Prevention of Infective Endocarditis Guidelines From the American Heart Association A Guideline From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group Walter Wilson, MD, Chair; Kathryn A. Taubert, PhD, FAHA; Michael Gewitz, MD, FAHA; Peter B. Lockhart, DDS; Larry M. Baddour, MD; Matthew Levison, MD; Ann Bolger, MD, FAHA; Christopher H. Cabell, MD, MHS; Masato Takahashi, MD, FAHA; Robert S. Baltimore, MD; Jane W. Newburger, MD, MPH, FAHA; Brian L. Strom, MD; Lloyd Y. Tani, MD; Michael Gerber, MD; Robert O. Bonow, MD, FAHA; Thomas Pallasch, DDS, MS; Stanford T. Shulman, MD, FAHA; Anne H. Rowley, MD; Jane C. Burns, MD; Patricia Ferrieri, MD; Timothy Gardner, MD, FAHA; David Goff, MD, PhD, FAHA; David T. Durack, MD, PhD The Council on Scientific Affairs of the American Dental Association has approved the guideline as it relates to dentistry. In addition, this guideline has been endorsed by the American Academy of Pediatrics, Infectious Diseases Society of America, the International Society of Chemotherapy for Infection and Cancer,* and the Pediatric Infectious Diseases Society. Background The purpose of this statement is to update the recommendations by the American Heart Association (AHA) for the prevention of infective endocarditis that were last published in 1997. Methods and Results A writing group was appointed by the AHA for their expertise in prevention and treatment of infective endocarditis, with liaison members representing the American Dental Association, the Infectious Diseases Society of America, and the American Academy of Pediatrics. The writing group reviewed input from national and international experts on infective endocarditis. The recommendations in this document reflect analyses of relevant literature regarding procedure-related bacteremia and infective endocarditis, in vitro susceptibility data of the most common microorganisms that cause infective endocarditis, results of prophylactic studies in animal models of experimental endocarditis, and retrospective and prospective studies of prevention of infective endocarditis. MEDLINE database searches from 1950 to 2006 were done for English-language papers using the following search terms: endocarditis, infective endocarditis, prophylaxis, prevention, antibiotic, antimicrobial, pathogens, organisms, dental, gastrointestinal, genitourinary, streptococcus, enterococcus, staphylococcus, respiratory, dental surgery, pathogenesis, vaccine, immunization, and bacteremia. The reference lists of the identified papers were also searched. We also searched the AHA online library. The American College of Cardiology/AHA classification of recommendations and levels of *If these guidelines are applied outside of the United States of America, adaptation of the recommended antibiotic agents may be considered with respect to the regional situation. The American Heart Association 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. This guideline was approved by the American Heart Association Science Advisory and Coordinating Committee on March 7, 2007. 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A link to the Permission Request Form appears on the right side of the page. 2007 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.106.183095 AHA Guideline evidence for practice guidelines were used. The paper was subsequently reviewed by outside experts not affiliated with the writing group and by the AHA Science Advisory and Coordinating Committee. Conclusions The major changes in the updated recommendations include the following: (1) The Committee concluded that only an extremely small number of cases of infective endocarditis might be prevented by antibiotic prophylaxis for dental procedures even if such prophylactic therapy were 100% effective. (2) Infective endocarditis prophylaxis for dental procedures is reasonable only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis. (3) For patients with these underlying cardiac conditions, prophylaxis is reasonable for all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. (4) Prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of infective endocarditis. (5) Administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or gastrointestinal tract procedure. These changes are intended to define more clearly when infective endocarditis prophylaxis is or is not recommended and to provide more uniform and consistent global recommendations. (Circulation. 2007;116:1736-1754.) Key Words: AHA Scientific Statements cardiovascular diseases endocarditis prevention antibiotic prophylaxis Infective endocarditis (IE) is an uncommon but life- threatening infection. Despite advances in diagnosis, antimi- crobial therapy, surgical techniques, and management of com- plications, patients with IE still have high morbidity and mortality rates related to this condition. Since the last American Heart Association (AHA) publication on prevention of IE in 1997,1 many authorities and societies, as well as the conclusions of published studies, have questioned the efficacy of antimicro- bial prophylaxis to prevent IE in patients who undergo a dental, gastrointestinal (GI), or genitourinary (GU) tract procedure and have suggested that the AHA guidelines should be revised.2 5 Members of the Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the AHA Council on Cardiovascular Disease in the Young ( the Committee ) and a national and international group of experts on IE extensively reviewed data published on the prevention of IE. The Committee is especially grateful to a group of international experts on IE who provided content review and input on this document (see Acknowledg- ments). The revised guidelines for IE prophylaxis are the subject of this report. The writing group was charged with the task of perform- ing an assessment of the evidence and giving a classifica- tion of recommendations and a level of evidence (LOE) to each recommendation. The American College of Cardiol- ogy (ACC)/AHA classification system was used as follows. Classification of Recommendations: Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful, and effective. Class II: Conditions for which there is conflicting evi- dence and/or a divergence of opinion about the usefulness/ efficacy of a procedure or treatment. Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. Class IIb: Usefulness/efficacy is less well established by evidence/opinion. Class III: Conditions for which there is evidence and/or general agreement that a procedure/treatment is not useful/ effective and in some cases may be harmful. Level of Evidence: Level of Evidence A: Data derived from multiple random- ized clinical trials or meta-analyses. Level of Evidence B: Data derived from a single random- ized trial or nonrandomized studies. Level of Evidence C: Only consensus opinion of experts, case studies, or standard of care. History of AHA Statements on Prevention of IE The AHA has made recommendations for the prevention of IE for more than 50 years. In 1955, the first AHA document on this subject was published in Circulation.6 Table 1 shows a summary of the documents published from 1955 to 1997.1,6 13 The 1960 document called atten- tion to the possible emergence of penicillin-resistant oral microflora as a result of prolonged therapy for prevention of IE, and pediatric patients were included for the first time.8 Chloramphenicol was recommended for patients who were allergic to penicillin. In 1965, the Committee published for the first time a document devoted solely to the prophylaxis of IE and recognized the importance of enterococci after GI or GU tract procedures.9 The revised recommendations published in 1972 were endorsed for the first time by the American Dental Association (ADA) and emphasized the importance of maintenance of good oral hygiene.10 This version introduced a recommendation for ampicillin in patients undergoing a GI or GU tract proce- dure. The 1977 revisions categorized both patients and procedures into