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Behavior of health professionals concerning the recommendations for prophylaxis for infectious endocarditis in our setting: Are the guidelines followed?
Rev Clin Esp. 2017;217(2):79---86
Revista Clínica Española www.elsevier.es/rce
ORIGINAL ARTICLE
Behavior of health professionals concerning the recommendations for prophylaxis for infectious endocarditis in our setting: Are the guidelines followed?夽 P. Anguita a , F. Castillo b , P. Gámez c , F. Carrasco d , R. Roldán e , B. Jurado f , J.C. Castillo d , E. Martín d , M. Anguita c,d,∗ a
Departamento de Cirugía, Clínica iDental, Madrid, Spain Sección de Cardiología, Hospital de Puertollano, Ciudad Real, Spain c Instituto Cardiodental, Córdoba, Spain d Servicio de Cardiología, Hospital Universitario Reina Sofía, Córdoba, Spain e Colegio Oficial de Dentistas, Córdoba, Spain f Colegio Oficial de Médicos, Córdoba, Spain b
Received 29 July 2016; accepted 11 October 2016 Available online 12 January 2017
KEYWORDS Infectious endocarditis; Antibiotic prophylaxis; Clinical practice guidelines
Abstract Objectives: The prophylaxis regimens for infectious endocarditis recommended by the clinical practice guidelines have recently changed. We do not know whether the current regimens are correctly followed in our setting. Our objective was to describe the approaches of various health professionals concerning these guidelines. Materials and methods: We conducted a survey in Cordoba, using a 16-item online questionnaire on this topic. We randomly selected a sample of 180 practitioners (20 cardiologists, 80 dentists and 80 primary care physicians), of whom 173 responded. Results: Half of the participants were men; 52% had more than 20 years of professional experience. Some 88.3% of the participants considered that prophylaxis of endocarditis is effective (77.8% of the cardiologists, 93.7% of the dentist; p = .086). In general, prophylaxis is performed in conditions of clearly established risk (>90% of those surveyed). However, prophylaxis is also performed in a high proportion of cases with no risk of endocarditis, varying between 30 and 60% according to the procedure (mostly the dentists, between 36 and 67%, followed by the primary
夽
Please cite this article as: Anguita P, Castillo F, Gámez P, Carrasco F, Roldán R, Jurado B, et al. Conducta de los profesionales sanitarios ante las recomendaciones de profilaxis de endocarditis infecciosa en nuestro medio: ¿se siguen las guías?. Rev Clin Esp. 2017;217:79---86. ∗ Corresponding author. E-mail address: [email protected] (M. Anguita). 2254-8874/© 2016 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
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P. Anguita et al. care physicians, between 28 and 59%). The antibiotic regimens employed varied significantly. The primary care physicians were furthest from the recommended regimen (only 25.8% used the recommended regimen vs. 54.4% of dentists and 72.2% of cardiologists; p = .002). Conclusions: Compliance with the recommendations on prophylaxis for endocarditis should be improved in our setting. We observed a tendency, especially among noncardiologists, to ‘‘overindicate’’ the prophylaxis. © 2016 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
PALABRAS CLAVE Endocarditis infecciosa; Profilaxis antibiótica; Guías de práctica clínica
Conducta de los profesionales sanitarios ante las recomendaciones de profilaxis de endocarditis infecciosa en nuestro medio: ¿se siguen las guías? Resumen Objetivos: Las pautas de profilaxis de endocarditis infecciosa recomendadas por las guías de práctica clínica han cambiado recientemente. Se desconoce en nuestro medio si se siguen correctamente las pautas actuales. Nuestro objetivo es describir las actitudes de diferentes profesionales sanitarios ante ellas. Material y métodos: Hemos realizado una encuesta en Córdoba, mediante un cuestionario online con 16 ítems sobre este tema. Se seleccionó aleatoriamente una muestra de 180 profesionales (20 cardiólogos, 80 dentistas, 80 médicos de atención primaria), de la cual contestaron 173. Resultados: La mitad eran varones, teniendo más de 20 a˜ nos de ejercicio profesional el 52%. El 88,3% consideró que la profilaxis de endocarditis es efectiva (cardiólogos, 77,8%, dentistas, 93,7%, p = 0,086). En general, se realiza profilaxis en las situaciones de riesgo claramente establecidas (>90% de los encuestados), pero también en una alta proporción de casos sin riesgo de endocarditis, que oscila entre el 30 y el 60% según los procedimientos (más los dentistas, entre el 36 y 67%, seguidos de los médicos de atención primaria, entre el 28 y 59%). Las pautas antibióticas usadas son muy variadas, siendo los médicos de primaria los que se alejan más de lo recomendado (solo un 25,8% usaban la pauta recomendada, frente a un 54,4% de dentistas y un 72,2% de cardiólogos, p = 0,002). Conclusiones: El seguimiento de las recomendaciones sobre profilaxis de endocarditis debe mejorarse en nuestro medio, observándose una tendencia, sobre todo en no cardiólogos, a una «sobreindicación» de la misma. © 2016 Elsevier Espa˜ na, S.L.U. y Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.
Background Infectious endocarditis (IE) is a severe disease, with hospital mortality rates of 18---23% and at 6 months after diagnosis of 22---27%, despite advances in its diagnosis and treatment.1---4 The prevention of IE is therefore essential. Before the publication of the 2007 US5 and 2009 European6 clinical practice guidelines (CPGs), IE prophylaxis was classically recommended for patients with heart disease of moderate to high risk (including hemodynamically significant valve lesions) who undergo oral/dental, gastrointestinal, respiratory and genitourinary procedures that could cause bleeding. Due to the lack of evidence on the usefulness of prophylaxis, these GPCs restricted the indications to cases of high-risk IE (prior IE, prosthetic valves, congenital cyanotic heart disease or those repaired with prosthetic material) and only for certain manipulations and oral/dental procedures.5,6 The British National Institute for Health and Care Excellence 2008 guidelines went a step further and recommended not
performing IE prophylaxis under any situation.7 A recent study published in England reported an increase in the incidence of IE after the publication and following of these British National Institute for Health and Care Excellence recommendations.8 The latest European CPGs on IE, published in 2015, maintained the recommendations of the 2009 guidelines.9 It is worth noting that there are also CPGs from Spanish dental societies, published in 2004 and 2006.10,11 These changes and the differences among the various CPGs, which are due in large part to the lack of evidence on the usefulness of IE prophylaxis,12 can lead to doubts about the procedure to follow when faced with patients with a possible risk of developing IE,13,14 which could result in an increase in the incidence of the disease. The aim of this study was to report the behavior of health professionals when faced with preventing IE and to compare the possible differences among the practitioners involved: cardiologists, dentists and primary care (PC) physicians. Our group has recently published preliminary data on the risk conditions
Behavior of health professionals concerning recommendations for prophylaxis Table 1
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Questions and variables included in the survey on prophylaxis for infectious endocarditis.
