Efficacy of Antibiotic Prophylactic Regimens for the Prevention of Bacterial Endocarditis of Oral...

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Journal of Dental Research

DOI: 10.1177/154405910708601203 2007; 86; 1142 J DENT RES

I. Tomás Carmona, P. Diz Dios and C. Scully Origin

Efficacy of Antibiotic Prophylactic Regimens for the Prevention of Bacterial Endocarditis of Oral

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(1) BACTERIAL ENDOCARDITIS OF ORAL ORIGIN

Bacterial endocarditis is an uncommon infection of the cardiacendothelium, with an incidence ranging between one and five

cases/100,000 population/yr (Bouza et al., 2001; Cecchi et al.,2004). Despite advances in diagnosis, antimicrobial therapy, andtreatment of complications, bacterial endocarditis continues to beresponsible for substantial morbidity and mortality (Heiro et al.,2006; Tran and Kjeldsen, 2006; Smith et al., 2007). The maincomplications deriving from bacterial endocarditis are valvulardestruction, heart failure, and emboli, requiring cardiac surgicaltreatment within 3 mos for almost 30% of patients (Heiro et al.,2006). In recent cohort series, some authors found a prevalence ofbacterial endocarditis mortality of 12-16% (Heiro et al., 2006; Tranand Kjeldsen, 2006; Smith et al., 2007), and suggested, aspredictive factors: age greater than 65 yrs, longer 'pump time',unstable hemodynamic status (Smith et al., 2007), prosthetic valveendocarditis, and Staphylococcus aureus infection (Tran andKjeldsen, 2006).

In the majority of retrospective studies published during the1990s, the oral cavity was identified as the portal of entry of thecausative microbial agent in 14-20% of patients with bacterialendocarditis (Manford et al., 1992; Sandre and Shafran, 1996;Hricak et al., 1998; Sekido et al., 1999), and the prevalence ofbacterial endocarditis of possible oral origin in recently publishedseries was similar to that reported in older series (Krcmery et al.,2003; Loupa et al., 2004; Knirsch et al., 2005). In 1995, for the firsttime, the oral origin of two cases of bacterial endocarditis wasdemonstrated by molecular biological techniques, since a completeconcurrence of identity was observed between the blood and oralcavity isolates (Fiehn et al., 1995). Recently, Streptococcus mutanswas isolated and characterized by the application of broad-rangepolymerase chain-reaction with DNA sequencing in heart valve anddental plaque specimens from a patient with bacterial endocarditis(Nomura et al., 2006).

• Causal OrganismsStreptococci, particularly the viridans group, continue to be thebacteria most frequently involved in bacterial endocarditis,affecting native cardiac valves (Hoen et al., 2002; Horacio Casabéet al., 2003), which, in most cases, presents with a subacuteclinical course (Thornton and Alves, 1981). Some authors (Hoenet al., 2002) call these "oral" streptococci, since the oral cavity istheir principal ecological reservoir, but it is certainly not the solereservoir of these bacteria. In most studies of bacterialendocarditis of oral origin, viridans group streptococci wereidentified in 70-75% of cases with positive blood cultures(Thornton and Alves, 1981; Tomás et al., 2002). In some studies,staphylococci have been identified in almost 50% of cases, mostinvolving artificial valves (Watanakunakorn and Burket, 1993;Watanakunakorn, 1994), and they are also responsible for > 60%of episodes of bacterial endocarditis in intravenous drug users(Carozza et al., 2006). Staphylococcus epidermidis and aureus arethe species most frequently involved (Hoen et al., 2002), and

ABSTRACTDespite the controversy about the risk of individualsdeveloping bacterial endocarditis of oral origin, numerousExpert Committees in different countries continue topublish prophylactic regimens for the prevention ofbacterial endocarditis secondary to dental procedures. Inthis paper, we analyze the efficacy of antibioticprophylaxis in the prevention of bacteremia followingdental manipulations and in the prevention of bacterialendocarditis (in both animal models and human studies).Antibiotic prophylaxis guidelines remain consensus-based,and there is scientific evidence of the efficacy ofamoxicillin in the prevention of bacteremia followingdental procedures, although the results reported do notconfirm the efficacy of other recommended antibiotics.The majority of studies on experimental models ofbacterial endocarditis have verified the efficacy ofantibiotics administered after the induction of bacteremia,confirming the efficacy of antibiotic prophylaxis in laterstages in the development of bacterial endocarditis. Thereis no scientific evidence that prophylaxis with penicillin iseffective in reducing bacterial endocarditis secondary todental procedures in patients considered to be "at risk". Ithas been suggested that there is a high risk of severeallergic reactions secondary to prophylacticallyadministered penicillins, but, in reality, very few caseshave been reported in the literature. It has beendemonstrated that antibiotic prophylaxis could contributeto the development of bacterial resistance, but only afterthe administration of several consecutive doses. Futureresearch on bacterial endocarditis prophylactic protocolsshould involve the re-evaluation of the time and route ofadministration of antibiotic prophylaxis, and a search foralternative antimicrobials.

KEY WORDS: endocarditis, bacteremia, dentistry,antibiotic prophylaxis.

Received December 17, 2006; Last revision May 21, 2007; AcceptedAugust 30, 2007

Efficacy of Antibiotic Prophylactic Regimens for thePrevention of Bacterial Endocarditis of Oral OriginI.Tomás Carmona1, P. Diz Dios1, and C. Scully2*1Special Needs Unit, School of Medicine and Dentistry, Santiago deCompostela University (Spain); and 3Eastman Dental Institute,University College London, 256 Gray's Inn Road, London WC1X 8LD,UK; *corresponding author, [email protected]

J Dent Res 86(12):1142-1159, 2007

CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE

1142 at Univ Santiago Compostela Bib on May 14, 2009 http://jdr.sagepub.comDownloaded from


J Dent Res 86(12) 2007 Efficacy of Antibiotic Prophylaxis 1143

although these species are considered commensal micro-organisms of the skin or nosocomial pathogens, they havealso been isolated from the oral cavity (Suzuki et al., 1997;Murdoch et al., 2004). Consequently, these micro-organismsmay also occasionally be responsible for bacterialendocarditis of oral origin (Tomás et al., 2002). Facultativeanaerobic Gram-negative bacteria of the HACEK(Haemophilus spp., Actinobacillus actinomycetemcomitans,Cardiobacterium hominis, Eikenella corrodens, Kingellaspp.) group were infrequently implicated in early studies ofbacterial endocarditis (Garvey and Neu, 1978), but acceptingthat they are difficult to culture and isolate, they may beresponsible for 3-5% of cases of bacterial endocarditis(Lepori et al., 2001; Paturel et al., 2004). The most frequentlyisolated HACEK micro-organism implicated is theperiodontopathogen Actinobacillus (now Aggregatibacter)actinomycetemcomitans (Paturel et al., 2004). The obligateanaerobic bacteria were considered to be etiological agents in2-16% of cases of bacterial endocarditis (Brook, 2002). Theoral cavity constitutes one of the principal ecologicalreservoirs for some of these micro-organisms, principallyFusobacterium spp., Bacteroides (Porphyromonas) spp., andPeptostreptococcus spp. (Garvey and Neu, 1978). In a recentanalysis of 51 cases of bacterial endocarditis caused by Gram-negative obligate anaerobic bacteria, the oral cavity wasimplicated in 40% of cases in which the portal of entry wasidentified (Bisharat et al., 2001).

Broad-range polymerase chain-reaction is used to targetcommonly shared bacterial 16S rRNA genes (via pan-bacterialprimers). Subsequently, direct sequencing is used to detect anddifferentiate bacteria. This molecular method improves themicrobiological diagnosis of bacterial endocarditis, not onlyfor fastidious, slow-growing, and/or non-culturable bacteria,but also for easy-to-culture pathogens (Breitkopf et al., 2005).The results of using the polymerase chain-reaction techniqueto identify bacterial DNA in excised valvular tissue of patientswith bacterial endocarditis confirmed that streptococci werethe predominant bacteria, followed by staphylococci (Lang etal., 2004). It has even been suggested that this molecularapproach should be included as an additional major criterion inthe Duke's classification scheme (Millar et al., 2001).However, the costs and quality of databases are majorobstacles to implementation of 16S rRNA gene sequencing inthe routine clinical microbiology laboratory (Boudewijns etal., 2006). Other disadvantages of DNA-based methods arethat they do not distinguish between living and deadorganisms, results are sometimes difficult to interpret, andDNA may persist without any evidence of infection (Rovery etal., 2005). In consequence, currently, the polymerase chain-reaction method is especially useful when the causative agentof bacterial endocarditis is fastidious, or when the specimen istaken during antimicrobial treatment (Kotilainen et al., 2006).

Broad-range polymerase chain-reaction has allowed for thedetection of oral pathogens such as Streptococcus mutans andActinobacillus actinomycetemcomitans in about 70% and 31%of cardiovascular tissue samples, respectively (Nakano et al.,2006, 2007). So far, in contrast, the results of polymerasechain-reaction-based screening to detect bacteremia followingdental procedures did not show a good correlation with thoseobtained by means of standard blood cultures (Kinane et al.,2005; Savarrio et al., 2005).

• PathogenesisEndocarditis is the result of the interaction among host factorsthat predispose the endothelium to infection, transientbacteremia, and tissue tropism and virulence of the circulatingbacteria. The pathogenesis of endocarditis can be divided intofive stages: (1) injury of the endothelial surface of the valve,(2) formation of a sterile thrombus composed of platelets andfibrin, (3) adherence of bacteria, (4) microcolony formation bythe bacteria, and (5) vegetation biofilm maturation andembolization (Parsek and Singh, 2003) (Fig.).

The normal cardiac valve endothelium is resistant tocolonization by bacteria and does not activate plateletaggregation (Rodgers et al., 1983). Endothelium injury mainlyresults from turbulent blood flow caused by pre-existingcardiac lesions, such as a defective valve or a congenital defect(high-velocity jet stream from a high- to low-pressure chamber,or created by a pressure gradient across a narrowed orificebetween 2 chambers, or a high-velocity jet), but in some casesdamage follows direct endocardium trauma (cardiac surgery orcatheterism), or may be associated with malignancy andconnective tissue disorders (Rodbard, 1963; Lopez et al., 1987;Maté del Tio et al., 1997).

