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Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score [published correction appears in JAMA. 2007;297:1433]. JAMA. 2007;297:611 619. 440. D Agostino RB, Wolf PA, Belanger AJ, Kannel WB. Stroke risk pro- file: adjustment for antihypertensive medication: the Framingham Study. Stroke. 1994;25:40 43. 441. Lumley T, Kronmal RA, Cushman M, Manolio TA, Goldstein S.A stroke prediction score in the elderly: validation and Web-based application. J Clin Epidemiol. 2002;55:129 136. 442. Bineau S, Dufouil C, Helmer C, Ritchie K, Empana JP, Ducimeti re P, Alp rovitch A, Bousser MG, Tzourio C. Framingham stroke risk func- tion in a large population-based cohort of elderly people: the 3C study. Stroke. 2009;40:1564 1570. 443. Moons KG, Bots ML, Salonen JT, Elwood PC, Freire de Concalves A, Nikitin Y, Sivenius J, Inzitari D, Benetou V, Tuomilehto J, Koudstaal PJ, Grobbee DE. Prediction of stroke in the general population in Europe (EUROSTROKE): is there a role for fibrinogen and electrocardiogra- phy? J Epidemiol Community Health. 2002;56(suppl 1):i30 i36. 444. Tanne D, Yaari S, Goldbourt U. Risk profile and prediction of long-term ischemic stroke mortality: a 21-year follow-up in the Israeli Ischemic Heart Disease (IIHD) Project. Circulation. 1998;98:1365 1371. 445. Chambless LE, Heiss G, Shahar E, Earp MJ, Toole J. Prediction of ischemic stroke risk in the Atherosclerosis Risk in Communities Study [published correction appears in Am J Epidemiol. 2004;160:927]. Am J Epidemiol. 2004;160:259 269. 446. Seedat S, Scott KM, Angermeyer MC, Berglund P, Bromet EJ, Brugha TS, Demyttenaere K, de Girolamo G, Haro JM, Jin R, Karam EG, Kovess-Masfety V, Levinson D, Medina Mora ME, Ono Y, Ormel J, Pennell BE, Posada-Villa J, Sampson NA, Williams D, Kessler RC. Cross-national associations between gender and mental disorders in the World Health Organization World Mental Health Surveys.


Cross-national associations between gender and mental disorders in the World Health Organization World Mental Health Surveys. Arch Gen Psychiatry. 2009;66:785 795. 447. Cook NR, Paynter NP, Eaton CB, Manson JE, Martin LW, Robinson JG, Rossouw JE, Wassertheil-Smoller S, Ridker PM. Comparison of the Framingham and Reynolds risk scores for global cardiovascular risk prediction in the multiethnic Women s Health Initiative. Circulation. 2012;125:1748 1756. 448. Wassertheil-Smoller S, McGinn A, Allison M, Ca T, Curb D, Eaton C, Hendrix S, Kaplan R, Ko M, Martin LW, Xue X. Improvement in stroke risk prediction: role of C-reactive protein and lipoprotein-associated phos- in the Women s Health Initiative. Int J Stroke. October 23, 2012. doi:10.1111/j.1747-4949.2012.00860.x. http://onlinelibrary.wiley. 2013. 449. Hermes W, Franx A, van Pampus MG, Bloemenkamp KW, van der Post JA, Porath M, Ponjee G, Tamsma JT, Mol BW, de Groot CJ. 10-Year cardiovascular event risks for women who experienced hypertensive dis- orders in late pregnancy: the HyRAS study. BMC Pregnancy Childbirth. 2010;10:28.


AHA Scientific Statement Background Infective endocarditis is a potentially lethal disease that has undergone major changes in both host and pathogen. The epidemiology of infective endocarditis has become more complex with today s myriad healthcare- associated factors that predispose to infection. Moreover, changes in pathogen prevalence, in particular a more common staphylococcal origin, have affected outcomes, which have not improved despite medical and surgical advances. Methods and Results This statement updates the 2005 iteration, both of which were developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of theYoung. It includes an evidence-based system for diagnostic and treatment recommendations used by the American College of Cardiology and the American Heart Association for treatment recommendations. Conclusions Infective endocarditis is a complex disease, and patients with this disease generally require management by a team of physicians and allied health providers with a variety of areas of expertise. The recommendations provided in this document are intended to assist in the management of this uncommon but potentially deadly infection. The clinical variability and complexity in infective endocarditis, however, dictate that these recommendations be used to support and not supplant decisions in individual patient management. Key Words: AHA Scientific Statements anti-infective agents echocardiography endocarditis infection 2015 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000296 TheAmerican HeartAssociation makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.


Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on May 12, 2015, and the American Heart Association Executive Committee on June 12, 2015. A copy of the document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. The American Heart Association requests that this document be cited as follows: Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Tleyjeh IM, Rybak MJ, Barsic B, Lockhart PB, Gewitz MH, Levison ME, Bolger AF, Steckelberg JM, Baltimore RS, Fink AM, O Gara P, Taubert KA; on behalf of the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132:1435 1486. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page.


A link to the Copyright Permissions Request Form appears on the right side of the page. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications A Scientific Statement for Healthcare Professionals From the American Heart Association Endorsed by the Infectious Diseases Society of America Larry M. Baddour, MD, FAHA, Chair; Walter R. Wilson, MD; Arnold S. Bayer, MD; Vance G. Fowler, Jr, MD, MHS; Imad M. Tleyjeh, MD, MSc; Michael J. Rybak, PharmD, MPH; Bruno Barsic, MD, PhD; Peter B. Lockhart, DDS; Michael H. Gewitz, MD, FAHA; Matthew E. Levison, MD; Ann F. Bolger, MD, FAHA; James M. Steckelberg, MD; Robert S. Baltimore, MD; Anne M. Fink, PhD, RN; Patrick O Gara, MD, FAHA; Kathryn A. Taubert, PhD, FAHA; on behalf of the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council Infective endocarditis (IE) is an uncommon infectious dis- ease with an annual incidence ranging from 3 to 7 per 100000 person-years in the most contemporary population Although relatively rare, IE continues to be char- acterized by increased morbidity and mortality and is now the third or fourth most common life-threatening infection syndrome, after sepsis, pneumonia, and intra-abdominal abscess. Globally, in 2010, IE was associated with 1.58 mil- lion disability-adjusted life-years or years of healthy life lost as a result of death and nonfatal illness or impairment.4 Epidemiological surveys from France and the International Collaboration on Endocarditis have confirmed that the epide- miological profile of IE has changed substantially.


Globally, in 2010, IE was associated with 1.58 mil- lion disability-adjusted life-years or years of healthy life lost as a result of death and nonfatal illness or impairment.4 Epidemiological surveys from France and the International Collaboration on Endocarditis have confirmed that the epide- miological profile of IE has changed substantially. Although the overall IE incidence has remained stable,1,2,5 9 the incidence of IE caused by Staphylococcus aureus has increased, and S aureus is now the most common causative organism in most of the industrialized world. The emergence of S aureus IE is due in part to the increasing importance of healthcare contact as a leading risk associated with infection. Characteristics of IE patients have also shifted toward an increased mean patient age, a higher proportion of prosthetic valves and other car- diac devices, and a decreasing proportion of rheumatic heart disease. Moreover, the proportion of IE patients undergoing surgery has increased over time to reach 50%.1,10,11 In addition to these temporal epidemiological changes, major new findings from multiple diagnostic, prognostic, and therapeutic studies have been published since the last iteration of the American Heart Association (AHA) statement on diagnosis and management of IE complications was published in 2005.12 For example, the rapid detection of pathogens from valve tissue from patients undergoing surgery for IE by polymerase chain reaction (PCR) has been validated. Moreover, diagnostic inno- vations have emerged through new imaging techniques such as 3-dimensional (3D) echocardiography, head-to-toe multislice computed tomography (CT), and cardiac magnetic resonance imaging (MRI). Furthermore, the role of cerebral MRI and magnetic resonance angiography in the diagnosis and manage- ment of IE has been better defined in several studies.


Furthermore, the role of cerebral MRI and magnetic resonance angiography in the diagnosis and manage- ment of IE has been better defined in several studies. In addi- tion, several risk stratification models for quantifying morbidity and mortality in IE patients overall and particularly in those undergoing valve surgeries have been developed and validated. Finally, daptomycin has been evaluated in the treatment of S aureus bacteremia and IE in a randomized, controlled trial.13 Several rigorously conducted observational studies11,14 16 and a randomized, controlled trial17 have examined the impact and timing of valve surgery in IE management. In addition, updated international management guidelines have been published.18,19 The present AHA IE Writing Committee conducted com- prehensive and focused reviews of the literature published between January 2005 and October 2013 to update the previous version of the guidelines. Literature searches of the PubMed/ MEDLINE databases were undertaken to identify pertinent articles. Searches were limited to the English language. The major search terms included endocarditis, infective endocardi- tis, infectious endocarditis, intracardiac, valvular, mural, infec- tion, diagnosis, bacteremia, case definition, epidemiology, risks, demographics, injection drug use, echocardiography, microbiology, culture-negative, therapy, antibiotic, antifungal, antimicrobial, antimicrobial resistance, adverse drug effects, drug monitoring, outcome, meta-analysis, complications, abscess, heart failure, embolic events, stroke, conduction abnormalities, survival, pathogens, organisms, treatment, sur- gery, indications, valve replacement, valve repair, ambulatory care trials, and prevention. In addition, the present statement includes a new section, Surgical Therapy.


