Costantinides

REVIEW ARTICLE
et al

Antibiotic Prophylaxis of Infective Endocarditis in

Dentistry: Clinical Approach and Controversies

Fulvia Costantinidesa/Emanuele Clozzab/Giulia Ottavianic/Margherita Gobboc/

Giancarlo Tirellid/Matteo Biasottoe
Purpose: Infective endocarditis (IE) in high-risk patients is a potentially severe complication which justifies the admin-
istration of antibiotics before invasive dental treatment. This literature review presents the current guidelines for anti-
biotic prophylaxis and discusses the controversial aspects related to the antibiotic administration for prevention of IE.

Results: According to the guidelines of the American Heart Association, individuals who are at risk to develop IE follow-
ing an invasive dental procedure still benefit from antibiotic prophylaxis. In contrast, the guidelines of the National In-
stitute for Health and Clinical Excellence in England and Wales have recommended that prophylactic antibiotic treat-
ment should no longer be performed in any at-risk patient. Bacteraemia following daily routines such as eating and
toothbrushing may be a greater risk factor for the development of IE than the transient bacteraemia that follows an
invasive dental procedure. However, a single administration of a penicillin derivate 30 to 60 minutes pre-operatively
still represents the main prophylactic strategy to prevent bacteraemia.

Conclusions: Presently, there is not enough evidence that supports and defines the administration of antibiotics to
prevent IE. The authors suggest performing a risk-benefit evaluation in light of the available guidelines before a deci-
sion is made about administration.

Key words: antibiotic prophylaxis, bacteraemia, current guidelines, endocarditis

Oral Health Prev Dent 2014;12:305-311 Submitted for publication: 03.12.12; accepted for publication: 11.04.13
doi: 10.3290/j.ohpd.a32133

It is currently estimated that more than 60% of all

bacterial infections in humans (and up to 80% of
chronic infections) are related to the microbial
growth in biofilms and to the host-response mech-
anism. To date, the most overwhelming evidence of
the pathogenic relationship between humans and
biofilms is based on microscopy, revealing the pres-
ence of these communities at the site of infection
or in prosthetic implants recovered from patients
(Moscoso et al, 2009).
The ability of bacteria to form biofilms is consid-
ered a virulence factor; in fact, the most severe is-
a
Assistant Professor, Dental Science School, University of Trieste,
Italy.
b
Resident, Ashman Department of Periodontology and Implant
Dentistry, New York University College of Dentistry, NY, USA.
c
Postgraduate Fellow, Dental Science School, University of Trieste,
Italy.
d
Associate Professor and Director, Ear-Nose-Throat Division, Uni-
versity of Trieste, Italy.
e agent of IE prompted a series of studies on the use
Researcher, Dental Science School, University of Trieste, Italy.
Correspondence: Dr. Fulvia Costantinides, Dental Science School,
Piazza dell’Ospitale 1, 34100 Trieste, Italy. Tel: +39-040-399-2254,
Fax: +39-040-399-2193. Email: f.costantinides@fmc.units.it
sues caused by bacterial biofilms include the per-
sistence of infection and the resistance to
conventional antibiotic therapy and immune re-
sponses. Clinically, biofilms are considered a pri-
mary cause of a majority of infections, such as oti-
tis media, pneumonia in cystic fibrosis patients
and endocarditis (Anderson et al, 2013).
Infective endocarditis (IE) is an infection of the
endocardium induced most frequently by staphylo-
cocci or streptococci that lead to general or sys-
temic symptoms of infection, embolic phenomena
and endocardial vegetations. The pathogenesis of
IE is mainly attributed to the formation of septic
vegetations, which are fibrin-platelet complexes
embedded with bacteria on heart valves. The per-
sistent nature of biofilms can also induce inflam-
mation and contribute directly to chronic bactere-
mia and thromboembolic events, which are serious
complications associated with IE (Jung et al, 2012).
The documented role of bacteria as the causal
of antibiotic prophylaxis against bacteraemia. It is
known that most of the procedures performed in
the oral cavity (e.g. tooth extraction, apical surgery