high- and low-risk groups.11 This resulted in complex tables with many footnotes. The 1984 recom- mendations attempted to simplify prophylactic regimens by providing clear lists of procedures for which prophy- laxis was and was not recommended and reduced postpro- cedure prophylaxis for dental, GI, and GU tract procedures to only 1 oral or parenteral dose.12 In 1990, a more complete list of cardiac conditions and dental or surgical procedures for which prophylaxis was and was not recom- mended was provided.13 These previous recommendations rec- ognized the potential medical-legal risks associated with IE prophylaxis and suggested that the recommendations were Wilson et al Prevention of Infective Endocarditis 1737 intended to serve as a guideline, not as established standard of care. The most recent AHA document on IE prophylaxis was published in 1997.1 The 1997 document stratified cardiac conditions into high-, moderate-, and low-risk (negligible risk) categories, with prophylaxis not recommended for the low-risk group.1 An even more detailed list of dental, respi- ratory, GI, and GU tract procedures for which prophylaxis was and was not recommended was provided. The 1997 document was notable for its acknowledgment that most cases of IE are not attributable to an invasive procedure but rather are the result of randomly occurring bacteremias from routine daily activities and for its acknowledgment of possi- ble IE prophylaxis failures. Rationale for Revising the 1997 Document It is clear from the above chronology that the AHA guidelines for IE prophylaxis have been in a process of evolution more than 50 years. The rationale for prophylaxis was based largely on expert opinion and what seemed to be a rational and prudent attempt to prevent a life-threatening infection. On the basis of the ACC and AHA Task Force on Practice Guide- lines evidence-based grading system for ranking recommen- dations, the recommendations in the AHA documents pub- lished during the past 50 years would be Class IIb, LOE C. Accordingly, the basis for recommendations for IE prophy- laxis was not well established, and the quality of evidence was limited to a few case-control studies or was based on expert opinion, clinical experience, and descriptive studies that utilized surrogate measures of risk. Over the years, other international societies have published recommendations and guidelines for the prevention of IE.14,15 Recently, the British Society for Antimicrobial Chemother- apy issued new IE prophylaxis recommendations.15 This group now recommends prophylaxis before dental procedures only for patients who have a history of previous IE or who have had cardiac valve replacement or surgically constructed pulmonary shunts or conduits. The fundamental underlying principles that drove the formulation of the AHA guidelines and the 9 previous AHA documents were that (1) IE is an uncommon but life- threatening disease, and prevention is preferable to treatment of established infection; (2) certain underlying cardiac con- ditions predispose to IE; (3) bacteremia with organisms known to cause IE occurs commonly in association with invasive dental, GI, or GU tract procedures; (4) antimicrobial prophylaxis was proven to be effective for prevention of experimental IE in animals; and (5) antimicrobial prophylaxis was thought to be effective in humans for prevention of IE associated with dental, GI, or GU tract procedures. The Committee believes that of these 5 underlying principles, the first 4 are valid and have not changed during the past 30 years. Numerous publications have questioned the validity of the fifth principle and suggested revision of the guidelines, primarily for reasons as shown in Table 2. Another reason that led the Committee to revise the 1997 document was that over the past 50 years, the AHA guide- lines on prevention of IE became overly complicated, making it difficult for patients and healthcare providers to interpret or remember specific details, and they contained ambiguities and some inconsistencies in the recommendations. The deci- sion to substantially revise the 1997 document was not taken lightly. The present revised document was not based on the results of a single study but rather on the collective body of evidence published in numerous studies over the past 2 decades. The Committee sought to construct the present recommendations such that they would be in the best interest Table 1. Summary of 9 Iterations of AHA-Recommended Antibiotic Regimens From 1955 to 1997 for Dental/Respiratory Tract Procedures* Year (Reference) Primary Regimens for Dental Procedures 1955 (6) Aqueous penicillin 600 000 U and procaine penicillin 600 000 U in oil containing 2% aluminum monostearate administered IM 30 minutes before the operative procedure 1957 (7) For 2 days before surgery, penicillin 200 000 to 250 000 U by mouth 4 times per day. On day of surgery, penicillin 200 000 to 250 000 U by mouth 4 times per day and aqueous penicillin 600 000 U with procaine penicillin 600 000 U IM 30 to 60 minutes before surgery. For 2 days after, 200 000 to 250 000 U by mouth 4 times per day. 1960 (8) Step I: prophylaxis 2 days before surgery with procaine penicillin 600 000 U IM on each day Step II: day of surgery: procaine penicillin 600 000 U IM supplemented by crystalline penicillin 600 000 U IM 1 hour before surgical procedure Step III: for 2 days after surgery: procaine penicillin 600 000 U IM each day 1965 (9) Day of procedure: procaine penicillin 600 000 U, supplemented by crystalline penicillin 600 000 U IM 1 to 2 hours before the procedure For 2 days after procedure: procaine penicillin 600 000 U IM each day 1972 (10) Procaine penicillin G 600 000 U mixed with crystalline penicillin G 200 000 U IM 1 hour before procedure and once daily for the 2 days after the procedure 1977 (11) Aqueous crystalline penicillin G (1 000 000 U IM) mixed with procaine penicillin G (600 000 U IM) 30 minutes to 1 hour before procedure and then penicillin V 500 mg orally every 6 hours for 8 doses. 1984 (12) Penicillin V 2 g orally 1 hour before, then 1 g 6 hours after initial dose 1990 (13) Amoxicillin 3 g orally 1 hour before procedure, then 1.5 g 6 hours after initial dose 1997 (1) Amoxicillin 2 g orally 1 hour before procedure IM indicates intramuscularly. *These regimens were for adults and represented the initial regimen listed in each version of the recommendations. In some versions, 1 regimen was included. of patients and providers, would be reasonable and prudent, and would represent the conclusions of published studies and the collective wisdom of many experts on IE and relevant national and international societies. Potential Consequences of Substantive Changes in Recommendations Substantive changes in recommendations could (1) violate long-standing expectations and practice patterns; (2) make fewer patients eligible for IE prophylaxis; (3) reduce mal- practice claims related to IE prophylaxis; and (4) stimulate prospective studies on IE prophylaxis. The Committee and others16 recognize that substantive changes in IE prophylaxis guidelines may violate long-standing expectations and prac- tice patterns by patients and healthcare providers. The Com- mittee recognizes that these new recommendations may cause concern among patients who have previously received anti- biotic prophylaxis to prevent IE before dental or other procedures and are now advised that such prophylaxis is unnecessary. Table 2 includes the main talking points that may be helpful for clinicians in reeducating their patients about these changes. To recommend such changes demands due diligence and critical analysis. For 50 years, since the publication of the first AHA guidelines on the prevention of IE,6 patients and healthcare providers assumed that antibiotics administered in association with a bacteremia-producing procedure effectively prevented IE in patients with underly- ing cardiac risk factors. Patients were educated about