In addition, the present statement includes a new section, Surgical Therapy. This work addresses primarily IE in adults; a more detailed review of the unique features of IE in children is available in another statement from the AHA Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease.20 The committee also published state- ments on endocarditis that complicates electrophysiological (pacemakers, intracardiac defibrillators),21 ventricular assist, and other nonvalvular cardiac devices.22 Evidence-Based System for Diagnostic and Treatment Recommendations The writing group was charged with the task of performing an evidence-based assessment of the data and providing a class of recommendation and a level of evidence for each recom- mendation according to the American College of Cardiology/ AHA classification system (http://circ.ahajournals.org/ manual/manual_IIstep6.shtml). The class of recommendation is an estimate of the size of the treatment effect, considering risks versus benefits, in addition to evidence or agreement that a given treatment or procedure is or is not useful or effective or in some situations may cause harm. The level of evidence is an estimate of the certainty or precision of the treatment effect. The Writing Group reviewed and assessed the strength of evidence supporting each recommendation with the level of evidence ranked as A, B, or C according to the specific defini- tions included in Table 1. For certain conditions for which data were either unavailable or inadequate, recommendations were based on expert consensus and clinical experience, and these were ranked as Level of Evidence C. The scheme for the class of recommendations and levels of evidence is summarized in Table 1, which also provides suggested phrases for writing recommendations within each class of recommendation.


For certain conditions for which data were either unavailable or inadequate, recommendations were based on expert consensus and clinical experience, and these were ranked as Level of Evidence C. The scheme for the class of recommendations and levels of evidence is summarized in Table 1, which also provides suggested phrases for writing recommendations within each class of recommendation. Diagnosis The diagnosis of IE is straightforward in the minority of patients who present with a consistent history and classic oslerian manifestations: sustained bacteremia or fungemia, evidence of active valvulitis, peripheral emboli, and immu- nological vascular phenomena. In most patients, however, the textbook history and physical examination findings may be few or absent. Cases with limited manifestations of IE may occur early during IE, particularly among patients who are injection drug users (IDUs), in whom IE is often the result of acute S aureus infection of right-sided heart valves. Acute IE may evolve too quickly for the development of immunologi- cal vascular phenomena, which are more characteristic of the later stages of the more insidious subacute form of untreated IE. In addition, valve lesions in right-sided IE usually do not create the peripheral emboli and immunological vascular phe- nomena that can result from left-sided valvular involvement. Right-sided IE, however, can cause septic pulmonary emboli. The variability in clinical presentation of IE and the importance of early accurate diagnosis require a diagnostic strategy that is both sensitive for disease detection and spe- cific for its exclusion across all forms of the disease. In 1994, Durack and colleagues23 from the Duke University Medical Center proposed a diagnostic schema that stratified patients with suspected IE into 3 categories: definite, possible, and rejected cases (Tables 2 and 3).


In 1994, Durack and colleagues23 from the Duke University Medical Center proposed a diagnostic schema that stratified patients with suspected IE into 3 categories: definite, possible, and rejected cases (Tables 2 and 3). Baddour et al Infective Endocarditis in Adults 1437 A diagnosis of IE with the original Duke criteria was based on the presence of either major or minor clinical cri- teria (Tables 2 and 3). The Duke criteria gave diagnostic weight to bacteremia with staphylococci or enterococci only, on the basis of the location of acquisition and with- out an apparent primary focus; these types of bacteremia have the highest risk of being associated with IE.23,25,26 The Duke criteria incorporated echocardiographic find- ings into the diagnostic strategy (Tables 2 and 3; see the Echocardiography section). Six common but less specific findings of IE were included as minor criteria in the original Duke schema (Tables 2 and 3). In the mid to late 1990s, direct analyses of the Duke crite- ria were made in 12 major studies27 38 including nearly 1700 patients composed of geographically and clinically diverse groups (adult, pediatric, and older adult [ 60 years of age] patients; patients from the community; IDU and non-IDU patients; and those with both native and prosthetic valves). The confirmed the high sensitivity and specificity of the Duke criteria and the diagnostic utility of echocardiography in identifying clinically definite cases. Moreover, a retrospective study of 410 patients showed good agreement (72% 90%) between the Duke criteria and clinical assessment by infec- tious disease experts blinded to underlying IE risk factors.39 Table 1. Applying Classification of Recommendations and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak.


Applying Classification of Recommendations and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. Several refinements have been made to both the major and minor Duke criteria. In the original Duke criteria, bacteremia resulting from S aureus or enterococci was considered to fulfill a major criterion only if it was community acquired because ample literature suggested that this parameter was an important surro- gate marker for underlying IE.27 However, an increasing number of more contemporary studies documented IE in patients experi- encing nosocomial staphylococcal bacteremia. For example, of 59 consecutive patients with S aureus IE, 45.8% had nosocomial infections, and 50.8% had a removable focus of infection.39 In an analysis of 262 patients at the Duke University Medical Center who had hospital-acquired S aureus bacteremia, 34 (13%) were subsequently diagnosed with definite IE.