1. Specialty Cardiologist Dentist (odontologist, stomatologist) Primary care physician 2. Age in years. Less than 30 Between 30 and 45 Between 45 and 65 More than 65 3. Sex Male Female sex 4. Years of professional work Less than 10 Between 10 and 20 Between 21 and 30 More than 30 5. How many cases of infectious endocarditis do you think occur every year in Cordoba? Less than 10 Between 20 and 25 Between 50 and 100 More than 100 6. What do you think is the mortality in the acute phase of infectious endocarditis at this time? Less than 1% 5---10% 20---30% More than 50% 7. Do you believe that prophylaxis for infectious endocarditis is effective? Yes No I’m not sure; there is insufficient data to confirm or deny it. 8. Do you perform prophylaxis for infectious endocarditis in your clinical practice? Yes No 9. Which of the following recommendations do you follow for performing prophylaxis of infectious endocarditis in oral/dental manipulations? The recommendations of the 2007 American Heart Association guidelines The recommendations of the 2015 European Society of Cardiology guidelines The recommendations of the 2008 NICE guidelines The recommendations of the dental scientific societies None in particular; I base it on my knowledge and experience. 10. For patients you consider at risk of developing endocarditis, indicate the procedures or oral/dental manipulations for which you would indicate/perform endocarditis prophylaxis (in the absence of oral infection that requires a specific antibiotic treatment) Oral/gingival surgery Yes No Dental implants Yes No Dental cleanings Yes No Local anesthesia Yes No Extraction of dental pieces Yes No Suture removal Yes No Making impressions for fixed prosthesis or on implants Yes No Making impressions for removable prosthesis Yes No Placement/adjustment of removable prosthesis Yes No Placement/adjustment of fixed prosthesis or on implants Yes No
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Table 1
(Continued)
Placement of orthodontic brackets Endodontics Fillings Intraoral radiographs
Yes Yes Yes Yes
No No No No
11. When patients who have heart disease come for a dental consultation in which an oral/dental procedure or manipulation that you consider has a risk of developing endocarditis, for what type of cardiac lesion would you indicate/perform prophylaxis? Patients with any type of valvular prosthesis Yes No Patient with a coronary stent Yes No Patient who underwent a coronary bypass Yes No Patient with pacemaker or implantable defibrillator Yes No Patient with prior endocarditis Yes No Mild mitral prolapse Yes No Significant aortic valve disease Yes No Significant mitral valve disease Yes No Congenital cyanotic heart disease or with prosthetic material Yes No ASD, VSD or closed ductus with no residual defects Yes No ASD, VSD or closed ductus with residual defects Yes No Patient with atrial fibrillation but no structural heart disease No Yes 12. In patients who are not allergic to beta-lactams and for whom you indicate endocarditis prophylaxis, what is your first choice of antibiotic? Amoxicillin Amoxicillin/clavulanate Clindamycin Oral cephalosporin Levofloxacin Ampicillin and parenteral gentamicin Others 13. For patients who are allergic to beta-lactams and for whom you indicate endocarditis prophylaxis, what is your first choice of antibiotic? Metronidazole Amoxicillin/clavulanate Clindamycin Oral cephalosporin Levofloxacin Ampicillin and parenteral gentamicin Others 14. What is the dosage regimen for the antibiotic that you use for endocarditis prophylaxis? Single dose 1 h before the dental procedure Two doses, the first dose 1 h before the procedure and the second dose 6 h after the procedure Three days (a day before and 2 days after) Three doses (half an hour before, and at 8 and 24 h) Depends on the risk of the procedure and the patient’s risk I only administer antibiotics if there is a clinical infection, for the time required (5---7 days) 15. Assuming you decide to use amoxicillin, what dose will you administer before the procedure? 500 mg 1g 2g 3g Amoxylavulanic 800/125 mg 16. What causal microorganisms of endocarditis do you expect to eliminate with the antibiotic prophylaxis in oral procedures? Staphylococci Enterococcus Streptococci viridans Gram-negative All of them Abbreviations: ASD, atrial septal defect; VSD, ventricular septal defect.
Behavior of health professionals concerning recommendations for prophylaxis for which IE prophylaxis should be performed.15 In this article, we present the final and overall results from the entire study.
Materials and methods The study was conducted between November and December 2015 in the hospital area Reina Sofia of Cordoba, using a survey that included 16 questions related to the characteristics of health professionals, overall concepts of IE and recommendations on its prophylaxis (Table 1). The variables of this questionnaire were designed by a consensus of the researchers (cardiologists, dentists and PC physicians). We randomly selected 180 practitioners in a health area, using the list of registered practitioners of the Official Schools of Physicians and Dentists of Cordoba and the cardiologist partners of the Andalusian Society of Cardiology (80 PC physicians from a total of 201 identified physicians, 80 dentists from 196, and 20 cardiologists from 25). Ninety-six percent (173) of those selected answered the survey (consisting of 18 cardiologists, 79 dentists and 76 PC physicians). All questions were designed in the form of qualitative variables. For the comparisons between the groups, we employed the chi-squared test. We considered a p value <.05 statistically significant. For the statistical analysis, we employed the statistical package SPSS version 12.