Damage to the endothelium triggers platelet andfibrinogen-fibrin deposition at the site. This sterile platelet-fibrin aggregate is called 'non-bacterial thrombotic endocarditis'(Rodgers et al., 1983), and is more receptive to colonization bybacteria than is the intact endothelium.

Transient bacteremia is a common event and occurs as aconsequence of skin or mucosal injuries, which are normallyladen with an endogenous flora. During transient bacteremias,micro-organisms can adhere to this non-bacterial thromboticendocarditis, which provides them with both nutrition andprotection from host defenses, especially leukocytes. Bacteriathat are typically found in patients with bacterial endocarditis,such as Streptococcus viridans, Staphylococcus aureus, or

Figure. Pathogenesis of bacterial endocarditis.



1144 Tomás Carmona et al. J Dent Res 86(12) 2007

Enterococcus spp., adhere more avidly to endothelium than dospecies that seldom cause bacterial endocarditis. Themechanism of this adherence is poorly understood. Bacterialexopolysaccharides, such as dextrans produced byStreptococcus sanguis and mutans, act as adhesins that bind toinjured valves (Scheld et al., 1978). Although the majority oforganisms present in the bloodstream after dentalmanipulations do not produce dextran, over 50% of theendocarditis cases are caused by dextran-producing oralstreptococci (Hehre and Neill, 1946). Microbial surfacecomponents recognizing adhesive matrix molecules, such asclumping factors A and B, fibronectin-binding proteins, andFimA factor, have also been implicated in Gram-positivebacteria adherence (Burnette-Curley et al., 1995; Schwarz-Linek et al., 2004; Rindi et al., 2006). Other compounds thatmay mediate adherence include fibrinogen, laminin, and typeIV collagen.

Bacterial-platelet interactions appear to be important inboth the induction of a vegetation and its enlargement aftercolonization. Interactions between streptococci and plateletsmay involve 3 sites (Herzberg, 1996):

(1) Expression of adhesins, which promotes adhesion withthe platelet membrane. A platelet adhesion receptor forStreptococcus sanguis and gordonii (GPIbalpha), hasbeen recently identified (Plummer and Douglas, 2006).

(2) The platelet-aggregation-associated protein, whichcontains a collagen-like epitope, induces plateletactivation and aggregation.

(3) Some streptococci strains express ecto-ATPase activity,which hydrolyzes ATP to ADP, an additional plateletagonist.

The host defenses include leukocytes, antibodies andcomplement, and platelet-derived bactericidal proteins(thrombocidins). Paradoxically, the host also responds toinvasion by activation of the clotting system by monocytetissue thromboplastin and release of pro-inflammatorycytokines (IL-1, IL-6, IL-8), which increases fibrin depositionand promotes growth of the vegetation (Thompson et al., 1982;Dankert et al., 2006).

If the bacteria trapped within the thrombus is resistant tothrombocidins, large numbers of tightly packed microcoloniesgrow (Marrie et al., 1987). The resultant vegetation iscomposed of successive layers of fibrin and clusters of bacteria,with rare red cells and leukocytes, almost always covered by alayer of fibrin on the luminal surface.

The pathophysiology of bacterial endocarditis includes: (1)local destructive effects of infection, leading to incompetentvalvular function, congestive heart failure, or atrioventricularconduction abnormalities; (2) embolization of fragments of thevegetation, resulting in infection or infarction of thesurrounding tissue (spleen, kidney, meninges, brain, bone,pericardium, synovium, or vitreous humor); (3) thehematogenous seeding of remote sites during continuousbacteremia (septic arthritis, osteomyelitis, splenic or kidneyabscesses, meningeal or brain abscesses); and (4) hostresponse, including release of pro-inflammatory cytokines thatprovoke "constitutional symptoms" (fever, fatigue, anorexia,weight loss, night sweats) and deposition of pre-formedimmune complexes (glomerulonephritis, Osler's nodes,

rheumatological manifestations).As we have described, in the classic model of the

development of bacterial endocarditis of oral origin, a sterilevegetation is invaded by oral micro-organisms as aconsequence of bacteremia. However, it has been suggestedthat a bacteremia of oral origin, instead of directly inducing theonset of bacterial endocarditis, could favor the initialthickening of the cardiac valves from atherosclerosis, makingthem more susceptible to bacterial adherence and subsequentcolonization (Drangsholt, 1998). In this new pathogenic model,several initial episodes of bacteremia would affect the cardiacvalve endothelium over a long period, until a later bacteremiaof days' or weeks' duration caused bacterial adherence andcolonization and established cardiac infection. Consequently,this model suggests that bacterial endocarditis of oral origin is achronic disease with a long latency period and a series of well-defined stages, but there is little evidence for this model, andthere are few studies on experimental animals of the long-termeffects of such bacteremias of oral origin on cardiacendothelium (Brodala et al., 2005).

(2) ANTIBIOTIC PROPHYLAXIS PROTOCOLSIn 1955, the American Heart Association published the firstprotocol for the prevention of bacterial endocarditis associatedwith dental procedures (American Heart Association, 1955).Since then, many Expert Committees in different countries havedrawn up different prophylactic regimens. In 1995, theEuropean Society of Cardiology, together with a group ofexperts from the International Society of Chemotherapy,published a European Consensus on bacterial endocarditisprophylaxis (Leport et al., 1995). In 2004, both the EuropeanSociety of Cardiology and the British Cardiac Society, togetherwith the Royal College of Physicians of London, drew upguidelines on the prevention of bacterial endocarditis associatedwith dental procedures (Horstkotte et al., 2004; Dental aspectsof endocarditis prophylaxis, 2004). The British Society ofAntimicrobial Chemotherapy published its first antibioticprophylaxis regimens for bacterial endocarditis in 1982(Antibiotic prophylaxis of infective endocarditis, 1982); thesewere revised and modified in 1986 (Simmons et al., 1986), 1990(Antibiotic prophylaxis of infective endocarditis, 1990), 1992(Simmons et al., 1992), and 2006 (Gould et al., 2006). TheAmerican Heart Association has published nine bacterialendocarditis prophylaxis protocols (American HeartAssociation, 1955, 1960, 1972; Hussar, 1965; Kaplan, 1977;Shulman et al., 1984; Dajani et al., 1990, 1997; Wilson et al.,2007), the latest revision being in 2007 (Wilson et al., 2007).The most recent bacterial endocarditis prophylaxis protocolspublished by the European Society of Cardiology, BritishCardiac Society-Royal College of Physicians, British Society ofAntimicrobial Chemotherapy, and American Heart Associationare summarized in Tables 1 and 2.

Despite the frequent updating of these antibiotic prophylaxisguidelines, the incidence of bacterial endocarditis of possible oralorigin has evidently not decreased. Various reasons have beensuggested to explain this situation: an increase in the number ofpatients susceptible to bacterial endocarditis and in the practiceof "at risk" procedures; the lack of compliance with theprophylactic regimens for the prevention of bacterial endocarditisby doctors, dentists, and patients; and the lack of efficacy ofprophylactic protocols (Delahaye and De Gevigney, 2001).




• American Heart AssociationGuidelines, 2007In these last guidelines, theAmerican Heart Associationintended to define more clearlywhen bacterial endocarditisprophylaxis is or is notrecommended, and to providemore consistent recommendations(Wilson et al., 2007). Theguidelines have been updatedbased on relevant l i teratureregarding dental proceduresproducing bacteremia and bacterialendocardit is , antimicrobialsusceptibil i ty of isolatesidentified in post-dentalmanipulation blood cultures,animal models, and studies onthe efficacy of antibioticprophylaxis. The major changesin the updated recommendationsinclude the following:— In the protocols on the prevention of bacterialendocarditis associated withdental procedures, published bythe American Heart Association inthe 1960s (American HeartAssociation, 1960; Hussar, 1965),the profile of the individualconsidered to be "at risk" ofbacterial endocarditis was apatient with rheumatic heartdisease or a congenital heart disease. In the first guidelinespublished by the British Society of Antimicrobial Chemotherapyin 1982 (Antibiotic prophylaxis of infective endocarditis, 1982),patients considered to be "at risk" of bacterial endocarditisincluded those with disturbances of the endocardium due tocongenital or acquired disease, those with heart valve disease,and those with prosthetic heart valves. Since then, several ExpertCommittees have defined the heart conditions catalogued as "atrisk" of bacterial endocarditis, also discussing the controversyconcerning the administration of antibiotic prophylaxis in casesof mitral stenosis without valve incompetence (Leport et al.,1995). In recent years, most updated guidelines have restrictedprophylaxis to high-risk patients (Gould et al., 2006). Followingthe last American Heart Association guidelines, bacterialendocarditis prophylaxis for dental procedures should berecommended only for patients with underlying cardiacconditions associated with the highest risk of adverse outcomefrom bacterial endocarditis. These cardiac conditions are:prosthetic cardiac valve, previous bacterial endocarditis,congenital heart disease (unrepaired defect, completely repaireddefect during the first 6 mos after the procedure, and repaireddefect with residual alterations), and cardiac transplantationrecipients who develop cardiac valvulopathy (Wilson et al.,2007).