Vol 12, No 4, 2014 305

Costantinides et al
and root scaling) cause bacteraemia, which may
subsequently lead to IE (Poveda-Roda et al, 2008).
The aim of this paper was to review the literature
concerning the current guidelines for antibiotic
prophylaxis and to discuss the controversial as-
pects related to antibiotic administration for the
prevention of IE in dental practice.
EPIDEMIOLOGY AND CLINICAL PATTERN
OF INFECTIVE ENDOCARDITIS
Approximately 10,000 to 15,000 new cases of IE
were diagnosed in the United States each year in
the early nineties (Bayer, 1993). However, IE is be-
coming more common in the U.S. than previously
believed and is steadily increasing. In 2013, Bor et
al published a national study on IE epidemiology in
the U.S. for the period 1998–2009. They found
that the number of unique endocarditis hospitalisa-
tions was 25,511 in 1998 (9.3 per 100,000 popu-
lation) rising to 38,976 in 2009 (12.7 per 100,000
population). However, the precise incidence of IE is
difficult to ascertain because case definitions have
varied from decade to decade, among different au-
thors and between different medical centers
(Tleyjeh et al, 2007). For instance, in northeastern
Italy, 1,863 subjects were hospitalised for IE be-
tween 2000 and 2008, with a corresponding crude
rate of 4.4 per 100,000 person-years, increasing
from 4.1 in 2000–2002 to 4.9 in 2006–2008. A
survey of IE in six regions in France in 1999 found
an incidence of 31 cases per 1,000,000 popula-
tion (Hoen et al, 2002).
Sex and age also have an impact on the inci-
dence of IE. Men predominate in most case series,
with male:female ratios ranging from 3:2 to 9:1
(Lerner and Weinstein, 1966; Watanakunakorn,
1977; Hill et al, 2007). More than half of all IE cas-
es in the United States and Europe occur in pa-
tients over the age of 60, and the median age of
patients has increased steadily during the past 40
years (Hill et al, 2007).
IE usually affects the left side of the heart and
the valves in descending order of frequency: mitral,
aortic, tricuspid and pulmonary. Important predis-
posing factors include: congenital heart disease
and rheumatic valve disease, calcified or bicuspid
aortic valves, mitral prolapse, hypertrophic subaor-
tic stenosis and prosthetic valves. Mural thrombus,
arteriovenous fistula, ventricular septal defect and
ductus arteriosus may provide further locations for
infection. Those lesions treated with antibiotics
306
may heal by means of endothelialisation of vegeta-
tions (Naber et al, 2004). The main complication of
the proliferation of endocarditis is heart failure due
to the direct effects of proliferating vegetations on
the heart valves, which are eventually destroyed.
Embolisms consisting of fragments of vegetations
can damage organs and tissues, including the
brain, lung, coronary arteries, spleen and the ex-
tremities of limbs. Subacute Bacterial Endocarditis
(SBE) is usually caused by different streptococci
and less commonly by Staphyloccoccus aureus,
Staphylococcus epidermidis and Haemophilus influ-
enzae (Oliver et al, 2008). Endocarditis on pros-
thetic valves (EPV) occurs in 2% to 3% of patients
within 1 year after valve replacement and 0.5% per
year thereafter. Right-Sided Endocarditis (RSE),
which involves the tricuspid valve and more rarely
the pulmonary valve and artery, may be induced by
drug abuse or central venous-related infections.
Untreated IE is always fatal. The mortality rate
varies greatly, depending on several factors: the
age and general condition of the patient, duration
of infection before treatment, severity of pre-exist-
ing illnesses, site of infection, susceptibility of mi-
croorganisms to antibiotics and the onset of com-
plications. RSE often responds to antibiotics,
showing a better prognosis than left-sided endocar-
ditis. The expected mortality for endocarditis from
streptococci species – without major complications
– is less than 10% when treated, but in practice,
mortality can be 100% when endocarditis is caused
by Aspergillus following valve replacement. Suc-
cessful therapy requires the maintenance of an el-
evated level of antibiotic in serum and an effective
surgical treatment to manage mechanical compli-
cations of resistant microorganisms (Mügge et al,
1989). Heart valve surgery (repair and/or valve re-
placement) is often advisable to eradicate infec-
tions that are untreatable with medications, espe-
cially in cases of early introduction or IE in
prosthetic valves. Heart surgery performed to cor-
rect acute valvular insufficiency and to remove for-
eign bodies are associated with a significantly in-
creased survival rate (Werner et al, 2003).
CURRENT GUIDELINES FOR ANTIBIOTIC
PROPHYLAXIS IN DENTISTRY
It has been reported that the percentage of endo-
carditis associated with dental procedures ranges
from 4% to 14% of all cases (Ellervall et al, 2007).
There has been a well-established practice of ad-
Oral Health & Preventive Dentistry

