HISTORY OF AMERICAN HEART ASSOCIATION STATEMENTS ON PREVENTION OF INFECTIVE ENDOCARDITIS

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	RATIONALE FOR REVISING THE 1997 DOCUMENT

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Over the years, other international societies have published recommendations and guidelines for the prevention of IE.^15,16 Recently, the British Society for Antimicrobial Chemotherapy issued new IE prophylaxis recommendations.¹⁶ 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.

Fundamental underlying principles that drove the formulation of the AHA guidelines and the nine 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 conditions 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 five underlying principles, the first four are valid and have not changed during the past 30 years. Numerous publications questioned the validity of the fifth principle and suggested revision of the guidelines, primarily for reasons shown in Box 2.

	POTENTIAL CONSEQUENCES OF SUBSTANTIVE CHANGES IN RECOMMENDATIONS

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Substantive changes in recommendations could (1) violate long-standing expectations and practice patterns, (2) make fewer patients eligible for IE prophylaxis, (3) reduce malpractice claims related to IE prophylaxis and (4) stimulate prospective studies on IE prophylaxis. The Committee and Ashrafian and Bogle¹⁷ recognize that substantive changes in IE prophylaxis guidelines may violate long-standing expectations of and practice patterns by patients and health care providers. The Committee recognizes that these new recommendations may cause concern among patients who have previously taken antibiotic prophylaxis to prevent IE before dental or other procedures and are now advised that such prophylaxis is unnecessary. Box 2 includes the main talking points that may be helpful for clinicians in re-educating their patients regarding 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,⁷ patients and health care providers assumed that antibiotics administered in association with a bacteremia-producing procedure effectively prevented IE in patients with underlying cardiac risk factors. Patients were educated about bacteremia-producing procedures and risk factors for IE, and they expected to receive antibiotic prophylaxis; health care providers, especially dentists, were expected to administer them. Patients with underlying cardiac conditions that have 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 procedure was effective and usually safe to prevent IE. Health care 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 health care 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 often were 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 health care providers to AHA recommendations for prophylaxis. 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. Accordingly, the Committee hopes that this document will result in greater clarity for patients, health care providers and consulting 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 answer definitively 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 Rheumatoid Fever, Endocarditis and Kawasaki Disease Committee, and other societies, and further revisions to the current document will be based on relevant studies.

	PATHOGENESIS OF INFECTIVE ENDOCARDITIS

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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 microorganism. 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, traumatizes 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 bloodstream 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 gingival crevice around teeth, oropharynx, GI tract, urethra or vagina, releases many different microbial species transiently into the blood stream. 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 anatomical localization of infection caused by these microorganisms. Mediators of bacterial adherence serve as virulence factors in the pathogenesis of IE. Numerous 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 fimbrial adhesion protein (FimA), which is a lipoprotein receptor antigen I that serves as a major adhesin to the fibrin platelet matrix of NBTE.¹⁸ Staphylococcal adhesins function in at least two ways. In one, microbial surface components recognizing adhesive matrix molecules facilitate the attachment of staphylococci to human extracellular matrix proteins and to medical devices, which become coated with matrix proteins after implantation. In the other, bacterial extra-cellular structures contribute to the formation of biofilm, which 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 streptococci and staphylococci.^19,20 The results of these experimental 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 rapidly as do bacteria in broth cultures to reach maximal microbial densities of 10⁸ to 10¹¹ colony-forming units (CFUs) 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 percent of the microorganisms 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.²¹

	RATIONALE FOR OR AGAINST PROPHYLAXIS OF INFECTIVE ENDOCARDITIS

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Historical background. Viridans group streptococci are part of the normal skin, oral, respiratory and GI tract flora, and they cause at least 50 percent of cases of community-acquired native valve IE not associated with intravenous drug use.²² 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, Osler²³ noted an association between bacteremia from surgery and IE. Okell and Elliott²⁴ in 1935 reported that 11 percent of patients with poor oral hygiene had positive blood cultures with viridans group streptococci, and that 61 percent of patients had viridans group streptococcal bacteremia with dental extraction.

The large majority of published studies have focused on dental procedures as a cause of infective endocarditis and the use of prophylactic antibiotics to prevent infective endocarditis in patients at risk.