bacteremia-producing procedures and risk factors for IE, and they expected to receive antibiotic prophylaxis; healthcare providers, especially dentists, were expected to administer them. Patients with underlying cardiac conditions that carry a lifetime risk of acquisition of IE, such as mitral valve prolapse (MVP), had a sense of reassurance and comfort that antibiotics administered in association with a dental proce- dure were effective and usually safe to prevent IE. Healthcare providers, especially dentists, felt a sense of obligation and professional and legal responsibility to protect their patients from IE that might result from a procedure. On the basis of recommendations in this revised document, substantially fewer patients will be recommended for IE prophylaxis. Cases of IE either temporally or remotely associated with an invasive procedure, especially a dental procedure, have frequently been the basis for malpractice claims against healthcare providers. Unlike many other infections for which there is conclusive evidence for the efficacy of preventive therapy, the prevention of IE is not a precise science. Because previously published AHA guidelines for the prevention of IE contained ambiguities and inconsistencies and were often based on minimal published data or expert opinion, they were subject to conflicting interpretations among patients, health- care providers, and the legal system about patient eligibility for prophylaxis and whether there was strict adherence by healthcare providers to AHA recommendations for prophy- laxis. This document is intended to identify which, if any, patients may possibly benefit from IE prophylaxis and to define, to the extent possible, which dental procedures should have prophylaxis in this select group of patients. Accord- ingly, the Committee hopes that this document will result in greater clarity for patients, healthcare providers, and consult- ing professionals. The Committee believes that recommendations for IE prophylaxis must be evidence based. A placebo-controlled, multicenter, randomized, double-blinded study to evaluate the efficacy of IE prophylaxis in patients who undergo a dental, GI, or GU tract procedure has not been done. Such a study would require a large number of patients per treatment group and standardization of the specific invasive procedures and the patient populations. This type of study would be necessary to definitively answer long-standing unresolved questions regarding the efficacy of IE prophylaxis. The Committee hopes that this revised document will stimulate additional studies on the prevention of IE. Future published data will be reviewed carefully by the AHA, the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, and other societies, and further revisions to the present document will be based on relevant studies. Pathogenesis of IE The development of IE is the net result of the complex interaction between the bloodstream pathogen with matrix molecules and platelets at sites of endocardial cell damage. In addition, many of the clinical manifestations of IE emanate from the host s immune response to the infecting microor- ganism. The following sequence of events is thought to result in IE: formation of nonbacterial thrombotic endocarditis (NBTE) on the surface of a cardiac valve or elsewhere that endothelial damage occurs, bacteremia, adherence of the bacteria in the bloodstream to NBTE, and proliferation of bacteria within a vegetation. Formation of NBTE Turbulent blood flow produced by certain types of congenital or acquired heart disease, such as flow from a high- to a low-pressure chamber or across a narrowed orifice, trauma- tizes the endothelium. This creates a predisposition for deposition of platelets and fibrin on the surface of the endothelium, which results in NBTE. Invasion of the blood- stream with a microbial species that has the pathogenic potential to colonize this site can then result in IE. Transient Bacteremia Mucosal surfaces are populated by a dense endogenous microflora. Trauma to a mucosal surface, particularly the Table 2. Primary Reasons for Revision of the IE Prophylaxis Guidelines IE is much more likely to result from frequent exposure to random bacteremias associated with daily activities than from bacteremia caused by a dental, GI tract, or GU tract procedure. Prophylaxis may prevent an exceedingly small number of cases of IE, if any, in individuals who undergo a dental, GI tract, or GU tract procedure. The risk of antibiotic-associated adverse events exceeds the benefit, if any, from prophylactic antibiotic therapy. Maintenance of optimal oral health and hygiene may reduce the incidence of bacteremia from daily activities and is more important than prophylactic antibiotics for a dental procedure to reduce the risk of IE. Wilson et al Prevention of Infective Endocarditis 1739 gingival crevice around teeth, oropharynx, GI tract, urethra, and vagina, releases many different microbial species tran- siently into the bloodstream. Transient bacteremia caused by viridans group streptococci and other oral microflora occurs commonly in association with dental extractions or other dental procedures or with routine daily activities. Although controversial, the frequency and intensity of the resulting bacteremias are believed to be related to the nature and magnitude of the tissue trauma, the density of the microbial flora, and the degree of inflammation or infection at the site of trauma. The microbial species entering the circulation depends on the unique endogenous microflora that colonizes the particular traumatized site. Bacterial Adherence The ability of various microbial species to adhere to specific sites determines the anatomic localization of infection caused by these microorganisms. Mediators of bacterial adherence serve as virulence factors in the pathogenesis of IE. Numer- ous bacterial surface components present in streptococci, staphylococci, and enterococci have been shown in animal models of experimental endocarditis to function as critical adhesins. Some viridans group streptococci contain a FimA protein that is a lipoprotein receptor antigen I (LraI) that serves as a major adhesin to the fibrin platelet matrix of NBTE.17 Staphylococcal adhesins function in at least 2 ways. In one, microbial surface components recognizing adhesive matrix molecules facilitate the attachment of staphylococci to human extracellular matrix proteins and to medical devices that become coated with matrix proteins after implantation. In the other, bacterial extracellular structures contribute to the formation of biofilm that forms on the surface of implanted medical devices. In both cases, staphylococcal adhesins are important virulence factors. Both FimA and staphylococcal adhesins are immunogenic in experimental infections. Vaccines prepared against FimA and staphylococcal adhesins provide some protective effect in experimental endocarditis caused by viridans group strepto- cocci and staphylococci.18,19 The results of these experimen- tal studies are highly intriguing, because the development of an effective vaccine for use in humans to prevent viridans group streptococcal or staphylococcal IE would be of major importance. Proliferation of Bacteria Within a Vegetation Microorganisms adherent to the vegetation stimulate further deposition of fibrin and platelets on their surface. Within this secluded focus, the buried microorganisms multiply as rap- idly as bacteria in broth cultures to reach maximal microbial densities of 108 colony-forming units per gram of vegetation within a short time on the left side of the heart, apparently uninhibited by host defenses in left-sided lesions. Right-sided vegetations have lower bacterial densities, which may be the consequence of host defense mechanisms active at this site, such as polymorphonuclear activity or platelet- derived antibacterial proteins. More than 90% of the micro- organisms in mature left- or right-sided valvular