antibiotics in perio2

Periodontology 2000, Vol. 10, 1996, 107-138
Printed in Denmark .All rights reserued
Coavrinht 0 Munksnaard 1996
PERIODONTOLOGY 2000
ISSN 0906-6713
Antibiotic prophylaxisand the
medicallycompromisedpatient
THOMAS
J. PALLASCH & J0 R GE N SLOTS
Antibioticprophylaxis involves the administration of
antibiotics to patients with no evidence of current
infection to prevent post-treatment microbial colon-
ization and complications. Antibiotic prophylaxis is
used in an attempt to diminish or eliminate bacter-
emic metastatic infections. The impression that anti-
biotic prophylaxis is almost universally successful
has led to its widespread use to prevent infections
ranging from very serious ones (infective endocar-
ditis involving cardiac valve prostheses) to trivial
ones (postoperative sequelae of routine dental treat-
ment).
As a public health prevention measure, antibiotic
prophylaxis substantially differs from fluoridation
and immunization.Administration of fluoride to pre-
vent dental caries and immunization against dread
infectious diseases are universally approved preven-
tive measures because they improve the health of vir-
tuallyallrecipients.An occasional adverse effectis ac-
cepted because of the great overall benefit.
The net benefit of antibiotic prophylaxis for infec-
tive endocarditis is more difficult to assess, as only a
few of the recipients ever benefit from it. Infective
endocarditis occurs in about 11-50 people per mil-
lion population per year, and at least 40% of affected
individuals exhibit no known risk factors. Most if not
all of this million people would have to receive anti-
biotic prophylaxis to prevent the statistical 11-50
cases. Antibiotic prophylaxis may induce multiple
antibiotic resistance in serious pathogens, allergy
and toxicity, and this combined with financial costs
requires stringent criteria for an acceptable risk-
benefit ratio.
This chapter describes the advantages and disad-
vantages of antibiotic prophylaxis in the prevention
of infective endocarditis, prosthetic joint infections
and brain abscesses, and of infections in patients
who are immunocompromised, asplenic, have im-
planted cardiac pacemakers or have received various
types of grafts. The issue of surgical antibiotic
prophylaxis is discussed briefly as well.
Since infectiveendocarditis provides the vast body
of knowledge about antibiotic prophylaxis, this dis-
order is discussed extensivelyto allow possible extra-
polation to other bacteremic at-risk situations. Den-
tally induced bacteremia as a cause of infective en-
docarditis and other nonoral infections is thoroughly
evaluated.
Principles of antibiotic
prophylaxis
Antibiotic prophylaxis is indicated if the infection to
be prevented is common but not fatal or if the infec-
tion is rare but carries an unacceptably high mor-
tality rate (330).Antibiotic prophylaxis is theoretic-
ally beneficial in protecting healthy individuals from
potentially serious (catastrophic) infections and/or
the prevention of infection of implanted foreign
bodies such as cardiac valve prostheses or vascular
grafts (243).
An antibiotic prophylaxis regimen must follow
certain principles: 1) the benefit of the prophylaxis
must outweigh the risk of taking the antibiotic (satis-
factory risk-benefit ratio), 2) the antibiotic must be
present in the blood and target tissues prior to dis-
semination of the organisms into the blood (42,43),
3) an antibiotic loading dose must be used (79), 4)
the choice of the antibiotic must be made on the
basis of the single most likely microorganism to
cause the infection (3611, 5) the antibiotic should be
continued only as long as microbial contamination
from the operative site continues (411, and 6) the
financial costs of the antibiotic prophylaxis must be
reasonably related to the risk of acquiring the infec-
tion and the costs of treating this infection and poss-
ible sequelae (a satisfactory cost-benefit ratio).
The potential medical harm from antibiotic
prophylaxis includes: 1) an increased risk of anti-
biotic-induced allergy and toxicity (if no antibiotic
prophylaxis is used, the drug-related adverse effects
107

Pullusch & Slots
are zero), 2) an increased risk of superinfection
(initiationof a new infection while treating a primary
infection), 3) selection of antibiotic-resistant micro-
organisms (damage to the host and environmental
microbial ecology), and 4) encouragement of care-
less, inept surgery (243).
Antibiotic prophylaxis may be medically, ethically
and legallyuntenable if: 1)the at-risk group to bene-
fit from the prophylaxis cannot be narrowly iden-
tified to prevent gross overuse of the antibiotics, 2)
prophylaxis is too random in efficacy to be reliable,
3) basic proof for efficacy is too limited, 4) antibiotic
prophylaxis causes more harm than the infection to
be prevented, 5) the bacteremia to be prevented is
too seldom a proximate cause of patient disease, and
6) the antibiotic is aimed at preventing infection by
any or all potential microbial pathogens rather than
deterring the colonization of a single microbial spe-
cies (43, 269, 361).
Bacteremia
In the 1930s it became clear that dental treatment
may induce bacteremia, with potential to produce
distant infections such as infective endocarditis (249,
284). Since 1955,antibiotic prophylaxis has been ad-
vocated to prevent such metastatic infections (71).
Antibiotic prophylaxis given prior to dental treat-
ment may prevent bacteremia in some clinical situ-
ations, with the caveat that it is impossible to predict
which patient will develop a bacteremic infection
and the risk associated with a particular treatment
procedure (124).Also, a prolonged incubation period
after initial colonization can make it difficult to de-
termine whether an infection results from a specific
dental procedure-induced bacteremia or from spon-
taneous bacteremia associated with daily living.
The probability of bacteremia associated with
dental procedures depends on the invasive pro-
cedure performed and the amount of oral inflam-
mation present. The proficiency of the microbial iso-
lation method may greatly influence the published
incidence rates of bacteremia. A strict anaerobic
technique may allow the detection of random spon-
taneous bacteremia in 60-80% of people at any given
time (110,211).
Table 1 shows the incidence of bacteremic epi-
sodes from dental treatment is not markedly higher
than that resulting from oral hygiene and mastica-
tion procedures (17, 110, 150,238).Dental treatment
and random nature-associated cases of bacteremia
are of low-grade intensity, usually 1-10 bacterial
colonies per ml of blood, compared with the lo3 to
1 Table 1.The incidence of bacteremia with
dental treatment and oral hygiene procedures
(17, 110, 150,238)
Dental treatment
bacteremia Oral hygiene bacteremia
Tooth extraction: 51-85% Toothbrushing: 0-2676
Periodontal surgery: 36-88% Dental flossing:20-58%
1 Scaling and root planing: Toothpicks: 20-40%
8-80%
Periodontal prophylaxis: Irrigation devices: 7.50%
Endodontics: 0-15% Chewing: 17-51%
0-40%
lo9 bacterial colonies per ml of blood needed to in-
duce experimental infective endocarditis. Also, the
bacteremia is usually of short duration, with the
blood becoming sterile in less than 15-30 minutes
(72, 372). The highest yield of microorganisms from
blood samples is obtained at 30 seconds after the
onset of the dentally induced bacteremia (277),un-
derscoring the effectiveness of the host defense in
clearing microbes from the blood.
Traumatic procedures (extraction, periodontal
therapy) can cause higher rates of bacteremia than
less invasive therapy (dental prophylaxis and endo-
dontics). Routine endodontic therapy may carry a
negligible risk for bacteremia (18).Needle aspiration
of a dentoalveolar abscess may not induce bacterem-
ia, whereas incision of the same abscess may carry a
25% risk of bacteremia (119). Studies of suture re-
moval detected incidence rates of bacteremia of 5%
(195) and 16% (removal of 5 sutures (131)).Neither
study (131,195)recommended antibiotic prophylaxis
prior to suture removalin cardiac-risk patients except
subjects in the very high-risk category (cardiac valve
prostheses and previous infectiveendocarditis).
In contrast to early studies (68, 134, 199,2061, it is
now recognized that the severity of gingival in-
flammation correlates positively with the incidence
and magnitude of bacteremia (17, 110, 150, 249,
305). Also, infective endocarditis has been detected
more frequently in periodontally diseased than in
periodontally healthy rats (250). Nevertheless, bac-
teremia can occur in patients with clinicallyhealthy
gingiva (306).Edentulous patients may develop bac-
teremia and endocarditis as well (76,310).
Efficient microbial isolation techniques reveal that
antibiotic prophylaxis may not significantly reduce
the incidence of bacteremia after dental extraction
(152).Bacteremic events, particularly those of a ran-
108