Results Half of those surveyed were men (87), 12% were younger than 30 years, 31% were between 30 and 45 years of age, and 57% were older than 45 years. Twenty-five percent of those surveyed had less than 10 years of professional practice, 23% had 10---20 years, 42% had 21---30 years, and 10% had more than 30 years. There were no differences in this regard among cardiologists, dentists and PC physicians. In terms of their perception of the incidence and severity of IE, 9% of the responders indicated that the incidence rate of IE in Cordoba was less than 10 cases per year, 45% indicated it was 20---25 cases per year, 35% indicated it was 50---100, and 11% stated that it was more than 100 cases per year. Therefore, 9% of the responders underestimated the incidence of IE in Cordoba, and 46% overestimated it (the incidence rate of IE in our center is 20---25 cases per year).15 In terms of early mortality in the active phase of IE, 12% of the responders thought that it was <1%, 44% thought it was 5---10%, 31% thought it was 20---30%, and 13% thought it was >50%. Therefore, 56% of the responders underestimated the mortality and 13% overestimated it. Among the cardiologists, the predominant response was a mortality rate of 20---30% (62%). Among the dentists and PC physicians, the predominant response was 5---10% (46% and 44%, respectively; p = .055). Table 2 shows the perceptions on the effectiveness of IE prophylaxis and the CPGs followed. Most of those surveyed believed that this prophylaxis is effective and employ it in their daily practice. However, cardiologists believed in its effectiveness the least (p = .086). The cardiologists stated that they mostly followed the European CPGs, the dentists stated that they followed the scientific society
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guidelines,10,11 and the PC physicians followed the European guidelines (37.9%) or none at all (47%). Table 3 lists the oral/dental procedures in which those surveyed indicated (or not) IE prophylaxis for a patient at risk of developing IE. In most situations with a clear indication for performing prophylaxis (surgery, implants, extractions and endodontics) or not (radiographs, anesthesia, sutures removal, making impressions for any type of prosthesis, placement of removable prosthesis and placement of orthodontic brackets), we observed a high rate of compliance with the recommendations, except for endodontics and local anesthesia (Table 3). The cardiologists also recommended more prophylaxis in cases of radiographs, making impressions, placement of removable prosthesis and fillings. Table 4 indicates the heart diseases for which IE prophylaxis would be performed (or not) for risky oral/dental manipulations. The three indications currently established by the US and European CPGs (prosthetic valves, previous IE, congenital cyanotic heart disease or repaired with prosthetic material) were considered indications for prophylaxis by the 3 groups of practitioners in a percentage close to 90---100% (Table 4). For previously accepted indications that are now not recommended (such as significant mitral or aortic valvular heart disease), prophylaxis is still applied by a very high proportion of the 3 groups, although significantly greater by the noncardiologists (Table 4). Lastly, even in conditions with no risk or a very low risk of IE (pacemakers, aortocoronary bypass, stents, isolated atrial fibrillation, mild mitral prolapse, interventricular and interatrial presentations and closed ductus without defects), prophylaxis is performed for 33---60% of cases, although in a significantly smaller proportion by the cardiologists. Table 5 lists the responses related to the antibiotic regimens employed for the prophylaxis. The most widely used regimen is that recommended by the guidelines (amoxicillin, in a single 2-g dose 1 h before the oral/dental procedure). When asked about the microorganisms the respondents expected to eliminate with the IE prophylaxis, 73% of the cardiologists indicated only Streptococcus viridans. Sixtytwo percent of the dentists and 53% of the PC physicians also thought that this regimen would prevent infections by other microorganisms, such as enterococcus, staphylococci and gram-negative bacilli.
Discussion The main conclusion from this survey is that there is enormous variability in our setting in the conduct regarding IE prophylaxis. There is a significant lack of knowledge concerning the magnitude, importance and microbiology of IE. Most of those surveyed believe that IE prophylaxis is effective and use it in their clinical practice, although they follow different guidelines and recommendations (the European guidelines for the cardiologists, those of scientific societies for the dentists and none or the European ones for the PC physicians). With regard to the various dental or oral procedures of risk, the dentists and PC physicians were closest in terms of the recommended prophylaxis, while the cardiologists excessively recommended IE prophylaxis when faced with low-risk manipulations. The reverse happened with
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Table 2
Perception of the effectiveness of endocarditis prophylaxis and clinical practice guidelines followed. Total
Cardiologists
Dentists
PC
p-Value
Believes that IE prophylaxis is effective Performs IE prophylaxis in their practice Clinical practice guidelines followed European 2009---2015 British (NICE) 2008
88.3% 90.8%
77.8% 94.4%
93.7% 98.7%
84.8% 80.3%
35% 1.2%
77.8% 0%
22.8% 0%
37.9% 3%
American Heart Association 2007 Dental Societies None, I base it on my own experience
16% 22.1% 25.8%
11.1% 0% 11.1%
24.1% 41.8% 11.4%
7.6% 4.5% 47%
p = .086 p = .001 p < .001
Abbreviations: PC, primary care; IE, infectious endocarditis.
Table 3 Oral/dental procedures and manipulations in which endocarditis prophylaxis is indicated or not for patients with risk of developing endocarditis. Total
Cardiologists
Dentists
PC
p-Value
With indication in the CPGs Oral/gingival surgery Dental implants Dental cleanings Endodontics Dental piece extractions Placement/adjustment of fixed prosthesis
98.8% 97.5% 49.1% 69.3% 90.8% 28.2%
100% 100% 55.6% 83.3% 88.9% 61.1%
98.7% 100% 70.9% 59.5% 100% 7.6%
98.5% 93.9% 21.2% 77.3% 80.3% 43.9%
NS NS p < .001 p = .027 p < .001 p < .001
With no indication in the CPGs Making impressions for fixed prosthesis or on implants Making impressions for removable prosthesis Placement/adjustment of removable prosthesis Placement orthodontic brackets Fillings Local anesthesia Intraoral radiographs
9.2% 7.4% 15.3% 8% 20.9% 18.4% 2.5%
16.7% 16.7% 33.3% 22.2% 38.9% 38.9% 11.1%
8.9% 3.8% 1.3% 3.8% 10.1% 22.8% 1.3%
7.6% 9.1% 27.3% 9.1% 28.8% 7.6% 1.5%
NS NS p < .001 p = .031 p = .003 p = .004 p = .042
Abbreviations: PC, primary care; CPGs, European or US clinical practice guidelines; NS, not significant.