— In 1960, the American Heart Association stated that the dental procedures in which prophylaxis was indicated

were tooth extractions and gingival treatments, specifying thatthese procedures frequently caused "transitory bacteremias", andthat the bacteremias were of a higher intensity in patients withoral infections (American Heart Association, 1960). Some yearslater, the American Heart Association recognized theimpossibility of predicting which dental procedures could beresponsible for causing bacterial endocarditis. The treatmentsassociated with gingival bleeding—in which antibioticprophylaxis was recommended—included scaling, and amongthe procedures in which prophylaxis was not indicated wereincluded the adjustment of orthodontic appliances and theexfoliation of primary teeth (Kaplan, 1977). The British Societyof Antimicrobial Chemotherapy has recently summarized theindications for antibiotic prophylaxis for high-risk patients,stating that it should be given for "all dental proceduresinvolving dento-gingival manipulation or endodontics" (Gould etal., 2006). Following the most recent American HeartAssociation guidelines, prophylaxis is recommended for alldental procedures that involve manipulation of gingival tissue orthe periapical region of teeth, or perforation of the oral mucosa.This includes procedures such as biopsies, suture removal, andplacement of orthodontic bands, but it does not include routineanesthetic injections through non-infected tissue, the taking ofdental radiographs, placement of removable prosthodontic ororthodontic appliances, placement of orthodontic brackets, oradjustment of orthodontic appliances. There are other events for

Table 1. Bacterial Endocarditis Prophylaxis Protocol (oral regimen) for Dental Procedures Recommendedby the European Society of Cardiology (ESC) in 2004, the British Cardiac Society and the Royal College ofPhysicians of London (BCS-RCP) in 2004, the British Society of Antimicrobial Chemotherapy (BSAC) in2006, and by the American Heart Association (AHA) in 2007

Standard Regiman (oral)

ESC, 2004 Not allergic to penicillin: 2 g of amoxicillin 1 hr before treatmentAllergic to penicillin: 600 mg of clindamycin 1 hr before treatment

500 mg of azithromycin or clarithromycin 1 hr before treatment

BCS and RCP, 2004 Not allergic to penicillin: 3 g of amoxicillin 1 hr before treatmentAllergic to penicillin: 600 mg of clindamycin 1 hr before treatmentUnable to swallow capsulesa: 500 mg of azithromycin 1 hr before treatment

BSAC, 2006 Not allergic to penicillin: 3 g of amoxicillin 1 hr before treatmentAllergic to penicillin: 600 mg of clindamycin 1 hr before treatmentUnable to swallow capsulesb: 500 mg of azithromycin 1 hr before treatment

AHA, 2007 Not allergic to penicillin: 2 g of amoxicillin 1 hr before treatmentAllergic to penicillin: 2 g of cefalexin 1 hr before treatmentb

600 mg of clindamycin 1 hr before treatment500 mg of azithromycin or clarithromycin 1 hr before treatment

a In Great Britain, clindamycin is not available in oral suspension.b The cephalosporins must not be administered to persons with immediate hypersensitivity reactions to

penicillin (urticaria, angio-edema, or anaphylaxis). For children, the AHA and ESC recommend:amoxicillin (50 mg/kg bodyweight), clindamycin (20 mg/kg bodyweight), cefalexin (50 mg/kgbodyweight), or azithromycin or clarithromycin (15 mg/kg bodyweight). For children, the BCS, RCP,and BSAC recommend: amoxicillin (> 10 yrs, adult dose; 5-10 yrs, 1.5 g; < 5 yrs, 750 mg),clindamycin (> 10 yrs, adult dose; 5-10 yrs, 300 mg; < 5 yrs, 150 mg), and azithromycin (> 10 yrs,adult dose; 5-10 yrs, 300 mg; < 5 yrs, 200 mg).




which prophylaxis is not recommended, such as shedding ofdeciduous teeth and trauma to the lips or oral mucosa (Wilson etal., 2007).

— In 1960, the American Heart Association pronounced itselfin favor of administering an antibiotic prophylactic regimenthat consisted of several injections of penicillin from 2 daysbefore up to 2 days after the session of dental treatment(American Heart Association, 1960). The British Society ofAntimicrobial Chemotherapy, in its first guidelines, suggested asingle prophylactic regimen, for all patients considered to be"at risk" of bacterial endocarditis, of a single dose ofamoxicillin before the dental procedure (Antibiotic prophylaxisof infective endocarditis, 1982). The British Society ofAntimicrobial Chemotherapy substituted penicillin V—previously recommended by the American Heart Association(Kaplan, 1977)—for amoxicillin, due to its more favorablepharmacokinetic and pharmacodynamic characteristics(Antibiotic prophylaxis of infective endocarditis, 1982). TheAmerican Heart Association was the first to recommenderythromycin in patients with a history of allergy to penicillin(Kaplan, 1977), but in 1992, the British Society of Antimicrobial Chemotherapy definitively replacederythromycin with clindamycin in patients allergic to penicillin (Simmons et al., 1992). In 1995, the EuropeanSociety of Cardiology performed a critical review of the prophylaxis protocols drawn up by the different national committees, noting clear differences between

countries, although all included a simple or standard regimenand another more complex regimen for use in specialcircumstances. In general, the standard guidelines consisted ofthe oral administration of a single dose of antibiotic which, inthe majority of countries, was amoxicillin, and clindamycinwas the antibiotic of choice in patients allergic to the beta-lactams (Leport et al., 1995). The prophylactic protocolcurrently updated by the American Heart Association continuesrecommending amoxicillin as the antibiotic of choice for oralprophylaxis. For individuals who are allergic to penicillins oramoxicillin, the use of cefalexin or another first-generation oralcephalosporin, clindamycin, azithromycin, or clarithromycin isrecommended. Because of possible cross-reactions, acephalosporin should not be administered to patients with ahistory of anaphylaxis, angio-edema, or urticaria after treatmentwith any form of penicillin, including ampicillin or amoxicillin.Patients who are unable to tolerate an oral antibiotic may betreated with ampicillin, ceftriaxone, or cefazolin, administeredintramuscularly or intravenously. For ampicillin-allergicpatients who are unable to tolerate an oral agent, prophylaxis isrecommended with parenteral cefazolin, ceftriaxone, orclindamycin (Wilson et al., 2007).

It has been estimated that the number of cases of bacterialendocarditis that result from a dental procedure is very small.In consequence, the American Heart Association concludedthat only an extremely small number of cases of bacterialendocarditis might be prevented by antibiotic prophylaxis for

Table 2. Bacterial Endocarditis Prophylaxis Protocol (parenteral regimen) for Dental Procedures Recommended by the European Society of Cardiology(ESC) in 2004, the British Cardiac Society and the Royal College of Physicians of London (BCC-RCP) in 2004, the British Society of AntimicrobialChemotherapy (BSAC) in 2006, and the American Heart Association (AHA) in 2007

Parenteral Regimen

ESC, 2004 Not allergic to penicillin: 2 g of ampicillin or amoxicillin (IV) 30-60 min before treatment

BCS and RCP, 2004 Not allergic to penicillin: 2 g of ampicillin or amoxicillin (IV) at induction of anesthesiaAllergic to penicillin: 300 mg of clindamycin (IV)a at induction of anesthesia

150 mg of clindamycin (oral or IV) 6 hrs after the first dose

Patients with valve prostheses and/or previous episodes of bacterial endocarditisNot allergic to penicillin: 2 g of amoxicillin + 1.5 mg/kg bodyweight of gentamicin (IV) 30 min before treatment

1 g of amoxicillin (oral or IV) 6 hrs after the first doseAllergic to penicillin: 1 g of vancomycin (IV)b + 1.5 mg/kg bodyweight gentamicin (IV) before treatment

BSAC, 2006 Not allergic to penicillin: 1 g of amoxicillin (IV) just before treatment or at induction of anesthesiaAllergic to penicillin: 300 mg of clindamycin (IV)a just before treatment or at induction of anesthesia

AHA, 2007 Not allergic to penicillin: 2 g of ampicillin (intramuscularly or IV) 30 min before treatmentAllergic to penicillin: 1 g of cefazolin or ceftriaxone (intramuscularly or IV) 30 min before treatmentc

600 mg of clindamycin (intramuscularly or IV) 30 min before treatment

a Given over at least 10 min.b Given over 2 hrs.c The cephalosporins must not be administered to persons with immediate hypersensitivity reactions to penicillin (urticaria, angio-edema, or

anaphylaxis). For children, the AHA and ESC recommend: ampicillin or amoxicillin (50 mg/kg bodyweight), clindamycin (20 mg/kgbodyweight), or cefazolin or ceftriaxone (50 mg/kg bodyweight). For children, the BCS, RCP, and BSAC recommend: ampicillin or amoxicillin (>10 yrs, adult dose; 5-10 yrs, 500 mg; < 5 yrs, 250 mg) and clindamycin (> 10 yrs, adult dose; 5-10 yrs, 150 mg; < 5 yrs, 75 mg). With respectto the patients with valve prostheses and/or previous episodes of bacterial endocarditis, for children, the BSAC recommends: amoxicillin (> 10yrs, adult dose; < 10 yrs, 1 g) and vancomycin (> 10 yrs, adult dose; < 10 yrs, 20 mg/kg bodyweight).




dental procedures, even if such prophylactic regimens were100% effective. Finally, this Expert Committee stated the needfor prospective placebo-controlled studies of antibioticprophylaxis of bacterial endocarditis, to evaluate the efficacy ofbacterial endocarditis prophylaxis (Wilson et al., 2007).

(3) EFFICACY OF ANTIBIOTIC PROPHYLAXIS IN THE PREVENTION OF BACTEREMIAFOLLOWING DENTAL PROCEDURES

• Prevalence and DurationThere are many published studies on the efficacy of antibioticprophylaxis administered by oral route in the prevention ofbacteremia secondary to dental procedures, but they haveimportant differences with respect to the type and dose ofantibiotic used, and the time of administration (Shanson et al.,1978, 1985; Josefsson et al., 1985; Roberts et al., 1987; Seftonet al., 1990; Göker and Güvener, 1992; Hall et al., 1993,

1996b; Aitken et al., 1995; Vergis et al., 2001; Lockhart et al.,2004; Diz Dios et al., 2006) (Table 3). Probably influenced bythe idea that bacteremia secondary to dental procedures is of atransitory nature (Dajani et al., 1997), few studies have beenpublished on the effect of antimicrobial prophylaxis on theduration of post-dental manipulation bacteremia.