Antibiotic prophylaxis and the medically compromised patient
dom nature, seem to be much more common than
previously thought, and antibiotic prophylaxis may
not prevent them as well as previously assumed.
Dentists are often accused of causing infective en-
docarditis, brain abscess and orthopedic prosthesis
infection when such infections occur in the days or
months after dental therapy. Such cases should be
evaluated in the light of the ubiquitous nature of
random bacteremia. In evaluating the relative risk of
bacteremia from patient self-manipulation pro-
cedures (plaque control and mastication), Gunther-
0th (150) calculated the cumulative monthly bacter-
emic exposure to be 5376 minutes for self-induced
oral procedures versus 6 minutes for a dental extrac-
tion. Everett & Hirschmann (110) and others (100)
stated that “the link between a case of endocarditis
and a recent procedure causing bacteremia cannot
be proved because asymptomatic, low-grade bacter-
emia occurs very commonly since they are related to
everyday events such as chewing and cleaning the
teeth.” Frequent transient bacteremia represents a
greater cumulative risk for endocarditis than oc-
casional dental procedures (103).
Antibiotic prophylaxis to prevent bacteremia
Conflicting data exist on the efficacy of antibiotic
prophylaxis in preventing orally induced bacteremia.
Using prophylactic parenteral penicillin according to
the American HeartAssociation’sguidelines, Baltch et
al. (9)found at 5minutes after bacteremic induction a
bacteremic incidence of 58-76% with no use of anti-
biotics versus 14-16% with antibiotic prophylaxis,
and at 30 minutes an incidence of 26-51% versus 3-
9%. Hall et al. (152)questioned the issue of antibiotic
prevention of bacteremia by showing the failure of
both penicillin V (2g) and amoxicillin (3g) to signifi-
cantly prevent bacteremia after dental extraction.
Many studies equate the ability of antibiotic
prophylaxis to reduce or eliminate bacteremia with
the ability to prevent infective endocarditis. How-
ever, antibiotics may not prevent infective endocar-
ditis by bactericidal blood activity (103) but may do
so by decreasing microbial adherence to damaged
cardiac valves or by eliminating bacteria after their
attachment to cardiac valves (103, 120, 233).
Oral health and the prevention of bacteremia
Good oral health reduces the likelihood of infective
endocarditis and other bacteremic infections in at-
risk patients (150, 346). With excellent oral hygiene,
the prevalence of bacteremia after dental extraction
is approximately the same as when antibiotic chem-
oprophylaxis is employed; oral sepsis doubles the
risk of bacteremia (150).The American Heart Associ-
ation recommends: “Individuals who are at risk for
developing bacterial endocarditis should establish
and maintain the best possible oral health.” Kaye
(192)stated that: “... maintaining a good state of oral
health, which will decrease dailybacteremia, is prob-
ably more important in preventing endocarditis than
the application of antibiotic prophylaxis before spe-
cific dental procedures.” Unfortunately, physicians
may not advise at-risk patients of the need for excel-
lent oral hygiene to prevent metastatic infections.
Antiseptic mouthwashes
Antiseptic mouthwashes applied immediately prior
to dental procedures may reduce the incidence and
severity of bacteremia (17, 216, 346). Useful agents
may include chloramine-T (336), povidone-iodine
(216), iodine and glycerin (17) and chlorhexidine
(346). The antiseptic of choice is chlorhexidine ap-
plied via gentle oral rinsing for 1-2 minutes prior to
dental treatment. The American Heart Association
recommends chlorhexidine irrigation of the gingival
sulcus or painting chlorhexidine on isolated dried
gingiva for 3-5 minutes before treatment (79). How-
ever, Lofthus et al. (212) found no difference in the
magnitude of bacteremia after scaling or root plan-
ing for patients given subgingival irrigation with
chlorhexidine, saline or controls. Ordinarily, chlor-
hexidine will be used immediately prior to dental
treatment after the systemic antibiotic prophylaxis
has reached adequate blood levels, but chlorhex-
idine alone without systemic prophylaxis in low-risk
patients may be appropriate.
Sustained or repeat frequent interval usage of
chlorhexidine may not be recommended (253, 254),
as this may result in the selection of resistant
streptococci such as Streptococcus sanguis (335),en-
teric gram-negative rods, pseudomonads and enter-
ococci (105, 115, 116, 273, 321, 359). These organ-
isms can colonize the oral cavity and could induce a
type of endocarditis associated with higher mortality
rates (100) than that of,viridans streptococci.
Infective endocarditis
Infective endocarditis is a microbial infection of the
endocardial surface usually involving cardiac valves.
Prior to the antibiotic era, infective endocarditis was
uniformly fatal and was classified as acute, subacute
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Pallasch & Slots
or chronic depending on the rapidity of the develop-
ment of symptoms and subsequent death. Most en-
docarditis today would correspond to the old classi-
fication of subacute bacterial endocarditis. Infective
endocarditis is currently classified according to 1)
the offending microorganism (streptococcal, sta-
phylococcal, fungal, etc.), 2) whether the endocar-
ditis affects the original cardiac valve (native valve
endocarditis) or a prosthetic replacement valve
(prosthetic valve endocarditis) or 3) whether special
circumstances have been responsible for the acqui-
sition of the infective endocarditis, including noso-
comial (hospital-acquired) endocarditis or intra-
venous drug abuse (156).
The principal risk factors for infective endocarditis
are damage to the endocardium from congenital or
rheumatic heart disease, age-induced degeneration
of cardiac valves and/or repeated insult from turbu-
lent blood flow,which induces platelet and fibrin de-
position (nonbacterial thrombotic vegetation) and
subsequent infection via blood-borne bacteria (bac-
teremia). Contributing factors include the degree
and type of valvular damage, frequency and type of
bacteremia, microorganism pathogenicity, capability
of the microorganism to adhere to the cardiac valves
and host defense mechanisms (326).Infective endo-
carditis may be the result of a single episode of failed
host defense during thousands of repeat bacteremic
insults over a lifetime (252).
Epidemiology of infective endocarditis
The incidence of infective endocarditis ranges from
11 to 50 cases per million population per year (75,
122, 365, 376). A prospective infective endocarditis
study from the Netherlands found an incidence rate
of 19per million population (350).The prevalence of
infective endocarditis is 1.7 to 4.9 cases per 100,000
person-years in the United States and 2 per 100,000
person-years in England and Wales (156,326), com-
puted to about 8000-10,000 annual cases in the
United States (259, 326) and 1500 annual cases in
England and Wales (247).
The incidence of endocarditis has not declined
since the advent of antibiotics in the 1940s (16, 112,
185, 192, 246).This might suggest that: 1) antibiotic
prophylaxis may be improperly applied (ineffective
drug, dose or timing), 2) antibiotic prophylaxis may
not be effective, 3) antibiotic prophylaxis may not
be directed towards the correct at-risk population, 4)
predisposing factors for infective endocarditis have
changed (a decline in rheumatic and congenital
heart disease more than offset by an increase in car-
diac prostheses, intravenous drug abuse and a gen-
erally aging population), 5) infective endocarditis
may have “a life of its own” occurring randomly
without any significant influence of predisposing
factors or 6) infective endocarditis could be the re-
sult of a single failed host defense amid repetitive
cases of bacteremia (246, 252).
Men are at significantly greater risk for infective
endocarditis than women (156, 326). In the era be-
fore antibiotics, infective endocarditis was a disease
of the young, with an average age of 35 years (363).
More than one-half the current cases occur in people
over the age of 60 (376) with a risk ratio of 8.8 for
people over age 65 compared with those under age
65 (156, 326). Forty-two percent of institutionalized
elderly people may have at least one cardiac risk fac-
tor for infective endocarditis (113). The increase in
the average age of incidence of infective endocarditis
reflects the decrease in rheumatic heart disease sec-
ondary to the decline of rheumatic fever in industri-
alized countries, the remarkable success of open
heart surgery in correcting congenital heart defects
and the increased risk in elderly people due to
greater use of invasive vascular procedures (such as
catheters and parenteral nutrition), cardiac valve
prostheses, chronic immunosuppressive disease and
geriatric calcific aortic stenosis (156).In developing
countries, rheumatic heart disease remains a major
risk factor for infective endocarditis (221).
Risk factors for infective endocarditis
Certain forms of cardiac disease, notably valvular
dysfunction, predispose to infective endocarditis.
The infective endocarditis incidence of 1.7-4.9 cases
per 100,000 person-years in the general population
(156, 326) increases to 380-440 cases per 100,000
person-years with rheumatic heart disease and to a
mean 120 cases per 100,000 person-years with con-
genital heart disease (ranging from 220 per 100,000
person-years for surgically uncorrected ventricular
septa1defect to 20 per 100,000person-years for con-
genital pulmonic stenosis) (326).The risk for surgic-
ally corrected valvular disease is 60 per 100,000 per-
son-years (326).
The incidence of infective endocarditis in people
with mitral valve prolapse with regurgitation is 52
per 100,000 person-years. People with mitral valve
prolapse without regurgitation exhibit the same inci-
dence of infective endocarditis as the general popu-
lation (4.6 per 100,000person-years) (326).Individ-
uals with acquired cardiac valvular disease (stenosis
and regurgitation) have a proportional increase in
110

Table 2.Antibiotic prophylaxis requirements for various medical conditions
(79, 100, 103, 122, 198,252, 293)
Previous infectiveendocarditis
Cardiacvalve prosthesis
Coarctationof the aorta
Rheumaticheart disease
Hypertrophiccardiomyopathy
Ventriculoatrialshunt
Cardiactransplants w
Mitral valve surgery
Mitral valve prolapse with regu
Indwellingcatheter (
Congenitalheart disease:
Aortic stenosis
Bicuspid aortic valve
Complexcyanoticheart di
Patent ductus arteriosus
Systemicpulmonary atter
Tetralogyof FaHot
Ventricularseptal defect
Surgicallyrepaired in
hemodynamicabno
ns with residual
~
Prophylaxisrecommended Prophylaxisnot recommended
Secundum atrialseptal defect
without valvulardysfunction
planted defibrillators
or innocent heart murmurs
er surgerywithout residua for:"
Arterialgraftsd
Arterialgraftsd
' Antibiotic prophylaxis is indicated for thickened and/or redundant mitral valvesparticularly in men age 45 years or older.
' Lesionswith minimal or no hemodynamic abnormality.
'' Unsettled or controversial; probably only for major vessel grafts such as the aorta.
Anribioticprophylaxis may (but not must) be used for orthopedic prosthesis patients with insulin-dependent diabetes mellitus, rheumatoid arthritis or
advanced periodontal disease,on immunosuppressive drugs includingcorticosteroidsor who have been reoperated.
the risk ratio for infective endocarditis (326).A bicus-
pid aortic valve, which can be associated with coarc-
tation of the aorta, constitutes a risk for infective en-
docarditis (50, 104). Intravenous drug abusers have
a risk rate of infective endocarditis of 2-5% per year,
which is significantly higher than that associated
with rheumatic heart disease (290).A study showed
43%of 106patients with recurrent infectiveendocar-
ditis to be intravenous drug addicts (7).Forty-eight
percent of the people who died from intravenous
drug abuse overdose had signs on autopsy of either
past or present infective endocarditis (94).Accord-
ingly, those with the highest risk of infective endo-
carditis are patients with rheumatic heart disease,
cardiac valve prostheses (308-630 per 100,000 per-
son-years), a prior episode of infective endocarditis
(300-740 per 100,000person-years) and intravenous
drug abusers (326).
Table 2 places patients into two risk categories for
infective endocarditis: patients who may benefit
from antibiotic prophylaxis and those who may not
because they are at such minimal risk that the
dangers from the antibiotic therapy outweigh the
risk of contracting infective endocarditis (79, 100,
103, 122, 198,252, 293).
Microbiology of infective endocarditis
Streptococcal and staphylococcal strains cause the
vast majority of infective endocarditis. The propen-
sity of these organisms to elicit endocarditis is due
to at least three factors: 1)their main habitat on skin
and mucous membranes, which allows for frequent
entry into the blood as random or treatment-
induced bacteremia, 2) an exceptional ability to
adhere to damaged cardiac valves, and 3) an ability
to survive and thrive in the nonbacterial thrombotic
vegetation of the cardiac valve.
In the era before antibiotics, more than 80% of all
endocarditis cases were caused by streptococci (the
viridans group, enterococci, beta-hemolytic and
Streptococcuspneumoniae) (278, 343). In the 1970%
111

