Oral Diseases (2014) 20, 325–328 doi:10.1111/odi.12221 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd All rights reserved www.wiley.com


Infective endocarditis prophylaxis P Diz Dios OMEQUI Research Group, School of Medicine and Dentistry, Santiago de Compostela University, Santiago de Compostela, Spain

Antibiotic prophylaxis for infective endocarditis continues to be administered empirically, although its indications are ever more restrictive. Some expert committees have even suggested that antibiotic prophylaxis is unnecessary, rekindling the controversy between those who defend the scientific evidence and those working in clinical practice; in any case, this proposal will facilitate the undertaking of prospective placebocontrolled trials, so necessary to resolve this issue. In the meantime, the most prudent approach is to adopt the recommendations proposed by the expert committees in each country. Oral Diseases (2014) 20, 325–328 Keywords: bacteraemia; focal infection; infective endocarditis; antibiotic prophylaxis

Distant site infection A focal infection is a generalised or localised infection caused by the dissemination of micro-organisms or their toxic products from a primary focus of infection. More than a century ago, it was suggested that the oral cavity could be the origin of a focal infection, due mainly to the haematogenous spread of bacteria when the organisms reach the bloodstream (bacteraemia). Acceptance of the theory of focal infection has varied over time; in the early decades of the 20th century, Frank Billings (Billings, 1916) and his pupil, Edward Rosenow (Rosenow, 1921), were the most fervent advocates of this theory, basing their support on experimental studies that suggested that oral bacteria presented a pathogenic affinity for specific body structures (‘theory of elective localisation’) and that, in certain situations, oral bacteria could alter their genotypic characteristics (‘theory of bacterial transmutation’). The critics of the theory of focal infection argued that the responsible infectious agents had not been identified, that

Correspondence: Pedro Diz Dios, Departamento de Estomatologıa. Facultad de Medicina y Odontologıa. Universidad de Santiago de Compostela, c/ Entrerrıos sn, 15782 Santiago de Compostela, Spain. Tel: +34 881812344; Fax: +34 981562226, E-mail: [email protected] Received 10 December 2013; accepted 13 December 2013

focal infections appeared even in patients in whom serial tooth extractions had been performed (‘therapeutic edentulism’) and that the clinical course of patients with teeth was similar to that of edentulous patients. In 1935, Okell and Elliott (Okell and Elliott, 1935) were the first researchers to evaluate the appearance of bacteraemia in patients undergoing tooth extraction under general anaesthesia. They detected positive blood cultures in 61% of patients five minutes after completing the procedure. Over the following two decades, there was a resurgence of the theory of focal infection, supported by numerous case reports and epidemiological studies on infective endocarditis (IE) of probable oral origin, as well as numerous research projects into bacteraemia secondary to tooth extraction. Although focal infection of oral origin can affect any organ in the body, IE is considered the most important because of its prevalence and its high morbidity and mortality. The incidence of IE varies between countries, within an estimated range of 3–10 episodes/100 000 person-years. The oral cavity is thought to be the portal of entry of the responsible micro-organism in 14% to 20% of cases (Knirsch et al, 2005). This estimation has been criticised by some researchers who argue that patients with valves infected by bacteria that typically colonise the oral cavity have not always undergone previous dental manipulation; furthermore, evidence on the genetic concordance between bacteria isolated from the heart valves, the bloodstream and the oral cavity of patients with IE is scarce. The first study that demonstrated the oral origin of the micro-organisms in two cases of IE was published in 1995 (Fiehn et al, 1995); in that study, molecular biology techniques were used to demonstrate the matching genetic identity of bacterial isolates obtained simultaneously from peripheral blood samples and from the oral cavity.

