Committee is responsible for ensuring that all potential conflicts of interest relevant to the programme are declared to the participants prior to the CME activities.166. Heart 2006. Circulation 2007. Jaussi A. Council on Cardiovascular Surgery and Anesthesia. Graninger R. Tong DC. Peters G. Fulford M. 2. Leport C. IE in pregnancy is extremely rare.363:139 –149. Shulman ST. all authors participating in this programme have disclosed potential conflicts of interest that might cause a bias in the article. Falace DA. ¨ ¨ Handrick W. 6.376 and have been associated with colonic disease. Gould FK. 9. American Heart Association: endorsed by the Infectious Diseases Society of America. Baddour LM. Cowie M. M. Infective endocarditis in the elderly IE in the elderly (.379 Part 6. Budaj A. with the same indications as for younger patients. Filipatos G.374. Tani LY. 7. Mazzotta G. Eur Heart J 2004. that IE in advanced age is associated with poor prognosis and with a high complication rate. and is either a complication of a pre-existing cardiac lesion or the result of intravenous drug abuse. Nishimura RA.375 Fewer elderly patients are treated by surgery. Bolger AF. Rowley AH. and Kawasaki Disease. the vegetations in the elderly have been reported to be smaller375 and to carry a lower embolic risk. 5. Burns JC. Mehlhorn U. Takahashi M. Lengyel M. Dean V. Erbel R. Danchin N. Bolger A. In compliance with EBAC/EACCME guidelines. Pallasch T. 10. Baumgartner B. Management of infective endocarditis.380. Horstkotte D. Blanc JJ.org/cgi/hierarchy/oupcme_node. Freed MD.29: 615 –616. Levison ME. Fowler VG Jr. Gutschik E. Perry JD. Ferrieri P. Elliott TS. and Kawasaki Disease Committee. Moreillon P.166. Kuhl S. Que YA. Duval X.208 In some studies. Gattringer R. Erbel R. Goff D.118:887 –896. Baddour LM. Herrmann M. 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Sandoe JA. J Antimicrob Chemother 2006. Gerber MA. though not consistently. Vardas P. Council on Cardiovascular Disease in the Young.373 and 33% of patients were older than 67 years in a French registry. Infective endocarditis: diagnosis. Lepper PM. Follath F.25:267 –276. Gewitz M. 4.189:301 –302.7% of elderly patients with IE.50 years old and peaked at 145 cases per million between 70 and 80 years of age. Baddour LM. Niebel J. Wilson W. Guidelines on prevention. 3.372. von Graevenitz A. Lockhart PB.374. Mutters R.208. Fernandez Burgos E. Becker HJ. multiple valve involvement. Endocarditis. Rapid detection of IE and appropriate treatment is important in reducing the risk of both maternal and foetal mortality.oxfordjournals. Pallasch TJ. Baltimore RS. Taubert KA. Heart 2005.375 A gastrointestinal source of infection has been described more commonly in elderly patients. Steckelberg JM. and the Councils on Clinical Cardiology.166. Wilson WR.116:1736 –1754. diagnosis. Group D streptococci (S. Infective endocarditis. Shulman ST. Deckers J. Thiene G. Bonow RO. Kern P. ACC/AHA 2008 Guideline Update on Valvular Heart Disease: Focused Update on Infective Endocarditis. Jeyasingham MS. Tani LY. and Cardiovascular Surgery and Anesthesia. while foetal mortality is 29%. Circulation 2005. probably in relation to a higher operative risk related to advanced age and frequent co-morbidity.381 The incidence of IE during pregnancy has been reported to be 0. References 1. Maternal mortality approaches 33%. Roberts GJ. Horstkotte D. Heying R. Gewitz MH. Infective endocarditis during pregnancy A challenge for the physician during pregnancy in the cardiac patient is the changing cardiovascular physiology which can mimic cardiac disease and confuse the clinical picture. and high embolic risk. Prophylaxis of infective endocarditis: French recommendations 2002. Faxon DP. Newburger JW. bovis) are an increasingly frequent cause of IE. Naber CK. 8. and treatment of infective endocarditis (new version 2009)’ is accredited by the European Board for Accreditation in Cardiology (EBAC).372 Negative blood cultures were recently observed in 16. Schmaltz AA. O’Gara PT. most deaths relating to HF or an embolic event. Lancet 2004. which is an institution of the European Union of Medical Specialists (UEMS).91:715 –718. especially in the elderly. Working Party of the British Society for Antimicrobial C. Watkin RW. Oto A.69 Finally. Delahaye F.ehj and European Society of Cardiology http://www. New guidelines for infective endocarditis: a call for collaborative research. Durack DT. Gerber M. Carabello BA.006%. Council on Cardiovascular Disease in the Young. and the Council on Clinical Cardiology. Strom BL. the incidence of IE increased between 1991 and 1999 among patients .208 Enterococcal IE has also been shown to be more frequent in older patients. Vahanian A. Ferrieri P. Gardner T. Int J Antimicrob Agents 2007. Rosenhek R. Newburger JW. and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Lindahl B.378 However. Moreillon P. in which colonic lesions are frequent and may cause occult bleeding.372. Leyh RG. and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever. Moulds RF. Smiseth OA.80 In the French surveys.382 Therefore. the task force on infective endocarditis of the European society of cardiology. antimicrobial therapy. Gohlke-Barwolf C.14 Previous reports have shown. Burns JC. Soler-Soler J. Habib G. Franzen D. Garcia MA. EBAC works according to the quality standards of the European Accreditation Council for Continuing Medical Education (EACCME). older age has been associated with poor prognosis in the majority of recent studies.382 Close attention should be paid to any pregnant woman with unexplained fever and a cardiac murmur. Bayer AS. Cabell CH.92:124 –130. Ertl G. Med J Aust 2008. Circulation 2008. and to a higher incidence of more aggressive pathogens in this cohort. Foweraker J. Stroke. Horstkotte D. 11.372 The relative incidence of IE affecting the elderly was 26% in the Euro Heart Survey. O’Rourke RA.org/guidelines. CME questions for this article are available at: European Heart Journal http://cme. surgical treatment appears as a reasonable option in the elderly. Takahashi M. ¨ . ¨ Mugge A.escardio.

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