For example, of 59 consecutive patients with S aureus IE, 45.8% had nosocomial infections, and 50.8% had a removable focus of infection.39 In an analysis of 262 patients at the Duke University Medical Center who had hospital-acquired S aureus bacteremia, 34 (13%) were subsequently diagnosed with definite IE. Therefore, the modi- fied Duke criteria (Tables 2 and 3) recommend the inclusion of S aureus bacteremia as a major criterion, regardless of whether the infection is hospital acquired (with or without a removable source of infection) or community acquired.24 Specific serological data have been included in the Duke IE diagnostic schema to establish the pathogenic agents of culture-negative IE more precisely (ie, as a surrogate for positive blood cultures). These serological criteria would be applied in circumstances in which the pathogenic organism is slow growing in routine blood cultures (eg, Brucella spe- cies) or requires special blood culture media (eg, Bartonella species, Legionella species, Tropheryma whipplei, fungi, and Mycobacterium species) or in which the organism is not culturable (eg, Coxiella burnetii, the agent of Q fever). For example, in the original Duke criteria, a positive serology for Q fever was considered a minor microbiological criterion. Subsequently, Fournier et al40 studied 20 pathologically con- firmed cases of Q fever IE. When the original Duke criteria were used, 4 of the 20 patients were classified as having pos- sible IE. When Q fever serological results and a single blood culture positive for C burnetii were considered to be a major criterion, however, each of these 4 cases was reclassified from possible IE to definite IE. On the basis of these data, specific serological data as a surrogate marker for positive blood cul- tures have now been included in the Duke criteria.


On the basis of these data, specific serological data as a surrogate marker for positive blood cul- tures have now been included in the Duke criteria. Thus, an anti phase I immunoglobulin G antibody titer 1:800 or a single blood culture positive for C burnetii should be a major criterion in the modified Duke schema.24 Serological tests and PCR-based testing for other diffi- cult-to-cultivate organisms such as Bartonella quintana or Tropheryma whippelii also have been discussed as future major criteria. At present, there are significant methodologi- cal problems associated with proposing antibody titers that are positive for Bartonella and Chlamydia species or PCR-based testing for T whippelii as a major criterion in the Duke schema. For example, IE caused by Bartonella and Chlamydia species often are indistinguishable in serological test results because Low sensitivity is a major limitation of PCR unless cardiac valvular tissue is available for testing.42 45 Few centers provide timely PCR-based testing for these rare causes of IE. Therefore, the inclusion of these assays as major criteria should be deferred until the serodiagnostic and PCR approaches can be standardized and validated in a sufficient number of cases of these rare types of IE, the aforementioned technical problems are resolved, and the availability of such assays becomes more widespread. The expansion of minor criteria to include elevated eryth- rocyte sedimentation rate or C-reactive protein, the presence of newly diagnosed clubbing, splenomegaly, and microscopic hematuria also has been proposed. In a study of 100 consecu- tive cases of pathologically proven native valve IE (NVE), inclusion of these additional parameters with the existing Duke minor criteria resulted in a 10% increase in the fre- quency of cases being deemed clinically definite, with no loss of specificity.


In a study of 100 consecu- tive cases of pathologically proven native valve IE (NVE), inclusion of these additional parameters with the existing Duke minor criteria resulted in a 10% increase in the fre- quency of cases being deemed clinically definite, with no loss of specificity. The major limitations of the erythrocyte sedi- mentation rate and C-reactive protein are that they are non- specific and particularly challenging to interpret in patients with comorbid conditions. These additional parameters have not been formally integrated into the modified Duke criteria,24 however, which are universally accepted. One minor criterion from the original Duke schema, echocardiogram consistent with IE but not meeting major criterion, was re-evaluated. This criterion originally was used in cases in which nonspecific valvular thickening was detected by transthoracic echocardiography (TTE). In a reanalysis of patients in the Duke University database (containing records collected prospectively on >800 cases of definite and possible IE since 1984), this echocardiographic criterion was used in only 5% of cases and was never used in the final analysis of any patient who underwent transesophageal echocardiogra- phy (TEE). Therefore, this minor criterion was eliminated in the modified Duke criteria.24 Finally, adjustment of the Duke criteria to require a mini- mum of 1 major plus 1 minor criterion or 3 minor criteria as a floor to designate a case as possible IE (as opposed to findings consistent with IE that fall short of definite but not rejected ) has been incorporated into the modified criteria to reduce the proportion of patients assigned to the IE possible category. This approach was used in a series of patients ini- tially categorized as possible IE by the original Duke criteria. Table 2.