Recent studies have confirmed the efficacy of amoxicillinin the prevention of bacteremia following dental manipulation.In a paper published in 2001, a reduction of almost 80% in theprevalence of post-extraction bacteremia after prophylaxis with3 g of amoxicillin was reported (Vergis et al., 2001). Inchildren, 50 mg/kg bodyweight of amoxicillin significantlyreduced bacteremias secondary to nasal intubation (from 18%to 4%), restorative dental treatment and professional oralhygiene (from 20% to 6%), and tooth extractions (from 76% to15%) (Lockhart et al., 2004). These authors also tested theeffect of the prophylactic regimen on the duration of post-dental manipulation bacteremia: Forty-five minutes after the

Table 3. Principal Studies Published on the Effect of Oral Antibiotic Prophylaxis on the Prevalence of Bacteremia Secondary to Dental Manipulations

No. Patients Prophylactic Regimen* Prevalence of BacteremiaAuthor, Year ≤ 5 min 10-15 min 30 min 45 min-1 hr 24 hrs

Shanson et al., 1978 120 adults CONTROL (no prophylaxis) 70%a

PEN V (2 g, 1 hr before) 20%a

AMX (2 g, 1 hr before) 25%a

Josefsson et al., 1985 51 adults CONTROL (no prophylaxis) 55% 30%PEN V (2 g, 1-1.5 hrs before) 50% 15%EM (500 mg, 1.5-2.5 hrs before) 55% 20%

Shanson et al., 1985 82 adults PLACEBO 43%b

EM (1.5 g, 1 hr before) 15%b

Roberts et al., 1987 94 children CONTROL (no prophylaxis) 38%AMX (50 mg/kg, 2 hrs before) 2%

Sefton et al., 1990 60 adults PLACEBO 65%b

EM (1.5 g, 1-1.5 hrs before) 60%b

JM (1.5 g, 1-1.5 hrs before) 70%b

Göker and Güvener, 1992 50 adults PLACEBO 44% 28% 8%CM (150 mg, 1 hr before)c 40% 24% 0%

Hall et al., 1993 60 adults PLACEBO 95% 80%PEN V (2 g, 1 hr before) 90% 70%AMX (3 g, 1 hr before) 85% 60%

Aitken et al., 1995 40 adults EM (1.5 g, 1-1.5 hrs before) 60%b

CM (600 mg, 1 hr before) 40%b

Hall et al., 1996a 38 adults EM (1 g, 1.5 hr before) 79% 58%CM (600 mg, 1.5 hr before) 84% 53%

Vergis et al., 2001 21 adults CONTROL (no prophylaxis) 90%AMX (3 g, 1-2 hrs before) 9%

Lockhart et al., 2004 100 children PLACEBO 76% 18% 16% 14%AMX (50 mg/kg, 1 hr before) 15% 2% 0% 0%

Diz Dios et al., 2006 221 adults CONTROL (no prophylaxis) 96% 64% 20%AMX (2 g, 1-2 hrs before) 46% 11% 4%CM (600 mg, 1-2 hrs before) 85% 70% 22%MXF (400 mg, 1-2 hrs before) 57% 24% 7%

* PEN = penicillin; AMX = amoxicillin; EM = erythromycin; JM = josamycin; CM = clindamycin; MXF = moxifloxacin.a The culture under aerobic and anaerobic conditions was performed in only 20 people in each group.b Percentage of positive blood cultures of a streptococcal nature.c This dose was administered every 6 hrs for 4 days.




completion of treatment, the percentages of positive bloodcultures were 14% in the "placebo group" vs. 0% in the"amoxicillin group" (Lockhart et al., 2004). In a trial publishedin 2006, the efficacies of different antibiotics in the preventionof bacteremia following dental extractions were evaluated. Theprevalences of bacteremia in the "control group" and the"amoxicillin group" were 96% and 46%, respectively, at 30 secafter dental extractions, and 20% and 4%, respectively, 1 hrlater (Diz Dios et al., 2006).

In contrast, other authors did not find that prophylaxis withpenicillin V or amoxicillin significantly reduced the prevalenceor magnitude of post-extraction bacteremia (Hall et al., 1993).The percentages of positive blood cultures obtained in thisseries during surgery were 95% in the "placebo group", 90% inthe "penicillin V group", and 85% in the "amoxicillin group".Furthermore, antibiotic prophylaxis did not affect the type ofbacteremia: The predominant micro-organisms in all threegroups were Streptococcus intermedius, and the most frequentobligate anaerobic bacteria were Actinomyces spp.,Peptostreptococcus spp., and Veillonella spp. These authorsattributed their results to the use of the lysis-filtrationtechnique, among other factors, since this provides a higherpercentage of bacterial isolates with respect to other culturemethods. However, it has been recently shown that the Bactecsystem is more sensitive than the lysis-filtration technique fordetecting post-extraction bacteremia of very low intensity(Lucas et al., 2002a). In this trial (Hall et al., 1993), thepercentage of positive post-extraction blood cultures at 10 minafter completion of the surgery was 80% in the "placebo group"and 60% in the "amoxicillin group", although the authorsconcluded that amoxicillin did not significantly influence theduration of the post-extraction bacteremia. Calculating the β-error and the statistical power of the results obtained in thisstudy, we found that the probability of obtaining statisticalsignificance, if it existed, was only 29% (when it should begreater than 80%), due to the sample size (20 persons in eachgroup), which was so small that the investigators could notexclude the possibility that the lack of significance might bedue to chance (Calatayud and Martín, 2003).

With respect to orally administered antibiotics withbacteriostatic activity, 1 study published in 1985 compared theeffect of a 500 mg dose of erythromycin with that of 2 g ofpenicillin V on the prevalence of bacteremia secondary to theremoval of impacted or partially erupted mandibular thirdmolars (Josefsson et al., 1985). There were no differences inthe prevalence of bacteremia between the "prophylaxisgroups", although the percentage of positive blood cultures 10min after completion of the surgical manipulation was lower inthe patients receiving antibiotics than in controls. One studysupported that erythromycin stearate (1.5 g) significantlyreduced the frequency of positive post-extraction blood cultures(from 43% to 15%) (Shanson et al., 1985). Other authorscompared the effect of oral administration of 1.5 g oferythromycin with that of 1.5 g of josamycin (Sefton et al.,1990). In contrast to the findings in previous series, and basedon the percentages of positive blood cultures detected (60% and70% in the "erythromycin group" and "josamycin group",respectively, vs. 65% in the "placebo group"), these authorsstated that none of these macrolides significantly affected thefrequency of blood cultures due to Streptococcus spp. (Seftonet al., 1990).

One study evaluated the prophylactic effect of 600 mg oralclindamycin vs. 1.5 g of erythromycin, and found clindamycinto be more active than erythromycin (Aitken et al., 1995). Asimilar study, however, did not find significant differences inthe percentage of positive blood cultures or in theconcentrations of the bacterial isolates during the extraction or10 min after completion (Hall et al., 1996b). The prevalence ofbacteremia during the extraction was 79% in the "erythromycingroup" and 84% in the "clindamycin group" and, at 10 min,58% and 53%, respectively. Although the number ofbacteremias of streptococcal etiology was not affected by thetype of antibiotic administered, the proportion of thoseproduced by obligate anaerobic bacteria was reduced to half inthe patients receiving clindamycin, compared with those onerythromycin (Hall et al., 1996b).

To date, we have found only 2 studies where the results ofa "clindamycin group" were compared with those obtained in a

Table 4. Principal Studies Published on the Effect of Parenteral Antibiotic Prophylaxis on the Prevalence of Bacteremia Secondary to DentalManipulations

Author, Year No. Patients Prophylactic Regimen* Prevalence of Bacteremia< 5 min 30 min

Elliott and Dunbar, 1968 151 children CONTROL 55%BENZYLPEN (500,000 IU intramuscularly, 30 min-1 hr before) 8%

Baltch et al., 1982a 62 adults CONTROL 59% 27%PEN G (2 million IU IV, 45-55 min before) 34% 12%

Baltch et al., 1982b 56 adults CONTROL 61% 25%PEN G (2 million IU IV, 45 min-1 hr before) 11% 15%

Hess et al., 1983 82 children PEN G (550,000 or 1.2 million IU intramuscularly, 45 min before)a 21%Kaneko et al., 1995 26 adults VCM (1 g IV, 1 hr before) 38%Roberts and Holzel, 2002 77 children AMP (627 ± 259 mg IV, immed. before) 17%

TEICO + AMIK (6 + 15 mg/kg IV, immed. before) 22%

* BENZYLPEN = benzylpenicillin; PEN = penicillin; VCM = vancomycin; AMP = ampicillin; TEICO = teicoplanin; AMIK = amikacin; IU = international units; IV = intravenous; immed.= immediately.

a Doses administered to children under and over 6 yrs of age, respectively.




"control group" (Göker and Güvener, 1992; Diz Dios et al.,2006). One of these studies reported a 44% rate of bacteremiasecondary to the removal of impacted mandibular third molarsin a "control group" vs. 40% in the "clindamycin group" (Gökerand Güvener, 1992). These authors also found no effect ofclindamycin on the prevalence of post-extraction bacteremia 1 hr after completion of the manipulation, since this was 28%in the "placebo group" and 24% in the "clindamycin group"(Göker and Güvener, 1992). These findings could be attributedto the use of low doses of clindamycin (150 mg instead of the600 mg recommended in the latest bacterial endocarditisprophylaxis protocols) (Horstkotte et al., 2004; Dental aspectsof endocarditis prophylaxis, 2004; Gould et al., 2006; Wilsonet al., 2007). All the blood cultures obtained at 24 hrs in thepatients receiving antibiotic prophylaxis were sterile, althoughthese findings are not a reflection of the efficacy of a singledose, since these authors administered the clindamycin every 6hrs for 4 days (Göker and Güvener, 1992). In the other study,the prevalences of bacteremia in the "control group" and the"clindamycin group" were 96% and 85%, respectively, at 30sec after dental extractions, and 20% and 22%, respectively, 1hr later (Diz Dios et al., 2006).