ministering antibiotics to patients who are at risk of
developing IE prior dental treatment. The rationale
for this is that a high circulating dose of antibiotics
may prevent the development of infected vegeta-
tion on damaged endocardium (Tomás Carmona et
al, 2007). In vivo, prophylactic antibiotics are be-
lieved to act by interfering with three of the major
stages in the pathogenesis of IE: bacteraemia (by
reducing the number of microorganisms in blood),
adherence (by decreasing the affinity of microor-
ganisms for heart valves) and multiplication of mi-
croorganisms on the heart valves (by interfering
with the metabolic activity of the microorganisms)
(Hall et al, 1993).
Guidelines in many countries have recommend-
ed that before invasive dental procedures, antibiot-
ics should be administered to people at high risk of
IE. According to the guidelines from the American
Heart Association (AHA), subjects with prosthetic
cardiac valves, previous IE, unrepaired cyanotic
congenital heart disease (CHD), completely re-
paired congenital heart defect with prosthetic ma-
terial or device during the first six months after the
procedure, repaired CHD with residual defects at
the site or adjacent to the site of a prosthetic patch
or prosthetic device, and cardiac transplantation
recipients who develop cardiac valvulopathy are at
risk of developing IE when they undergo an invasive
dental procedure (Gould et al, 2006; Wilson et al,
2007). The AHA withdrew the advice to cover gas-
trointestinal and urogenital interventions, but iden-
tified the manipulation of gingival tissue or the
periapical region of teeth or perforation of the oral
mucosa as invasive dental procedures, which com-
monly occur in oral surgery.
For high-risk patients, prophylaxis is still recom-
mended for all dental procedures that in general
involve the manipulation of teeth and gingival tis-
sues or endodontics. When possible, a pre-opera-
tive mouthwash with 0.2% chlorhexidine gluconate
should be administered.
In Tables 1 and 2, guidelines for IE prophylaxis in
children and adults according to the AHA and to the
British Society for Antimicrobial Therapy (BSAT) are
shown (Gould et al, 2006; Wilson et al, 2007). A
recent guideline provided by the National Institute
for Health and Clinical Excellence (NICE) in England
and Wales has recommended that prophylactic an-
tibiotic treatment should not be used for any at-risk
patient undergoing a dental procedure (Stokes et
al, 2008). In summary, the guideline recommends
that prophylaxis should not be given to adults or
children undergoing dental or non-dental interven-
Vol 12, No 4, 2014
Costantinides et al
tional procedures if they bear structural cardiac de-
fects at risk of IE. The basis for this recommenda-
tion is that: 1) there is no consistent association
between dental or non-dental interventional pro-
cedures and the development of IE; 2) regular
toothbrushing almost certainly produces a greater
risk of endocarditis than a single dental procedure;
3) the clinical efficacy of antibiotic prophylaxis is
not proven and 4) antibiotic prophylaxis during den-
tal procedures is not cost effective and increases
the number of deaths due to anaphylaxis.
DISCUSSION
Three main guidelines for antibiotic prophylaxis pro-
moted by the AHA, BSAT and NICE are currently
available. According to the guidelines from the
American Heart Association and from the British
Society for Antimicrobial Therapy, people who are
at risk of developing IE after an invasive dental pro-
cedure benefit from antibiotic prophylaxis. A single
administration of a penicillin derivate 30 to 60 min-
utes before the procedure remains the main pro-
phylactic strategy to prevent bacteraemia.
However, it has been demonstrated that the
presence of antibiotics such as penicillin did not
prevent bacterial biofilm formation in vitro in the
presence of plasma components and platelets.
Moreover, prophylaxis with penicillin or other antibi-
otics failed to prevent colonisation or biofilm forma-
tion in situ when tested in a rat model of endocar-
ditis with predamaged valves (Jung et al, 2012). In
vivo, the evidence for bacteraemia reduction or pre-
vention by antibiotic prophylaxis is also unclear. In
a study by Hall et al (1996), the incidence of bacte-
raemia with viridans streptococci was 79% in pa-
tients treated with Cefaclor and 50% in a placebo
group during tooth extraction. No difference in the
incidence or magnitude of bacteraemia was ob-
served when the two patient groups were com-
pared (Hall et al, 1996). Even studies which show
reduction in bacteraemia do not show reduction in
IE (Shanson et al, 1985; Roberts et al, 1987). Also,
bacterial resistance to antibiotics could be involved
in the inefficacy of the prophylaxis. Recently, a re-
duced susceptibility of oral streptococci to penicil-
lin was recorded in 13.4% of cases (Pasquantonio
et al, 2012).
The NICE in England and Wales recommended
that prophylactic antibiotic treatment should no
longer be used for any at-risk patient, considering
that it was demonstrated that regular toothbrushing
307
Costantinides et al