Antibiotic prophylaxis guidelines Although the evidence for a relationship between distant site infections and bacteraemia secondary to dental manipulation is weak, and no causal relationship has been demonstrated between dental procedures and the onset of IE, numerous researchers in the first half of the 20th century proposed local (i.e. cauterisation) or systemic (i.e. self-vaccination) prophylactic measures to prevent bacteraemia of oral origin. More than 25 indications for antibiotic

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prophylaxis (AP) have been described based on the potential for infection involving a medical device or condition. In 1955, soon after the initiation of the large-scale manufacture of penicillin, the American Heart Association (AHA) drew up the first guidelines on the administration of AP before surgical procedures – including dental procedures – for the prevention of IE (AHA, 1955). Since that time, numerous expert committees have proposed different prophylactic regimens; the most important of these guidelines (in addition to those of the AHA), due to their impact on the clinical community, are those of the European Society of Cardiology (ESC) and of the British Society for Antimicrobial Chemotherapy (BSAC). The AP guidelines for the prevention of IE have undergone periodic revisions in which the general tonic has been a progressive restriction of the indications for AP, maintaining exclusively those in which IE was considered to be associated with the highest risk of an adverse outcome (e.g. the mortality of IE due to viridans group streptococci on native valves is estimated at 5% compared to 20% on prosthetic valves) (Wilson et al, 2007; Habib et al, 2009). The justification for this restriction of the indications for AP is based mainly on two considerations: the absence of a change in the incidence and mortality of IE in recent decades, and variations in the epidemiology of the disease, which affects an older population and is associated with an increase in the use of invasive techniques, with a reduction in the number of cases of streptococcal aetiology and an increase in the cases that affect structurally normal hearts (Moreillon and Que, 2004). The indications for AP include procedures that require the manipulation of the gingival or periapical region of the teeth or perforation of the oral mucosa; it has been established that some procedures, such as anaesthetic injection through non-infected tissue, do not require AP (Wilson et al, 2007; Habib et al, 2009). However, our group has determined that certain invasive techniques, such as the elevation of mucoperiosteal flaps and implant placement in edentulous areas, are associated with a very low prevalence of bacteraemia (Pi~ neiro et al, 2010), whilst some anaesthetic techniques, such as intraligamental anaesthesia, and other apparently innocuous diagnostic manipulations, such as periodontal probing, more commonly cause bacteraemia (Daly et al, 2001). The 2008 Australian guidelines established a new category of procedures (including techniques such as the placement of orthodontic bands) that required AP only if multiple procedures were being performed, the procedure was prolonged or periodontal disease was present (Infective Endocarditis Prophylaxis Expert Group, 2008); this has probably served only to introduce further confounding factors. It would therefore appear that the at-risk procedures need to be redefined, paying particular attention to the critical area formed by the gingival sulcus and periodontal pockets. In 1960, the AHA established a prophylactic regimen that consisted of the administration of a number of intramuscular injections of penicillin, starting 48 hours before the dental treatment session and continuing for 48 hours afterwards (AHA, 1960). Since that time, the antibiotic of choice and the preferred route of administration have been

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modified. The intramuscular or intravenous administration of antibiotics such as penicillin, vancomycin or gentamicin has gradually been replaced by the current proposal to use a single oral dose of amoxicillin (Wilson et al, 2007; Habib et al, 2009). The initial recommendation for penicillin-allergic patients was to use oral erythromycin at a dose of 250 mg every six hours (American Heart Association, 1960), but in 1990 this was substituted by clindamycin because of the high prevalence of undesirable gastrointestinal effects associated with erythromycin (Simmons et al, 1990). There is also controversy regarding the complimentary use of antiseptics. The BSAC proposed the use of a 1-minute mouthwash with 10 ml of 0.2% chlorhexidine (Gould et al, 2006), whereas, in its most recent guidelines, the AHA did not recommend this method (Wilson et al, 2007). Our group performed a randomised controlled trial in a group of patients undergoing tooth extraction under general anaesthesia, and we found that chlorhexidine reduced in particular the duration of postextraction bacteraemia (Tomas et al, 2007); this finding probably reflects a marked reduction in the size of the bacterial inoculum due to the direct action of the antiseptic on the flora in the oral cavity, and we therefore recommended the routine use of 0.2% chlorhexidine before any dental procedure. However, it has been suggested that the indiscriminate clinical use of chlorhexidine may lead to the emergence of new clones with reduced susceptibility. In addition, the MHRA (an executive agency of the Department of Health of the United Kingdom) has recently published a medical device alert for medicinal products containing chlorhexidine following numerous reports of anaphylactic reactions after their use.