Pallasch & Slots
the incidence of streptococcal endocarditis began to
decline to the present 50-60%, with 30-40% of all
cases now due to viridans streptococci prominent in
but not exclusive to the human oral cavity (S. sang-
uis, Streptococcus mitis, Streptococcus anginosus,
Streptococcus saliuarius and Streptococcus mutans)
(278,343).At the New York City Hospital, S. sanguis
and S. mitis each accounted for 31-47% of all virid-
ans streptococcal endocarditis cases for a combined
total of 64-87% (278).S. sanguisis generally regarded
as the single most common causative micro-
organism for infective endocarditis (100).About 3%
of all infective endocarditis is caused by S. pneumon-
iae and a lesser percent by beta-hemolytic strepto-
cocci (278).
In a study of 2345 infective endocarditis episodes
from 1933-1987 (3431, the percentage of each group
of organismswas: streptococci (56.4%),staphylococci
(24.9%), gram-negative organisms (5.7%), others
(2.7%),
fungi (1%)
and culture-negative (9.3%).In 372
episodes of infectiveendocarditis in intravenous drug
abusers, 59.8%were due to staphylococci (almost ex-
clusively Staphylococcus aureus), 20.1% to strepto-
cocci,and 7.8%to gram-negative species (343).In 269
episodes (343)of early prosthetic valve endocarditis,
the percent of each organisms was: streptococci
(8.9%),staphylococci (47.9%),gram-negative organ-
isms (17.1%),fungi (13.4%),and other (11.2%).The
microbiologyof late prosthetic valve endocarditis (94)
was streptococci (36.4%), staphylococci (39.4%),
gram-negativespecies (10.5%),fungi (5.0%)and other
(5.5%).Nosocomial infective endocarditis is due pri-
marily to S. aureus,then Staphylococcus epidermidis,
Enterococcusand Candidaspecies (317).Pediatric in-
fective endocarditis in neonates is caused primarily
by S. aureus,S. epidermidis and Group B streptococci,
and in children under 2 years of age by viridans
streptococci, S. aureus, S. epidermidis and S. pneu-
moniae (333).
The decline in streptococcal infective endocarditis
probably reflects a rise in the proportion of intra-
venous drug abusers, prosthetic valve patients and
nosocomial-associated staphylococcal endocarditis
and the increase in endocarditis due to the HACEK
group of organisms: Haemophilus influenzae
Waemophilus parainfluenzae, Haemophilus aphro-
philus),Actinobacillus actinomycetemcomitans, Car-
diobacterium hominis, Eikenella corrodensand King-
ella kingae (11, 32, 167).The incidence of infective
endocarditis due to group B streptococci (Streptococ-
cus agalactiae)and to gastrointestinal Streptococcus
bouis and Enterococcusfaecalis is also increasing in
elderly people (278). The Enterobacteriaceae rarely
112
cause endocarditis (1671,and the list is long for very
rare causative microorganisms of endocarditis (304).
Pathogenesis of infective endocarditis
Healthy normal vascular endothelium is resistant to
microbial colonization (123,209).However, once this
endothelium, usually in the region of a cardiac valve,
is damaged by turbulent blood flow, direct trauma
or age- or disease-dependent degeneration, platelets
and fibrin may deposit on the valve surface to form
a nonbacterial thrombotic vegetation (209).If blood-
borne bacteria adhere to the surface of the nonbac-
terial thrombotic vegetation, additional layers of fi-
brin and platelets may cover these bacteria to isolate
them from host defenses and allow further growth
of the organisms (234).The bacterial density of the
infected vegetation can reach 109-101*colony-form-
ing units per gram of tissue (209). Bacteria dis-
lodging from the valvular vegetation produce the
characteristic bacteremia of endocarditis.
Microbial vegetation tends to occur in areas with
high pressure gradients and turbulent blood flow,
usually on the atrial aspect of the atrioventricular
valves and the ventral aspect of the aortic valve (226,
244). Microbes in a high-pressure stream moving
into a low-pressure sink deposit immediately distal
to the obstructed area in a process known as the
Venturi effect (281).Anatomical or physiologicalpro-
cesses (stenosis, calcification, improper valve clo-
sure, regurgitation and a high-velocity jet stream)
that cause turbulence (and a cardiac murmur) there-
fore contribute significantly to the process of infec-
tive endocarditis.
The major streptococcal and staphylococcal spe-
cies in endocarditis can readily attach to and multi-
ply on damaged cardiac valves (144, 188). Attach-
ment molecules of gram-positive bacteria (197) in-
clude microbial polysaccharide (dextran) glycocalyx
(85),lipoteichoic acid (161) and exopolymer “slime”
from catheter-infecting staphylococci (175). The
host receptors include selectins, integrins, fibronec-
tins and other glycoproteins (153,161, 188, 196,203).
Animal models of infective endocarditis
Rabbit (97, 128) and rat (291) aortic valve models of
infective endocarditis provide most of the evidence
for the role of bacteremia in the causation of infective
endocarditis and for the efficacyof antibiotic prophy-
laxis. In its simplest form, a plastic catheter is placed
across the aorticvalve to produce trauma, and inocula
of bacteria are injected intravenously to induce endo-

carditis. To cause endocarditis in many animals, the
catheter must be left in place (344)and large inocula
(lo4to 109colony-formingunits per ml) must be used
(136).These animal models indicate that a damaged
cardiac valve is required to initiate infective endocar-
ditis, that blood-borne microorganisms can adhere to
such valves and that antibiotic prophylaxis before or
even possibly after the onset of such a bacteremia
may prevent endocarditis. However, animal models
have been criticized because 1)the catheter must be
left in place to reliably establish infective endocar-
ditis, 2) the bacterial inocula needed to initiate infec-
tive endocarditis are much greater than the 10’to 102
colony-forming units per ml seen in human bactere-
mia, 3) the animal infective endocarditis is much
more acute than its human counterpart, and 4) very
large doses of antibiotics are sometimes needed to
prevent infectiveendocarditis in these animal models
while much smaller doses are used in humans (136,
372).
Diagnosis of infective endocarditis
The diagnostic criteria for infective endocarditis
have undergone change since William Osler (356)
proposed the classic model of the disease: 1)predis-
posing cardiac valve disease, 2) persistent bacterem-
ia, 3) embolic phenomenon (cutaneous and visceral)
and 4) active cardiac pathology. In 1981,von Reyn et
al. (355) stratified cases as definite, probable, poss-
ible and rejected, based on the variable presence of
blood cultures, new regurgitant murmurs, fever, vas-
cular phenomena, and predisposing heart disease.
Steckelberg et al. (324) simplified the von Reyn cri-
teria and included echocardiographic findings.
In 1994, Durack et al. (102) proposed new guide-
lines for diagnosis of infective endocarditis, consist-
ing of major criteria (typical blood cultures and a
positive transesophageal echocardiogram) and mi-
nor criteria (predisposing cardiac disease, fever, vas-
cular and immunological phenomena, suggestive
echocardiogram and microbiology). The positive
echocardiographic criteria include an oscillating in-
tracardiac mass (vegetation),abscess or new partial
dehiscence of a prosthetic valve. Typical blood cul-
tures would include viridans streptococci, HACEK
organisms, or community-acquired S. aureus or En-
terococcus. Blood culture criteria include samples
drawn 12 hours apart or 3 of 4 positive blood cul-
tures with the first and last sample drawn at least 1
hour apart. These “Duke” criteria have been judged
superior to those of von Reyn primarily because of
the inclusion of echocardiographic data (15), but
they have also been criticized for lessening the re-
liance on the classic Oslerian criteria of sustained
bacteremia, vascular phenomenon and predisposing
heart disease (356).
Signs and symptoms of infective endocarditis
Early therapeutic intervention with infective endo-
carditis can greatly reduce morbidity and mortality.
Unfortunately, the signs and symptoms of early in-
fective endocarditis can resemble simple influenza.
Initial signs and symptoms are fever, malaise,
night chills, anorexia, myalgia and arthralgia (44).
Other less common but important criteria are back
pain, polyarthritis, splenomegaly and anemic pallor
(44).A new or changing cardiac murmur is common.
Other signs and symptoms result from the formation
and dissemination of emboli to the brain (cerebral
emboli, cerebritis and mycotic aneurysms), kidney
(infarction and abscess), lung (cough, hemoptysis
and abscess), spleen (infarct), heart (arterial oc-
clusion and myocarditis) and skin (petechiae of the
palate, mucosa and conjunctiva).Additional periph-
eral phenomena include Osler’s nodes (smallpurple,
tender nodules in the pulp of fingers and toes),Jane-
way lesions (small, erythematous maculae on palms
and the soles of the feet), and Roth spots (pale-cent-
ered oval retinal hemorrhages). Progressive conges-
tive heart failure is an ominous sign.
Laboratory findings
Blood cultures are critical in the diagnosis and treat-
ment of infective endocarditis (194). Three blood
cultures should be taken minimally at 1 hour apart
over 24 hours (194).Two positive blood cultures are
diagnostic for infective endocarditis in 78% of cases
and 3 positive cultures in over 90% of cases (194).
Culture-negative endocarditis occurs in approxi-
mately 5% of cases and can be due to antibiotics
given prior to hospitalization or to difficulty in isol-
ating and growing certain microorganisms, includ-
ing the HACEK group, nutritionally deficient strepto-
cocci (Bs or pyridoxal-dependent), Brucella, Le-
gionella, Corynebacterium, Neisseria, Nocardia,
Chlamydia, mycobacteria, fungi and Rickettsieae
(184, 194).
Other laboratory findings in infective endocarditis
(184,194)include a normochromic, norniocytic ane-
mia (79-go%), elevated erythrocyte sedimentation
rate (90-100%), microscopic hematuria (30-50%),
proteinuria (50-65%), leukocytosis (20-30%), leuko-
penia (5-15%), circulating immune complexes (65-
113