Table 1 Recommended IE prophylaxis during interventions in the oral cavity in children

American Heart Association Guidelines (2007) British Society for Antimicrobial Therapy Guidelines (2006)

Regimen: single dose 30

Situation Agent to 60 min before procedure Agent Regimen

750 mg (< 5 years of age)

50 mg / kg 1.5 g (5 to 10 years of age)
Oral Amoxicillin Amoxicillin
3 g (> 10 years of age)
1 h before procedure

250 mg (< 5 years of age)

Unable to Ampicillin, Cefa- 500 mg (5 to 10 years of age)
50 mg / kg IM or IV
take oral zolin or Amoxicillin 1 g (> 10 years of age)
medication Ceftriaxone IV just before procedure or at induction of
anaesthesia

Cephalexin * § 50 mg / kg
150 mg (< 5 years of age)
Allergic to Clindamycin 20 mg / kg 300 mg (5 to 10 years of age)
Clindamycin
penicillin 600 mg (> 10 years of age)
Azithromycin or 1 h before procedure
15 mg / kg
Clarithromycin

75 mg (< 5 years of age)

Cefazolin§ or 150 mg (5 to 10 years of age)
Allergic to 50 mg / kg IM or IV Clindamycin
Ceftriaxone 300 mg (> 10 years of age)
penicillin or IV given over at least 10 min
ampicillin and
unable to 200 mg (< 5 years of age)
take oral 300 mg (5 to 10 years of age)
medication Clindamycin 20 mg / kg IM or IV Azithromycin 500 mg (> 10 years of age)
Oral suspension for patients that cannot
swallow capsules 1 h before procedure
* or other first- or second-generation oral cephalosporin in equivalent adult or paediatric dosage. §Cephalosporins should not be used in pa-
tients with immediate hypersensitivity reaction to penicillin (urticaria, angioedema or anaphylaxis).

Table 2 Recommended IE prophylaxis during interventions in the oral cavity in adults

American Heart Association Guidelines (2007) British Society for Antimicrobial Therapy Guidelines (2006)

Regimen: single dose 30

Situation Agent to 60 min before procedure Agent Regimen

Oral Amoxicillin 2g Amoxicillin 3 g 1 h before procedure

Unable to Ampicillin 2 g IM or IV
1 g IV just before procedure or at
take oral Cefazolin or Amoxicillin
1 g IM or IV induction of anaesthesia
medication Ceftriaxone

Cephalexin * § 2g

Allergic to Clindamycin 600 mg

Clindamycin 600 mg 1 h before procedure
penicillin
Azithromycin or
500 mg
Clarithromycin

Allergic to Cefazolin§ or
1 g IM or IV Clindamycin 300 mg IV given over at least 10 min
penicillin or Ceftriaxone
ampicillin and
unable to 500 mg oral suspension for patients that
take oral Clindamycin 600 mg IM or IV Azithromycin cannot swallow capsules 1 h before
medication procedure

* or other first- or second-generation oral cephalosporin in equivalent adult or paediatric dosage. § Cephalosporins should not be used in pa-
tients with immediate hypersensitivity reaction to penicillin (urticaria, angioedema or anaphylaxis).