This approach was used in a series of patients ini- tially categorized as possible IE by the original Duke criteria. Table 2. Definition of IE According to the Modified Duke Criteria* Definite IE Pathological criteria Microorganisms demonstrated by culture or histological examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen; or pathological lesions; vegetation or intracardiac abscess confirmed by histological examination showing active endocarditis Clinical criteria 2 Major criteria, 1 major criterion and 3 minor criteria, or 5 minor criteria Possible IE 1 Major criterion and 1 minor criterion, or 3 minor criteria Rejected Firm alternative diagnosis explaining evidence of IE; or resolution of IE syndrome with antibiotic therapy for 4 d; or no pathological evidence of IE at surgery or autopsy with antibiotic therapy for 4 d; or does not meet criteria for possible IE as above IE indicates infective endocarditis. Modifications appear in boldface. *These criteria have been universally accepted and are in current use. Reprinted from Li et al24 by permission of the Infectious Diseases Society of America. Copyright 2000, the Infectious Diseases Society of America. Baddour et al Infective Endocarditis in Adults 1439 With the guidance of the diagnostic floor, a number of these cases were reclassified as rejected for IE.24 Follow-up in these reclassified patients documented the specificity of this diagnostic schema because no patients developed IE during the subsequent 12 weeks of observation. Thus, on the basis of the weight of clinical evidence involving nearly 2000 patients in the current literature, it appears that patients suspected of having IE should be clini- cally evaluated, with the modified Duke criteria as the primary diagnostic schema.


Thus, on the basis of the weight of clinical evidence involving nearly 2000 patients in the current literature, it appears that patients suspected of having IE should be clini- cally evaluated, with the modified Duke criteria as the primary diagnostic schema. It should be pointed out that the Duke cri- teria were originally developed to facilitate epidemiological and clinical research efforts so that investigators could com- pare and contrast the clinical features and outcomes of various case series of patients. Extending these criteria to the clinical practice setting has been somewhat more difficult. It should also be emphasized that full application of the Duke criteria requires detailed clinical, microbiological, radiological, and echocardiographic queries. Because IE is a heterogeneous disease with highly variable clinical presentations, the use of these criteria alone will never suffice. Criteria changes that add sensitivity often do so at the expense of specificity and vice versa. The Duke criteria are meant to be a guide for diag- nosing IE and must not replace clinical judgment. Clinicians may appropriately and wisely decide whether or not to treat an individual patient, regardless of whether the patient meets or fails to meet the criteria for definite or possible IE by the Duke criteria. We believe, however, that the modifications of the Duke criteria (Tables 2 and 3) will help investigators who wish to examine the clinical and epidemiological features of IE and will serve as a guide for clinicians struggling with dif- ficult diagnostic problems. These modifications require fur- ther validation among patients who are hospitalized in both community-based and tertiary care hospitals, with particular attention to longer-term follow-up of patients rejected as hav- ing IE because they did not meet the minimal floor criteria for possible IE.


These modifications require fur- ther validation among patients who are hospitalized in both community-based and tertiary care hospitals, with particular attention to longer-term follow-up of patients rejected as hav- ing IE because they did not meet the minimal floor criteria for possible IE. The diagnosis of IE must be made as soon as possible to initiate appropriate empirical antibiotic therapy and to iden- tify patients at high risk for complications who may be best managed by early surgery. In cases with a high suspicion of IE based on either the clinical picture or the patient s risk fac- tor profile such as injection drug use, another focus of car- diovascular infection, including catheter-related bloodstream infections caused by S aureus, or a history of previous IE, the presumption of IE often is made before blood culture results are available. Identification of vegetations and incremental valvular insufficiency with echocardiography often com- pletes the diagnostic criteria for IE and affects the duration of therapy. Although the use of case definitions to establish a diagnosis of IE should not replace clinical judgment,46 the recently modified Duke criteria24 have been useful in both epidemiological and clinical trials and in individual patient management. Clinical, echocardiographic, and microbiologi- cal criteria (Tables 2 and 3) are used routinely to support a diagnosis of IE, and they do not rely on histopathological confirmation of resected valvular material or arterial embolus. If suggestive features are absent, then a negative echocardio- gram should prompt a more thorough search for alternative sources of fever and sepsis. In light of these important func- tions, at least 3 sets of blood cultures obtained from separate venipuncture sites should be obtained, with the first and last samples drawn at least 1 hour apart.


In light of these important func- tions, at least 3 sets of blood cultures obtained from separate venipuncture sites should be obtained, with the first and last samples drawn at least 1 hour apart. In addition, echocardiog- raphy should be performed expeditiously in patients suspected of having IE. Recommendations 1. At least 3 sets of blood cultures obtained from dif- ferent venipuncture sites should be obtained, with the first and last samples drawn at least 1 hour apart (Class I; Level of Evidence A). 2. Echocardiography should be performed expedi- tiously in patients suspected of having IE (Class I; Level of Evidence A). Table 3.