As a result of these early 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 based on the following factors: (1) bacteremia causes endocarditis; (2) viridans group streptococci are part of the normal oral flora and enterococci are part of the normal GI and GU tract flora; (3) these microorganisms were usually susceptible to antibiotics recommended for prophylaxis; (4) antibiotic prophylaxis prevents viridans group streptococcal or enterococcal experimental endocarditis 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 streptococci 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 of 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 bacteremia from a dental procedure; and (4) the exposure over time of frequently occurring bacteremia from routine daily activities 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 (10–100 percent), periodontal surgery (36–88 percent), scaling and root planing (8–80 percent), teeth cleaning (up to 40 percent), rubber dam matrix/wedge placement (9–32 percent) and endodontic procedures (up to 20 percent).^25–31 Transient bacteremia also occurs frequently during routine daily activities unrelated to a dental procedure: tooth brushing and flossing (20–68 percent), use of wooden toothpicks (20–40 percent), use of water irrigation devices (7–50 percent) and chewing food (7–51 percent).^{27–30,32–37} Considering that the average person living in the United States has fewer than two dental visits per year, the frequency of bacteremia from routine daily activities is far greater.

There has been a disproportionate focus on the frequency of bacteremia associated with dental procedures rather than 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 crevices.^25,38–41 Approximately 30 percent 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 of these are viridans group streptococci, the most common microbiological cause of community-acquired native valve IE in nonintravenous drug users.²² In healthy mouths, a thin surface of mucosal epithelium separates potentially pathogenic bacteria from entering the bloodstream and lymphatic system. Anaerobic microorganisms commonly are responsible for periodontal disease and frequently enter the bloodstream but rarely cause IE, with fewer than 120 cases reported.⁴² Viridans group streptococci are antagonistic to periodontal pathogens and predominate in a clean, healthy mouth.⁴³

Few published studies exist on the magnitude of bacteremia 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 CFUs of bacteria per milliliter), similar to that resulting from routine daily activities, and is less than that used to cause experimental IE in animals (10⁶–10⁸ CFUs of bacteria/mL).^21,44,45 Although the infective dose required to cause IE in humans is unknown, the number of microorganisms 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 two weeks before the onset of symptoms of IE.^2–4

The role of duration of bacteremia on the risk of acquisition of IE is uncertain.^46,47 Early studies reported that sequential 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.^25,46–52 More recent studies support these data but report a small percentage of positive blood cultures from 30 to 60 minutes after tooth extraction.^44,53,54 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 recommendation 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.^{24,30,31,39,46,55–62} Nevertheless, available evidence supports an emphasis on maintaining good oral hygiene and eradicating dental disease to decrease the frequency of bacteremia from routine daily activities.^{46,57–59,63,64} In patients with poor oral hygiene, the frequency of positive blood cultures just before dental extraction may be similar to that after extraction.^63,64

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.⁶⁵ 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 percent.^{24,25,28,30,46,49,53,55,58,66–68} However, numerous other dental procedures have been reported to be associated with risks of bacteremia that are similar to that resulting from tooth extraction.^{28,29,48,52,55,57,59,69–72} A precise determination of the relative risk of bacteremia resulting from a specific dental procedure in patients with or without dental disease probably is not possible.^28,73,74

Bleeding often occurs during a dental procedure in patients with or without periodontal disease. Previous AHA guidelines recommended antibiotic prophylaxis for dental procedures for which bleeding was anticipated but not for procedures for which bleeding was not anticipated.¹ However, no data show that visible bleeding during a dental procedure is a reliable predictor for bacteremia.⁶³ These ambiguities in the previous AHA guidelines led to further uncertainties among health care providers about which dental procedures should be covered by prophylaxis.

These factors complicated recommendations in previous AHA guidelines on prevention of IE, which 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.

The ability of antibiotic therapy to prevent or reduce the frequency, magnitude or duration of bacteremia associated with a dental procedure is controversial.

