View / Download pdf version of this article
The pathogenesis of infective endocarditis
Infective endocarditis is an infection of the inner layer of the heart’s valves and chambers, which can damage cardiac
structures and spread to other areas of the body.1 The condition generally begins around an abnormal valve
(e.g. degenerative, rheumatic, prosthetic or damaged from previous endocarditis) or where turbulent blood flow damages
the cardiac endothelium.1 An initial non-infected platelet-fibrin thrombus is colonised by microorganisms
transiently circulating in the blood.1 Deposition of more fibrin, platelet aggregation and microorganism
proliferation then combine to form an infected outgrowth, referred to as a vegetation.1 The infective process
may cause damage to the valve and surrounding structures or infection and/or infarction in other areas of the body due
to embolism of vegetation fragments.1 Infective endocarditis is always fatal unless treated,2 and
even with appropriate treatment it is associated with a one-year mortality rate of nearly 40%.3
Are prophylactic antibiotics indicated to prevent endocarditis associated with dental procedures?
Approximately one-third of cases of infective endocarditis in New Zealand are caused by streptococci that occur normally
in the oral cavity,4 and are associated with plaque, dental caries, gingivitis and peri-odontitis. Microorganisms
generally need to enter the blood stream for infective endocarditis to develop.
Oral streptococci most often enter the blood stream due to routine activities such as teeth brushing, flossing or chewing,
especially if the peri-odontium is unhealthy. This spontaneous bacteraemia is low-grade and brief but very frequent and
is thought to cause most cases of oral streptococcal endocarditis.5
Streptococci also enter the blood stream during and after invasive dental procedures involving manipulation of gingival
tissue or perforation of the oral mucosa, or gastrointestinal procedures such as oesophageal dilation.3 The
magnitude and duration of procedure-associated bacteraemia are greater than with spontaneous bacteraemia and the hypothesis
that this can lead to endocarditis has driven the use of antibiotic prophylaxis with dental procedures for decades. Although
there are indirect data in animals and humans suggesting a likely benefit of prophylaxis, the data are somewhat contradictory
and there is currently no high quality evidence that antibiotic prophylaxis is either effective or ineffective.6 However,
in the absence of good data supporting one strategy or the other, New Zealand and most international guidelines continue
to recommend antibiotic prophylaxis for selected dental and other procedures in high risk people.
What do the New Zealand guidelines recommend for prophylactic antibiotics?
The New Zealand guidelines for the prevention of infective endocarditis emphasise that all people who are at risk of
developing this infection need to take particular care to remain free of dental disease.7 This is best achieved
by regular visits to professionally trained dental staff and the appropriate use of toothbrushes, dental floss and other
plaque-control products, e.g. antibacterial mouthwashes.7 New Zealand has a disproportionately high number
of young Māori and Pacific peoples affected by rheumatic valvular heart disease as well as dental and periodontal disease.7 It
is therefore of added importance that optimal oral health is maintained within Māori and Pacific communities.
People with high risk cardiac conditions
In New Zealand, people with any of the following are clinically considered to be at high risk of developing infective
- A prosthetic heart valve, either biological or mechanical
- Rheumatic valvular heart disease
- Previous endocarditis
- Unrepaired cyanotic congenital heart disease or a repair procedure within the last six months
- Cardiac shunts or conduits for palliation
It is estimated that a person with a prosthetic heart valve has a risk of developing infective endocarditis that is
50 times higher than a person in the general population; this risk is highest in the 6 – 12 months following valve replacement.3 For
an unknown reason, infective endocarditis occurs twice as often in males as females, although females are more likely
to have a worse prognosis.5
A New Zealand study of 336 patients (266 with definite infective endocarditis and 70 with probable endocarditis) found
that almost one-third of all patients had prosthetic valve endocarditis, 10% had a previous episode of endocarditis and
4% had underlying rheumatic heart disease. Traditionally rheumatic heart disease has been considered a major risk factor
for infective endocarditis and this result was less than might have been expected given the high incidence of rheumatic
fever among Māori and Pacific communities.4
High risk dental procedures
Prophylactic antibiotics are recommended in New Zealand for people at high risk of developing infective endocarditis
who are undergoing dental procedures involving manipulation of either gingival tissue or tooth root region or perforation
of the oral mucosa, or tonsillectomy/adenoidectomy.7
People at high-risk who are undergoing the following routine dental procedures do NOT require prophylactic antibiotics:7
- Routine dental anaesthetic injections through non-infected tissue
- Dental x-rays
- Placement of removable prosthodontic or orthodontic appliances
- Adjustment of orthodontic appliances
- Placement of orthodontic brackets
- Losing deciduous teeth
- Treatment of bleeding due to trauma to the lips or oral mucosa
Prophylactic antibiotics are also not recommended in people at high risk of developing infective endocarditis who are
undergoing non-dental invasive procedures (other than tonsillectomy/adenoidectomy) unless they require surgery at an anatomical
location where there is already established infection, e.g. respiratory or gastrointestinal infection.