Echocardiography should be performed expedi- tiously in patients suspected of having IE (Class I; Level of Evidence A). Table 3. Definition of Terms Used in the Modified Duke Criteria for the Diagnosis of IE* Major criteria Blood culture positive for IE Typical microorganisms consistent with IE from 2 separate blood cultures: Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus; or community-acquired enterococci in the absence of a primary focus, or microorganisms consistent with IE from persistently positive blood cultures defined as follows: at least 2 positive cultures of blood samples drawn >12 h apart or all 3 or a majority of 4 separate cultures of blood (with first and last sample drawn at least 1 h apart) Single positive blood culture for Coxiella burnetii or anti phase 1 IgG antibody titer 1:800 Evidence of endocardial involvement Echocardiogram positive for IE (TEE recommended for patients with prosthetic valves, rated at least possible IE by clinical criteria, or complicated IE [paravalvular abscess]; TTE as first test in other patients) defined as follows: oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; abscess; or new partial dehiscence of prosthetic valve or new valvular regurgitation (worsening or changing or pre-existing murmur not sufficient) Minor criteria Predisposition, predisposing heart condition, or IDU Fever, temperature >38 C Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions Immunological phenomena: glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factor Microbiological evidence: positive blood culture but does not meet a major criterion as noted above (excludes single positive cultures for coagulase- negative staphylococci and organisms that do not cause endocarditis) or serological evidence of active infection with organism consistent with IE Echocardiographic minor criteria eliminated HACEK indicates Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species; IDU, injection drug use; IE, infective endocarditis; IgG, immunoglobulin G; TEE transesophageal echocardiography; and TTE, transthoracic echocardiography.


Modifications appear in boldface. *These criteria have been universally accepted and are in current use. Reprinted from Li et al24 by permission of the Infectious Diseases Society of America. Copyright 2000, the Infectious Diseases Society of America. Echocardiography Echocardiography is central to the diagnosis and management of patients with IE. As previously stated (Table 3), echocar- diographic evidence of an oscillating intracardiac mass or vegetation, an annular abscess, prosthetic valve partial dehis- cence, and new valvular regurgitation are major criteria in the diagnosis of IE. Both TTE and TEE are done in many patients with IE dur- ing initial evaluation and subsequent follow-up and provide complementary information. Therefore, TTE should be done initially in all cases of suspected IE (Figure). If any circum- stances preclude the securing of optimal echocardiographic windows, including chronic obstructive lung disease, previous thoracic or cardiovascular surgery, morbid obesity, or other conditions, then TEE should be performed as soon as pos- sible after TTE. When TTE is negative and clinical suspicion remains low, then other clinical entities should be considered. If TTE shows vegetations but the likelihood of complications is low, then subsequent TEE is unlikely to alter initial medi- cal management. On the other hand, if clinical suspicion of IE or its complications is high (eg, prosthetic valve or new atrioventricular block), then a negative TTE will not definitely rule out IE or its potential complications, and TEE should be performed first.


On the other hand, if clinical suspicion of IE or its complications is high (eg, prosthetic valve or new atrioventricular block), then a negative TTE will not definitely rule out IE or its potential complications, and TEE should be performed first. Investigation in adults has shown TEE to be significantly more sensitive than TTE for the detection of veg- etations and abscesses.47 In the setting of a prosthetic valve, transthoracic images are greatly hampered by the structural components of the prosthesis and are inadequate for assess- ment of the perivalvular area where those infections often Although cost-effectiveness calculations suggest that TEE should be the first examination in adults with suspected IE (Table 4), particularly in the setting of staphylococcal bac- many patients are not candidates for immediate TEE because of having eaten within the preceding 6 hours or because the patients are in institutions that cannot provide 24-hour TEE services. When TEE is not clinically possible or must be delayed, early TTE should be performed without delay. Although TTE will not definitively exclude vegeta- tions or abscesses, it will allow identification of very-high- risk patients, establish the diagnosis in many, and guide early treatment decisions. Although interesting results suggest that there may be a high negative predictive value of TTE in some further work is needed to better define the subgroup of patients with bloodstream infection caused by S aureus who need only TTE to evaluate for IE. Many findings identified by TEE also can be detected on TTE. Concurrent TTE images can serve as a baseline for rapid and noninvasive comparison of vegetation size, valvular insufficiency, or change in abscess cavities during the course of the patient s treatment should clinical dete- rioration occur.