Some authors have evaluated the efficacy of parenteralantibiotic prophylaxis (intramuscular or intravenous) on thereduction of the prevalence of bacteremia following dentalmanipulations (Elliott and Dunbar, 1968; Baltch et al., 1982a,b;Hess et al., 1983; Kaneko et al., 1995; Roberts and Holzel,2002) (Table 4). One trial demonstrated that prophylaxis withintramuscular benzylpenicillin was more effective in childrenin the prevention of post-extraction bacteremia (8% vs. 55% inthe controls) than 3 oral doses of 125-250 mg of penicillin(36% vs. 55% in the controls) (Elliott and Dunbar, 1968).Another study compared intravenous penicillin G (2 million IUby intravenous infusion over 30-40 min) with orallyadministered penicillin G (500 mg-1 g 30 min before theprocedure) in patients undergoing tooth extractions undergeneral or local anesthesia, and found the prevalence ofbacteremia 30 min after completion of the tooth extractions tobe low, and similar in both groups (12% and 14%,respectively), and lower than that in patients without antibioticprophylaxis and undergoing tooth extractions under local orgeneral anesthesia (27% and 52%, respectively) (Baltch et al.,1982a). The percentages of post-extraction blood cultures inwhich Streptococcus spp. were isolated, and of the cultureswith polymicrobial etiology, were lower in the patientsreceiving prophylaxis with penicillin (intravenous or oral)compared with percentages in controls (Baltch et al., 1982a).This same research group evaluated the bacteremia secondaryto ultrasound scaling in 56 patients with periodontal disease:Twenty-eight had cardiopathies and received 2 million IU ofpenicillin G from 45 min to 1 hr before treatment, and theremaining 28 were healthy controls who received no antibioticprophylaxis. Thus, the group found that prophylaxis achievedsignificant differences in the percentage of positive bloodcultures obtained 5 min after completion of the manipulation(61% and 11%, respectively) and in the polymicrobial bloodcultures (43% and 7%, respectively) (Baltch et al., 1982b).

One trial detected a 21% rate of positive post-extractionblood cultures in children with cardiopathies who had receivedprophylaxis with intramuscular penicillin (Hess et al., 1983).Other authors analyzed various intravenous prophylactic

regimens in children with congenital heart defects undergoingdental treatment under general anesthetic (Roberts and Holzel,2002). The most frequently applied protocols were ampicillin(mean dose, 627 mg), and teicoplanin in combination withamikacin (6 mg/kg bodyweight and 50 mg/kg bodyweight,respectively). Similar percentages of positive blood cultureswere found with both regimens (17% and 22%, respectively);these rates were significantly lower than those reported inchildren who did not receive antibiotic prophylaxis (Robertsand Holzel, 2002).

In contrast, another trial found intravenous vancomycin tobe fairly ineffective in the prevention of bacteremia secondaryto dental extractions, since 38% of the patients who receivedthis glycopeptide had positive post-manipulation blood cultures(Kaneko et al., 1995).

To provide new prophylactic antimicrobial alternatives,some authors have investigated the prevalence of bacteremiafollowing dental manipulations after the administration ofantibiotics not included in the bacterial endocarditisprophylaxis protocols recommended by the Expert Committees,and in force at the time of study. One study evaluated theefficacy of 2 g of oral metronidazole, compared with 2 g oralpenicillin V or placebo (Head et al., 1984). Although penicillinV prophylaxis was associated with a lower prevalence of post-extraction bacteremia (20% vs. 52% in the "metronidazolegroup" and vs. 84% in the "placebo group"), it is interesting tonote that Gram-negative obligate anaerobes were isolated fromthe blood cultures of four (16%) patients receiving penicillin G,whereas they were not identified in any of the cultures frompatients receiving metronidazole (Head et al., 1984). One trialreported that an intravenous bolus of 400 mg of teicoplaninsignificantly reduced the post-extraction streptococcalbacteremia (from 32% in the "control group" to 2% in the"teicoplanin group"); its efficacy was also superior to that ofintramuscular 1 g of amoxicillin given 20 to 30 min beforeanesthetic induction (Shanson et al., 1987). Another studydemonstrated that patients receiving 1.5 g of cefuroximeintravenously had a significantly lower rate of bacteremia aftermultiple dental extractions than did controls. This finding wasalso seen after 10 min (79% and 23%, respectively) and 30 min(69% and 20%, respectively) of commencement of the surgicalmanipulation (Wahlmann et al., 1999). In contrast, otherauthors did not achieve a reduction in the prevalence of post-extraction bacteremia after the oral administration of 200 mg ofoxafloxacin and 375 mg of sultamicillin 1 hr before theintervention, findings which were probably affected by the lowdoses used (Göker and Güvener, 1992). One study found thatoral 1 g of cefaclor did not influence the prevalence ormagnitude of the post-extraction bacteremia caused by viridansgroup streptococci or obligate anaerobic bacteria (either duringthe manipulation or 10 min later) (Hall et al., 1996a). In arecent paper, the effect of a single oral dose of 400 mg ofmoxifloxacin showed this to be effective, significantly reducingthe prevalence (at 30 sec) and duration (at 15 min and 1 hr) ofpositive blood cultures secondary to dental extractions (54%,21%, and 4%, respectively, in the "moxifloxacin group" vs.96%, 64%, and 20%, respectively, in the "control group") (DizDios et al., 2006).

From the first data published in 1956, another appealingline of research arose, that of topically administered antibioticprophylaxis (Bender and Pressman, 1956). In one trial, the use




of pre-operative topical vancomycin (starting 4 days before thedental treatment) resulted in a lower percentage of positivepost-curettage or post-extraction blood cultures (25% and 69%,respectively), than after the application of a placebo (47% and94%, respectively), but the differences between the groupswere not significant (Bartlett and Howell, 1973). Other authorshave evaluated the effect of topically applied amoxicillin on theprevalence of post-extraction bacteremia (Vergis et al., 2001).The study group was comprised of 10 controls and 15 patientswho performed a double mouthwash with amoxicillin for 1-2min. Although the amoxicillin reduced the percentage of post-extraction bacteremia compared with that in controls (53% vs.90%), the sample size was too small to reach statisticalsignificance (Vergis et al., 2001).

• IntensityAfter a detailed review of the literature, we found only a fewstudies in which the effect of antibiotic prophylaxis on themagnitude of post-dental manipulation bacteremia was studied(Josefsson et al., 1985; Hall et al., 1993, 1996b). One trialreported that the concentration of bacteria in the post-extractionblood cultures was significantly lower in patients receivingantibiotic prophylaxis (500 mg dose of erythromycin or 2 g ofpenicillin V) than in controls (Josefsson et al., 1985). Bycontrast, other authors demonstrated that prophylaxis withamoxicillin or clindamycin did not significantly reduce themagnitude of the positive post-extraction blood cultures (Hallet al., 1993, 1996b).

The small number of colony-forming units (CFU)/mLusually detected in positive blood cultures associated withdental manipulations probably makes it difficult to interpret thepossible effects of antibiotic prophylaxis on the intensity ofpost-manipulation bacteremia (Roberts et al., 2000; Lucas et al.,2002b).

(4) EFFICACY OF ANTIBIOTIC PROPHYLAXIS IN THEPREVENTION OF BACTERIAL ENDOCARDITIS

• Animal ModelsIn 1970, a study demonstrated that the insertion of a polyethylenecatheter into a rabbit heart led to the appearance of a small sterilevegetation, which favored bacterial colonization after theinjection of an infectious bolus (Garrison and Freedman, 1970).Since then, animal models have been key to the study of theefficacy of antibiotics in the prevention of bacterial endocarditis.The common characteristic of all these studies is that theanimals, at the time of inoculation of the micro-organisms intothe bloodstream, had serum levels of antibiotics similar to thosedetected in humans after receiving standard prophylactic doses.These investigations have enabled workers to define accuratelythe time-course of cardiac infection and the influence of the sizeof the bacterial inoculum in its etiopathogenesis. However,results obtained on the efficacy of antibiotic prophylaxis inexperimental models cannot necessarily be extrapolated tohumans (Mizen and Woodnutt, 1988; Vogelman et al., 1988).Other problems have also been attributed to this type of study,such as the need for placement of an intra-cardiac catheter toinduce the initial lesion, and the size of the bacterial inoculumnecessary to infect the animals (Glauser and Francioli, 1987).

The first studies revealed that antibiotic prophylaxis waseffective, preventing the onset of experimental bacterial

endocarditis in rabbits, although prophylactic regimens variedin efficacy (Durack and Petersdorf, 1973). "Bacterial death"was said to be the mechanism responsible for the success ofprophylaxis (Southwick and Durack, 1974). Modifying theexperimental model previously described (Garrison andFreedman, 1970), investigators produced sterile cardiacvegetations by inserting a polyethylene catheter into the heartsof rabbits and then infecting them by the intravenous injectionof 108 CFU of a Streptococcus sanguis strain originallyisolated from a patient with bacterial endocarditis (Durack andPetersdorf, 1973). The success of antibiotic prophylaxis wasdetermined based on the results of the conventional culture ofthe endocardial vegetations, 24 hrs after the administration ofthe antibiotics. The results of this study revealed thatintramuscular penicillin G (150 mg/kg bodyweight), combinedwith streptomycin (15 mg/kg bodyweight) or procainepenicillin (250 mg/kg bodyweight) and penicillin G (150mg/kg bodyweight) combined with benzathine penicillin (7.5mg/kg bodyweight) were effective in the prevention ofbacterial endocarditis. In contrast, lower doses of penicillin Gdid not significantly reduce the number of rabbits thatdeveloped cardiac infection. In consequence, this trialdemonstrated the need to achieve high serum concentrations ofpenicillin and to maintain the bactericidal activity in the serumfor 6-8 hrs as essential in preventing bacterial endocarditis. Inthis study, the efficacy of other bactericidal agents, such asvancomycin, was also demonstrated, while antibiotics such ascefalexin, cefaloridine, and rifampicin did not prevent cardiacinfection. To explain these findings, it was suggested that thebactericidal agents used in the prophylaxis protocols had tocause "total bacterial death", since the survival of only 0.1% ofthe bacteria could still be sufficient to cause bacterialendocarditis (Durack and Petersdorf, 1973).

In a trial published in 1986, different oral regimens ofamoxicillin (associated with probenecid), and an intramuscularcombination of penicillin G, streptomycin, and probenecidwere administered 1 hr after the inoculation of 104, 106, and 108

CFU of penicillin- and amoxicillin-sensitive Streptococcussanguis to rabbits with experimentally induced cardiacvegetations (Pujadas et al., 1986). The combination ofpenicillin G, streptomycin, and probenecid provided protectionagainst all the bacterial concentrations used. The administrationof a single dose of amoxicillin and probenecid preventedcardiac infection in rabbits infected with 104 CFU, but itsefficacy decreased with larger bacterial inoculations. However,the prophylaxis based on 2 oral doses of amoxicillin andprobenecid (the second dose administered 10 hrs after the first)was completely effective in preventing bacterial endocarditis,independently of inoculum size, and these authors thereforefavored the administration of a second dose of amoxicillin andthe incorporation of probenecid in patients considered to be at"high risk" of bacterial endocarditis and about to undergo adental procedure that involved the potential passage of "highmagnitude bacterial inocula" into the bloodstream (Pujadas etal., 1986).