Pallasch & Slots
loo%), rheumatoid factor (5-50%) and cryoglobuli-
nemia (20-95%).
Incubation period and time to hospitalization
The incubation period for infective endocarditis de-
notes the time from the onset of the bacteremia (and
assumed valvular colonization) to the first signs and
symptoms of the disease. A bacteremic event must
have occurred within the range of a known incuba-
tion period in order to be etiologically implicated in
endocarditis. However, several factors make it diffi-
cult to impossible to delineate the proximate cause
of infective endocarditis.
It is not possible to distinguish between a case of
bacteremia due to a specific event (dentaltreatment)
and one of the spontaneous random cases of bactere-
mia that occurwith dailyliving (100,110).DNA analy-
sis, antibiograms and other microbial fingerprinting
techniques can determine the simultaneouspresence
of the same strain in the mouth, blood and cardiac
tissue and help establish causality. Nevertheless,
these methods cannot prove that the organism enter-
ed the blood from a specific dental treatment rather
than from eating or oral hygiene procedures that oc-
curred before or after the dental appointment.
The median incubation period for 76 cases of in-
fective endocarditis was assessed to be 5 days for en-
terococcal and 7 days for streptococcal cases, and
85% of all cases showed symptoms within 2 weeks
(323).Six of the 76 cases were judged to have an in-
cubation period of 1 month or greater (323).A study
in the Netherlands (351) lists a mean interval of 14
days (range of 0-175 days) between the dental pro-
cedure and the onset of endocarditis signs and
symptoms. Intravenous drug abuse patients usually
show an incubation period of less than 1week (290).
It then appears that any bacteremic event 30 days
or longer prior to the onset of streptococcal infective
endocarditis is highly unlikely as a candidate for its
proximate cause (351).A bacteremic event occurring
7 and 14 days prior to the onset of a streptococcal
infective endocarditis has only a statistical prob-
ability of causation of 50% and 15%, respectively
(323). Most probably, the signs and symptoms of
streptococcal endocarditis begin 2 weeks or less after
the initiating bacteremic event (44, 278).
In acute endocarditis, the incubation period for S.
aureus (the major causative organism) appears to be
2-5 days in humans and as short as 8-24 hours in
laboratory animals, compared to 1-7 days for other
organisms (53, 54, 114, 189, 3401. S. pneumoniae,
Streptococcus pyogenes, Neisseria meningitidis and
Neisseria gonorrhoeae may also cause acute endocar-
ditis and exhibit a short incubation period (363).
Infective endocarditis from S. epidermidis has a
relatively indolent clinical course and exhibits an in-
cubation period longer than that of streptococci. Sta-
phylococcal endocarditis is rarely, if ever, of oral ori-
gin (108, 109, 272). Fastidious, slow-growing micro-
organisms such as nutritionally variant streptococci
and the HACEK group may show relatively long in-
cubation periods.
The time from the onset of endocarditis signs and
symptoms to the presentation of the patient at the
hospital (time of diagnosis) can vary from 0 to 400
days. These unlikely extremes may be due to faulty
retrospective data. In 5 clinical studies (220,260,261,
355, 3651, the mean time to hospitalization was 58
days (range of means, 31-73 days) for viridans
streptococci, 12days (range of means, 8-19 days) for
S. aureus and 37-41 days for S. epidermidis. A study
in the Netherlands found the mean time to hospital-
ization to be 27 days for native valve endocarditis
and 11.5days for prosthetic valve endocarditis (350).
For S. aureus endocarditis, the mean duration of ill-
ness before hospitalization was 6.5 days for drug ad-
dicts and 6.0 days for nonaddicts with a range of 1
to 60 days (57).
The duration of the time to hospitalization is in-
fluenced by the organism virulence, host resistance,
and antibiotic therapy prior to hospitalization given
mistakenly to treat the early influenza-like symp-
toms of infective endocarditis. In the Bergen Univer-
sity Hospital, the time to hospitalization for sta-
phylococcal infective endocarditis was 2.8 days with
no antibiotic therapy and 10.4 days with antibiotics,
and for streptococcal infective endocarditis 26.6 days
with no antibiotics and 46.6 days with antibiotics
(202). Thus, symptomatic treatment of infective en-
docarditis before hospital diagnosis can substantially
delay the onset of diagnosis and treatment.
A sterile blood culture 2 months after termination
of antibiotic therapy defines clinical cure. The cure
rate of infective endocarditis is greater than 90%for
viridans streptococci, 75-83% for gram-negative or-
ganisms, 60-75% for S. aureus and 40-50% for fungi
(139).The survival rate of native valve endocarditis
was 60% at 5 years and 40% at 10years in one survey
(139) and 81% at 10 years in another study (341).
The relapse rate of infective endocarditis, defined as
infection with the same organism within 6 months
of the previous episode (292),is 2.7-4% (325, 341).
The recurrence rate of infective endocarditis is 4.5%
(3411, with an average recurrence interval of 3.4
years (292).
114

Antibiotic prophylaxisand the medically compromisea panenr
Complications of infective endocarditis
Cardiac or extracardial complications can arise from
infective endocarditis. The most serious and life-
threatening complication is left side (congestive)
heart failure (325). If this is unresponsive to medi-
cation within 24-48 hours, mitral or aortic valve re-
placement is usually indicated. Other cardiac com-
plications include myocardial or perivalvular ab-
scesses, pericarditis, myocardial conduction defects
(arrhythmia),and myocardial infarction due to coro-
nary artery embolism (325).
Most extracardial complications are due to the pe-
ripheralization of emboli detached from soft, friable
cardiac vegetation to the brain, lungs, spleen, kid-
neys or heart. These emboli seed most often to the
brain along the path of the middle cerebral artery,
commonly resulting in stroke. Other central nervous
system complications include leakage or rupture of
mycotic aneurysms (due to destruction or aneurys-
mal dilation of the arterial wall) and metastatic in-
fected emboli producing brain abscesses or menin-
gitis (200). Emboli in S. aureus endocarditis occur
early and are often multiple while the emboli of viri-
dans streptococcal endocarditis are almost always
single and occur later in the disease process (200,
325).
Other adverse sequelae include headache (often
a warning sign of mycotic aneurysm or impending
cerebral hemorrhage), metastatic infection, renal
failure, septic arthritis, and immune phenomena
such as Janewaylesions, Osler nodes, and Roth spots
(200,325).
Dental causation of infective endocarditis
Dental treatment rendered in the months preceding
the onset of the endocarditis is commonly blamed
for the disease. Such attitudes are fostered by an ig-
norance of the medical literature on endocarditis,
lack of any reasonable consideration of the incuba-
tion period of the disease, the inability to conceptu-
alize random spontaneous bacteremias, and the
need to blame somebody. Research data indicate
that dental treatment is responsible for only a small
percentage of cases of infective endocarditis.
Oral streptococci cause less than 25% of all infec-
tive endocarditis cases (192).Fewer than 15%of pa-
tients with infective endocarditis had medical or
dental treatment in the previous 3 months (58, 110,
173), and a much smaller percentage within a few
weeks of the onset of the infective endocarditis. Gun-
theroth (150) and the Royal College of Physicians of
London and the British Cardiac Society (16) indi-
cated that 4% or less of all infective endocarditis
cases are related to dental treatment-induced bac-
teremia. Oakley (2471 suggested that if “spon-
taneous” bacteremia causes 96% of all infective en-
docarditis, they rather than the dentist may also
have caused the remaining 4%. Guntheroth (150)
stated: “Afterall, blaming the dentist for endocarditis
is probably no more reasonable that blaming the
cardiologist for a myocardial infarction.” Durack
(101) concluded that it is difficult to establish any
single procedure known to cause bacteremia as the
“proximate cause” in a case of endocarditis and even
more difficult to prove the failure of a practitioner to
administer antibiotics as the direct cause of endo-
carditis.
Antibiotic prophylaxis to prevent endocarditis
The rationale for antibiotic prophylaxis to prevent
infective endocarditis assumes that: 1) specific car-
diac defects (rheumatic heart disease, congenital
heart disease, mitral valve prolapse and cardiac valve
prostheses) predispose to infective endocarditis; 2)
the majority of infective endocarditis cases are
caused by streptococci and other microbes suscep-
tible to the recommended antibiotics; 3) the risk for
infective endocarditis is increased due to bacteremia
from oral, gastrointestinal or genitourinary manipu-
lation; 4) antibiotics decrease the incidence or sever-
ity of such cases of bacteremia; and 5) even without
bactericidal activity, antibiotics prevent microbial
adherence to damaged cardiac valves or suppress
the growth of attached bacteria (192).
The above assumptions are more or less true de-
pending on specific circumstances; however, they
must be placed in the context of the specific clinical
situation and the process of risk-benefit determi-
nation. Kaye (1921 determined that antibiotic
prophylaxis may prevent at most 10%of all endocar-
ditis cases. A prospective study in the Netherlands
(351) indicated that antibiotic prophylaxis prevents
5.7% of all native valve endocarditis and 3.8% of all
prosthetic valve endocarditis. It then follows that, if
antibiotic prophylaxis is 49% effective, this practice
would prevent 5 endocarditis cases per year in the
Netherlands, with a population of 14.5 million (353)
and, by extrapolation, 50 endocarditis cases per year
in the United States assuming 145 million people at
risk for endocarditis. Optimal antibiotic prophylaxis
might prevent 240-480 cases of endocarditis annu-
ally in the United States (103).
The proponents of antibiotic prophylaxis object to
115