Concurrent TTE images can serve as a baseline for rapid and noninvasive comparison of vegetation size, valvular insufficiency, or change in abscess cavities during the course of the patient s treatment should clinical dete- rioration occur. For tricuspid vegetations or abnormalities of the right ventricular outflow tract, visualization may be enhanced by choosing TTE rather than TEE.52 Finally, many cardiologists believe TTE is superior to TEE for quantifying hemodynamic dysfunction manifested by valvular regurgi- tation, ventricular dysfunction, and elevated left and right ventricular filling pressures and pulmonary artery pressure. These echocardiographic findings can occur in patients who have no heart failure symptoms. Both TEE and TTE may produce false-negative results if vegetations are small or have embolized.53 Even TEE may miss initial perivalvular abscesses, particularly when the study is performed early in the patient s illness.54 In such cases, the Figure. An approach to the diagnostic use of echocardiography (echo). Rx indicates prescription; TEE, transesophageal echocardiography; and TTE, transthoracic echocardiography. *For example, a patient with fever and a previously known heart murmur and no other stigmata of infective endocarditis (IE). High initial patient risks include prosthetic heart valves, many congenital heart diseases, previous endocarditis, new murmur, heart failure, or other stigmata of endocarditis. High-risk echocardiographic features include large or mobile vegetations, valvular insufficiency, suggestion of perivalvular extension, or secondary ventricular dysfunction (see text). Modified from Baddour et al.12 Copyright 2005, American Heart Association, Inc. Baddour et al Infective Endocarditis in Adults 1441 incipient abscess may be seen only as nonspecific perivalvu- lar thickening, which on repeat imaging across several days may become more recognizable as it expands and develops a cavity. Similarly, perivalvular fistulas and pseudoaneurysms develop over time, and negative early TEE images do not exclude the potential for their development.


Similarly, perivalvular fistulas and pseudoaneurysms develop over time, and negative early TEE images do not exclude the potential for their development. False-positive results from TEE or TTE studies may occur when valvular abnormalities are seen that may not be related to a current infection. Previous scarring, severe myxomatous change, and even normal structures such as Lambl excres- cences may be indistinguishable from active changes in the valves. As echocardiographic technology improves with higher frequencies and refined beam-forming technology, subtle findings continue to be recognized and may add to the category of indeterminate findings. One approach to minimiz- ing confusion from these latter structures is to exploit the high frame rates that are often available with current equipment to improve temporal resolution and to clearly visualize rap- idly moving structures such as microcavities from prosthetic valves or fibrillar components. Several echocardiographic features identify patients at high risk for a complicated course or with a need for surgery (Table 5). These features include large (>10 mm in diameter) vegetations, severe valvular insufficiency, abscess cavities or pseudoaneurysms, valvular perforation or dehiscence, and evidence of decompensated heart failure.21 The ability of echo- cardiographic features to predict embolic events is limited.55 57 The greatest risk of embolic complications appears to occur with large ( 10 mm) vegetations on the anterior mitral leaf- Vegetation size and mobility may be taken into account, along with bacteriological factors and other indications for surgery, when considering early surgery to avoid emboliza- tion, although mobility characteristics alone should not be the principal driver as a surgical indication.59 Recommendation 1. TTE should be performed in all cases of suspected IE (Class I; Level of Evidence B).


TTE should be performed in all cases of suspected IE (Class I; Level of Evidence B). Repeat Echocardiography If the initial TTE images are negative and the diagnosis of IE is still being considered, then TEE should be performed as soon as possible (Table 4). Among patients with an initially positive TTE and a high risk for intracardiac complications, including perivalvular extension of infection, TEE should be obtained as soon as possible. Repeating the TEE in 3 to 5 days (or sooner if clinical findings change) after an initial negative result is recommended when clinical suspicion of IE In some cases, vegetations may reach a detectable size in the interval, or abscess cavities or fistulous tracts may become evident. An interval increase in vegetation size on serial echocardiography despite the administration of appro- priate antibiotic therapy has serious implications and has been associated with an increased risk of complications and the need for surgery.60 Repeat TEE should be done when a patient with an initially positive TEE develops worrisome clinical features during antibiotic therapy. These features, including unexplained progression of heart failure symptoms, change in cardiac murmurs, and new atrioventricular block or arrhyth- mia, should prompt emergent evaluation by TEE if possible. Recommendations 1. TEE should be done if initial TTE images are nega- tive or inadequate in patients for whom there is an ongoing suspicion for IE or when there is concern for intracardiac complications in patients with an initial positive TTE (Class I; Level of Evidence B). 2. If there is a high suspicion of IE despite an initial negative TEE, then a repeat TEE is recommended in 3 to 5 days or sooner if clinical findings change (Class I; Level of Evidence B). 3.