Soon the dilemma arose as to whether the "bacterial death"induced by the antibiotic prophylaxis could fail in patients withbacterial endocarditis caused by Streptococcus spp. showingtolerance to amoxicillin (minimum bactericidalconcentration/minimum inhibitory concentration [MBC/MIC] ≥32 mg/L) (Glauser et al., 1983). A study of the efficacy of a




single dose of amoxicillin on the prevention of bacterialendocarditis in rats, after the inoculation of Streptococcus spp.with different sensitivity profiles to this beta-lactam, found thatamoxicillin was bactericidal in an inoculum-independent manneragainst bacteria not tolerant of this antibiotic, signifying that itwas active against inocula up to 1000 times higher than theInfective Dose90 (ID90) (Glauser et al., 1983). Furthermore,protection against bacteria tolerant to amoxicillin was principallydue to the inhibition of bacterial adherence to the cardiacvegetations, through an inoculum-dependent action, with areduction in efficacy when the size of the bacterial inoculum wasincreased (Glauser et al., 1983). Confirming this theory, otherauthors, in in vitro studies, observed that the adhesion ofStreptococcus sanguis to fibrin and platelet coagula decreasedafter the administration of penicillin or amoxicillin, probably as aconsequence of the effects of these antibiotics on bacterialstructures such as teichoic and lipoteichoic acids, or on certainspecific proteins of the cell surface (Christensen et al., 1985;Kusser et al., 1985; Nealon et al., 1986).

A study published in 1987 on the prevention ofexperimentally induced streptococcal bacterial endocarditis inrabbits showed that amoxicillin was much more effective thancephradine (Longman et al., 1987). In the first 4 hrs, the serumlevels of amoxicillin were higher than the MICs and MBCs ofthe Streptococcus sanguis inoculated, whereas the concentrationsof cephradine were lower than the MBC of this micro-organism,underlining the importance of achieving high serum levels of theantibiotics for several hrs for the prevention of bacterialendocarditis (Longman et al., 1987).

A trial was designed with a computer-controlled system forthe continuous infusion of antibiotic, aiming to simulate in ratsthe pharmacokinetic characteristics of a single dose of 3 g ofamoxicillin in humans (Fluckiger et al., 1994). In thisexperiment, detectable blood levels of amoxicillin were achievedfor more hours than after the injection of a single intravenousbolus (9 hrs vs. 4.5 hrs), enabling these rats to be protectedagainst much larger bacterial inocula (up to 100 times higher).Consequently, these authors stated that the prolonged presence ofamoxicillin in the bloodstream led to the activation of otherdefense mechanisms. On this basis, it was speculated thatamoxicillin, under "non-bactericidal" conditions, could inhibitthe growth of bacteria adherent to cardiac vegetations, favoringtheir elimination by host defense mechanisms such asmicrobicidal platelet proteins (Fluckiger et al., 1994). Based onthis hypothesis, and taking into account that bacterial growth onthe vegetations is significant by 4 hrs after the onset of thebacteremic episode (Moreillon et al., 1986), the efficacy of thepost-bacteremic phase administration of amoxicillin in theprevention of experimental endocarditis was evaluated in rabbitsand rats (James et al., 1987; Berney and Francioli, 1990); thesestudies demonstrated that prophylaxis was effective if it wasadministered up to 2 hrs after an ID90, but that this effect was notachieved when the beta-lactam was administered 4 or 6 hrs afterinjection of the bacterial inoculum (James et al., 1987; Berneyand Francioli, 1990).

Another mechanism of action of amoxicillin proposed in theprevention of bacterial endocarditis is the separation of thebacteria adhering to the vegetation due to structuralmodifications in their cell walls (Lowy et al., 1983a). However,in vitro experiments have not confirmed this after exposure tobacteriostatic concentrations of amoxicillin for 4 hrs, a period

that simulates the time of exposure to amoxicillin in vivo(Moreillon et al., 1986). Nevertheless, this mechanism of actioncould not be definitively excluded, due to the methodologicaldifficulties involved in demonstrating a phenomenon in whichprobably only a small number of bacteria are involved (Berneyand Francioli, 1990).

A study compared the efficacy of single doses ofclarithromycin and clindamycin in the prophylaxis ofexperimentally induced streptococcal bacterial endocarditis inrats, demonstrating that both prophylactic regimens weresuccessful in preventing the onset of bacterial endocarditisafter the inoculation of an ID90 or up to 100 times higher(Vermot et al., 1996). Since it is rare to find such largeinocula from the bloodstream after dental procedures, it hasbeen suggested that these antibiotics provided wide safetymargins for bacterial endocarditis prophylaxis in humans(Vermot et al. , 1996). It has been demonstrated thatclindamycin inhibits the adherence of the viridans groupstreptococci to sterile vegetations by interfering withglycocalyx synthesis (Dall et al., 1990).

In 1997, a trial was published on the efficacy ofazithromycin and clarithromycin in the prevention of bacterialendocarditis in rabbits after the intravenous infusion of 5 x105 CFU of Streptococcus milleri, comparing this with theeffects of other antimicrobial agents frequently used forprophylaxis (amoxicillin, erythromycin, and clindamycin)(Rouse et al., 1997). Cardiac infection developed in 88% ofanimals not receiving prophylaxis, in 9% of those receivingerythromycin, and in only 0-2.5% of those receiving the otherantibiotics (Rouse et al., 1997). It has been demonstrated thatazithromycin is effective in preventing experimentalstreptococcal endocarditis (protecting 94% of animalschallenged with Streptococcus oralis), but, againstmethicillin-resistant Staphylococcus aureus-challengedanimals, it was less effective than vancomycin (59% and94%, respectively) (Tsitsika et al., 2000).

Recently, other authors have investigated the prophylacticefficacy of fluoroquinolones (antibiotics not included in thebacterial endocarditis prophylaxis protocols) in preventingstreptococcal aortic valve endocarditis (Katsarolis et aI.,2000; Sakka et al., 2005). One of these trials reported that asingle dose of moxifloxacin (15 mg/kg intravenouslyadministered) prevented endocarditis in 80% of rabbitschallenged with 107 CFU of Streptococcus oralis . Inconsequence, these authors concluded that moxifloxacin wasat least as effective as ampicillin in preventing streptococcalendocarditis (Sakka et al., 2005).

To achieve a better simulation of the specific conditionsof bacterial endocarditis secondary to dental manipulations inhumans, investigators designed a study on the efficacy ofsingle doses of amoxicillin and erythromycin on theprevention of bacterial endocarditis after extracting teeth withperiodontal disease from rats with sterile cardiac vegetationsinduced by a catheter (Malinverni et al., 1988). In the animalsreceiving antibiotic prophylaxis, the percentage of positivepost-extraction blood cultures fell by only between 20% and40% with respect to the rates observed in controls. However,the prophylactic administration of amoxicillin orerythromycin was effective in preventing bacterialendocarditis (only 10% and 7%, respectively, of the ratsreceiving prophylaxis with these antibiotics developed




bacterial endocarditis vs. 89% of the control rats), allowingthese authors (Malinverni et al., 1988), in agreement withother researchers (Glauser et al., 1983), to suggest thepotential participation of other protective mechanisms,distinct from "bacterial death" in the bloodstream, in thesuccess of antibiotic prophylaxis.

• Human StudiesAlthough it has been demonstrated that certain antibiotics areeffective in preventing bacterial endocarditis in experimentalanimals (Glauser et al., 1983; Berney and Francioli, 1990; Dall etal., 1990), the efficacy of prophylaxis in humans has not beenanalyzed (Little, 1998). This type of study would include largenumbers of patients per treatment group, requiring thestandardization of the dental procedures and the patientcharacteristics. It has been suggested that a series with more than6000 cardiac patients receiving a prophylaxis regimen or aplacebo before undergoing a dental procedure would benecessary for a definitive evaluation of the effectiveness ofantibiotic prophylaxis (Durack, 1995). Other authors haveestimated that a randomized, controlled trial would require theinclusion of approximately 60,000 patients "at risk" of bacterialendocarditis over a period of 2 yrs (Oliver et al., 2004).

It has been stated that antibiotic prophylaxis does not preventthe onset of bacterial endocarditis in 100% of cases (Durack,1995). In 1983, a series was published including 52 cases ofbacterial endocarditis in patients with predisposing cardiaclesions, with a history of previous dental procedures, and whohad received a prophylactic regimen with penicillin orerythromycin (Durack et al., 1983). The prophylactic protocolrecommended by the American Heart Association in 1977(Kaplan, 1977) had been administered in only six of the 52 cases;consequently, the majority of the patients had received"inadequate" prophylactic cover, allowing it to be suggested that,in many patients developing bacterial endocarditis, this could bedue to the use of regimens differing from the guidelinespublished by the various Expert Committees. Many surveysperformed among physicians and general dental practitionershave demonstrated that the type and dose of antibioticadministered to patients susceptible to bacterial endocarditisundergoing "at risk" dental procedures varied considerably, withthe percentage of responders adhering to the American HeartAssociation and British Society of Antimicrobial Chemotherapyprotocols varying between 6% and 96% (Hashway and Stone,1982; Nelson and van Blaricum, 1989; Vuille and Bloch, 1992;Forbat and Skehan, 1993). Recently, in a survey performed inSpain among "high risk" patients, only 34% confirmed that theyhad been informed by their cardiologists about the need forantibiotic prophylaxis in some specific situations (Caballero-Borrego et al., 2006). Furthermore, it has been suggested that theefficacy of the preventive strategy could be affected by the lowcompliance index of the patients, since, in a series of 318 Dutchpatients in whom antibiotic prophylaxis for bacterial endocarditiswas indicated, only 22% complied adequately with theprescription (van der Meer et al., 1992a).