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 is the administration of antibiotic prophylaxis for a dental procedure. However, there are no observational or controlled studies to 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.^25,75 Some studies reported that antibiotics administered before a dental procedure reduced the frequency, nature or duration of bacteremia,^54,76,77 while others did not.^25,67,78,79 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.^53,54,77 However, no data show that such a reduction as a result of amoxicillin therapy reduces the risk of or prevents IE. Hall and colleagues⁷⁹ 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 percentage of patients with positive cultures 10 minutes after tooth extraction.^25,67 In a separate study, Hall and colleagues⁷⁸ reported that patients treated with cefaclor did not have a reduction of postprocedure bacteremia compared with untreated control subjects. Contradictory published results from two studies showed reduction of postprocedure bacteremia by erythromycin in one⁷⁶ but lack of efficacy for erythromycin or clindamycin in another.⁷⁹ Finally, results are contradictory regarding 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 mouthrinse were effective,⁸⁰ while others showed no statistically significant benefit.^53,81 Topical antiseptic rinses do not penetrate beyond 3 mm into the periodontal 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 physiological bacteremias from routine daily activities compared with the bacteremia from a dental procedure. Guntheroth⁸² estimated a cumulative exposure of 5,370 minutes of bacteremia over a one-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 to a duration of bacteremia lasting six to 30 minutes associated with a single tooth extraction. Roberts⁶³ estimated that tooth brushing two times daily for one year had a 154,000 times greater risk of exposure to bacteremia than that resulting from a single tooth extraction. The cumulative exposure during one year to bacteremia from routine, daily activities may be as high as 5.6 million times greater than that resulting from a single tooth extraction, the dental procedure reported to be most likely to cause a bacteremia.⁶³

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 patient. 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 estimates of bacteremia from routine daily activities are off by a factor of 1,000, it is likely that the frequency and cumulative duration of exposure to bacteremia from routine daily events over one year are much higher than those resulting from dental procedures.

Results of clinical studies of IE prophylaxis for dental procedures. There are no prospective randomized placebo controlled studies on the efficacy of antibiotic prophylaxis to prevent IE in patients who undergo a dental procedure. Data from published 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 require 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 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 prolonged.^81,83–85

van der Meer and colleagues⁸⁶ 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 procedures 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 percent effective. van der Meer and colleagues⁸⁷ performed a two-year case-control study. Among patients for whom prophylaxis was recommended, five of 20 cases of IE occurred despite receiving antibiotic prophylaxis. They concluded that prophylaxis was not effective. In a separate study, van der Meer and colleagues⁸⁸ reported that there was poor awareness of recommendations for prophylaxis among both patients and health care 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 this study, control subjects without IE were more likely to have undergone a dental procedure than were cases of IE (P = .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 percent effective.

The studies are in agreement with a recently published French study of the estimated risk of IE in adults with predisposing cardiac conditions who underwent dental procedures with or without antibiotic prophylaxis.⁸⁹ These authors concluded 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 resulting from a dental procedure. One study reported that 10 to 20 percent of patients with IE caused by oral flora underwent a preceding dental procedure (within 30 or 180 days of onset).⁸⁶ 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 overestimated for a number of reasons. For 60 years, noted opinion leaders in medicine suggested a link between bacteremia-causing dental procedures and IE,²⁴ and for 50 years the AHA published regularly updated guidelines that emphasized the association between dental procedures and IE and recommended antibiotic prophylaxis.¹ Additionally, bacteremia-producing dental procedures are common; it is estimated that at least 50 percent 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 procedures 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 period. Many case reports and reviews have included cases with a remote preceding dental procedure, often three to six months before the diagnosis of IE. Studies suggest that the time frame between bacteremia and the onset of symptoms of IE is usually seven to 14 days for viridans group streptococci or enterococci. Reportedly, 78 percent of such cases of IE occur within seven days of bacteremia and 85 percent within 14 days.⁹⁰ Although the upper time limit is not known, it is likely that many cases of IE with incubation periods longer than two weeks after a dental procedure were attributed incorrectly to the procedure. These and other factors have led to a heightened awareness among patients and health care providers of the possible association with dental procedures and IE, which likely has led to substantial overreporting of cases attributable to dental procedures.

Only an extremely small number of cases of infective endocarditis might be prevented by antibiotic prophylaxis even if it were 100 percent effective.