If there is a high suspicion of IE despite an initial negative TEE, then a repeat TEE is recommended in 3 to 5 days or sooner if clinical findings change (Class I; Level of Evidence B). 3. Repeat TEE should be done after an initially posi- tive TEE if clinical features suggest a new develop- ment of intracardiac complications (Class I; Level of Evidence B). Intraoperative Echocardiography Preoperative surgical planning for patients with IE will ben- efit from echocardiographic delineation of the mechanisms of valvular dysfunction or regions of myocardial abscess forma- tion (Table 5). The use of aortic homografts is facilitated by preoperative estimates of annular size, which allow the selec- tion of appropriately sized donor tissues.61,62 Intraoperatively, echocardiographic goals include assessment of not only Table 4. Use of Echocardiography During Diagnosis and Treatment of Endocarditis Early Echocardiography as soon as possible (<12 h after initial evaluation) TEE preferred; obtain TTE views of any abnormal findings for later comparison TTE if TEE is not immediately available TTE may be sufficient in small children Repeat echocardiography TEE after positive TTE as soon as possible in patients at high risk for complications TEE 3 5 d after initial TEE if suspicion exists without diagnosis of IE or with worrisome clinical course during early treatment of IE Intraoperative Prepump Identification of vegetations, mechanism of regurgitation, abscesses, fistulas, and pseudoaneurysms Postpump Confirmation of successful repair of abnormal findings Assessment of residual valve dysfunction Elevated afterload if necessary to avoid underestimating valve insufficiency or presence of residual abnormal flow Completion of therapy Establish new baseline for valve function and morphology and ventricular size and function TTE usually adequate; TEE or review of intraoperative TEE may be needed for complex anatomy to establish new baseline TEE indicates transesophageal echocardiography; and TTE, transthoracic echocardiography.


Use of Echocardiography During Diagnosis and Treatment of Endocarditis Early Echocardiography as soon as possible (<12 h after initial evaluation) TEE preferred; obtain TTE views of any abnormal findings for later comparison TTE if TEE is not immediately available TTE may be sufficient in small children Repeat echocardiography TEE after positive TTE as soon as possible in patients at high risk for complications TEE 3 5 d after initial TEE if suspicion exists without diagnosis of IE or with worrisome clinical course during early treatment of IE Intraoperative Prepump Identification of vegetations, mechanism of regurgitation, abscesses, fistulas, and pseudoaneurysms Postpump Confirmation of successful repair of abnormal findings Assessment of residual valve dysfunction Elevated afterload if necessary to avoid underestimating valve insufficiency or presence of residual abnormal flow Completion of therapy Establish new baseline for valve function and morphology and ventricular size and function TTE usually adequate; TEE or review of intraoperative TEE may be needed for complex anatomy to establish new baseline TEE indicates transesophageal echocardiography; and TTE, transthoracic echocardiography. the obviously dysfunctional valve but also the other valves and contiguous structures. Post cardiopulmonary bypass images should confirm the adequacy of the repair or replace- ment and document the successful closure of fistulous tracts. Perivalvular leaks related to technical factors should be docu- mented to avoid later confusion about whether such leaks are the result of recurrent infection. During postpump imaging, it is often necessary to augment afterload to reach representative ambulatory levels to avoid underestimation of regurgitant jet size and significance and to ensure that abnormal communi- cations were closed.63 Afterload augmentation, however, may not mimic actual awake physiology and may still lead occa- sionally to an inaccurate evaluation of the awake postopera- tive hemodynamic state.


During postpump imaging, it is often necessary to augment afterload to reach representative ambulatory levels to avoid underestimation of regurgitant jet size and significance and to ensure that abnormal communi- cations were closed.63 Afterload augmentation, however, may not mimic actual awake physiology and may still lead occa- sionally to an inaccurate evaluation of the awake postopera- tive hemodynamic state. Echocardiography at the Completion of Therapy All patients who have experienced an episode of IE remain at increased risk for recurrent infection indefinitely. Many believe that it is extremely important for the future care of these patients to establish a new baseline for valvular morphology, including the presence of vegetations and valvular insufficiency, once treatment has been completed. Documentation of heart rate, heart rhythm, and blood pres- sure at the time of echocardiographic study is important because changes in these conditions may explain future differences in valvular insufficiency independent of pathol- ogy (Table 4). TTE is reasonable for this evaluation because spectral Doppler interrogation for functionality metrics is more thorough than TEE. TEE, however, may be mer- ited to define the new baseline in some patients with poor acoustic windows or complicated anatomy such as after extensive debridement and reconstruction. Although intra- operative postpump TEE views may be adequate for this new baseline, they should be reviewed for adequacy and repeated if necessary. Some patients will have significant valvular dysfunction at the end of otherwise successful antimicrobial treatment that will require eventual valvular surgery. Posttreatment echocardiography can guide both medical management and the discussion of the appropriate timing of such interventions. Recommendation 1. TTE at the time of antimicrobial therapy comple- tion to establish baseline features is reasonable (Class IIa; Level of Evidence C).