vegetations are metabolically inactive rather than in an active growth phase and are therefore less responsive to the bactericidal effects of antibiotics.20 Rationale for or Against Prophylaxis of IE Historical Background Viridans group streptococci are part of the normal skin, oral, respiratory, and GI tract flora, and they cause at least 50% of cases of community-acquired native valve IE not associated with intravenous drug use.21 More than a century ago, the oral cavity was recognized as a potential source of the bacteremia that caused viridans group streptococcal IE. In 1885, Osler22 noted an association between bacteremia from surgery and IE. Okell and Elliott23 in 1935 reported that 11% of patients with poor oral hygiene had positive blood cultures with viridans group streptococci and that 61% of patients had viridans group streptococcal bacteremia with dental extraction. As a result of these early studies and subsequent studies, during the past 50 years, the AHA guidelines recommended antimicrobial prophylaxis to prevent IE in patients with underlying cardiac conditions who underwent bacteremia- producing procedures on the basis of the following factors: (1) bacteremia causes endocarditis; (2) viridans group strep- tococci are part of the normal oral flora, and enterococci are part of the normal GI and GU tract flora; (3) these microor- ganisms were usually susceptible to antibiotics recommended for prophylaxis; (4) antibiotic prophylaxis prevents viridans group streptococcal or enterococcal experimental endocardi- tis in animals; (5) a large number of poorly documented case reports implicated a dental procedure as a cause of IE; (6) in some cases, there was a temporal relationship between a dental procedure and the onset of symptoms of IE; (7) an awareness of bacteremia caused by viridans group strepto- cocci associated with a dental procedure exists; (8) the risk of significant adverse reactions to an antibiotic is low in an individual patient; and (9) morbidity and mortality from IE are high. Most of these factors remain valid, but collectively, they do not compensate for the lack of published data that demonstrate a benefit from prophylaxis. Bacteremia-Producing Dental Procedures The large majority of published studies have focused on dental procedures as a cause of IE and the use of prophylactic antibiotics to prevent IE in patients at risk. Few data exist on the risk of or prevention of IE associated with a GI or GU tract procedure. Accordingly, the Committee undertook a critical analysis of published data in the context of the historical rationale for recommending antibiotic prophylaxis for IE before a dental procedure. The following factors were considered: (1) frequency, nature, magnitude, and duration of bacteremia associated with dental procedures; (2) impact of dental disease, oral hygiene, and type of dental procedure on bacteremia; (3) impact of antibiotic prophylaxis on bactere- mia from a dental procedure; and (4) the exposure over time of frequently occurring bacteremia from routine daily activ- ities compared with bacteremia from various dental procedures. Frequency, Nature, Magnitude, and Duration of Bacteremia Associated With a Dental Procedure Transient bacteremia is common with manipulation of the teeth and periodontal tissues, and there is a wide variation in reported frequencies of bacteremia in patients resulting from dental procedures: tooth extraction (10% to 100%), periodon- tal surgery (36% to 88%), scaling and root planing (8% to 80%), teeth cleaning (up to 40%), rubber dam matrix/wedge placement (9% to 32%), and endodontic procedures (up to 20%).24 30 Transient bacteremia also occurs frequently during routine daily activities unrelated to a dental procedure, such as tooth brushing and flossing (20% to 68%), use of wooden toothpicks (20% to 40%), use of water irrigation devices (7% to 50%), and chewing food (7% to 51%).26 29,31 36 Consider- ing that the average person living in the United States has fewer than 2 dental visits per year, the frequency of bactere- mia from routine daily activities is far greater. There has been a disproportionate focus on the frequency of bacteremia associated with dental procedures rather than on the species of bacteria recovered from blood cultures. Studies suggest that more than 700 species of bacteria, including aerobic and anaerobic Gram-positive and Gram- negative microorganisms, may be identified in the human mouth, particularly on the teeth and in the gingival crevic- es.24,37 40 Approximately 30% of the flora of the gingival crevice is streptococci, predominantly of the viridans group. Of the more than 100 oral bacterial species recovered from blood cultures after dental procedures, the most prevalent are viridans group streptococci, the most common microbiolog- ical cause of community-acquired native valve IE in non in- travenous drug users.21 In healthy mouths, a thin surface of mucosal epithelium prevents potentially pathogenic bacteria from entering the bloodstream and lymphatic system. Anaer- obic microorganisms are commonly responsible for periodon- tal disease and frequently enter the bloodstream but rarely cause IE, with fewer than 120 cases reported.41 Viridans group streptococci are antagonistic to periodontal pathogens and predominate in a clean, healthy mouth.42 Few published studies exist on the magnitude of bactere- mia after a dental procedure or from routine daily activities, and most of the published data used older, often unreliable microbiological methodology. There are no published data that demonstrate that a greater magnitude of bacteremia, compared with a lower magnitude, is more likely to cause IE in humans. The magnitude of bacteremia resulting from a dental procedure is relatively low ( 104 colony-forming units of bacteria per milliliter), similar to that resulting from routine daily activities, and is less than that used to cause experimental IE in animals (106 colony-forming units of bacteria per milliliter).20,43,44 Although the infective dose required to cause IE in humans is unknown, the number of microorganisms present in blood after a dental procedure or associated with daily activities is low. Cases of IE caused by oral bacteria probably result from the exposures to low inocula of bacteria in the bloodstream that result from routine daily activities and not from a dental procedure. Additionally, the vast majority of patients with IE have not had a dental procedure within 2 weeks before the onset of symptoms of The role of duration of bacteremia on the risk of acquisi- tion of IE is uncertain.45,46 Early studies reported that sequen- tial blood cultures were positive for up to 10 minutes after tooth extraction and that the number of positive blood cultures dropped sharply after 10 to 30 minutes.24,45 51 More recent studies support these data but report a small percentage of positive blood cultures from 30 to 60 minutes after tooth extraction.43,52,53 Intuitively, it seems logical to assume that the longer the duration of bacteremia, the greater the risk of IE, but no published studies support this assumption. Given the preponderance of published data, there may not be a clinically significant difference in the frequency, nature, magnitude, and duration of bacteremia associated with a dental procedure compared with that resulting from routine daily activities. Accordingly, it is inconsistent to recommend prophylaxis of IE for dental procedures but not for these same patients during routine daily activities. Such a recommenda- tion for prophylaxis for routine daily activities would be impractical and unwarranted. Impact of Dental Disease, Oral Hygiene, and Type of Dental Procedure on Bacteremia It is assumed that a relationship exists between poor oral hygiene, the extent of dental and periodontal disease, the type of dental procedure, and the frequency, nature, magnitude, and duration of bacteremia, but the presumed relationship is controversial.23,29,30,38,45,54 61 Nevertheless, available evi- dence supports an emphasis on maintaining good oral hy- giene and eradicating dental disease to decrease the frequency of bacteremia from routine daily activities.45,56 58,62,63 In patients with poor oral hygiene, the frequency of positive blood cultures just before dental extraction may be similar to that after extraction.62,63 More than 80 years ago, it was suggested that poor oral hygiene and dental disease were more important as a cause of IE than were dental procedures.64 Most studies since that time have focused instead on the risks of bacteremia associated with dental procedures. For example, tooth extraction is thought to be the dental procedure most likely to cause bacteremia, with an incidence ranging from 10% to 100%.