A retrospective analysis of 52 cases of bacterial endocarditis,attributed to a possible failure of the antibiotic prophylaxis, couldnot confirm that the profiles of antimicrobial sensitivity of theisolates responsible for the cardiac infection represented a riskfactor in those persons in whom the prophylactic regimen wasadministered correctly (Durack et al., 1983). However, severalcases are to be found in the literature, such as one that referred to

a patient receiving intravenous erythromycin during a surgicalprocedure for maxillary sinusitis (and also on the followingdays), who later developed bacterial endocarditis due toerythromycin-resistant Streptococcus sanguis (the isolatepresented a MIC value to erythromycin of 40 mg/L) (Eng et al.,1982). On this subject, it has been indicated that the principalreason for re-evaluation of the current prophylactic protocols forbacterial endocarditis is the growing prevalence of bacterialresistance, particularly in Streptococcus spp. (Durack, 1998).Furthermore, it has been demonstrated that these resistances areassociated with the expression of certain genes that may betransferred between bacteria in the oral ecosystem (Durack,1998). However, the efficacy of prophylaxis with amoxicillin inthe prevention of bacterial endocarditis in rabbits that hadpreviously been inoculated with isolates of Streptococcussanguis resistant to this beta-lactam has been demonstrated,leading to the suggestion that the profiles of antimicrobialsensitivity tested in vitro do not represent a predictive factor forthe efficacy of antibiotic prophylaxis (Longman et al., 1992).

Some authors have suggested that, even assuming thatantibiotic prophylaxis was effective in 100% of cases, itsadministration would prevent only a small number of cases ofbacterial endocarditis (van der Meer et al., 1992b; Strom et al.,1998; Duval et al., 2006). In a retrospective analysis of 427cases of bacterial endocarditis, of which 275 were patientsclassified as "at risk", 64 patients (23%) had undergone a dentalprocedure requiring prophylaxis in the 180 days prior to theonset of symptoms of bacterial endocarditis, but only 17 hadreceived a bacterial endocarditis prophylaxis regimen. Thesefindings enabled the authors to conclude that: "Assuming anincubation period of 180 days, the administration ofprophylaxis would have avoided cardiac infection in 47patients, representing only 17% of the bacterial endocarditisdiagnosed in patients with heart disease undergoing proceduresrequiring prophylaxis" (van der Meer et al., 1992b). It wasestimated that, even with antibiotic prophylaxis with a 100%efficacy, the incidence of bacterial endocarditis would bereduced by only two cases/1,000,000 population/yr,considering a frequency of five cases of bacterialendocarditis/100,000 population/yr in the general population(Strom et al., 1998). In a recent study, the estimated risk ofdeveloping bacterial endocarditis was 1 in 10,700 and 1 in54,300 for persons with prosthetic- and native-valve-predisposing cardiac conditions, respectively, after undergoingan "at risk" dental procedure and not having receivedprophylaxis (Duval et al., 2006).

The Cochrane group published a meta-analysis thatevaluated whether the prophylactic administration of penicillinbefore the performance of invasive dental treatments in patients"at risk" of bacterial endocarditis affected the prevalence of thecardiac infection (Oliver et al., 2004). Of the 108 studiesanalyzed, only one (van der Meer et al., 1992b) satisfied theinclusion criteria. In consequence, these authors concluded thatthere is currently no scientific evidence that prophylaxis withpenicillin is effective in reducing bacterial endocarditissecondary to dental procedures in patients considered to be "atrisk" (Oliver et al., 2004). For some experts, the effectivenessof the prophylactic administration of antibiotics in theprevention of bacterial endocarditis could be limited even ifadministered correctly, since it is difficult to identify theprecise moment at which the bacteremia responsible for thecardiac infection occurs, and because there are cases of




bacterial endocarditis in patients with unknown pre-existingcardiac valve abnormalities but eligible for prophylaxis(Oakley, 1987; van der Meer, 2002). It has been recentlysuggested that the use of antibiotic prophylaxis to preventbacterial endocarditis caused by dental procedures must be re-assessed, based on the above recent evidence (Wahl andPallasch, 2005). These authors consider that at least 99% ofthose given antibiotic prophylaxis for bacterial endocarditis areunlikely to receive any benefit (Wahl and Pallasch, 2005).

(5) RISK-BENEFIT RELATIONSHIP OF ANTIBIOTIC PROPHYLAXISAlthough it is impossible to calculate accurately the risk ofonset of severe allergic reactions secondary to theadministration of penicillins, it has been estimated that thiscould occur in 0.04-0.2% of patients (Finch, 1990; InternationalRheumatic Fever Study Group, 1991), with an associatedmortality of one case per 60,000 exposures to penicillin (16 permillion prescriptions) (Idsoe et al., 1968). Other authors havesuggested that the mortality indices could be considerablyhigher, one case per 2000-2500 exposures to penicillin(Atkinson and Kaliner, 1992).

In the mid-1980s, the first studies were published thatevaluated the benefit of antibiotic prophylaxis, taking intoaccount the number of bacterial-endocarditis-related deathsavoided by the prophylaxis, and the number of deaths caused bysevere allergic reactions to penicillins (Bor and Himmelstein,1984; Clemens and Ransohoff, 1984; Tzukert et al., 1986). Oneof these studies estimated that 47 cases of bacterial endocarditiscould occur for every 10 million dental procedures performed inpatients with mitral valve prolapse, if antibiotic prophylaxis wasnot administered, and that two of these would lead to the death ofthe patient. If prophylaxis with penicillin was prescribed at eachvisit, the number of cases of bacterial endocarditis would fall tofive, and there would be no deaths due to this cause, but up to175 individuals could die as a consequence of allergic reactionsto the penicillin (Bor and Himmelstein, 1984). Other authorscalculated the annual mortality rate due to bacterial endocarditisof dental origin, and that attributable to antibiotic prophylaxis inpatients with rheumatic heart disease and undergoing dentaltreatment, estimating that, in a population of 100 million, therewould be approximately 26 deaths per yr due to bacterialendocarditis secondary to dental procedures. Considering apopulation of 3.4 million patients with rheumatic heart diseasewho would presumably attend a dental consultation once a yr,with the routine administration of prophylactic cover withpenicillin, there would be around 136 deaths annually due toanaphylactic shock (Tzukert et al., 1986). In the United States, itwas estimated that allergic reactions to penicillin could beresponsible for 400 to 800 deaths per yr, whereas theadministration of antibiotic prophylaxis would prevent onlybetween 240 and 480 cases of bacterial endocarditis, implying ahigher mortality index associated with allergic reactions topenicillins (Tzukert et al., 1986; Pallasch, 1989), particularly ifwe consider that the bacterial endocarditis of oral etiology causedby Streptococcus viridans is lethal in less than 10% of cases.Assuming an incidence of bacterial endocarditis of 11-50cases/1,000,000 population/yr, and an associated mortality rateof 25-40%, vs. a mortality due to anaphylactic reactionssecondary to penicillin of 16 cases/1,000,000 population/yr,investigators concluded that the mortality due to bacterial

endocarditis exceeded that due to allergic reactions to penicillinonly when the maximum values of the incidence of bacterialendocarditis and associated mortality were assumed (50 cases/1million population/yr and 40%, respectively) (Pallasch, 1989).

It has been suggested that the development of allergicreactions secondary to the use of penicillins depends on thedose and duration of treatment (Dukes and Aronson, 2000). Areview published in 1999 stated that there have been no casesreported in the literature of serious allergic reactions in patientswith no history of allergy to penicillin after receiving a singleoral dose of 2 g of amoxicillin (Wynn et al., 1999). However, acase of an allergic reaction to oral prophylactic amoxicillinadministered prior to dental treatment has been recentlyreported (Sadaghiani et al., 2005). To our knowledge, only onecase of pseudomembranous colitis secondary to a single dose of600 mg of clindamycin has been reported (Bombassaro et al.,2001). In contrast, it has been reported that almost half thepatients receiving a prophylactic regimen of oral erythromycin(1.5 g 1 hr before the procedure and 0.5 g 6 hrs later) hadadverse gastrointestinal effects (Sefton et al., 1990).

Although some authors stated that the use of antibiotics forprophylactic purposes in dental practice was not a significantabuse of antibiotics and, therefore, of the development ofbacterial resistance, others contradict this statement in relationto the administration of several prophylactic doses (Tong andRothwell, 2000). It has been shown that a single dose of 3 g ofamoxicillin did not lead to a significant increase in the numberof salivary-resistant streptococci, but that the administration ofa second or third dose caused a marked rise in the percentageof resistant isolates, which persisted for 4 to 7 wks (Woodmanet al., 1985; MacGregor and Hart, 1986). In a trial published in1987, 4 g of phenoxymethyl penicillin were orallyadministered over a period of 10 hrs (divided into 3 doses) to29 healthy volunteers who were not carriers of penicillin-resistant Streptococcus viridans, and by 6 hrs, streptococciresistant to this beta-lactam were isolated in nine individuals(31%), and these persisted for 9 days (Leviner et al., 1987).The prevalence of amoxicillin-resistant Streptococcus spp. wasalso investigated in a group of 12 volunteers taking 2 oraldoses of 3 g of amoxicillin (at an interval of 8 hrs), repeatingthe process weekly on five occasions. After the administrationof the final dose, all the individuals had amoxicillin-resistantoral Streptococcus spp., still present in all the individuals 13wks after the final dose of the antibiotic (Southall et al., 1983).With respect to the prophylactic protocols involvingmacrolides, in a study published in the 1908s, 3 doses oferythromycin stearate (total dose, 2 g) were administered ontwo occasions to 10 healthy persons, at an interval of 1 wk.After the second dose, erythromycin-resistant Streptococcusspp. were isolated from the oral cavities of all the participants,and isolates with very high MIC values (ranging between 16and > 256 mg/L) were detected in four persons. These resistantisolates remained detectable for up to 23 wks after theadministration of the drug in eight of the 10 volunteers, and infive people, the resistance persisted for up to 43 wks (Harrisonet al., 1985). In 1990, a trial was designed to evaluate whetherthe administration of 2 doses of erythromycin and josamycinaffected the selection of resistant streptococci in the oral cavity(Maskell et al., 1990). These authors observed that the lowproportion of resistant micro-organisms present before theadministration of the antibiotic prophylaxis increasedsignificantly 48 hrs after administration of the macrolides. Thepercentages of streptococci resistant to the antibiotics




administered, with MICs of 1, 4, and 64 mg/L, were 23%,17%, and 6%, respectively, for erythromycin, and 13%, 6%,and 4%, respectively, for josamycin (Maskell et al., 1990).