308 Oral Health & Preventive Dentistry


and other everyday activities almost certainly pre-
sent a far greater risk of IE than a single dental pro-
cedure because of repeated exposure to bacterae-
mia with oral flora (Delahaye et al, 2004). Recently,
Tomás et al (2012) published a systematic review on
periodontal health status and bacteraemia from dai-
ly oral activities. Results showed that toothbrushing
is the activity for which there is greatest evidence of
an influence of the prevalence of bacteraemia de-
pending on the state of oral hygiene, gingival or per-
iodontal status (Tomás et al, 2012). Thus, attention
was shifted from procedure-related bacteraemia to
cumulative bacteraemia. It is postulated that daily
bacteraemia is six million times greater than bacte-
raemia after a single extraction (Roberts, 1999).
Furthermore, evidence is lacking that bacterae-
mia occurring during dental treatment significantly
increases the risk of endocarditis. A Cochrane re-
view by Oliver et al (2008) did not find any evidence
of a benefit from prophylactic administration of
penicillin in prevention of IE during invasive dental
procedures (Seymour et al, 2000; Naber et al,
2004).
A recent report by the Working Party of the BSAT
stated that probably the most important factor in
reducing the risk of IE in susceptible individuals is
good oral hygiene and, for this reason, the preven-
tive approach should facilitate access to high-qual-
ity dental care (Gould et al, 2006).
Another reason for recommending restricting an-
tibiotic prophylaxis regards antibiotic-related ad-
verse effects, e.g. anaphylaxis. Although the AHA,
BSAT and NICE specifically discuss anaphylaxis,
Gopalakrishnan et al (2010) reported that the
guidelines place various emphasis on this point.
Anaphylactic reactions are very rare and both AHA
and NICE recognise this fact. At the same time, the
guidelines also acknowledge that there is a lack of
evidence demonstrating a clear benefit from antibi-
otic prophylaxis. Nevertheless, Gopalakrishnan et
al (2010) underline that based on the lack of clear
benefit, even theoretical or rare risks like anaphy-
lactic reactions have to be factored in when making
public health recommendations affecting large pa-
tient populations (as anaphylactic reactions could
be fatal), as was discussed in the NICE guidance.
The NICE recommendations are not currently
universally accepted. Some cardiologists, cardiac
surgeons and oral surgeons still employ prophylac-
tic antibiotics in IE-risk patients, especially consid-
ering that in the majority of the studies published
on antibiotic prophylaxis and post-dental extrac-
tion bacteraemia, the authors confirm the efficacy
Vol 12, No 4, 2014
Costantinides et al
of penicillins in significantly reducing the number
of subjects developing bacteraemia (Tomás et al,
2008). It should be borne in mind that since IE is
a life-threatening condition, the absence of evi-
dence of benefit from prophylaxis is not the same
as evidence of its absence (Mohindra, 2009). A
recent study attempted to quantify modification in
prescription of prophylactic antibiotics before inva-
sive dental procedures for patients at risk of IE
and any concurrent variation in the incidence of IE
subsequent to the introduction of the NICE clinical
guideline (in March 2008) recommending the ces-
sation of antibiotic prophylaxis in the United King-
dom (Thornhill et al, 2011). Those authors found
that after the introduction of the guideline, a large
(78.6%) and rapid decrease occurred in prescrib-
ing antibiotic prophylaxis. However, no significant
increase in the number of IE cases above the long-
term baseline trend over this period was detected.
Neither was there a significant increase in the rate
of IE-related deaths in hospitals nor a significant
increase in the number of cases due to strepto-
cocci of possible oral origin. The authors stressed
the fact that frequent episodes of bacteraemia fol-
lowing daily routines such as eating and tooth-
brushing may be a greater risk factor for the devel-
opment of IE than the transient bacteraemia that
follows an invasive dental procedure. However,
they could not exclude the possibility that residual
antibiotic prophylaxis could be indicated for a sub-
set of patients with highest risk of IE, particularly
those with prosthetic heart valves or a history of IE
that might still benefit from antibiotic prophylaxis.
To more directly answer this question, they sug-
gested that a carefully designed, randomised, pla-
cebo-controlled trial of antibiotic prophylaxis in
these patients would be required.
Thus, there is still no solid evidence about
whether prophylaxis is effective or ineffective
against IE in people at risk who are about to un-
dergo an invasive dental procedure. Moreover, few
randomised controlled trials, controlled clinical tri-
als or cohort studies were available to demonstrate
a real benefit and, as reported by Bach (2010–
2011), the arguments for and against prophylaxis
must also take into consideration that the practical
guidelines should be compatible with ethical care.
CONCLUSIONS
The main concern for patients is the dualism be-
tween the status quo and the new guidelines, which
309
Costantinides et al
is likely to perturb many dental practitioners. Re-
fusal to change practice – derived from the highest
professional choice of best care for individual pa-
tients – should be respected. Presently, there is
not enough evidence that supports and defines the
administration of antibiotics to prevent IE. Thus,
the decision on whether to prescribe antibiotic
prophylaxis is based on a risk assessment consid-
ering that the factors involved in the risk-benefit
evaluation may be approached differently by differ-
ent experts. Where national guidelines for antibiot-
ic prophylaxis exist, the dentist must follow these,
but ethically, practitioners need to carefully discuss
the potential benefit and harm of antibiotic cover-
age with their patients.
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