* However, numerous other dental procedures have been re- ported to be associated with risks of bacteremia that are similar to that resulting from tooth extraction. A precise determination of the relative risk of bacteremia that results from a specific dental procedure in patients with or without dental disease is probably not possible.27,72,73 Bleeding often occurs during a dental procedure in patients with or without periodontal disease. Previous AHA guide- lines recommended antibiotic prophylaxis for dental proce- dures in which bleeding was anticipated but not for proce- dures for which bleeding was not anticipated.1 However, no data show that visible bleeding during a dental procedure is a reliable predictor of bacteremia.62 These ambiguities in the previous AHA guidelines led to further uncertainties among healthcare providers about which dental procedures should be covered by prophylaxis. *References 23, 24, 27, 29, 45, 48, 52, 54, 57, and 65 67. References 27, 28, 47, 51, 54, 56, 58, and 68 71. Wilson et al Prevention of Infective Endocarditis 1741 These factors complicated recommendations in previous AHA guidelines on prevention of IE that suggested antibiotic prophylaxis for some dental procedures but not for others. The collective published data suggest that the vast majority of dental office visits result in some degree of bacteremia; however, there is no evidence-based method to decide which procedures should require prophylaxis, because no data show that the incidence, magnitude, or duration of bacteremia from any dental procedure increase the risk of IE. Accordingly, it is not clear which dental procedures are more or less likely to cause a transient bacteremia or result in a greater magnitude of bacteremia than that which results from routine daily activities such as chewing food, tooth brushing, or flossing. In patients with underlying cardiac conditions, lifelong antibiotic therapy is not recommended to prevent IE that might result from bacteremias associated with routine daily activities.5 In patients with dental disease, the focus on the frequency of bacteremia associated with a specific dental procedure and the AHA guidelines for prevention of IE have resulted in an overemphasis on antibiotic prophylaxis and an underemphasis on maintenance of good oral hygiene and access to routine dental care, which are likely more important in reducing the lifetime risk of IE than the administration of antibiotic prophylaxis for a dental procedure. However, no observational or controlled studies support this contention. Impact of Antibiotic Therapy on Bacteremia From a Dental Procedure The ability of antibiotic therapy to prevent or reduce the frequency, magnitude, or duration of bacteremia associated with a dental procedure is controversial.24,74 Some studies reported that antibiotics administered before a dental proce- dure reduced the frequency, nature, and/or duration of bac- teremia,53,75,76 whereas others did not.24,66,77,78 Recent studies suggest that amoxicillin therapy has a statistically significant impact on reducing the incidence, nature, and duration of bacteremia from dental procedures, but it does not eliminate bacteremia.52,53,76 However, no data show that such a reduc- tion as a result of amoxicillin therapy reduces the risk of or prevents IE. Hall et al78 reported that neither penicillin V nor amoxicillin therapy was effective in reducing the frequency of bacteremia compared with untreated control subjects. In patients who underwent a dental extraction, penicillin or ampicillin therapy compared with placebo diminished the percentage of viridans group streptococci and anaerobes in culture, but there was no significant difference in the percent- age of patients with positive cultures 10 minutes after tooth extraction.24,66 In a separate study, Hall et al77 reported that cefaclor-treated patients did not have a reduction of postpro- cedure bacteremia compared with untreated control subjects. Contradictory published results from 2 studies showed reduc- tion of postprocedure bacteremia by erythromycin in one75 but lack of efficacy for erythromycin or clindamycin in another.78 Finally, results are contradictory with regard to the efficacy of the use of topical antiseptics in reducing the frequency of bacteremia associated with dental procedures, but the preponderance of evidence suggests that there is no clear benefit. One study reported that chlorhexidine and povidone iodine mouth rinse were effective,79 whereas others showed no statistically significant benefit.52,80 Topical anti- septic rinses do not penetrate beyond 3 mm into the periodon- tal pocket and therefore do not reach areas of ulcerated tissue where bacteria most often gain entrance to the circulation. On the basis of these data, it is unlikely that topical antiseptics are effective to significantly reduce the frequency, magnitude, and duration of bacteremia associated with a dental procedure. Cumulative Risk Over Time of Bacteremias From Routine Daily Activities Compared With the Bacteremia From a Dental Procedure Guntheroth81 estimated a cumulative exposure of 5370 min- utes of bacteremia over a 1-month period in dentulous patients resulting from random bacteremia from chewing food and from oral hygiene measures, such as tooth brushing and flossing, and compared that with a duration of bacteremia lasting 6 to 30 minutes associated with a single tooth extraction. Roberts62 estimated that tooth brushing 2 times daily for 1 year had a 154 000 times greater risk of exposure to bacteremia than that resulting from a single tooth extrac- tion. The cumulative exposure during 1 year to bacteremia from routine daily activities may be as high as 5.6 million times greater than that resulting from a single tooth extrac- tion, the dental procedure reported to be most likely to cause Data exist for the duration of bacteremia from a single tooth extraction, and it is possible to estimate the annual cumulative exposure from dental procedures for the average individual. However, calculations for the incidence, nature, and duration of bacteremia from routine daily activities are at best rough estimates, and it is therefore not possible to compare precisely the cumulative monthly or annual duration of exposure for bacteremia from dental procedures compared with routine daily activities. Nevertheless, even if the esti- mates of bacteremia from routine daily activities are off by a factor of 1000, it is likely that the frequency and cumulative duration of exposure to bacteremia from routine daily events over 1 year are much higher than those that result from dental procedures. Results of Clinical Studies of IE Prophylaxis for Dental Procedures No prospective, randomized, placebo-controlled studies exist on the efficacy of antibiotic prophylaxis to prevent IE in patients who undergo a dental procedure. Data from pub- lished retrospective or prospective case-control studies are limited by the following factors: (1) the low incidence of IE, which requires a large number of patients per cohort for statistical significance; (2) the wide variation in the types and severity of underlying cardiac conditions, which would re- quire