Although the absolute risk for IE from a dental procedure is impossible to measure precisely, the best available estimates are as follows: if dental treatment causes 1 percent 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 one case of IE per 14 million dental procedures.^42,91,92 The estimated absolute risk rates for IE from a dental procedure in patients with underlying cardiac conditions are MVP one per 1.1 million procedures, CHD one per 475,000, RHD one per 142,000, presence of a prosthetic cardiac valve one per 114,000 and previous IE one per 95,000 dental procedures.^42,92 Although these calculations of risk are estimates, it is likely that the number of cases of IE that results from a dental procedure is exceedingly small. Therefore, the number of cases that could be prevented by antibiotic prophylaxis, even if 100 percent effective, is similarly small. One would not expect antibiotic prophylaxis to be near 100 percent 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 use of the 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 patients per 1 million patients who receive a dose of penicillin.^93,94 Among patients with a prior penicillin use, 36 percent of fatalities from anaphylaxis occurred in those with a known allergy to penicillin, compared with 64 percent of fatalities among those with no history of penicillin allergy.⁹⁵ These calculations are at best rough estimates of, 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 health care providers’ recall of events. A prospective study is necessary to accurately determine the risk of fatal anaphylaxis 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 50 years, the Committee is unaware of any cases reported to the AHA of fatal anaphylaxis resulting from the administration 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 prophylactic agent for patients who do not have a history of type I hypersensitivity reaction to a penicillin, such as anaphylaxis, urticaria or angioedema. Fatal anaphylaxis from a cephalosporin is estimated to be less common than from penicillin and is estimated to be approximately one case per 1 million patients.⁹⁶ Fatal reactions to a single dose of a macrolide or clindamycin are extremely rare.^97,98 There has been only one case report of documented Clostridium difficile colitis after a single dose of prophylactic clindamycin.⁹⁹

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 published evidence suggests that of the total number of cases of IE that occur annually, it is likely that an exceedingly small number of these cases are caused by bacteremia-producing dental procedures. Accordingly, only an extremely small number of cases of IE might be prevented by antibiotic prophylaxis even if it were 100 percent effective. The vast majority of cases of IE caused by oral microflora most likely result from random bacteremias 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 outcome from IE and those conditions that predispose to the acquisition of IE.

	CARDIAC CONDITIONS AND ENDOCARDITIS

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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 three distinct issues: (1) What underlying 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 two conditions?

Underlying conditions over a lifetime that have the highest predisposition to the acquisition of endocarditis. In Olmsted County, Minn., the incidence of IE in adults ranged from five to seven cases per 100,000 person-years.¹⁰⁰ This incidence has remained stable during the past four decades and is similar to that reported in other studies.^101–104 Previously, RHD was the most common underlying condition predisposing to endocarditis, and RHD is still common in developing countries.¹⁰⁰ In developed countries, the frequency of RHD has declined, and MVP is the most common underlying condition in patients with endocarditis.¹⁰⁵

Few published data quantitate the lifetime risk of acquisition of IE associated with a specific underlying cardiac condition. Steckelberg and Wilson⁹¹ reported the lifetime risk of acquisition of IE, which ranged from five per 100,000 patient-years in the general population with no known cardiac conditions to 2,160 per 100,000 patient-years in patients who underwent replacement of an infected prosthetic cardiac valve. In that study, the risk of IE per 100,000 patient-years was 4.6 in patients with MVP without an audible cardiac murmur and was 52 in patients with MVP with an audible murmur of mitral regurgitation. Per 100,000 patient-years, the lifetime risk (380–440) for RHD was similar to that (308–383) for patients with a mechanical or bio-prosthetic 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 (PVE), 2,160. In a separate study, the risk of IE per 100,000 patient-years was 271 in patients with congenital aortic stenosis and was 145 in patients with ventricular septal defect.¹⁰⁶ In that study, the risk of IE before closure of 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 use 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 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 different 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 different intra-cardiac 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 data from Steckelberg and Wilson⁹¹ and Strom and colleagues,² it is clear that the underlying conditions discussed above represent a lifetime increased risk of acquisition of IE compared with patients with no known underlying cardiac condition. Accordingly, when using previous AHA guidelines in the decision to recommend IE prophylaxis for a patient scheduled to undergo a dental, GI or GU tract procedure, health care 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, health care 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.

Prophylaxis for dental procedures more than six months after the procedure is not recommended provided that there is no residual defect from the repair.

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 combination, which further increases morbidity and mortality. 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 Box 3 virtually always have an increased risk of adverse outcome. For example, patients with viridans group streptococcal PVE have a mortality of approximately 20 percent or greater^107–110; whereas, the mortality from patients with viridans group streptococcal native valve IE is 5 percent or less.^{109,111–117} Similarly, the mortality of enterococcal PVE is higher than that of native valve enterococcal IE.^{108,109,115,118} Moreover, patients with PVE 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.