Critics of antibiotic prophylaxis The main argument against the administration of AP is probably the fact that, at the present time, there is no conclusive evidence of the efficacy of AP for the prevention of distant site infections and, specifically, of IE secondary to dental procedures in patients considered to be at risk (Glenny et al, 2013). Amoxicillin continues to be the drug of choice for the prevention of bacteraemia of oral origin in patients with no history of allergy to the beta-lactams. Randomised clinical trials have shown that this antibiotic significantly reduces bacteraemia caused by dental manipulations, although it does not completely eliminate the risk (Diz Dios et al, 2006). In contrast, there is no conclusive scientific evidence that other antibiotics, such as clindamycin, effectively reduce the prevalence of bacteraemia secondary to dental procedures, although the majority of studies on experimental models have confirmed the efficacy of AP on later stages in the development of IE. Other arguments against the administration of AP are beta-lactam antibiotic allergy and the development of antibiotic-resistant bacteria. It has been suggested that the administration of AP with amoxicillin leads to a high risk of allergic reactions, but very few cases have actually been reported in the literature after a single oral dose of the antibiotic; severe allergic reactions to oral amoxicillin have been estimated to occur with a frequency of 0.9 per

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million patients and, to our knowledge, there have been no reports of fatal anaphylaxis after oral amoxicillin prophylaxis for IE. The emergence of antibiotic resistance is a significant public health concern; it has been shown that the administration of antibiotics can contribute to the development, selection and transmission of bacterial resistance, but only after the administration of several consecutive doses. A final concern involves the cost to the healthcare system. Contradictory results have been published on the cost-effectiveness of AP for at-risk patients undergoing dental procedures; this is probably due to marked differences in the baseline risk of developing IE in the populations in which the estimations were performed (National Institute for Health and Clinical Excellence, 2008). In some countries, such as the USA, it has been estimated that AP gives rise to significant healthcare costs (Lockhart et al, 2013), but their results cannot be extrapolated to other countries in which the administration of AP to patients at highest risk represents only a small percentage of all antibiotics prescribed by dentists.

The NICE guidelines In the context of the restrictive policy on AP, the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom published new guidelines in 2008 which surprised the scientific community as they proposed that ‘AP against IE is not recommended for people undergoing dental procedures’ (NICE, 2008). This proposal was applicable even to the highest risk patients, independently of the type of dental procedure they were undergoing. The NICE experts based their recommendation on two main premises: the lack of available evidence to determine whether AP reduces the incidence of IE in at-risk patients, and more interestingly, they considered that ‘it is biologically implausible that a dental procedure would lead to a greater risk of IE than regular toothbrushing’. On this subject, it has been confirmed that bacteraemia is caused by activities of daily living, such as chewing or toothbrushing, and its prevalence could be underestimated as its intensity may possibly fail to reach the threshold of detection of conventional techniques; however, the clinical repercussions of these episodes of bacteraemia are still unknown. In a recent systematic review, our group found that little evidence was available on this subject in the literature and we observed that the accumulation of bacterial plaque and the degree of gingival inflammation affected the prevalence of bacteraemia secondary to toothbrushing, which would support the importance of oral hygiene as a preventive measure (Tomas et al, 2012). Two years after the introduction of the NICE guidelines, it was found that there had been a significant reduction in the number of prescriptions of AP in the UK (an estimated reduction of 78.6%), but there had been no marked increase in the incidence of new cases or deaths due to IE (Thornhill et al, 2011). The NICE guidelines have generated further controversy in the scientific community and some experts have criticised the proposals, dismantling the arguments one by one and explaining why they still recommended the

administration of AP to high-risk patients undergoing high-risk dental procedures (Chambers et al, 2011).