a large number of patients with specific matched control subjects for each cardiac condition; and (3) the large variety of invasive dental procedures and dental disease states, which would be difficult to standardize for control groups. These and other limitations complicate the interpretation of the results of published studies of the efficacy of IE prophylaxis in patients who undergo dental procedures. Although some retrospective studies suggested that there was a benefit from prophylaxis, these studies were small in size and reported insufficient clinical data. Furthermore, in a number of cases, the incubation period between the dental procedure and the onset of symptoms of IE was van der Meer and colleagues85 published a study of dental procedures in the Netherlands and the efficacy of antibiotic prophylaxis to prevent IE in patients with native or prosthetic cardiac valves. They concluded that dental or other proce- dures probably caused only a small fraction of cases of IE and that prophylaxis would prevent only a small number of cases even if it were 100% effective. These same authors86 performed a 2-year case-control study. Among patients for whom prophy- laxis was recommended, 5 of 20 cases of IE occurred despite receiving antibiotic prophylaxis. The authors concluded that prophylaxis was not effective. In a separate study,87 these authors reported poor awareness of recommendations for pro- phylaxis among both patients and healthcare providers. Strom and colleagues2 evaluated dental prophylaxis and cardiac risk factors in a multicenter case-control study. These authors reported that MVP, congenital heart disease (CHD), rheumatic heart disease (RHD), and previous cardiac valve surgery were risk factors for the development of IE. In that study, control subjects without IE were more likely to have undergone a dental procedure than were those with cases of IE (P 0.03). The authors concluded that dental treatment was not a risk factor for IE even in patients with valvular heart disease and that few cases of IE could be prevented with prophylaxis even if it were 100% effective. These studies are in agreement with a recently published French study of the estimated risk of IE in adults with predis- posing cardiac conditions who underwent dental procedures with or without antibiotic prophylaxis.88 These authors con- cluded that a huge number of prophylaxis doses would be necessary to prevent a very low number of IE cases. Absolute Risk of IE Resulting From a Dental Procedure No published data accurately determine the absolute risk of IE that results from a dental procedure. One study reported that 10% to 20% of patients with IE caused by oral flora underwent a preceding dental procedure (within 30 or 180 days of onset).85 The evidence linking bacteremia associated with a dental procedure with IE is largely circumstantial, and the number of cases related to a dental procedure is overes- timated for a number of reasons. For 60 years, noted opinion leaders in medicine suggested a link between bacteremia- causing dental procedures and IE,23 and for 50 years, the AHA published regularly updated guidelines that emphasized the association between dental procedures and IE and recom- mended antibiotic prophylaxis.1 Additionally, bacteremia- producing dental procedures are common; it is estimated that at least 50% of the population in the United States visits a dentist at least once a year. Furthermore, there are numerous poorly documented case reports that implicate dental proce- dures associated with the development of IE, but these reports did not prove a direct causal relationship. Even in the event of a close temporal relationship between a dental procedure and IE, it is not possible to determine with certainty whether the bacteremia that caused IE originated from a dental procedure or from a randomly occurring bacteremia as a result of routine daily activities during the same time period. Many case reports and reviews have included cases with a remote preceding dental procedure, often 3 to 6 months before the diagnosis of IE. Studies suggest that the time frame between bacteremia and the onset of symptoms of IE is usually 7 to 14 days for viridans group streptococci or enterococci. Reportedly, 78% of such cases of IE occur within 7 days of bacteremia and 85% within 14 days.89 Although the upper time limit is not known, it is likely that many cases of IE with incubation periods longer than 2 weeks after a dental procedure were incorrectly attributed to the procedure. These and other factors have led to a heightened awareness among patients and healthcare providers of the possible association between dental procedures and IE, which likely has led to substantial overreporting of cases attributable to dental procedures. Although the absolute risk for IE from a dental procedure is impossible to measure precisely, the best available esti- mates are as follows: If dental treatment causes 1% of all cases of viridans group streptococcal IE annually in the United States, the overall risk in the general population is estimated to be as low as 1 case of IE per 14 million dental procedures.41,90,91 The estimated absolute risk rates for IE from a dental procedure in patients with underlying cardiac conditions are as follows: MVP, 1 per 1.1 million procedures; prosthetic cardiac valve, 1 per 114 000; and previous IE, 1 per 95 000 dental procedures.41,91 Although these calculations of risk are estimates, it is likely that the number of cases of IE that result from a dental procedure is exceedingly small. Therefore, the number of cases that could be prevented by antibiotic prophylaxis, even if 100% effective, is similarly small. One would not expect antibiotic prophylaxis to be near 100% effective, however, because of the nature of the organisms and choice of antibiotics. Risk of Adverse Reactions and Cost-Effectiveness of Prophylactic Therapy Nonfatal adverse reactions, such as rash, diarrhea, and GI upset, occur commonly with the use of antimicrobials; however, only single-dose therapy is recommended for dental prophylaxis, and these common adverse reactions are usually not severe and are self-limited. Fatal anaphylactic reactions were estimated to occur in 15 to 25 individuals per 1 million patients who receive a dose of penicillin.92,93 Among patients with a prior penicillin use, 36% of fatalities from anaphylaxis occurred in those with a known allergy to penicillin compared with 64% of fatalities among those with no history of penicillin allergy.94 These calculations are at best rough estimates and may overestimate the true risk of death caused by fatal anaphylaxis from administration of a penicillin. They are based on retrospective reviews or surveys of patients or on healthcare providers recall of events. A prospective study is necessary to accurately determine the risk of fatal anaphy- laxis resulting from administration of a penicillin. For 50 years, the AHA has recommended a penicillin as the preferred choice for dental prophylaxis for IE. During these Wilson et al Prevention of Infective Endocarditis 1743 50 years, the Committee is unaware of any cases reported to the AHA of fatal anaphylaxis resulting from the administra- tion of a penicillin recommended in the AHA guidelines for IE prophylaxis. The Committee believes that a single dose of amoxicillin or ampicillin is safe and is the preferred prophy- lactic agent for individuals who do not have a history of type I hypersensitivity reaction to a penicillin, such as anaphy- laxis, urticaria, or angioedema. Fatal anaphylaxis from a cephalosporin is estimated to be less common than from penicillin, at approximately 1 case per 1 million patients.95 Fatal reactions to a single dose of a macrolide or clindamycin are extremely rare.96,97 There has been only 1 case report of documented Clostridium difficile colitis after a single dose of Summary Although it has long been assumed that dental procedures may cause IE