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.^126–130 In addition, multiple series and reviews reported that the presence of prosthetic material^131,132 and complex cyanotic heart disease in patients of very young age (newborns and infants younger than 2 years)^133,134 are two factors associated with the worst prognoses from IE. Some types of CHD may be repaired completely without residual cardiac defects. In Box 3, the Committee recommends prophylaxis for dental procedures for these patients during the first six months after the procedure. In these patients, endothelialization of prosthetic material or devices occurs within six months after the procedure.¹³⁵ The Committee does not recommend prophylaxis for dental procedures more than six 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 Box 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 exceedingly 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 (Box 3), IE prophylaxis for dental procedures may be reasonable, even though we acknowledge that the effectiveness is unknown (Class IIb, LOE B).

Compared with previous AHA guidelines, under these revised guidelines, many fewer patients would be candidates to receive IE prophylaxis. We believe these revised guidelines are in the best interest of the patients and health care providers and are based on the best available published data and expert opinion. Additionally, the change in emphasis to recommend 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 conditions identified in Box 3. Thus, IE prophylaxis is no longer recommended in this group of patients.

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 enterococci has increased dramatically during the past two decades. This increased resistance has reduced the efficacy and number of antibiotics available for the treatment of IE.

	REGIMENS RECOMMENDED

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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 two hours after the procedure. However, administration of the dosage after the procedure should be considered only when the patient did not receive the preprocedural 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 recommended for patients with conditions listed in Box 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 (Box 4). Although IE prophylaxis may be reasonable for these patients, its effectiveness is unknown (Class IIb, LOE C). This includes procedures such as biopsies, suture removal and placement of orthodontic bands, but does not include routine anesthetic injections through noninfected tissue, taking dental radiographs, placement of removable prosthodontic or orthodontic appliances, 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 primary teeth and trauma to the lips and oral mucosa.

View this table: [in this window] [in a new window]   BOX 4 Dental procedures for which endocarditis prophylaxis is recommended for patients in Box 3.

Among 352 blood culture isolates of viridans group streptococci, resistance rates were 13 percent for penicillin, 15 percent for amoxicillin, 17 percent for ceftriaxone, 38 percent for erythromycin and 96 percent for cephalexin.¹³⁷ The rank order of decreasing level of activity of cephalosporins in that study was cefpodoxime equal to ceftriaxone, greater than cefprozil, equal to cefuroxime, and cephalexin was the least active. In other studies, resistance of viridans group streptococci to penicillin ranged from 17 to 50 percent^138–143 and resistance to ceftriaxone from 22 to 42 percent.^132,141 Ceftriaxone was two to four times more active in vitro than was cefazolin.^132,141 Similarly high rates of resistance were reported for macrolides, ranging from 22 to 58 percent^{138,142,144,145}; resistance to clindamycin ranged from 13 to 27 percent.^{129,130,132,138,139,141}

Most of the strains of viridans group streptococci in the above-cited studies were recovered from patients with serious underlying illnesses, including malignancies and febrile neutropenia. These patients are at increased risk of infection and colonization by multiple drug-resistant microorganisms, including viridans group streptococci. Accordingly, these strains may not be representative of susceptibility patterns of viridans group streptococci recovered from presumably normal patients who undergo a dental procedure. Diekema and colleagues¹³⁸ reported that 32 percent of strains of viridans group streptococci were resistant to penicillin in patients without cancer. King and colleagues¹⁴⁵ reported erythromycin resistance in 41 percent of streptococci recovered from throat cultures in otherwise healthy patients who presented with mild respiratory tract infections. In that study, after treatment with either azithromycin or clindamycin, the percentage of resistant streptococci increased to 82 percent and 71 percent, respectively. Accordingly, the resistance rates of viridans group streptococci are similarly high in otherwise healthy patients or in patients with serious underlying diseases.

The impact of viridans group streptococcal resistance on antibiotic prevention of IE is unknown. If resistance in vitro is predictive of lack of clinical efficacy, the high resistance rates of viridans group streptococci provide additional support for the assertion that prophylactic therapy for a dental procedure is of little, if any, value. It is impractical to recommend prophylaxis with only those antibiotics, such as vancomycin or a fluoroquinolone, that are highly active in vitro against viridans group streptococci. There is no evidence that such therapy is effective for prophylaxis of IE, and their use might result in the development of resistance of viridans group streptococci and other microorganisms to these and other antibiotics.