Table 4 Heart diseases for which endocarditis prophylaxis is indicated or not when a patient undergoes an oral/dental procedure with a risk of endocarditis. Total
Cardio
Currently indicated in the CPGs Carrier of valvular prosthesis Previous endocarditis Congenital cyanotic heart disease or repaired with prosthetic material
96.9% 97.5% 88.3%
100% 100% 100%
Not indicated in the current CPGs but with prior indication Significant aortic valve disease Significant mitral valve disease Pacemaker or ICD carrier Congenital heart disease with complete correction
84% 86.5% 33.7% 73.6%
Never indicated Coronary stent Aortocoronary bypass Mild mitral prolapse ASD, VSD or closed ductus with no residual defects Atrial fibrillation but no structural heart disease
49.7% 56.4% 49.7% 60% 30.1%
Dentists
PC
p-Value
94.9% 100% 86.1%
98.5% 93.9% 87.9%
NS p = .049 NS
66.7% 66.7% 50% 66.7%
84.4% 84.4% 40.5% 72.2%
87.9% 93.9% 21.2% 77.3%
p = .09 p = .009 p = .015 NS
5.6% 0% 22.2% 33.3% 5.6%
67.1% 69.6% 58.2% 67.1% 36.7%
40.9% 56.1% 47% 59.1% 28.8%
p < .001 p < .001 p = .019 p = .030 p = .033
Abbreviations: ASD, atrial septal defect; CPGs, clinical practice guidelines (European and US); ICD, implantable cardioverter defibrillator; NS, not significant; PC, primary care; VSD, ventricular septal defect.
Behavior of health professionals concerning recommendations for prophylaxis Table 5
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Antibiotic regimens employed for endocarditis prophylaxis. Total
First-line antibiotic in patients not allergic to beta-lactam agents Indicated Amoxicillin Not indicated Amoxi/clavulanate Other regimens First-line antibiotic in patients allergic to beta-lactam agents Indicated Clindamycin Not indicated Cephalosporin Metronidazole Other Dosage regimen employed Indicated Single dose 1 hour before Not indicated Two doses, 1 h before and 6 h after Others Dose of amoxicillin in single regimen Indicated 2g Not indicated 1g Other doses
Cardiologists
Dentists
PC
p-Value p = .002
66.3%
83.3%
77.2%
48.5%
30.7% 3%
11.1% 5.6%
22.8% 0%
45.5% 6% p = .030
57.7%
66.7%
67.1%
43.9%
8.6% 9.2% 14.5%
0% 5.6% 27.7%
8.9% 8.9% 14.1%
10.6% 10.6% 33.9% p = .002
44.9%
72.2%
54.4%
25.8%
27% 24.1%
11.1% 16.7%
30.4% 15.2%
27.3% 46.9% p < .001
47.2%
50%
63.3%
27.3%
30.1% 12.7%
27.8% 22.2%
27.8% 8.9%
33.3% 49.4%
Abbreviations: PC, primary care; h, hour.
heart diseases for which IE prophylaxis is indicated, where we observed an excess of indications by the dentists and PC physicians in no-risk situations (coronary stent, aortocoronary bypass, atrial fibrillation with no heart disease).6,9 This is the philosophy described by a number of authors as the ‘‘just in case’’ philosophy.12 Although amoxicillin is the most widely used antibiotic according to the guidelines’ recommendations, many PC physicians and dentists use regimens other than those recommended.5,6,9 Moreover, most dentists and PC physicians and more than 25% of cardiologists mistakenly believe that preventive antibiotic treatment eradicates the common causal microorganisms of IE. These results agree with the previously published information in Spain,13,14 which indicates that there has been little progress in our understanding of the recommendations of IE prophylaxis. The excess use of prophylaxis by cardiologists in conditions previously considered risky (but not since 2007---2009) might be due to the belief, on one hand, that it is worth administering a simple antibiotic regimen with barely any adverse effects to prevent potential cases of a disease as severe as IE12 and, on the other, that the lack of evidence in the guidelines reflects the absence of studies with sufficient statistical weight to demonstrate it. The excess indications by dentists and PC physicians in conditions of low or no risk can only be explained by the lack of knowledge of the etiopathogenesis of IE. Moreover, it is possible that the opinions of these practitioners are
merely speculative for uncommon conditions in their clinical practice, such as congenital heart disease. This study’s limitations are those of a voluntary completion survey, although the prior random selection of those surveyed and the high percentage of responses (96%) strengthens the survey’s value. The number of cardiologists in absolute terms is low compared to that of other physicians, which is due to their lower relative numbers. Moreover, our data are limited to a health area of the province of Cordoba and thus cannot be extrapolated to other geographical areas. The reason for including only the dependent area of our hospital was to ensure greater sample homogeneity of the surveyed practitioners, who are informed of the recommended standards for prophylaxis by the Department of Cardiology, given that other areas might disseminate different prophylaxis regimens. National studies with larger sample sizes are needed to confirm this assumption. If this assumption were true, it seems warranted to prepare training strategies in this clinical situation for all practitioner groups involved, which would require the coordination and collaboration of all scientific societies involved.
Conflicts of interest The authors declare that they have no conflicts of interest.
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Acknowledgements The authors would like to thank the Official Schools of Physicians and Dentists of Cordoba for their assistance in developing this study.
Annex. Web addresses for checking the recommendations on prophylaxis for infectious endocarditis eurheartj.oxfordjournals.org/content/early/2015/08/28/ eurheartj.ehv319 www.uptodate.com/../antimicrobial-prophylaxisforbacterial-endocarditis http://www.catcardio.cat/pdfs/fitxa%203.pdf https://www.nice.org.uk/Guidance/CG64
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P. Anguita et al. 6. Habib G, Hoen B, Tornos P, Thuny F, Prendegast B, Vilacosta I, et al. The Task Force for the prevention, diagnosis and treatment of infective endocarditis of the ESC. Eur Heart J. 2009;30:2369---413. 7. Richey R, Wray D, Stokes T. Prophylaxis against infective endocarditis: summary of NICE guidance. Br Med J. 2008;336:770---1. 8. Dayer MJ, Jones S, Prendergast B, Baddour LM, Lockhart PB, Thornhill MH. Incidence of infective endocarditis in England, 2000---13: a secular trend, interrupted time-series analysis. Lancet. 2014;385:1219---28. 9. Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, DelZotti F, et al. Task force for the management of infective endocarditis of the ESC. 2015 Guidelines for the management of infective endocarditis. Eur Heart J. 2015;36:3075---128. 10. Tomas-Carmona I, Diz-Dios P, Limeres-Posse J, Outumuro-Rial M, Caama˜ no-Duran F, Fernández-Feijoo J, et al. Pautas de profilaxis antibiótica de endocarditis bacteriana recomendadas por na. Med Oral. 2004;9:56---62. los odontólogos en Espa˜ 11. Gutiérrez JL, Bagán JV, Bascones A, Llamas R, Llena J, Morales A, et al. Documento de consenso sobre la utilización de profilaxis antibiótica en cirugía y procedimientos dentales. Sociedad espa˜ nola de Cirugía oral y Máxilofacial. Avances Odontoest. 2006;22:41---67. 12. Shaw D, Conway DI. Pascal’s Wager, infective endocarditis and the no-lose philosophy in medicine. Heart. 2010;96:15---8. 13. Torres F, Renilla A, Flórez JP, Secades S, Benito EM, de la Hera JM. Grado de conocimiento de la profilaxis de endocardinoles. Rev Esp Cardiol. tis infecciosa entre los dentistas espa˜ 2012;65:1134---5. 14. González de Molina M, Fernández-Guerrero JC, Azpitarte J. Endocarditis infecciosa. Grado de discordancia entre lo recomendado por las guías clínicas y lo realizado en la práctica. Rev Esp Cardiol. 2002;55:793---880. 15. Castillo F, Castillo JC, Anguita P, Roldán R, Gámez P, Anguita M. ¿Se siguen en nuestro medio las recomendaciones de profilaxis de endocarditis infecciosa? Diferencias entre los profesionales sanitarios implicados (carta). Aten Primaria. 2016, doi:10.1016/j.aprim.2016.02.009.