Pallasch & Slots
such data based on their conviction that antibiotic
prophylaxis is highly effective and that endocarditis
is so serious a disease that antibiotic prophylaxis is
mandatory regardless of any contradictory infor-
mation. The issue is unlikely to be settled soon, as
the appropriate double-blind study would require
6000 at-risk patients (101) and probably would en-
counter strong ethical concerns by institutional hu-
man experimentation committees. Possibly all that
can be agreed on now is that the effectiveness of
antibiotic prophylaxis in infective endocarditis has
not been determined in controlled human clinical
trials (79, 150,311).
The American Heart Association, British Society
for Antimicrobial Chemotherapy and others have de-
veloped guidelines for antibiotic prophylaxis in in-
fectiveendocarditis based upon in vitro studies, clin-
ical experience, animal models and assessment of
the bacteria likely to produce a bacteremia from a
given site and most likely to produce infective endo-
carditis (79).The guidelines do not include consider-
ations of risk-benefit (number of people harmed by
the preventive measures versus by the disease) and
cost-benefit (money saved by preventing rather than
treating the disease).
The bactericidal action of penicillins occurs too
slowly to effectivelykill blood-borne bacteria within
seconds or a few minutes (103, 135, 214). Instead,
antibiotics in endocarditis prophylaxis may alter
bacterial cell surfaces (86, 294, 373) to reduce mi-
crobial attachment to damaged cardiac endothelium
or decrease the ability of attached microbes to multi-
ply. Future chemicals designed to prevent microbial
adherence to damaged cardiac valves may serve as
adjuncts to antibiotic prophylaxis or as the sole pre-
ventive agents against endocarditis.
Antibiotic prophylaxis regimens
Antibiotic prophylaxis should be instituted for pa-
tients at high risk for contracting endocarditis and
should be avoided for low- to no-risk patients. Table
2 delineates these two categories of patients.
Table 3 lists the guidelines for infective endocar-
ditis prevention as published by the American Heart
Association in 1990 and by the British Society for
Antimicrobial Chemotherapy in 1992.The guidelines
of the Swiss Working Group for Prophylaxis of Bac-
terial Endocarditis, the European Society of Cardi-
ology and the Scandinavian Society for Anti-
microbial Chemotherapy are similar to the those of
the British Society for Antimicrobial Chemotherapy.
New American Heart Association guidelines may in-
clude single or optional second dose prophylaxis,
better delineation of at-risk dental procedures and
posttreatment prophylaxis in selected cases.
The 1990 American Heart Association guidelines
made significant changes from the previous recom-
mendations: 1)the abolishment of the need for par-
enteral prophylaxis for patients with cardiac valve
Table 3. Oral infective endocarditis antibiotic prophylaxis regimens for dental procedures according to
the American Heart Association” (79)and the British Societyfor Antimicrobial Chemotherapyb (308,309)
American Heart Associationc British Societyfor Antimicrobial Therapy
Adults: 3 g 1hour prior to the procedure and no second dose
Children: 5-10 years: half adult dose
Under 5 years: quarter adult dose
Not recommended
Amoxicillin
_ _ ~
Adults: 3 g 1hour prior to the procedure and 1.5g 6 hours
after the initial dose
Children: 50 mg/kg initially and 25 mglkg
6 hours later (total dose not to exceed adult dose)
Adults: ethylsuccinate (800rng) or stearate (1g) 2 hours
before procedure; half the first dose 6 hours after initial dose
Children: 20 mg/kg initially and 10mglkg 6 hours later
(total dose not to exceed adult dose).
____~
Erythromycin
~.
_ _ ~ _
Clindamycin
___-
Adults: 300 mg 1hour before procedure and 150mg 6 hours
after initial dose
Children: 10mglkg initially and 5 mgikg 6 hours later
(total dose not to exceed adult dose)
Adults: 600 mg single oral dose 1hour before procedure and
no second dose
Children: 5-10 years: half adult dose
Under 5 years: quarter adult dose
~~ ~
a For dental procedures known to induce gingival or mucosal bleeding, including professional cleaning except simple adjustment of orthodontic appliances,
’) For denral extraction, scaling or periodontal surgery under local anesthesia or no anesthesia: for special patients who should be referred to a hospital,
‘ Revised American Heart Association guidelines are anticipated in 1996-1997.
fillings above the gingiva and local anesthetic injections (except intraligamentary injections).
see references 308, 309.
116

prostheses, 2) recognition of hypertrophic cardio-
myopathy as an endocarditis risk, 3) prophylaxis not
recommended for patients with cardiac pacemakers
or implanted defibrillators, for mitral valve prolapse
without regurgitation except for men over age 45
years and for local anesthetic injections (except in-
traligamentary) and restorations above the gingiva,
4) the acknowledgement that these recommenda-
tions are not the standard of care for all cases, 5) that
all dental care should be completed before cardiac
surgery, 6) that all at-risk dental patients should
maintain the best possible oral health, and 7) that
random cases of bacteremia may result from poor
oral hygiene or periodontal and periapical infections
(79).
The 1990 American Heart Association guidelines
also recommended amoxicillin rather that penicillin
V as the antibiotic of choice, since the blood level for
3 g of amoxicillinat 1hour is 30 pg/ml and at 5 hours
is 3.6 pg/ml, but for 2 g of penicillin V is only 14 pg
and 0.7 pg, respectively (301). A recent study indi-
cates that an initial dose of 2 g of amoxicillin may
provide adequate blood levels for prophylaxis prior
to dental or oral treatment procedures (83).The 800-
mg dose of erythromycin ethylsuccinate recom-
mended by the American Heart Association has been
questioned as inadequate, since 400 mg of the succi-
nate salt is more bioequivalent to 250 mg than to 500
mg of other erythromycins (230,329).The American
Heart Association suggests that both doses would
achieve adequate blood levels against streptococci,
that the higher doses of the succinate salt will result
in greater gastrointestinal upset and that substi-
tutions of other erythromycin preparations are ac-
ceptable (80).It would seem best to double the dose
of the erythromycin ethylsuccinate preparation
(1600mg for the initial dose and 800 mg for the sec-
ond dose) or to use an erythromycin base or stearate
preparation.
A. actinomycetemcomitansis of particular concern
since it is closely associated with localized juvenile
periodontitis, occurs in about one third of advanced
cases of adult periodontitis and may be resistant to
the penicillins (313).A. actinomycetemcomitans en-
docarditis has developed after periodontal surgery or
other dental procedures despite penicillin or ery-
thromycin and vancomycin prophylaxis (312).If the
requisite culture indicates high numbers of penicil-
lin-resistant A. actinomycetemcomitans in endocar-
ditis-susceptible individuals, systemic tetracycline
hydrochloride (250 mg 4 times daily for 21 days) or
metronidazole and amoxicillin (250 mg of each 3
times daily for 8 days) may be used to eradicate the
organisms prior to any dental treatment. After a 1-
day wait, dental treatment should then be carried
out utilizing the standard American Heart Associ-
ation or the British Societyfor Antimicrobial Chemo-
therapy regimens directed against viridans strepto-
cocci (253).
The 1992British Societyfor Antimicrobial Chemo-
therapy guidelines differ from those of the past in:
1) new pediatric doses; 2) hospital referral for pa-
tients with a cardiac prosthetic valve requiring gen-
eral anesthesia or with a history of previous endocar-
ditis and for patients undergoing general anesthesia
who are allergic to penicillin or who have had peni-
cillin more than once in the previous month; 3) re-
placement of vancomycin with teicoplanin; and 4)
replacement of erythromycin with clindamycin (308,
309). The British Society for Antimicrobial Chemo-
therapy states that only one case of pseudomembra-
nous colitis has been reported after a single dose of
clindamycin (308). Other British Society for Anti-
microbial Chemotherapy recomI;,endations include
avoidance of intraligamentary injections in endocar-
ditis at-risk patients and the application of a 1%
chlorhexidine gel to dry gingiva or a 0.2% chlorhex-
idine mouthwash 5 minutes prior to dental pro-
cedures (308, 309). The British Society for Anti-
microbial Chemotherapy recommends endocarditis
antibiotic prophylaxis only for dental procedures
that involve dental extraction or periodontal scaling
or surgery, whereas the American Heart Association
currently recommends prophylaxis for all dental
procedures that induce gingival bleeding.
Dentist and physician compliance
The compliance rate of dentists and physicians with
recommended antibiotic prophylaxis regimens for
infective endocarditis appears to fall short of satis-
factory performance. In surveys from 1975-1984,
only 15-20% of United States dentists complied with
the American Heart Association guidelines for endo-
carditis prevention (39, 98, 158, 285). By 1989, 39-
55% of United States dentists at least recognized the
current American Heart Association oral penicillin V
dosage (241, 287). In a United States dental school
teaching endocarditis chemoprophylaxis, only 35%
of patients received the correct antibiotic regimen
and then in only 11%of situations with possible bac-
teremia (237). In a 1988 survey, 55-93% of United
States dentists used less than the recommended in-
itial antibiotic dose and 37-90% Iess than the recom-
mended postoperative dose (286). In 1987 in the
Southwest region of the United Kingdom, 71% of
117

Pallasch & Slots
dentists employed the 3 gram British Society for
Antimicrobial Chemotherapy amoxicillin dose (298).
In a 1990 study in Denmark, 76% of dentists iden-
tified dental patients with cardiac prostheses but
only 31% used antibiotic prophylaxis for deep scal-
ing in such patients (151).
In 1989,only 27%of surveyed United States phys-
icians identified the correct antibiotic regimens for
various at-risk cardiac patients versus 39% of United
States dentists (241).In a 1984 London survey, only
17-49% of various medical practitioners recognized
the recommended regimens of the British Societyfor
Antimicrobial Chemotherapy and of the American
Heart Association (142). In a 1992 survey in the
Netherlands, only 69% of the patients at-risk for in-
fectiveendocarditis ever received any medical advice
about antibiotic prophylaxis and only 23% received
antibiotic prophylaxis (352). In 1968 in Belfast and
Glasgow, only 19% of patients received medical ad-
vice regarding the risk of dental treatment and infec-
tive endocarditis; in 1989,this had increased to 36-
41% (96).In a survey of United States hospital prac-
tice regarding infective endocarditis chemoprophyl-
axis for cardiac valve prosthesis patients, 61% of pa-
tients received some type of antibiotic prophylaxis
prior to invasive medical procedures but only 30%
conformed to the American Heart Association guide-
lines (38). In a Canadian hospital, 22% of indicated
patients received the American Heart Association
prophylaxis regimen (288).
Overprescribing also occurs with antibiotic
prophylaxis. At least 20% of Scottish dentists used
antibiotic prophylaxis when it was not warranted
(40).In 1988, Sadowsky & Kunzel (286) showed that
19%of United States dentists considered myocardial
infarction, 40% coronary bypass, and 70% a history
of rheumatic fever without rheumatic heart disease
as an indication for endocarditis chemoprophylaxis
although no such indications ever existed.
Failure of antibiotic prophylaxis
In contrast to the lack of clinical scientific evidence
on the effectiveness of antibiotic prophylaxis for en-
docarditis, data exist on the failure of such prophy-
laxis to prevent endocarditis. In 1983, the American
Heart Association reported 52 apparent failures of
infective endocarditis chemoprophylaxis; 12% re-
ceived the standard 1977 regimen and 88% a non-
recommended schedule (99).The offending micro-
organism in most of the cases was susceptible in vi-
tro to the prophylactic antibiotic. Some cases did not
reveal an incubation period consistent with that for
streptococci, raising the possibility that the anti-
biotic prophylaxis was effective but that the causa-
tive bacteremia occurred subsequent to the discon-
tinuation of the prophylaxis (via spontaneous bac-
teremia).
Antibiotic prophylaxis may not completely or even
substantially reduce postoperative bacteremia (357).
Macrolide antibiotics (erythromycin,josamycin) and
placebo used after dental extraction were associated
with the same magnitude of bacteremia (49).Penicil-
lin V or amoxicillin may fail to eliminate bacteremia
after dental extraction (8,9,152,160,166)and prevent
endocarditis in humans (88, 99, 185, 227, 360). The
reason that previous studies did not detect significant
numbers of bacteria in blood after antibiotic prophy-
laxis may in part have been inadequate microbial iso-
lation techniques. The penicillins are not rapidly bac-
tericidal against many organisms (135,214).
Microbial resistance to antibiotic prophylaxis
Repeated use of antibiotic prophylaxis can result in
the selection of drug-resistant oral streptococci,
which may appearwithin afewhours to days and per-
sist for weeks to months. Selectionof resistant organ-
isms may result in loss of efficacyand/or the develop-
ment of more pathogenic bacteremic organisms.
The problem of resistance is particularly important
for erythromycin (307). Erythromycin regimens for
infective endocarditis prevention given on 3 separate
occasions 1 week apart resulted in resistant oral
streptococci that persisted for 23-43 weeks (157).Two
doses of erythromycin (1.5g followed 6 hours later by
0.5 g) caused a substantial increase in streptococcal
resistance detected at 48 hours and persisted above
preantibiotic levels for 3months (225).
Fleming et al. (118) detected an increase in
streptococcal resistance to penicillin V prescribed
weekly for 3 weeks but found the resistant strains
to comprise less than 1%of total oral streptococcal
isolates. High resistance of many oral streptococci (S.
sanguis) appeared after 3 g of amoxicillin given
weekly for up to 5weeks;however,the resistance had
greatly declined by 6 weeks after the last antibiotic
dose (319).In patients with no oral penicillin-resis-
tant viridans streptococci prior to prescribing 4 g of
penicillin V over 10hours, resistant streptococci ap-
peared at 6 hours after the first dose in 31% of sub-
jects and persisted up to 9 days (201). Suggestions
have been made regarding reasonable spacing be-
tween dental appointments to reduce the problem
of antibiotic-resistant streptococci: 6 weeks (319),2
weeks (3071,9 days (201)and 7 days (79).The Amer-
118