Choosing the prophylactic antibiotic regimen
Amoxicillin is the first-line prophylactic antibiotic for people undergoing invasive dental procedures who are at high
risk of developing endocarditis.7 Clindamycin or clarithromycin are possible alternatives for people in whom
amoxicillin treatment is inappropriate or potentially ineffective (Table 1).7 To ensure that levels in the
blood are maximal at the time of procedure, the antibiotic should be given in the following timeframes:7
- Orally, one hour before the procedure
- Intramuscularly (IM), 30 minutes before the procedure
- Intravenously (IV), immediately before the procedure
If the patient inadvertently does not receive an antibiotic prior to the dental procedure, it may be administered up
to two hours later, although the effectiveness of the prophylaxis may be reduced.7
People requiring surgery at sites where there is established infection
In addition to when invasive dental procedures are performed, people who are at high risk of developing infective endocarditis
also require prophylactic antibiotics if they undergo surgery at an anatomical site that is actively infected; if major
surgery is planned, a prophylactic antibiotic is likely to be administered anyway. The choice of antibiotic for these
patients is dependent on the site of the infected tissue. For example:7
- Upper respiratory tract infections – amoxicillin is preferred with clindamycin or clarithromycin as alternatives
- Gastrointestinal, hepatobiliary, genitourinary, obstetric or gynaecological infections – amoxicillin is preferred
with vancomycin as an alternative
- Skin or musculoskeletal infections – flucloxacillin is preferred. A cephalosporin, e.g. cefazolin, is an alternative
for patients with a mild penicillin allergy, e.g. simple rash, and clindamycin for patients with a severe
penicillin allergy, e.g. anaphylaxis, or if methicillin-resistant Staphylococcus aureus (MRSA) is suspected
Antibiotic regimens for the prophylaxis of infective endocarditis for high risk people undergoing invasive dental procedures7
Amoxicillin 2 g, single dose, orally, IV or IM
Amoxicillin 50 mg/kg (maximum 2 g), single dose, orally, IV or IM
Alternatives for patients who:
- Have a penicillin allergy
- Are taking long-term penicillin, e.g. for rheumatic fever prevention
- Have taken a penicillin or cephalosporin in the previous month
Clindamycin, 600 mg, single dose, orally, IV or IM;
Clarithromycin* 500 mg, single dose, orally.
Clindamycin, 15 mg/kg (maximum 600 mg), single dose, orally, IV or IM;
Clarithromycin* 15 mg/kg (maximum 500 mg), single dose, orally.
*Clarithromycin has a number of potentially serious interactions with other medicines -
see NZF for details
Have changes in prescribing affected the incidence of endocarditis?
The routine use of prophylactic antibiotics for infective endocarditis prevention began in the 1950s. In 2007, there
was a change in thinking when the American Heart Foundation (AHA) produced guidance recommending that antibiotics should
be limited to patients who had the highest lifetime risk of infective endocarditis and specifically only prior to invasive
dental procedures.8 The National Heart Foundation of New Zealand produced similar guidelines in 2008,7 as
did the European Society of Cardiology in 2009.5
The principle reason for the reduction in antibiotic use was that the risk of a person developing infective endocarditis
following a dental procedure is very low, even for those with a high lifetime risk. For example, it is estimated that
the likelihood of a person with a previous episode of infective endocarditis having a repeat occurrence following a dental
procedure is 1 in 95 000 procedures.8 It has also been estimated that the sum of spontaneous bacteraemia
from twice daily tooth brushing for one year is over 150,000 times that of one dental extraction procedure.9 Based
on these estimates it was argued that the use of prophylactic antibiotics for people other than those at the highest lifetime
risk of infective endocarditis would prevent very few cases of infective endocarditis. In addition, widespread use of
antibiotics would result in an increased number of adverse reactions as well as contributing to the growing problem of
NICE guidelines recommend against prophylactic antibiotics for any patients
In 2008, the United Kingdom National Institute for Health and Care Excellence (NICE) went one step further than other
groups and recommended that antibiotics should no longer be prescribed solely for the prevention of infective endocarditis,
regardless of the patient’s risk.10 The NICE recommendation was based on clinical evidence as well as cost-effectiveness,
but was also strongly influenced by the possibility that the use of antibiotics for infective endocarditis prevention
may result in a net loss of life due to adverse effects associated with antibiotic use.10
Have the NICE guidelines gone too far?
A study two years after the introduction of the 2008 NICE guidelines failed to detect a significant increase in the
incidence of infective endocarditis in England compared with before the guidelines, however, there was some concern that
a clinically significant difference would not be detected within this time frame.11, 12 A further study by
the same authors in 2015 examined the number of antibiotic prescriptions dispensed for the prevention of infective endocarditis
and the incidence of infective endocarditis in England from 2000 to 2013. It was found that the number of prescriptions
fell sharply after the 2008 NICE guidelines were released and that there has subsequently been an increase in the incidence
of infective endocarditis in both high and lower risk people.12 Unfortunately, the authors do not say whether
these extra cases of endocarditis were caused by oral streptococci or related to dental procedures. The finding that the
incidence of infective endocarditis increased in people considered low risk, i.e. who would not have been prescribed antibiotics
anyway, suggests that reduced antibiotic prescribing may not be the reason for the observed increase in morbidity. For
example, it may be possible that improvements in the diagnosis of infective endocarditis or an increase in invasive staphylococcal
disease has resulted in an increasing incidence across the entire population. Although a causal relationship has not been
established between a reduction in prophylactic antibiotic prescribing and an increase in the incidence of infective endocarditis
in England, this finding has prompted NICE to review its 2008 guideline;13 the outcome of this review is
still to be announced.