A personal view At the present time, some cardiologists remain understandably concerned about the omission of AP. In general, the main guidelines applicable in Europe (Habib et al, 2009), the USA (Wilson et al, 2007) and Australia (Infective Endocarditis Prophylactics Expert Group, 2008) continue to recommend the administration of AP, though restricting its indications. The definition of ‘high-risk’ patients and procedures must itself be re-examined. For example, the incidence of IE has increased among elderly patients and patients with intracardiac devices, whereas cases associated with rheumatic fever are ever less common in industrialised countries, although the Australian guidelines still consider indigenous Australian patients with rheumatic heart disease a special population at high risk (Infective Endocarditis Prophylaxis Expert Group, 2008). Other situations that are not contemplated in the most recent guidelines should also be re-evaluated because, for example, our group found that the prevalence of bacteraemia secondary to tooth extractions is significantly higher when performed under general anaesthesia than when performed in a dental clinic under local anaesthetic (Barbosa et al, 2010). The argument of bacteraemia secondary to activities such as toothbrushing cannot be analysed in absolute terms without taking into account variables such as the magnitude and duration of the episodes; if this is not done, we may be obliged, for example, to reassess the risk benefit of certain oral hygiene techniques in the highest risk patients. Quantification of the bacterial inoculum could be particularly important in the study of this source of bacteraemia, but methods currently available are too insensitive and are limited to semi-quantitative techniques such as lysis-centrifugation or lysis-filtration; more sophisticated molecular biology procedures, such as 16S rDNA PCR, are useful to identify not only fastidious, slow-growing and/or non-culturable bacteria, but also easy-to-culture pathogens, although the threshold of detection of these techniques is still high at the present time and they therefore underestimate bacteraemia and are not useful in quantifying its magnitude. Oral bacteraemia is likely to occur with the majority of visits to the dentist, and if it is shown that the application of antiseptics before starting a dental procedure reduces the size of the inoculum of the secondary bacteraemia, this argument could be used to support the routine use of this method. A further issue that has not been widely debated is whether there is any other antibiotic or combination of antibiotics that is more effective than amoxicillin for the prevention of bacteraemia of oral origin. It has been suggested that the aetiology of IE has changed over recent decades and that staphylococci are now the leading cause of IE, ahead of oral streptococci (Moreillon and Que, 2004). This would justify the search for alternative antibiotics. The preliminary results of a randomised clinical trial that our group recently presented at the European Society of Cardiology Congress 2013 indicated that the combination Oral Diseases

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of amoxicillin plus clavulanic acid could be an excellent option (European Heart Journal 2013;34 [abstract supplement]:861). In many countries, the prophylactic antibiotic regimens are imported and their efficacy could therefore be affected by geographical factors such as regional variations in antimicrobial sensitivity. For instance, for patients with beta-lactam antibiotic allergy, the antibiotic alternatives suggested in the Australian guidelines (Infective Endocarditis Prophylaxis Expert Group, 2008) include not only of clindamycin but also lincomycin, vancomycin and teicoplanin; these are different options from those proposed by the ESC (Habib et al, 2009) and the AHA (Wilson et al, 2007). In Spain, clindamycin is ineffective for the prevention of bacteraemia secondary to tooth extraction, whereas the efficacy of a quinolone such as moxifloxacin is comparable to that of amoxicillin (Diz Dios et al, 2006). AP must be prescribed using an evidence-based approach and not defensively to avoid medico-legal repercussions. An important consequence of the NICE guidelines is that they remove the ethical and medico-legal barriers that have hindered the initiation of prospective placebo-controlled trials to investigate once and for all the efficacy of AP in the prevention of IE of oral origin. Whilst this happens, it would appear reasonable to adopt the recommendations proposed by the expert committees in each country, preferably drawn up from a multidisciplinary perspective; if no official national guidelines are available, it would be prudent to apply one of the major national guidelines on the subject.

Author contribution P D D drafted and wrote the manuscript. References American Heart Association (1955). Prevention of rheumatic fever and bacterial endocarditis through control of streptococcal infections. Circulation 11: 317–320. American Heart Association (1960). Prevention of rheumatic fever and bacterial endocarditis through control of streptococcal infections. Circulation 21: 151–155. Barbosa M, Carmona IT, Amaral B et al (2010). General anesthesia increases the risk of bacteremia following dental extractions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 110: 706–712. Billings F (1916). Focal infection: The Lane Medical Lectures. D. Appleton and Company: New York. Chambers JB, Shanson D, Hall R, Pepper J, Venn G, McGurk M (2011). Antibiotic prophylaxis of endocarditis: the rest of the world and NICE. J R Soc Med 104: 138–140. Daly CG, Mitchell DH, Highfield JE, Grossberg DE, Stewart D (2001). Bacteremia due to periodontal probing: a clinical and microbiological investigation. J Periodontol 72: 210–214. Diz Dios P, Tomas Carmona I, Limeres Posse J, Medina Henrıquez J, Fernandez Feijoo J, Alvarez Fernandez M (2006). Comparative efficacies of amoxicillin, clindamycin, and moxifloxacin in prevention of bacteremia following dental extractions. Antimicrob Agents Chemother 50: 2996–3002.