ican Heart Association recommends a 7-day interval
between appointments, with as much work done as
possible at each appointment (79). The British
Society for Antimicrobial Chemotherapy advises 14
days (307)and the use of vancomycin and teicoplan-
in with gentamicin parenterally for patients who
have taken penicillin more than once in the previous
month (308).
Risk-benefit and cost-benefit of antibiotic
prophylaxis
Present standards for official approval of a new drug,
therapy or treatment require at least a risk-benefit
analysis,but regimens for the prevention of infective
endocarditis or any other microbial metastatic dis-
ease have not received such evaluation.
One to ten percent of people given therapeutic
penicillin experience allergy (315, 349); the chance
of an allergic reaction with any given course of peni-
cillin therapy is 0.7-4% (256). Retrospective studies
(362)suggest that the incidence of penicillin allergy
varies with its route of administration: oral (0.3%),
intravenous (2.5%)and intramuscular (5%),but this
low incidence ascribed to oral penicillin has been
questioned due to limited data (177, 257). High oral
amoxicillin doses (3.5g) exhibit an allergy rate simi-
lar to that of intramuscular penicillin, indicating that
the dose rather than the route of administration is
the deciding factor in penicillin allergy (364).
The penicillins are the most common cause of
anaphylactic death in the United States, accounting
for 75%of all cases (258) and at least 400-800 annual
deaths (348).Mild local anaphylaxis may occur at a
rate of 1per 200 patient courses of the drug and se-
vere reactions at a rate of 1per 2000 to 2500 patient
penicillin exposures (6).A study of 32,430 monthly
benzathine penicillin injections for rheumatic fever
prevention resulted in an overall 3.2% allergy rate
and 0.2%for systemic anaphylaxis (180).The fatality
rate for penicillin by all routes of administration may
be 1 per 60,000 patient courses or 16 per million
population (177).
Assuming an infective endocarditis incidence rate
of 11-50 cases per million people per year, a 25-40%
mortality rate, and a 16 per million population mor-
tality rate from penicillin, Pallasch (252) calculated
that the death rate of endocarditis exceeded that of
penicillin anaphylaxis only with an endocarditis inci-
dence rate of 50 per million population and a mor-
tality rate of 40% (highest incidence and highest
mortality). Tzukert et al. (345) determined that 1.36
people per million population are likely to die from
penicillin anaphylaxis to prevent infective endocar-
ditis, whereas only 0.26 deaths per million popula-
tion are due to dentist-induced endocarditis. The
authors concluded that penicillin prophylaxis for in-
fective endocarditis is justified only for high-risk pa-
tients and only by oral administration.
Bor & Himmelstein (27)calculated that, in 10 mil-
lion patients with mitral valve prolapse undergoing
dental procedures, 47 nonfatal and 2 fatal cases of
infective endocarditis would occur without anti-
biotic prophylaxis. With penicillin prophylaxis, 5
cases of infective endocarditis would still occur
(prophylaxis 90% effective),and 175would die from
penicillin anaphylaxis (27).Using an oral penicillin
fatality rate of 0.9 per million population, Clemens &
Ransohoff (67) calculated that oral penicillin would
prevent 2.3 cases of endocarditis per million people
with mitral valve prolapse exposed to bacteremia,
but 0.9 deaths would occur from penicillin allergy. In
total, 1.4 lives per million people with mitral valve
prolapse would be saved at a cost of USD 2.6 million.
Gould & Buckingham (143) concluded that anti-
biotic prophylaxis prior to tooth extraction in endo-
carditis at-risk patients would prevent 5-7 deaths
and 22-35 nonfatal endocarditis cases per 10,000
dental extraction, resulting in a cost saving of GBP
300,000. Bor & Himmelstein (27) found the cost of
erythromycin antibiotic prophylaxis to be USD 20
million to prevent 35 cases of mitral valve prolapse
infective endocarditis (USD 570,000 per case).
Deuereux et al. (92) concluded that antibiotic
prophylaxis is reasonably cost-effective if restricted
to mitral valve prolapse with regurgitant murmurs.
If the annual incidence of infective endocarditis in
the United States is 8000 cases (259, 326) and the
lifetime cost of treatment is USD 46,000 per case
(1211,the total annual cost for treatment of infective
endocarditis approximates USD 368 million. Anti-
biotic prophylaxis may prevent 5-8% of endocarditis
cases and thus save annually USD 18.4 to 29.5 mil-
lion. If the cost of a 9-capsule amoxicillin dose is
about USD 6, the financial break-even point is 3-5
million doses per year. On a strict economic basis,
the prescription of more than 3-5 million prophy-
laxis dose regimens annually in the United States
may not be cost-effective.
Since viridans streptococci are responsible for
40% of the 8000 annual endocarditis cases (2781,
which have a 10%mortality rate (1391, these organ-
isms may cause 320 fatal endocarditis cases every
year in the United States. Ten percent of all endocar-
ditis cases may be prevented by antibiotic prophy-
laxis (192),translating to 32 fatal cases due to virid-
119

Pallasch & Slots
ans streptococci. If 5%are at known risk for infective
endocarditis and 200 million adults at 1.6 visits an-
nually seek dental care in the United States (320mil-
lion total visits annually), the prevention of 32 fatal
endocarditis cases (assuming all were due to dental
treatment) would require 16 million doses of amoxi-
cillin at USD 6, equal to USD 96 million or USD 3
million per case. If dental treatment is responsible
for 5%of the annual endocarditis cases in the United
States (400 cases) and the cost is USD 96 million to
premedicate all known at-risk patients, and as-
suming antibiotic prophylaxis is 100%effective, the
cost to prevent each endocarditis case would be USD
240,000 (versus USD 46,000 to treat each endocar-
ditis case). The validity of these elementary calcu-
lations needs to be verified in appropriate economic
models.
Antibioticprophylaxisindicated
Rheumatic heart disease
Rheumatic fever is a delayed, nonsuppurative sequel
to an upper respiratory (pharyngeal) infection with
group A streptococci and probably represents a hy-
persensitivity reaction to streptococcal antigens (22).
The incidence of rheumatic fever has greatly de-
clined in Europe and North America but remains
high in developing countries (22). Major manifes-
tations of rheumatic fever (Jones criteria (81)) in-
clude polyarthritis, carditis, subcutaneous nodules
in joint areas, erythema marginatum (characteristic
pink rash) and chorea (rapid, purposeless, involun-
tary movements of the face and extremities). Minor
Jones criteria include arthralgia, fever,prolonged P-R
interval and elevated erythrocyte sedimentation rate
and C-reactive protein. Strong support for the diag-
nosis of rheumatic fever is the presence of two major
or one major and two minor criteria, and evidence
of a recent group A streptococcal infection, such as
positive throat culture and rapid streptococcal anti-
gen test or an elevated or rising antibody titer (81).
A history of rheumatic fever is important because
of possible rheumatic heart disease and possible pre-
vious use of antibiotics to prevent recurrent rheu-
matic fever. Inflammatory rheumatic carditis may re-
sult in cardiac valve damage (rheumatic heart dis-
ease),particularly to the mitral valve, with a risk rate
for endocarditis of 380-440 cases per 100,000person-
years (326).Individuals with rheumatic heart disease
require endocarditis chemoprophylaxis but rheu-
matic fever patients with no rheumatic heart disease
require no prophylaxis (79,811.Patients at risk for en-
docarditis taking benzathine, intramuscular penicil-
lin, oral penicillin or erythromycin to prevent recur-
rent rheumatic fever need alternative antibiotic
prophylaxis when exposed to bacteremia, either ery-
thromycin or clindamycin as listed in Table 3.
Congenital heart disease
Congenital heart disease occurs at a rate of 4-10
cases per 1000live births (170) and may take several
forms (191): right to left cardiac shunts (atrial and
ventricular septal defects), communication between
the aortic and pulmonary arteries (patentductus art-
eriosus), obstructive lesions (tetralogy of Fallot) and
obstructive regurgitant lesions (aortic stenosis, pul-
monary stenosis, bicuspid aortic valve, coarctation
of the aorta and hypertrophic cardiomyopathy).
Congenital heart disease that has not been surgically
corrected carries a high risk for infective endocar-
ditis: 180-217 cases per 100,000person-years for aor-
tic stenosis (130, 299) and 145-220 per 100,000per-
son-years for ventricular septal defect (130, 326).
With surgical correction, the risk of endocarditis with
ventricular septal defect or patent ductus arteriosus
is minimal or none (370).
Aortic stenosis accounts for 3.3-11.0% of all con-
genital heart disease, but the disorder can also derive
from rheumatic heart disease, secondary calcifi-
cation of congenital bicuspid aortic valves or pri-
mary degenerative calcification of normal aortic
valves with increasing age (299).Individuals with hy-
pertrophic cardiomyopathy have an inheritable
asymmetry of the left ventricle that predisposes to
structural mitral valve deformity. If mitral regurgi-
tation is present, antibiotic prophylaxis is indicated
(264). About 5% of people with idiopathic hyper-
trophic subaortic stenosis eventually develop endo-
carditis (56).
Coarctation of the aorta is a congenital narrowing
of the aorta usually just beyond the origin of the left
subclavian artery in the aortic isthmus and consti-
tutes about 6% of all congenital heart disease (231).
This disorder is more common in men and is char-
acterized by hypertension in the arms, bounding ca-
rotid pulse and absent or delayed femoral pulses. It
is frequently associated with other cardiac abnor-
malities (bicuspid aortic valve, ventricular septal de-
fect and mitral valve regurgitation) which even after
corrective surgery, may place these patients at very
high risk for endocarditis (231).In later life, people
with surgically corrected coarctation of the aorta ex-
perience aortic valve calcification with murmurs that
also carries a risk for endocarditis (328).
120