in patients with underlying cardiac risk factors and that antibiotic prophylaxis is effective, scientific proof is lacking to support these assumptions. The collective pub- lished evidence suggests that of the total number of cases of IE that occur annually, it is likely that an exceedingly small number are caused by bacteremia-producing dental proce- dures. Accordingly, only an extremely small number of cases of IE might be prevented by antibiotic prophylaxis even if it were 100% effective. The vast majority of cases of IE caused by oral microflora most likely result from random bactere- mias caused by routine daily activities, such as chewing food, tooth brushing, flossing, use of toothpicks, use of water irrigation devices, and other activities. The presence of dental disease may increase the risk of bacteremia associated with these routine activities. There should be a shift in emphasis away from a focus on a dental procedure and antibiotic prophylaxis toward a greater emphasis on improved access to dental care and oral health in patients with underlying cardiac conditions associated with the highest risk of adverse out- come from IE and those conditions that predispose to the acquisition of IE. Cardiac Conditions and Endocarditis Previous AHA guidelines categorized underlying cardiac conditions associated with the risk of IE as those with high risk, moderate risk, and negligible risk and recommended prophylaxis for patients in the high- and moderate-risk categories.1 For the present guidelines on prevention of IE, the Committee considered 3 distinct issues: (1) What under- lying cardiac conditions over a lifetime have the highest predisposition to the acquisition of endocarditis? (2) What underlying cardiac conditions are associated with the highest risk of adverse outcome from endocarditis? (3) Should recommendations for IE prophylaxis be based on either or both of these 2 conditions? Underlying Conditions Over a Lifetime That Have the Highest Predisposition to the Acquisition of Endocarditis In Olmsted County, Minnesota, the incidence of IE in adults incidence has remained stable during the past 4 decades and is similar to that reported in other studies.100 103 Previously, RHD was the most common underlying condition predispos- ing to endocarditis, and RHD is still common in developing countries.99 In developed countries, the frequency of RHD has declined, and MVP is now the most common underlying condition in patients with endocarditis.104 Few published data quantitate the lifetime risk of acquisi- tion of IE associated with a specific underlying cardiac condition. Steckelberg and Wilson90 reported the lifetime risk of acquisition of IE, which ranged from 5 per 100 000 patient-years in the general population with no known cardiac conditions to 2160 per 100 000 patient-years in patients who underwent replacement of an infected prosthetic cardiac valve. In that study,90 the risk of IE per 100 000 patient-years was 4.6 in patients with MVP without an audible cardiac murmur and 52 in patients with MVP with an audible murmur of mitral regurgitation. Per 100 000 patient-years, the lifetime risk (380 to 440) for RHD was similar to that (308 to 383) for patients with a mechanical or bioprosthetic cardiac valve. The highest lifetime risks per 100 000 patient-years were as follows: cardiac valve replacement surgery for native valve IE, 630; previous IE, 740; and prosthetic valve replacement done in patients with prosthetic valve endocarditis, 2160. In a separate study, the risk of IE per 100 000 patient-years was 271 in patients with congenital aortic stenosis and 145 in patients with ventricular septal defect.105 In that same study, the risk of IE before closure of a ventricular septal defect was more than twice that after closure. Although these data provide useful ranges of risk in large populations, it is difficult to utilize them to define accurately the lifetime risk of acquisition of IE in an individual patient with a specific underlying cardiac risk factor. This difficulty is based in part on the fact that each individual cardiac condition, such as RHD or MVP, represents a broad spectrum of pathology from minimal to severe, and the risk of IE would likely be influenced by the severity of valvular disease. CHD is another underlying condition with multiple differ- ent cardiac abnormalities that range from relatively minor to severe, complex cyanotic heart disease. During the past 25 years, there has been an increasing use of various intracardiac valvular prostheses and intravascular shunts, grafts, and other devices for repair of valvular heart disease and CHD. The diversity and nature of these prostheses and procedures likely present different levels of risk for acquisition of IE. These factors complicate an accurate assessment of the true lifetime risk of acquisition of IE in patients with a specific underlying cardiac condition. On the basis of the data from Steckelberg and Wilson91 and others,2 it is clear that the underlying conditions discussed above represent a lifetime increased risk of acquisition of IE compared with individuals with no known underlying cardiac condition. Accordingly, when utilizing previous AHA guide- lines in the decision to recommend IE prophylaxis for a patient scheduled to undergo a dental, GI tract, or GU tract procedure, healthcare providers were required to base their decision on population-based studies of risk of acquisition of IE that may or may not be relevant to their specific patient. Furthermore, practitioners had to weigh the potential efficacy of IE prophylaxis in a patient who may neither need nor benefit from such therapy against the risk of adverse reaction to the antibiotic prescribed. Finally, healthcare providers had to consider the potential medicolegal risk of not prescribing IE prophylaxis. For dental procedures, there is a growing body of evidence that suggests that IE prophylaxis may prevent only an exceedingly small number of cases of IE, as discussed in detail above. Cardiac Conditions Associated With the Highest Risk of Adverse Outcome From Endocarditis Endocarditis, irrespective of the underlying cardiac condition, is a serious, life-threatening disease that was always fatal in the preantibiotic era. Advances in antimicrobial therapy, early recognition and management of complications of IE, and improved surgical technology have reduced the morbidity and mortality of IE. Numerous comorbid factors, such as older age, diabetes mellitus, immunosuppressive conditions or therapy, and dialysis, may complicate IE. Each of these comorbid conditions independently increases the risk of adverse outcome from IE, and they often occur in combina- tion, which further increases morbidity and mortality rates. Additionally, there may be long-term consequences of IE. Over time, the cardiac valve damaged by IE may undergo progressive functional deterioration that may result in the need for cardiac valve replacement. In native valve viridans group streptococcal or enterococcal IE, the spectrum of disease may range from a relatively benign infection to severe valvular dysfunction, dehiscence, congestive heart failure, multiple embolic events, and death; however, the underlying conditions shown in Table 3 virtually always have an increased risk of adverse outcome. For example, patients with viridans group streptococcal prosthetic valve endocarditis have a mortality rate of 20% or greater,106 109 whereas the mortality from patients with viridans group streptococcal native valve IE is 5% or less.108,110 116 Similarly, the mortality of enterococcal prosthetic valve endocarditis is higher than that of native valve enterococcal IE.107,108,114,117 Moreover, patients with prosthetic valve endocarditis are more likely than those with native valve endocarditis to develop heart failure, the need for cardiac valve replacement surgery, perivalvular extension of infection, and other complications. Patients with relapsing or