Revista Clínica Española www.elsevier.es/rce
ORIGINAL ARTICLE
Behavior of health professionals concerning the recommendations for prophylaxis for infectious endocarditis in our setting: Are the guidelines followed?夽 P. Anguita a , F. Castillo b , P. Gámez c , F. Carrasco d , R. Roldán e , B. Jurado f , J.C. Castillo d , E. Martín d , M. Anguita c,d,∗ a
Departamento de Cirugía, Clínica iDental, Madrid, Spain Sección de Cardiología, Hospital de Puertollano, Ciudad Real, Spain c Instituto Cardiodental, Córdoba, Spain d Servicio de Cardiología, Hospital Universitario Reina Sofía, Córdoba, Spain e Colegio Oficial de Dentistas, Córdoba, Spain f Colegio Oficial de Médicos, Córdoba, Spain b
Received 29 July 2016; accepted 11 October 2016 Available online 12 January 2017
KEYWORDS Infectious endocarditis; Antibiotic prophylaxis; Clinical practice guidelines
Abstract Objectives: The prophylaxis regimens for infectious endocarditis recommended by the clinical practice guidelines have recently changed. We do not know whether the current regimens are correctly followed in our setting. Our objective was to describe the approaches of various health professionals concerning these guidelines. Materials and methods: We conducted a survey in Cordoba, using a 16-item online questionnaire on this topic. We randomly selected a sample of 180 practitioners (20 cardiologists, 80 dentists and 80 primary care physicians), of whom 173 responded. Results: Half of the participants were men; 52% had more than 20 years of professional experience. Some 88.3% of the participants considered that prophylaxis of endocarditis is effective (77.8% of the cardiologists, 93.7% of the dentist; p = .086). In general, prophylaxis is performed in conditions of clearly established risk (>90% of those surveyed). However, prophylaxis is also performed in a high proportion of cases with no risk of endocarditis, varying between 30 and 60% according to the procedure (mostly the dentists, between 36 and 67%, followed by the primary
夽
Please cite this article as: Anguita P, Castillo F, Gámez P, Carrasco F, Roldán R, Jurado B, et al. Conducta de los profesionales sanitarios ante las recomendaciones de profilaxis de endocarditis infecciosa en nuestro medio: ¿se siguen las guías?. Rev Clin Esp. 2017;217:79---86. ∗ Corresponding author. E-mail address: [email protected] (M. Anguita). 2254-8874/© 2016 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
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P. Anguita et al. care physicians, between 28 and 59%). The antibiotic regimens employed varied significantly. The primary care physicians were furthest from the recommended regimen (only 25.8% used the recommended regimen vs. 54.4% of dentists and 72.2% of cardiologists; p = .002). Conclusions: Compliance with the recommendations on prophylaxis for endocarditis should be improved in our setting. We observed a tendency, especially among noncardiologists, to ‘‘overindicate’’ the prophylaxis. © 2016 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.
PALABRAS CLAVE Endocarditis infecciosa; Profilaxis antibiótica; Guías de práctica clínica
Conducta de los profesionales sanitarios ante las recomendaciones de profilaxis de endocarditis infecciosa en nuestro medio: ¿se siguen las guías? Resumen Objetivos: Las pautas de profilaxis de endocarditis infecciosa recomendadas por las guías de práctica clínica han cambiado recientemente. Se desconoce en nuestro medio si se siguen correctamente las pautas actuales. Nuestro objetivo es describir las actitudes de diferentes profesionales sanitarios ante ellas. Material y métodos: Hemos realizado una encuesta en Córdoba, mediante un cuestionario online con 16 ítems sobre este tema. Se seleccionó aleatoriamente una muestra de 180 profesionales (20 cardiólogos, 80 dentistas, 80 médicos de atención primaria), de la cual contestaron 173. Resultados: La mitad eran varones, teniendo más de 20 a˜ nos de ejercicio profesional el 52%. El 88,3% consideró que la profilaxis de endocarditis es efectiva (cardiólogos, 77,8%, dentistas, 93,7%, p = 0,086). En general, se realiza profilaxis en las situaciones de riesgo claramente establecidas (>90% de los encuestados), pero también en una alta proporción de casos sin riesgo de endocarditis, que oscila entre el 30 y el 60% según los procedimientos (más los dentistas, entre el 36 y 67%, seguidos de los médicos de atención primaria, entre el 28 y 59%). Las pautas antibióticas usadas son muy variadas, siendo los médicos de primaria los que se alejan más de lo recomendado (solo un 25,8% usaban la pauta recomendada, frente a un 54,4% de dentistas y un 72,2% de cardiólogos, p = 0,002). Conclusiones: El seguimiento de las recomendaciones sobre profilaxis de endocarditis debe mejorarse en nuestro medio, observándose una tendencia, sobre todo en no cardiólogos, a una «sobreindicación» de la misma. © 2016 Elsevier Espa˜ na, S.L.U. y Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.