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Fiehn NE, Gutschik E, Larsen T, Bangsborg JM (1995). Identity of streptococcal blood isolates and oral isolates from two patients with infective endocarditis. J Clin Microbiol 33: 1399–1401. Glenny AM, Oliver R, Roberts GJ, Hooper L, Worthington HV (2013). Antibiotics for the prophylaxis of bacterial endocarditis in dentistry. Cochrane Database Syst Rev 10: CD003813. Gould FK, Elliott TS, Foweraker J et al (2006). Guidelines for the prevention of endocarditis: report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 58: 896–898. Habib G, Hoen B, Tornos P et al (2009). Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009). The Task Force on the Prevention, Diagnosis and Treatment of Infective Endocarditis of the European Society of Cardiology. European Heart J 30: 2369–2413. Infective Endocarditis Prophylaxis Expert Group (2008). Prevention of Endocarditis 2008 update from Therapeutic Guidelines: Antibiotic Version 13, and Therapeutic Guidelines: Oral and Dental Version 1. Therapeutic Guidelines Limited: Melbourne. Knirsch W, Haas NA, Uhlemann F, Dietz K, Lange PE (2005). Clinical course and complications of infective endocarditis in patients growing up with congenital heart disease. Int J Cardiol 101: 285–291. Lockhart PB, Blizzard J, Maslow AL, Brennan MT, Sasser H, Carew J (2013). Drug cost implications for antibiotic prophylaxis for dental procedures. Oral Surg Oral Med Oral Pathol Oral Radiol 115: 345–353. Moreillon P, Que YA (2004). Infective endocarditis. Lancet 363: 139–149. National Institute for Health and Clinical Excellence (2008). Prophylaxis against infective endocarditis. Antimicrobial prophylaxis against infective endocarditis in adults and children undergoing interventional procedures. URL: ‘http://www.nice. org.uk/CG064 (accessed November 2013). Okell CC, Elliott SD (1935). Bacteremia and oral sepsis with special reference to the aetiology of subacute endocarditis. Lancet 2: 869–872. Pi~ neiro A, Tomas I, Blanco J, Alvarez M, Seoane J, Diz P (2010). Bacteraemia following dental implants’ placement. Clin Oral Implants Res 21: 913–918. Rosenow EC (1921). Result of experimental studies on focal infection and elective localization. Med Clin North Am 5: 573–592. Simmons NA, Cawson RA, Eykyn SJ et al (1990). Antibiotic prophylaxis of infective endocarditis: recommendations from the endocarditis working party of the British Society for Antimicrobial Chemotherapy (editorial). Lancet 13: 88–89. Thornhill MH, Dayer MJ, Forde JM et al (2011). Impact of the NICE guideline recommending cessation of antibiotic prophylaxis for prevention of infective endocarditis: before and after study. BMJ 342: d2392. Tomas I, Alvarez M, Limeres J et al (2007). Effect of chlorhexidine mouthwash on the risk of postextraction bacteremia. Infect Control Hosp Epidemiol 28: 577–582. Tomas I, Diz P, Tobıas A, Scully C, Donos N (2012). Periodontal health status and bacteraemia from daily oral activities: systematic review/meta-analysis. J Clin Periodontol 39: 213–228. Wilson W, Taubert KA, Gewitz M et al (2007). Prevention of Infective Endocarditis. Guidelines from the American Heart Association. J Am Dent Assoc 138: 739–745, 747-760.

Infective endocarditis prophylaxis.

Antibiotic prophylaxis for infective endocarditis continues to be administered empirically, although its indications are ever more restrictive. Some e...
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