The study from England was not the first to examine the relationship between antibiotic prescribing and rates of infective
endocarditis. Four studies conducted in America following the introduction of the modified 2007 AHA guidelines (which
recommended prophylaxis for less people and for fewer invasive procedures) also did not detect an increase in the incidence
of infective endocarditis, including streptococcal infections.14 –17 However, the cohort size of several
of the American studies was relatively small compared to the English study and one study was conducted only nine months
after the AHA guidelines were introduced.16 Another study demonstrated no increase in oral streptococcal
endocarditis in France in the six years following a guideline change in 2002 to reduced antibiotic prophylaxis.18
Keep calm and carry on
Over 60 years of published data still do not provide evidence on which to make strong recommendations for antibiotic
prophylaxis against endocarditis at the time of dental procedures. The 2008 New Zealand guidelines represent a conservative
consensus of local expert opinions and seven years after they were written there does not seem to be a good reason to
change these recommendations.
Thank you to Dr Richard Everts, Specialist Physician, Medical Microbiologist and Infectious Disease Specialist,
Nelson and Marlborough DHB and Eamon Duffy, Antimicrobial Stewardship Pharmacist, Pharmacy/Infectious Diseases,
Auckland DHB for expert review of this article.
- Karchmer A. Infective endocarditis. In: Harrision’s principles of internal medicine. McGraw Hill Medical; 2012. pp. 1052–63.
- Wood AJJ, Durack DT. Prevention of infective endocarditis. N Engl J Med 1995;332:38–44.
- Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart
disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
J Thorac Cardiovasc Surg 2014;148:e1–132.
- Walls G, McBride S, Raymond N, et al. Infective endocarditis in New Zealand: data from the International Collaboration
on Endocarditis Prospective Cohort Study. N Z Med J 2014;127:38–51.
- Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis
(new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European
Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J 2009;30:2369–413.
- Glenny AM, Oliver R, Roberts G, et al. Antibiotics for the prophylaxis of bacterial endocarditis in dentistry. Cochrane
Database Syst Rev 2013;(10):CD003813.
- The National Heart Foundation of New Zealand. New Zealand guideline for prevention of infective endocaritis associated
with dental and other medical interventions. 2008. Available from:
www.toiteorapublichealth.govt.nz/vdb/document/312(Accessed Jun, 2015).
- Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association:
a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council
on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and
Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007;116:1736–54.
- Roberts G. Dentists are innocent! ‘Everyday’ bacteremia is the real culprit: A review and assessment of the evidence
that dental surgical procedures are a principal cause of bacterial endocarditis in children. Pediatr Cardiol 1999;20:317–25.
- National Institute for Health and Care Excellence (NICE). Prophylaxis against infective endocarditis: antimicrobial
prophylaxis against infective endocarditis in adults and children undergoing interventional procedures. NICE, 2008. Available
from: www.nice.org.uk (Accessed Jun, 2015).
- Thornhill M, Dayer M, Forde J, et al. Impact of the NICE guideline recommending cessation of antibiotic prophylaxis
for prevention of infective endocarditis: before and after study. BMJ 2011;342.
- Dayer MJ, Jones S, Prendergast B, et al. Incidence of infective endocarditis in England, 2000–13: a secular trend,
interrupted time-series analysis. Lancet 2015;385:1219–28.
- National Institute for Health and Care Excellence (NICE). NICE to review its guidance on the use of antibiotics to
prevent infective endocarditis. NICE, 2014. Available from: www.nice.org.uk (Accessed Jun, 2015).
- Desimone DC, Tleyjeh IM, Correa de Sa DD, et al. Incidence of infective endocarditis caused by viridans group streptococci
before and after publication of the 2007 American Heart Association’s endocarditis prevention guidelines. Circulation
- Pasquali SK, He X, Mohamad Z, et al. Trends in endocarditis hospitalizations at US children’s hospitals: impact of
the 2007 American Heart Association Antibiotic Prophylaxis Guidelines. Am Heart J 2012;163:894–9.
- Rogers AM, Schiller NB. Impact of the first nine months of revised infective endocarditis prophylaxis guidelines
at a university hospital: so far so good. J Am Soc Echocardiogr 2008;21:775.
- Bikdeli B, Wang Y, Kim N, et al. Trends in hospitalization rates and outcomes of endocarditis among Medicare beneficiaries.
J Am Coll Cardiol 2013;62:2217–26.
- Duval X, Delahaye F, Alla F, et al. Temporal trends in infective endocarditis in the context of prophylaxis guideline
modifications: three successive population-based surveys. J Am Coll Cardiol 2012;59:1968–76.