Bicuspid aortic valve may be either congenital
or acquired (104) and is found in approximately
1% of the United States population, or about 2.5
million people (279). Some individuals with bicus-
pid aortic valve may function normally or become
only mildly dysfunctional for life, but for others
the valve becomes fibrotic, thickened and calcified,
leading to aortic stenosis and regurgitation (191,
279). Bicuspid aortic valve and coarctation of the
aorta commonly coexist. Bicuspid aortic valve may
only be discovered after infective endocarditis has
occurred.
Cardiac valve prostheses
A patient with a prosthetic cardiac valve is at very
high risk for contracting infective endocarditis: 308-
630 cases per 100,000 patient-years, 0.32-1.2% per
patient year or 1-4% during the lifetime of the valve
(93, 326). Prosthetic valve endocarditis accounts for
12-33% of all infective endocarditis and carries ap-
proximately the same risk as rheumatic heart disease
(326).The mortality rate for prosthetic valve endo-
carditis is about 40-50% (range, 25-64%) (326).
Staphylococci account for about 50% of all pros-
thetic valve endocarditis. The skin is the most com-
mon source of staphylococci, and dental procedures
may rarely if ever be the cause of staphylococci en-
docarditis (367).
Kawasaki disease
Kawasaki disease is a generalized vasculitis of un-
known etiology (possibly microbial) that usually oc-
curs before age 5 and is rare after age 8 years (82,
84).Kawasaki disease along with rheumatic fever are
the two leading causes of childhood-acquired heart
disease in the United States (339). The disease is
characterized by fever, mucosal inflammation, indu-
rative edema of the hands and feet, desquamation of
the fingertips, oral erythema and strawberry tongue,
arrhythmia, pericardial inflammation and coronary
artery aneurysms (82).Approximately 1%of children
with Kawasaki disease develop cardiac valve pathol-
ogy, principally mitral regurgitation requiring endo-
carditis chemoprophylaxis.
Mitral valve prolapse
Prolapse denotes the displacement of an organ or
part of an organ from its normal position through an
opening or into a cavity (263).The failure of the mi-
tral valve leaflets to coapt properly can result in
leaflet edge displacement toward or into the left at-
rial cavity (13),and when accompanied by a mid- to
late systolic click and late or holosystolic murmur,
may indicate the presence of mitral valve prolapse
(12, 74, 275). The mitral leaflets normally bulge
slightly into the atrial cavity upon closure (13).True
prolapse is seen when the leaflets billow (exagger-
ated physiological bulging), become “floppy” (ad-
vanced billowing with elongated chordae tendineae)
or become “flail” (leaflet edges fail to appose) (13).
Failure of leaflet apposition results in mitral regurgi-
tation and increased risk for endocarditis.
A mid-systolic click merely indicates the sound of
abnormal chordae tendineae being released (691,
whereas auscultation findings of mid- to late or ho-
losystolic murmurs may signal mitral regurgitation.
Yet the mitral valve may remain competent even
with floppy valves and a holosystolic displacement
of the mitral leaflets (69).It may therefore be difficult
to determine preciselywhen significant regurgitation
is present and endocarditis chemoprophylaxis is in-
dicated.
Mitral valve prolapse is basically two disorders, a
“syndrome” and “anatomic” (29, 59). The syndrome
is a neuroendocrine-autonomic nervous system dis-
order characterized by chest pain, fatigue, cardiac
arrhythmias, syncope and abnormalities primarily of
the sympathetic nervous system (29, 59). The ana-
tomic disorder can progress from a mild mid-systolic
click to a late or holosystolic murmur, leaflet bil-
lowing, thickened redundant valves, myxomatous
valve degeneration, progressive mitral regurgitation,
emboli and congestive heart failure (29, 69). Ana-
tomic mitral valve prolapse is associated with risk for
infective endocarditis and eventual prosthetic valve
placement.
Anatomic mitral valve prolapse occurs in 3% of
women and 5%of men over the age of 20 years (156,
368).An aberrant 37% incidence is found in people
with anorexia nervosa and 20% of young females,
probably reflecting a discrepancy between the heart
and valve sizes due to an abnormally low body
weight causing redundant mitral valves (156, 369).
Approximately5%of mitral valve prolapse cases pro-
gress to mitral regurgitation and eventual valve re-
placement; two-thirds of these cases are male (91,
367). Men are at twice the risk for endocarditis as
women, and the need for replacement valve surgery
increases greatly after 50 years of age (369).
The incidence of infective endocarditis in mitral
valve prolapse with regurgitation is 52 per 100,000
person-years versus 4.6 per 100,000person-years in
individuals without regurgitation versus 1.7-4.1 per
121

Pallasch & Slots
100,000person-years for endocarditis in the general
population (218,326).Patients with mitral valve pro-
lapse without regurgitation are at approximately the
same risk for endocarditis as the general population,
but those with regurgitation have a 13 times greater
risk for endocarditis. However, this risk is still much
lower than those of rheumatic heart disease, valve
prosthesis or recurrent infective endocarditis. A
thickened redundant mitral valve substantially in-
creases the risk for endocarditis (222).Infective en-
docarditis with mitral valve prolapse constitutes 13%
of all endocarditis cases (about 1150 annually) in a
population of 7 million people with mitral valve pro-
lapse in the United States (90).
The echocardiogram can help to reach the proper
diagnosis of mitral valve prolapse if interpreted cor-
rectly. The M-mode echocardiogram determines the
degree of posterior displacement of the mitral valve
leaflets, the 2D echocardiogram evaluates leaflet co-
aptation and valve size, thickness and redundancy
while the standard or the color flow Doppler echo-
cardiogram assesses the cardiac blood velocity and
direction of flow,which helps to determine the pres-
ence or degree of regurgitation (69, 111, 236). How-
ever, the Doppler echocardiogram falsely assigns
some degree of mitral valve regurgitation to 19-56%
of all individuals without any evidence of cardiac
disease (20, 62, 187,374) and detects inaudible mur-
murs that are not likely to predispose to endocarditis
(193). The potential overdiagnosis of mitral valve
prolapse may lead to unnecessary antibiotic prophy-
laxis for people with mitral valve prolapse without
regurgitation (27, 67, 192).
The proper diagnosis of mitral valve prolapse re-
quires clinical as well as laboratory findings (69,
11I), utilizing auscultation (the presence of a late or
holosystolic murmur) and echocardiography (pres-
ence of late systolic leaflet displacement, leaflet
bulging into the atrial cavity, thickened redundant
valves and/or Doppler regurgitation). Proper use of
these criteria will ensure that antibiotic prophylaxis
to prevent endocarditis is restricted to mitral valve
prolapse patients with mitral regurgitation.
Antibiotic prophylaxisunsettledor
not indicated
Vascular grafts
Infection of a prosthetic vascular graft is a serious
complication with high morbidity usually involving
graft removal and a mortality of 25-88% for aortic
grafts (10,46,248).The prevalence rates of prosthetic
vascular graft infections are 1.0-2.6% (46) to 1.0-
6.0% (10, 248). Over one-half occur within 1 month
of placement, but the possibility of infection is still
present 10 years after graft placement (46).The vast
majority of these infections are seeded at the time of
surgery (461, with up to 43% of surgical sites con-
taminated with primarily s. epidermidis (248). The
proximate cause of the vascular infection may be
very difficult to determine, as S. epidermidis may
have an incubation period from implantation to in-
fection of an average 41 months (248).
The predominant infecting organisms are S. epid-
ermidis, S. aureus, Escherichia coli, Pseudomonas
aerugimsa, Proteus mirabilis, nonoral Bacteroides,
Clostridium perfringens and enteric gram-negative
rods (46,248).Oralviridans streptococci are rare iso-
lates from vascular grafts (47); however, due to the
catastrophic nature of vascular graft infections, anti-
biotic prophylaxis may be indicated prior to dental
treatment (204, 2481, although this concept is not
universally accepted (M.J.Wahl, personal communi-
cation). The standard infective endocarditis regi-
mens of the American Heart Association and the
British Society for Antimicrobial Chemotherapy are
appropriate, although they are not specifically re-
commended by these groups for this purpose. Anti-
biotic prophylaxis, if used, should probably be re-
stricted to major vessel grafts such as the aorta.
Innocent heart murmurs
An adult patient with a history of a heart murmur as
a child is a common clinical finding, usually devoid
of any patient understanding of the age of initial de-
tection, etiology, or clinical significance. A murmur
lacking certain defining criteria is “physiological”,
“functional” or “innocent” and does not require en-
docarditis chemoprophylaxis according to the Amer-
ican Heart Association guidelines (79).The patient’s
present physician should be asked to determine the
clinical significance of the prior murmur. If this is
not possible, a negative history of rheumatic fever,
rheumatic or congenital heart disease coupled with
the patient never having been told by any physician
to have antibiotic prophylaxis before dental work
may be sufficient to indicate an innocent childhood
murmur.
The incidence of heart murmurs detected in
children range from 32-96% (297), with the prob-
ability of detection at some time in a child’s life of
greater than 50% (148,149).The three most common
innocent heart murmurs in children are: 1) a pul-
122