In Table 2, amoxicillin is the preferred choice for oral therapy because it is well-absorbed in the GI tract and provides high and sustained serum concentrations. For patients who are allergic to penicillins or amoxicillin, the use of cephalexin or another first-generation oral cephalosporin, clindamycin, azithromycin or clarithromycin is recommended. Even though cephalexin was less active against viridans group streptococci than other first-generation oral cephalosporins in one study,¹³⁷ cephalexin is included in Table 2. No data show superiority of one oral cephalosporin over another for prevention of IE, and generic cephalexin is widely available and is relatively inexpensive. Because of possible cross-reactions, a cephalosporin should not be administered to patients with a history of anaphylaxis, angioedema or urticaria after treatment with any form of penicillin, including ampicillin or amoxicillin. Patients who are unable to tolerate an oral antibiotic may be treated with ampicillin, ceftriaxone or cefazolin administered intramuscularly or intravenously. For patients who are allergic to ampicillin and are unable to tolerate an oral agent, therapy is recommended with parenteral cefazolin, ceftriaxone or clindamycin.

	SPECIFIC SITUATIONS AND CIRCUMSTANCES

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Patients receiving parenteral antibiotic therapy for IE may require dental procedures during antimicrobial therapy, particularly if subsequent cardiac valve replacement surgery is anticipated. In these cases, the parenteral antibiotic therapy for IE should be continued and the timing of the dosage adjusted to be administered 30 to 60 minutes before the dental procedure. This parenteral antimicrobial therapy is administered in such high doses that the high concentration would overcome any possible low-level resistance developed among mouth flora (unlike the concentration that would occur after oral administration).

Patients who receive anticoagulants. Intramuscular injections for IE prophylaxis should be avoided in patients who are receiving anticoagulant therapy (Class I, LOE A). In these circumstances, orally administered regimens should be given whenever possible. Intravenously administered antibiotics should be used for patients who are unable to tolerate or absorb oral medications.

Patients who undergo cardiac surgery. A careful dental evaluation is recommended so that required dental treatment may be completed whenever possible before cardiac valve surgery or replacement or repair of CHD. Such measures may decrease the incidence of late PVE caused by viridans group streptococci.

	OTHER CONSIDERATIONS

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There is no evidence that coronary artery bypass graft surgery is associated with a long-term risk for infection. Therefore, antibiotic prophylaxis for dental procedures is not needed for patients who have undergone this surgery. Antibiotic prophylaxis for dental procedures is not recommended for patients with coronary artery stents (Class III, LOE C). The treatment and prevention of infection for these and other endovascular grafts and prosthetic devices are addressed in a separate AHA article.¹⁴⁶ There are insufficient data to support specific recommendations for patients who have undergone heart transplantation. Such patients are at risk of acquired valvular dysfunction, especially during episodes of rejection. Endocarditis that occurs in a heart transplant patient is associated with a high risk of adverse outcome (Box 3).¹⁴⁷ Accordingly, the use of IE prophylaxis for dental procedures in cardiac transplant recipients who develop cardiac valvulopathy may be reasonable, but the usefulness is not well-established (Class IIb, LOE C) (Box 4). The use of prophylactic antibiotics to prevent infection of joint prostheses during potentially bacteremia-inducing procedures is not within the scope of this document.

	FUTURE CONSIDERATIONS

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Prospective placebo-controlled double-blinded studies of antibiotic prophylaxis of IE in patients who undergo a bacteremia-producing procedure would be necessary to evaluate accurately the efficacy of IE prophylaxis. Additional prospective case-control studies are needed. The AHA has made substantial revisions to previously published guidelines on IE prophylaxis. Based on our current recommendations, we anticipate that significantly fewer patients will receive IE prophylaxis for a dental procedure. Studies are necessary to monitor the effects, if any, of these recommended changes in IE prophylaxis. The incidence of IE could change or stay the same. Because the incidence of IE is low, small changes in incidence may take years to detect. Accordingly, we urge that such studies be designed and instituted promptly so that any change in incidence may be detected sooner rather than later. Subsequent revisions of the AHA guidelines on the prevention of IE will be based on the results of these studies and other published data.