Background Infectious endocarditis (IE) is a severe disease, with hospital mortality rates of 18---23% and at 6 months after diagnosis of 22---27%, despite advances in its diagnosis and treatment.1---4 The prevention of IE is therefore essential. Before the publication of the 2007 US5 and 2009 European6 clinical practice guidelines (CPGs), IE prophylaxis was classically recommended for patients with heart disease of moderate to high risk (including hemodynamically significant valve lesions) who undergo oral/dental, gastrointestinal, respiratory and genitourinary procedures that could cause bleeding. Due to the lack of evidence on the usefulness of prophylaxis, these GPCs restricted the indications to cases of high-risk IE (prior IE, prosthetic valves, congenital cyanotic heart disease or those repaired with prosthetic material) and only for certain manipulations and oral/dental procedures.5,6 The British National Institute for Health and Care Excellence 2008 guidelines went a step further and recommended not
performing IE prophylaxis under any situation.7 A recent study published in England reported an increase in the incidence of IE after the publication and following of these British National Institute for Health and Care Excellence recommendations.8 The latest European CPGs on IE, published in 2015, maintained the recommendations of the 2009 guidelines.9 It is worth noting that there are also CPGs from Spanish dental societies, published in 2004 and 2006.10,11 These changes and the differences among the various CPGs, which are due in large part to the lack of evidence on the usefulness of IE prophylaxis,12 can lead to doubts about the procedure to follow when faced with patients with a possible risk of developing IE,13,14 which could result in an increase in the incidence of the disease. The aim of this study was to report the behavior of health professionals when faced with preventing IE and to compare the possible differences among the practitioners involved: cardiologists, dentists and primary care (PC) physicians. Our group has recently published preliminary data on the risk conditions
Behavior of health professionals concerning recommendations for prophylaxis Table 1
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Questions and variables included in the survey on prophylaxis for infectious endocarditis.
1. Specialty Cardiologist Dentist (odontologist, stomatologist) Primary care physician 2. Age in years. Less than 30 Between 30 and 45 Between 45 and 65 More than 65 3. Sex Male Female sex 4. Years of professional work Less than 10 Between 10 and 20 Between 21 and 30 More than 30 5. How many cases of infectious endocarditis do you think occur every year in Cordoba? Less than 10 Between 20 and 25 Between 50 and 100 More than 100 6. What do you think is the mortality in the acute phase of infectious endocarditis at this time? Less than 1% 5---10% 20---30% More than 50% 7. Do you believe that prophylaxis for infectious endocarditis is effective? Yes No I’m not sure; there is insufficient data to confirm or deny it. 8. Do you perform prophylaxis for infectious endocarditis in your clinical practice? Yes No 9. Which of the following recommendations do you follow for performing prophylaxis of infectious endocarditis in oral/dental manipulations? The recommendations of the 2007 American Heart Association guidelines The recommendations of the 2015 European Society of Cardiology guidelines The recommendations of the 2008 NICE guidelines The recommendations of the dental scientific societies None in particular; I base it on my knowledge and experience. 10. For patients you consider at risk of developing endocarditis, indicate the procedures or oral/dental manipulations for which you would indicate/perform endocarditis prophylaxis (in the absence of oral infection that requires a specific antibiotic treatment) Oral/gingival surgery Yes No Dental implants Yes No Dental cleanings Yes No Local anesthesia Yes No Extraction of dental pieces Yes No Suture removal Yes No Making impressions for fixed prosthesis or on implants Yes No Making impressions for removable prosthesis Yes No Placement/adjustment of removable prosthesis Yes No Placement/adjustment of fixed prosthesis or on implants Yes No
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Table 1
(Continued)
Placement of orthodontic brackets Endodontics Fillings Intraoral radiographs
Yes Yes Yes Yes
No No No No
11. When patients who have heart disease come for a dental consultation in which an oral/dental procedure or manipulation that you consider has a risk of developing endocarditis, for what type of cardiac lesion would you indicate/perform prophylaxis? Patients with any type of valvular prosthesis Yes No Patient with a coronary stent Yes No Patient who underwent a coronary bypass Yes No Patient with pacemaker or implantable defibrillator Yes No Patient with prior endocarditis Yes No Mild mitral prolapse Yes No Significant aortic valve disease Yes No Significant mitral valve disease Yes No Congenital cyanotic heart disease or with prosthetic material Yes No ASD, VSD or closed ductus with no residual defects Yes No ASD, VSD or closed ductus with residual defects Yes No Patient with atrial fibrillation but no structural heart disease No Yes 12. In patients who are not allergic to beta-lactams and for whom you indicate endocarditis prophylaxis, what is your first choice of antibiotic? Amoxicillin Amoxicillin/clavulanate Clindamycin Oral cephalosporin Levofloxacin Ampicillin and parenteral gentamicin Others 13. For patients who are allergic to beta-lactams and for whom you indicate endocarditis prophylaxis, what is your first choice of antibiotic? Metronidazole Amoxicillin/clavulanate Clindamycin Oral cephalosporin Levofloxacin Ampicillin and parenteral gentamicin Others 14. What is the dosage regimen for the antibiotic that you use for endocarditis prophylaxis? Single dose 1 h before the dental procedure Two doses, the first dose 1 h before the procedure and the second dose 6 h after the procedure Three days (a day before and 2 days after) Three doses (half an hour before, and at 8 and 24 h) Depends on the risk of the procedure and the patient’s risk I only administer antibiotics if there is a clinical infection, for the time required (5---7 days) 15. Assuming you decide to use amoxicillin, what dose will you administer before the procedure? 500 mg 1g 2g 3g Amoxylavulanic 800/125 mg 16. What causal microorganisms of endocarditis do you expect to eliminate with the antibiotic prophylaxis in oral procedures? Staphylococci Enterococcus Streptococci viridans Gram-negative All of them Abbreviations: ASD, atrial septal defect; VSD, ventricular septal defect.
Behavior of health professionals concerning recommendations for prophylaxis for which IE prophylaxis should be performed.15 In this article, we present the final and overall results from the entire study.