recurrent IE are at greater risk of congestive heart failure and increased need for cardiac valve replacement surgery, and they have a higher mortality rate than patients with a first episode of native valve IE.118 124 Additionally, patients with multiple episodes of native or prosthetic valve IE are at greater risk of additional episodes of endocarditis, each of which is associated with the risk of more Published series regarding endocarditis in patients with CHD are underpowered to determine the extent to which a specific form of CHD is an independent risk factor for morbidity and mortality. Nevertheless, most retrospective case series suggest that patients with complex cyanotic heart disease and those who have postoperative palliative shunts, conduits, or other prostheses have a high lifetime risk of acquiring IE, and these same groups appear at highest risk for morbidity and mortality among all patients with CHD.125 129 In addition, multiple series and reviews reported that the presence of prosthetic material130,131 and complex cyanotic heart disease in patients of very young age (newborns and infants 2 years of age)132,133 are 2 factors associated with the worst prognoses from IE. Some types of CHD may be repaired completely without residual cardiac defects. As shown in Table 3, the Committee concludes that prophylaxis is reasonable for dental procedures for these patients during the first 6 months after the procedure. In these patients, endothelialization of prosthetic material or devices occurs within 6 months after the procedure.134 The Committee does not recommend prophylaxis for dental procedures more than 6 months after the procedure provided that there is no residual defect from the repair. In most instances, treatment of patients who have infected prosthetic materials requires surgical removal in addition to medical therapy with associated high morbidity and mortality rates. Should IE Prophylaxis Be Recommended for Patients With the Highest Risk of Acquisition of IE or for Patients With the Highest Risk of Adverse Outcome From IE? In a major departure from previous AHA guidelines, the Committee no longer recommends IE prophylaxis based solely on an increased lifetime risk of acquisition of IE. It is noteworthy that patients with the conditions listed in Table 3 with a prosthetic cardiac valve, those with a previous episode of IE, and some patients with CHD are also among those patients with the highest lifetime risk of acquisition of endocarditis. No published data demonstrate convincingly that the administration of prophylactic antibiotics prevents IE associated with bacteremia from an invasive procedure. We cannot exclude the possibility that there may be an exceed- ingly small number of cases of IE that could be prevented by prophylactic antibiotics in patients who undergo an invasive procedure. However, if prophylaxis is effective, such therapy should be restricted to those patients with the highest risk of adverse outcome from IE who would derive the greatest benefit from prevention of IE. In patients with underlying cardiac conditions associated with the highest risk of adverse outcome from IE (Table 3), IE prophylaxis for dental proce- Table 3. Cardiac Conditions Associated With the Highest Risk of Adverse Outcome From Endocarditis for Which Prophylaxis With Dental Procedures Is Reasonable Prosthetic cardiac valve or prosthetic material used for cardiac valve repair Previous IE Congenital heart disease (CHD)* Unrepaired cyanotic CHD, including palliative shunts and conduits Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization) Cardiac transplantation recipients who develop cardiac valvulopathy *Except for the conditions listed above, antibiotic prophylaxis is no longer recommended for any other form of CHD. Prophylaxis is reasonable because endothelialization of prosthetic material occurs within 6 months after the procedure. Wilson et al Prevention of Infective Endocarditis 1745 dures is reasonable, even though we acknowledge that its effectiveness is unknown (Class IIa, LOE B). Compared with previous AHA guidelines, under these revised guidelines, many fewer patients would be candidates to receive IE prophylaxis. We believe that these revised guidelines are in the best interest of patients and healthcare providers and are based on the best available published data and expert opinion. Additionally, the change in emphasis to restrict prophylaxis for only those patients with the highest risk of adverse outcome should reduce the uncertainties among patients and providers about who should receive prophylaxis. MVP is the most common underlying condition that predisposes to acquisition of IE in the Western world; however, the absolute incidence of endocarditis is extremely low for the entire population with MVP, and it is not usually associated with the grave outcome associated with the con- ditions identified in Table 3. Thus, IE prophylaxis is no longer recommended for this group of individuals. Finally, the administration of prophylactic antibiotics is not risk free, as discussed above. Additionally, the widespread use of antibiotic therapy promotes the emergence of resistant microorganisms most likely to cause endocarditis, such as viridans group streptococci and enterococci. The frequency of multidrug-resistant viridans group streptococci and entero- cocci has increased dramatically during the past 2 decades. This increased resistance has reduced the efficacy and num- ber of antibiotics available for the treatment of IE. Antibiotic Regimens General Principles An antibiotic for prophylaxis should be administered in a single dose before the procedure. If the dosage of antibiotic is inadvertently not administered before the procedure, the dosage may be administered up to 2 hours after the procedure. However, administration of the dosage after the procedure should be considered only when the patient did not receive the pre-procedure dose. Some patients who are scheduled for an invasive procedure may have a coincidental endocarditis. The presence of fever or other manifestations of systemic infection should alert the provider to the possibility of IE. In these circumstances, it is important to obtain blood cultures and other relevant tests before administration of antibiotics intended to prevent IE. Failure to do so may result in delay in diagnosis or treatment of a concomitant case of IE. Regimens for Dental Procedures Previous AHA guidelines on prophylaxis listed a substantial number of dental procedures and events for which antibiotic prophylaxis was recommended and those procedures for which prophylaxis was not recommended. On the basis of a critical review of the published data, it is clear that transient viridans group streptococcal bacteremia may result from any dental procedure that involves manipulation of the gingival or periapical region of teeth or perforation of the oral mucosa. It cannot be assumed that manipulation of a healthy-appearing mouth or a minimally invasive dental procedure reduces the likelihood of a bacteremia. Therefore, antibiotic prophylaxis is reasonable for patients with the conditions listed in Table 3 who undergo any dental procedure that involves the gingival tissues or periapical region of a tooth and for those procedures that perforate the oral mucosa (Table 4). Although IE pro- phylaxis is reasonable for these patients, its effectiveness is unknown (Class IIa, LOE C). This includes procedures such as biopsies, suture removal, and placement of orthodontic bands, but it does not include routine anesthetic injections through noninfected tissue, the taking of dental radiographs, placement of removable prosthodontic or orthodontic appli- ances, placement of orthodontic brackets, or adjustment of orthodontic appliances. Finally, there are other events that are not dental procedures and for which prophylaxis is not recommended, such as shedding of deciduous teeth and trauma to the lips and oral mucosa. 