In contrast, other authors demonstrated resistant oralstreptococci in patients who had received a prophylactic doseof penicillin V (2 g initially and 1 g 6 hrs later) on 3consecutive Mondays, but that these represented only 0.0003-0.41% of the total streptococcal population cultured (Fleminget al., 1990). In consequence, these authors concluded thatprophylaxis with penicillin V administered on a number ofconsecutive occasions (with an interval of 1 wk betweenadministrations) did not lead to significant levels of resistancein the Streptococcus spp. in the oral cavity (Fleming et al.,1990).

(6) RECOMMENDATIONS FOR FUTURE RESEARCH

• Antibiotic of ChoiceThe onset of bacterial endocarditis of oral origin involves thepresence of a previous bacteremia (Drangsholt, 1998). Morethan half of the studies published on antibiotic prophylaxis andpost-dental manipulation bacteremia have investigated theefficacy of the prophylactic administration of penicillins(Elliott and Dunbar, 1968; Shanson et al., 1978; Baltch et al.,1982a,b; Hess et al., 1983; Roberts et al., 1987; Hall et al.,1993; Vergis et al., 2001; Lockhart et al., 2004), and theirresults confirm the efficacy thereof. However, there are fewerstudies on the effect of the prophylactic administration of otherrecommended antibiotics (clindamycin, azithromycin, andcephalosporins) on the prevention of post-dental manipulationbacteremia (Josefsson et al., 1985; Sefton et al., 1990; Gökerand Güvener, 1992; Aitken et al., 1995; Hall et al., 1996a; DizDios et al., 2006), and their results do not confirm the efficacyof these antibiotics.

To date, most of the papers on the prevalence of post-dentalmanipulation bacteremia have confirmed that most of thebacteria isolated in the blood cultures are sensitive to theantibiotics recommended in the prophylaxis protocols by theExpert Committees (Shanson et al., 1978; Josefsson et al.,1985; Sefton et al., 1990; Hall et al., 1993, 1996b; Aitken etal., 1995). However, increasing resistance to the beta-lactams,macrolides, and lincosamides has recently been found in oralbacteria (Groppo et al., 2005), and this could restrict their usefor bacterial endocarditis prophylaxis. Recently, newantibiotics, such as the fluoroquinolones, have been shown tobe successful in the prophylaxis of bacteremia following toothextractions in humans (Diz Dios et al., 2006), and to preventendocarditis in animal models (Sakka et al., 2005).

It has been shown that the inefficacy of some antibioticprophylactic regimens for the prevention of post-dentalmanipulation bacteremia does not necessarily imply that thesecannot prevent the development of bacterial endocarditis(Glauser et al., 1983; Berney and Francioli, 1990; Dall et al.,1990). However, more scientific evidence of the effect ofantibiotic prophylaxis on the prevalence and duration ofbacteremia following dental procedures is needed, with analysisof the influence of the increasing prevalence of bacterialresistance in the oral ecosystem (Durack, 1998). Prophylacticalternatives such as oral antiseptics (i.e., chlorhexidine) (Tomáset al., 2007) and peptides that can interfere with bacterialadhesion should also be explored (Ito, 2006).

• Time of Administration of the Antibiotic ProphylaxisSome authors consider that the time of exposure of bacteria tothe antibiotic, in the first min after the development of abacteremia, is insufficient for this to be able to act effectively(Hall et al., 1993, 1996b). This view is supported by resultsobtained in vitro on the bactericidal activity of variousantibiotics against Streptococcus viridans (Glauser et al., 1983;Lowy et al., 1983b). In consequence, the significant reductionin the bacteremia in the first min after the completion of adental manipulation, reported in some series, is probably notdue to the action of the antibiotic in the general circulation.

In the majority of experimental studies of bacterialendocarditis in animals, the responsible micro-organisms areinoculated directly into the bloodstream. What these studies areactually investigating, therefore, is the effect of antibioticsadministered after the induction of bacteremia (Pelletier et al.,1975; Glauser and Francioli, 1982; Glauser et al., 1983;Pujadas et al., 1986). In contrast, some authors have suggestedthat the success of antibiotic prophylaxis in preventing post-dental manipulation bacteremia in humans could be due to theaction of the antibiotic on the bacteria in the oral cavity, beforethese invade the bloodstream (Bender et al., 1984; Aitken etal., 1995).

In addition to the concentration that the antibiotic reachesin the oral cavity and the antimicrobial sensitivity of oralbacteria, another factor which must be taken into account is thetime of exposure of the bacteria in the oral cavity to theantibiotic. Some authors have suggested that "the contact timeof the antibiotic with the bacteria in the gingival sulcus couldbe too short to ensure success of the prophylaxis in theprevention of post-dental manipulation bacteremia" (Hess etal., 1983). After a detailed review of the literature, we wereinterested to note that, in several of studies that reported theefficacy of antibiotic prophylaxis in the prevention of post-dental manipulation bacteremia, the antibiotic was administeredat least 2 hrs before the dental procedure (Shanson et al., 1978;Lockhart et al., 2004; Diz Dios et al., 2006). This situationcould favor the activity of the antibiotic at a "local level" and,therefore, its efficacy in the prevention of bacteremia followingdental manipulations.

If one assumes that this is a possible mechanism of localaction (Bender et al., 1984; Aitken et al., 1995), the timerecommended for administration of antibiotic prophylaxiscould be questioned. An increase in the time of contact betweenthe bacteria and the antibiotic in the oral cavity might decreasethe prevalence and size of a post-dental manipulationbacteremia.

• Route of Administration of the Antibiotic ProphylaxisIn agreement with previous prophylactic regimens proposed bythe British Society of Antimicrobial Chemotherapy (Simmonset al., 1992), the British Cardiac Society and the Royal Collegeof Physicians recently published intravenous regimens fordental procedures performed under general anesthesia, and forpatients with prosthetic heart valves and/or previous episodesof bacterial endocarditis (Dental aspects of endocarditisprophylaxis, 2004). On this matter, investigators have pointedout the "unnecessary use of intravenous prophylaxis for certainrisk groups" (Longman et al., 2004), basing this comment onthe American Heart Association guidelines, in whichintravenous prophylaxis is reserved for patients who cannot




take medication orally (Dajani et al., 1997; Wilson et al.,2007). This indication has also been stated in the latest BritishSociety of Antimicrobial Chemotherapy guidelines (Gould etal., 2006).

The efficacy of intravenous antibiotics for the prevention ofpost-dental manipulation bacteremia is similar to that found inseries in which the antibiotic prophylaxis was administeredorally (Baltch et al., 1982a,b; Roberts et al., 1987; Lockhart etal., 2004). The mechanism of action of antibiotic prophylaxis ata dento-alveolar level proposed by some authors couldrepresent a possible explanation (Bender et al., 1984; Aitken etal., 1995). The oral administration of therapeutic doses ofamoxicillin and clindamycin gives rise to high antibioticconcentrations in the gingival fluid (3-4 mg/L and 1-2 mg/L,respectively) (García et al., 1996).

Despite the fact that the intravenous route provides higherserum antibiotic concentrations at the time of the manipulationthan does oral administration (Roberts et al., 1987), severalauthors have demonstrated that the oral amoxicillin andclindamycin provide high serum concentrations in the first andsecond hrs after ingestion (15 and 25 mg/L, and 4.5 and 4.8mg/L, respectively), with high levels at 4-6 hrs (5 mg/L and 2mg/L, respectively), and detectable levels still present after 9-10 hrs (0.7 mg/L and 0.2 mg/L, respectively) (Shanson et al.,1978; Dan et al., 1997). Taking into account that bacterialgrowth in the vegetations starts significantly at around 4 hrsafter the onset of bacteremia (Moreillon et al.,1986), it has beenstated that the prolonged presence of amoxicillin andclindamycin in the bloodstream probably led to the activationof other defense mechanisms (Dall et al., 1990; Fluckiger et al.,1994).

The low compliance with intravenous guidelines by bothpatients and practitioners is clear and not surprising. Inconsequence, it may be important to carry out more studies onthe efficacy of oral prophylaxis in the prevention of post-dentalmanipulation bacteremia and experimental bacterialendocarditis in comparison with intravenous prophylaxis.

(7) CONCLUSIONS• In the last decades, prophylactic regimens for the

prevention of bacterial endocarditis secondary to dentalprocedures have been modified, but remain consensus-based.

• Studies on antibiotic prophylaxis and post-dentalmanipulation bacteremia are essential for investigation ofthe prevention of bacterial endocarditis of oral origin.There is scientific evidence of the efficacy of amoxicillinin the prevention of bacteremia following dentalprocedures. However, the results reported in theliterature do not confirm the efficacy of otherrecommended antibiotics.

• The majority of studies on animal models verified theefficacy of antibiotics administered after the inductionof bacteremia to prevent experimental bacterialendocarditis, confirming a complementary action ofantibiotic prophylaxis in later stages in the developmentof bacterial endocarditis.

• Currently, there is no scientific evidence that prophylaxiswith penicillin is effective in reducing bacterialendocarditis secondary to dental procedures in patientsconsidered to be "at risk".

• The literature reports very few cases of severe allergicreactions following prophylaxis with penicillin.

• It has been demonstrated that antibiotic prophylaxiscould contribute to development of bacterial resistance,but only when several prophylactic doses areadministered consecutively.

• Due to scarce scientific evidence on this topic, futureresearch on bacterial endocarditis prophylactic protocolsshould be carried out in relation to the antibiotic of choice,and the time and route of administration of the antibioticprophylaxis. Alternative prophylactic drugs, such as oralantiseptics and peptides, should also be explored.

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