Materials and methods The study was conducted between November and December 2015 in the hospital area Reina Sofia of Cordoba, using a survey that included 16 questions related to the characteristics of health professionals, overall concepts of IE and recommendations on its prophylaxis (Table 1). The variables of this questionnaire were designed by a consensus of the researchers (cardiologists, dentists and PC physicians). We randomly selected 180 practitioners in a health area, using the list of registered practitioners of the Official Schools of Physicians and Dentists of Cordoba and the cardiologist partners of the Andalusian Society of Cardiology (80 PC physicians from a total of 201 identified physicians, 80 dentists from 196, and 20 cardiologists from 25). Ninety-six percent (173) of those selected answered the survey (consisting of 18 cardiologists, 79 dentists and 76 PC physicians). All questions were designed in the form of qualitative variables. For the comparisons between the groups, we employed the chi-squared test. We considered a p value <.05 statistically significant. For the statistical analysis, we employed the statistical package SPSS version 12.
Results Half of those surveyed were men (87), 12% were younger than 30 years, 31% were between 30 and 45 years of age, and 57% were older than 45 years. Twenty-five percent of those surveyed had less than 10 years of professional practice, 23% had 10---20 years, 42% had 21---30 years, and 10% had more than 30 years. There were no differences in this regard among cardiologists, dentists and PC physicians. In terms of their perception of the incidence and severity of IE, 9% of the responders indicated that the incidence rate of IE in Cordoba was less than 10 cases per year, 45% indicated it was 20---25 cases per year, 35% indicated it was 50---100, and 11% stated that it was more than 100 cases per year. Therefore, 9% of the responders underestimated the incidence of IE in Cordoba, and 46% overestimated it (the incidence rate of IE in our center is 20---25 cases per year).15 In terms of early mortality in the active phase of IE, 12% of the responders thought that it was <1%, 44% thought it was 5---10%, 31% thought it was 20---30%, and 13% thought it was >50%. Therefore, 56% of the responders underestimated the mortality and 13% overestimated it. Among the cardiologists, the predominant response was a mortality rate of 20---30% (62%). Among the dentists and PC physicians, the predominant response was 5---10% (46% and 44%, respectively; p = .055). Table 2 shows the perceptions on the effectiveness of IE prophylaxis and the CPGs followed. Most of those surveyed believed that this prophylaxis is effective and employ it in their daily practice. However, cardiologists believed in its effectiveness the least (p = .086). The cardiologists stated that they mostly followed the European CPGs, the dentists stated that they followed the scientific society
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guidelines,10,11 and the PC physicians followed the European guidelines (37.9%) or none at all (47%). Table 3 lists the oral/dental procedures in which those surveyed indicated (or not) IE prophylaxis for a patient at risk of developing IE. In most situations with a clear indication for performing prophylaxis (surgery, implants, extractions and endodontics) or not (radiographs, anesthesia, sutures removal, making impressions for any type of prosthesis, placement of removable prosthesis and placement of orthodontic brackets), we observed a high rate of compliance with the recommendations, except for endodontics and local anesthesia (Table 3). The cardiologists also recommended more prophylaxis in cases of radiographs, making impressions, placement of removable prosthesis and fillings. Table 4 indicates the heart diseases for which IE prophylaxis would be performed (or not) for risky oral/dental manipulations. The three indications currently established by the US and European CPGs (prosthetic valves, previous IE, congenital cyanotic heart disease or repaired with prosthetic material) were considered indications for prophylaxis by the 3 groups of practitioners in a percentage close to 90---100% (Table 4). For previously accepted indications that are now not recommended (such as significant mitral or aortic valvular heart disease), prophylaxis is still applied by a very high proportion of the 3 groups, although significantly greater by the noncardiologists (Table 4). Lastly, even in conditions with no risk or a very low risk of IE (pacemakers, aortocoronary bypass, stents, isolated atrial fibrillation, mild mitral prolapse, interventricular and interatrial presentations and closed ductus without defects), prophylaxis is performed for 33---60% of cases, although in a significantly smaller proportion by the cardiologists. Table 5 lists the responses related to the antibiotic regimens employed for the prophylaxis. The most widely used regimen is that recommended by the guidelines (amoxicillin, in a single 2-g dose 1 h before the oral/dental procedure). When asked about the microorganisms the respondents expected to eliminate with the IE prophylaxis, 73% of the cardiologists indicated only Streptococcus viridans. Sixtytwo percent of the dentists and 53% of the PC physicians also thought that this regimen would prevent infections by other microorganisms, such as enterococcus, staphylococci and gram-negative bacilli.
Discussion The main conclusion from this survey is that there is enormous variability in our setting in the conduct regarding IE prophylaxis. There is a significant lack of knowledge concerning the magnitude, importance and microbiology of IE. Most of those surveyed believe that IE prophylaxis is effective and use it in their clinical practice, although they follow different guidelines and recommendations (the European guidelines for the cardiologists, those of scientific societies for the dentists and none or the European ones for the PC physicians). With regard to the various dental or oral procedures of risk, the dentists and PC physicians were closest in terms of the recommended prophylaxis, while the cardiologists excessively recommended IE prophylaxis when faced with low-risk manipulations. The reverse happened with
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Table 2
Perception of the effectiveness of endocarditis prophylaxis and clinical practice guidelines followed. Total
Cardiologists
Dentists
PC
p-Value
Believes that IE prophylaxis is effective Performs IE prophylaxis in their practice Clinical practice guidelines followed European 2009---2015 British (NICE) 2008
88.3% 90.8%
77.8% 94.4%
93.7% 98.7%
84.8% 80.3%
35% 1.2%
77.8% 0%
22.8% 0%
37.9% 3%
American Heart Association 2007 Dental Societies None, I base it on my own experience
16% 22.1% 25.8%
11.1% 0% 11.1%
24.1% 41.8% 11.4%
7.6% 4.5% 47%
p = .086 p = .001 p < .001
Abbreviations: PC, primary care; IE, infectious endocarditis.
Table 3 Oral/dental procedures and manipulations in which endocarditis prophylaxis is indicated or not for patients with risk of developing endocarditis. Total
Cardiologists
Dentists
PC
p-Value
With indication in the CPGs Oral/gingival surgery Dental implants Dental cleanings Endodontics Dental piece extractions Placement/adjustment of fixed prosthesis
98.8% 97.5% 49.1% 69.3% 90.8% 28.2%
100% 100% 55.6% 83.3% 88.9% 61.1%
98.7% 100% 70.9% 59.5% 100% 7.6%
98.5% 93.9% 21.2% 77.3% 80.3% 43.9%
NS NS p < .001 p = .027 p < .001 p < .001
With no indication in the CPGs Making impressions for fixed prosthesis or on implants Making impressions for removable prosthesis Placement/adjustment of removable prosthesis Placement orthodontic brackets Fillings Local anesthesia Intraoral radiographs
9.2% 7.4% 15.3% 8% 20.9% 18.4% 2.5%
16.7% 16.7% 33.3% 22.2% 38.9% 38.9% 11.1%
8.9% 3.8% 1.3% 3.8% 10.1% 22.8% 1.3%
7.6% 9.1% 27.3% 9.1% 28.8% 7.6% 1.5%
NS NS p < .001 p = .031 p = .003 p = .004 p = .042
Abbreviations: PC, primary care; CPGs, European or US clinical practice guidelines; NS, not significant.
Table 4 Heart diseases for which endocarditis prophylaxis is indicated or not when a patient undergoes an oral/dental procedure with a risk of endocarditis. Total
Cardio
Currently indicated in the CPGs Carrier of valvular prosthesis Previous endocarditis Congenital cyanotic heart disease or repaired with prosthetic material
96.9% 97.5% 88.3%
100% 100% 100%
Not indicated in the current CPGs but with prior indication Significant aortic valve disease Significant mitral valve disease Pacemaker or ICD carrier Congenital heart disease with complete correction
84% 86.5% 33.7% 73.6%
Never indicated Coronary stent Aortocoronary bypass Mild mitral prolapse ASD, VSD or closed ductus with no residual defects Atrial fibrillation but no structural heart disease
49.7% 56.4% 49.7% 60% 30.1%
Dentists
PC
p-Value
94.9% 100% 86.1%
98.5% 93.9% 87.9%
NS p = .049 NS
66.7% 66.7% 50% 66.7%
84.4% 84.4% 40.5% 72.2%
87.9% 93.9% 21.2% 77.3%
p = .09 p = .009 p = .015 NS
5.6% 0% 22.2% 33.3% 5.6%
67.1% 69.6% 58.2% 67.1% 36.7%
40.9% 56.1% 47% 59.1% 28.8%
p < .001 p < .001 p = .019 p = .030 p = .033
Abbreviations: ASD, atrial septal defect; CPGs, clinical practice guidelines (European and US); ICD, implantable cardioverter defibrillator; NS, not significant; PC, primary care; VSD, ventricular septal defect.
Behavior of health professionals concerning recommendations for prophylaxis Table 5
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Antibiotic regimens employed for endocarditis prophylaxis. Total
First-line antibiotic in patients not allergic to beta-lactam agents Indicated Amoxicillin Not indicated Amoxi/clavulanate Other regimens First-line antibiotic in patients allergic to beta-lactam agents Indicated Clindamycin Not indicated Cephalosporin Metronidazole Other Dosage regimen employed Indicated Single dose 1 hour before Not indicated Two doses, 1 h before and 6 h after Others Dose of amoxicillin in single regimen Indicated 2g Not indicated 1g Other doses
Cardiologists
Dentists
PC
p-Value p = .002
66.3%
83.3%
77.2%
48.5%
30.7% 3%
11.1% 5.6%
22.8% 0%
45.5% 6% p = .030
57.7%
66.7%
67.1%
43.9%
8.6% 9.2% 14.5%
0% 5.6% 27.7%
8.9% 8.9% 14.1%
10.6% 10.6% 33.9% p = .002
44.9%
72.2%
54.4%
25.8%
27% 24.1%
11.1% 16.7%
30.4% 15.2%
27.3% 46.9% p < .001
47.2%
50%
63.3%
27.3%
30.1% 12.7%
27.8% 22.2%
27.8% 8.9%
33.3% 49.4%
Abbreviations: PC, primary care; h, hour.
heart diseases for which IE prophylaxis is indicated, where we observed an excess of indications by the dentists and PC physicians in no-risk situations (coronary stent, aortocoronary bypass, atrial fibrillation with no heart disease).6,9 This is the philosophy described by a number of authors as the ‘‘just in case’’ philosophy.12 Although amoxicillin is the most widely used antibiotic according to the guidelines’ recommendations, many PC physicians and dentists use regimens other than those recommended.5,6,9 Moreover, most dentists and PC physicians and more than 25% of cardiologists mistakenly believe that preventive antibiotic treatment eradicates the common causal microorganisms of IE. These results agree with the previously published information in Spain,13,14 which indicates that there has been little progress in our understanding of the recommendations of IE prophylaxis. The excess use of prophylaxis by cardiologists in conditions previously considered risky (but not since 2007---2009) might be due to the belief, on one hand, that it is worth administering a simple antibiotic regimen with barely any adverse effects to prevent potential cases of a disease as severe as IE12 and, on the other, that the lack of evidence in the guidelines reflects the absence of studies with sufficient statistical weight to demonstrate it. The excess indications by dentists and PC physicians in conditions of low or no risk can only be explained by the lack of knowledge of the etiopathogenesis of IE. Moreover, it is possible that the opinions of these practitioners are
merely speculative for uncommon conditions in their clinical practice, such as congenital heart disease. This study’s limitations are those of a voluntary completion survey, although the prior random selection of those surveyed and the high percentage of responses (96%) strengthens the survey’s value. The number of cardiologists in absolute terms is low compared to that of other physicians, which is due to their lower relative numbers. Moreover, our data are limited to a health area of the province of Cordoba and thus cannot be extrapolated to other geographical areas. The reason for including only the dependent area of our hospital was to ensure greater sample homogeneity of the surveyed practitioners, who are informed of the recommended standards for prophylaxis by the Department of Cardiology, given that other areas might disseminate different prophylaxis regimens. National studies with larger sample sizes are needed to confirm this assumption. If this assumption were true, it seems warranted to prepare training strategies in this clinical situation for all practitioner groups involved, which would require the coordination and collaboration of all scientific societies involved.
Conflicts of interest The authors declare that they have no conflicts of interest.
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Acknowledgements The authors would like to thank the Official Schools of Physicians and Dentists of Cordoba for their assistance in developing this study.
Annex. Web addresses for checking the recommendations on prophylaxis for infectious endocarditis eurheartj.oxfordjournals.org/content/early/2015/08/28/ eurheartj.ehv319 www.uptodate.com/../antimicrobial-prophylaxisforbacterial-endocarditis http://www.catcardio.cat/pdfs/fitxa%203.pdf https://www.nice.org.uk/Guidance/CG64
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