monic systolic ejection murmur seen in the majority
of infants and children, 2) a vibratory murmur at the
lower left sternal border and 3) a venous hum due
to the intermittent collapsing of the superior vena
cava and the jugular vein (149). Such murmurs are
characteristically quiet, limited, of short duration,
increase with tachycardia and vary with posture and
respiration in an otherwise normal heart (149).
The soft childhood systolic murmur is the primary
diagnostic problem, as it may or may not indicate
cardiac disease. Guntheroth et al. (148, 149) and
Nadas (240)listed major and minor criteria to aid in
determining the seriousness of such a murmur, with
one major or two minor criteria diagnosing for heart
disease. Major criteria include a systolic murmur
louder than 3/6, a diastolic murmur (always path-
ological), congestive heart failure, cyanosis and ab-
normal blood pressure. Minor criteria are a systolic
murmur less than 3
1
’
6 together with an abnormal
electrocardiogram, chest X-ray or pulmonic second
sound. An astute pediatric cardiologist can delineate
between an innocent and pathological heart mur-
mur with great accuracy; the echocardiogram may
not significantly increase this accuracy but can give
a definitive diagnosis with a pathological murmur
(316).
Hemodialysis
Patients with indwelling catheters for any reason
have about 5%risk for endocarditis from catheter-
associated microorganisms (122, 320). Whether
these patients are at greater risk for dentally induced
bacteremic infective endocarditis (assuming no car-
diac risk factors are present) has not been investi-
gated nor has any risk-benefit ratio been established.
Some suggest antibiotic prophylaxis to prevent post-
treatment infectious complications (281, whereas
others cite data to indicate a higher postoperative
infection rate with antibiotic prophylaxis (232).
There seems to be no good reason why a person on
hemodialysis without any cardiac risk factors should
be at increased risk for endocarditis from dental
treatment.
Heart transplants
Antibiotic prophylaxis for endocarditis prevention is
ordinarily not required for heart transplant recipi-
ents, as they have not been shown to be at-risk for
bacteremic infections (268).However, such patients
are at-risk for cardiac valvular disorders, and a medi-
cal consultation is therefore appropriate.
Cardiac pacemakers
The American Heart Association does not rec-
ommend antibiotic prophylaxis for dental patients
with pacemakers and defibrillators (79).In a survey
of 453 physician members of the North American
Society of Pacing and Electrophysiology (354), 69%
did not recommend endocarditis antibiotic prophy-
laxis in people with permanent pacemakers or auto-
matic internal cardioverter defibrillators. In 28 epi-
sodes of bacteremia emanating from infected pace-
makers (481, 22 episodes were associated with s.
aureus, 2 with coagulase-negative staphylococci, 3
with gram-negative organisms, and 3 with strepto-
cocci and enterococci (one due to S. sanguis).Three
cases of endocarditis ensued, with two due to S. au-
reus and one to S. epidermidis. In 44 cases of pace-
maker endocarditis, none were due to viridans
streptococci and 75% due to staphylococci (5). The
consensus is that antibiotic prophylaxis is not war-
ranted in dental patients with pacemakers and de-
fibrillators.
Immunocompromised patients
Dental patients with a suppressed granulocyte count
may be at risk for bacteremia-induced infections.
Antibiotic prophylaxis has been suggested when the
granulocyte count falls to 3500 per mm3 (318),2000
per mm3 (89)or 1000per mm3 (21,although no con-
trolled clinical studies have documented the efficacy
of such a practice (2). Mortality in immunocom-
promised patients is increasing due to gram-nega-
tive bacteria particularly those highly resistant to the
beta-lactam agents, aminoglycosides, vancomycin
and the fluoroquinolones (300).Dental patients with
low granulocyte counts should only be treated on a
nonelective (emergency) basis.
The oral flora of immunocompromised individ-
uals can be unusual. In leukemic patients, the oral
flora is altered to one with a preponderance Klebsiel-
la pneumoniae, Enterobacter cloacae and E. coli (21,
125).Bone marrow transplant patients with leukem-
ia have a high oral presence of gram-negative enteric
rods (127); however, a major risk to bone marrow
transplant patients is septic shock caused by viridans
streptococci (327). In 69 episodes of septicemia in
bone marrow transplant patients, 24 were due to al-
pha-hemolytic streptococci and 29 to S. epidermidis
(163). In patients with cancer chemotherapy-in-
duced bone marrow depression and periodontal ab-
scesses, the isolated microorganisms were viridans
streptococci, Veillonella, Prevotella and Porphyro-
123

Pallasch & Slots
rnonasspecies (265).Viridans streptococci constitute
an increasing cause of bacteremia in cancer chemo-
therapy patients, with reported incidence rates of
14-39% (25, 26) and in severely neutropenic (less
than 100 neutrophils per mm3)patients with a mor-
tality of 6-30% (26).
The American Heart Association and the British
Society for Antimicrobial Chemotherapy regimens
seem to be appropriate antibiotic prophylaxis (al-
though they are not specifically recommended by
these groups for this purpose) against viridans
streptococci for cancer chemotherapy and bone
marrow transplant patients but might be inappropri-
ate for leukemic patients or leukemic and bone mar-
row transplant patients where agents like fluoro-
quinolones against gram-negative enteric rods (En-
terobacteriaceae) would likely be more effective.
However, the lack of any controlled clinical studies
makes these suggestions speculative. Also, the oral
microbiota may differ significantly from patient to
patient, suggesting that a microbiological evaluation
should form the basis for selecting the proper anti-
biotic.
Human immunodeficiency virus (HIV)-infected
patients receiving dental extraction, periodontal
surgery, endodontics and restorative dentistry are
not at greater risk of infectious complications than
non-HIV-infected patients, and antibiotic prophy-
laxis is not advised (137,215,270,280).Such prophy-
laxis might be potentially harmful if it results in over-
growth of Candida and other antibiotic-resistant
microbial pathogens in a severely immunocom-
promised host.
Splenectomized patients
Individuals without spleens have a small but signifi-
cant lifelong susceptibility to septicemia (sepsis)
probably due to reduced immunoglobulin M (IgM)
antibody and opsonization activity along with ab-
sent splenic clearance of certain encapsulated
microorganisms. S. pneumoniae is responsible for
50-60% of these septic episodes, followed by H. in-
fluenzae, N. meningitidis, E. coli and l? aeruginosa
(171,274). One study found viridans streptococci in
1 of 19 isolates (274) and another found “strepto-
cocci” in 11 of 349 isolates (171).
Severe infection in splenectomized patients may
occur at a rate of 0.42 per 100 person-years (1
splenectomized patient experiencing severe sepsis
every 238 person-years), with a mortality rate of 0.08
per 100 person-years (1 death every 1250 person-
years) (77). This infection rate is 12.6 times greater
than the general population (77).In a series of 12,514
patients (1711,severe infection occurred in 447 pa-
tients (3.6%)and death in 221 patients (1.7%).Only
11%of splenectomized patients appear to be aware
of this risk of infection (274).
Splenectomized patients should generally receive
the pneumococcal vaccine 2 weeks before splen-
ectomy, with additional doses 3-6 years later (274).
There is no data on the efficacyof antibiotic prophy-
laxis to prevent postsplenectomy infection (210,
2741, and such a practice is questionable due to the
varied and potentially high antibiotic resistance pat-
tern of the predominant causative microorganisms.
No clinical studies exist regarding antibiotic prophy-
laxis prior to dental or medical treatment procedures
(210). Antibiotic prophylaxis to prevent bacteremia
or postoperative infections is not indicated in
splenectomized dental patients as: 1) the vast ma-
jority of causative microorganisms are of nonoral
origin, 2) viridans streptococci are rarely if ever re-
sponsible, 3) the causative organisms are not likely
to be susceptible to common prophylactic anti-
biotics (penicillins, erythromycin),4) no risk-benefit
ratio has been established, and 5)no sound theoreti-
cal basis for such a practice exists.
Brain abscess
As with infective endocarditis, any dental treatment
or infection occurring within 3 or more months of
the onset of a brain abscess (focalsuppuration in the
brain parenchyma) may be alleged to be its proxi-
mate cause (viaa metastatic bacteremia). The charge
may then be made that antibiotic prophylaxis should
have been used to prevent such an event. However,
the incidence, etiology and clinical course of brain
abscesses indicates that the association with pre-
vious therapy too small and the risk from penicillin
is too great to warrant antibiotic prophylaxis.
The annual incidence of brain abscesses in hospi-
tal admissions in the United States is 1 per 10,000
(51, 129)and in Denmark 3.6 per million people per
year (95).Schliamser et al. (295)detected an increase
in brain abscesses in Sweden from 1.3 per million
population per year from 1974to 1977to 12 per mil-
lion population per year in 1983-1984. The differ-
ences in incidence probably reflect improved diag-
nosis with magnetic resonance imaging and compu-
terized tomography and inclusion of subdural
empyema and epidural abscess.
The pathogenesis of brain abscess requires the
presence of an area of ischemia or necrosis in the
brain and infecting microorganisms introduced from
124

outside the central nervous system across the blood-
brain barrier. Organisms may reach the brain by con-
tiguous spread from an adjacent infected area
(middle ear or paranasal sinus), direct head trauma
or the hematogenous route, usually via the middle
cerebral artery (190,375).Otitis media and sinusitis
account for 50-60% of the sources of brain abscess
in the United States (31,375), and otitis media alone
for 65% in China, and for 20-40% in Europe (371).
Brain abscesses can occur as metastatic infections
from the lungs and as a sequela to congenital heart
disease by allowing blood to bypass the pulmonary
microbial filtration system. Approximately20% of all
brain abscesses have no known source of infection
(371,375).
Brain abscesses are more common in males and
show a bimodal distribution, with a higher preva-
lence in young people and those over 40 years of age
(370). The classic triad of symptoms (fever, severe
headache and focal neurological deficit) occurs in
less than 50% of cases (371).Other signs and symp-
toms of brain abscess include papilledema (edema
of the optic disk), nuchal rigidity (neck stiffness),
seizures and hemiparesis (paralysisof one side of the
body).
Brain abscesses primarily locate about equally in
the frontal and temporal lobes followed by the fron-
toparietal, parietal, cerebellar and rarely the occipital
region (371).Frontal lobe abscesses usually originate
from the sinus, and temporal lobe abscesses usually
originate from the middle ear (190, 371, 375). Most
cases of bacteremia from the oral cavity locate in the
frontal and temporal lobes.
Streptococci constitute the majority of causative
microorganisms, with estimates ranging from 52-
80% of all isolated species (140, 337, 371, 375). The
single most common microorganism isolated in
brain abscesses may be S. anginosus (Streptococcus
millerz3 (371).In a study of 1773brain abscesses, 24%
were due to facultative streptococci, 12% to anaer-
obic streptococci, 23% to staphylococci (primarily
due to head trauma) 11%to P mirabitis (predomi-
nant in otitis media), 10%to Bacteroides, and 4% to
E. coti (337).Other isolated organisms include H. in-
jluenzae, Branhamella catarrhalis, I! aeruginosa, K.
pneumoniae, Enterobacter cloacae, S. pneumoniae,
Fusobacteriumand Veillorzella(337).
Britt et al. (35) determined the histological fea-
tures of brain abscesses after organism implantation,
using a canine streptococcal model with subsequent
confirmation by human studies (36).In canines, the
disease progresses as early cerebritis (day 1-31, late
cerebritis (day4-9), early capsule formation (day 10-
14) and late capsule formation on day 14 or later
(35).A similar sequence occurs in humans but poss-
ibly more slowly depending on the offending organ-
ism, direct or metastatic spread and degree of host
resistance (36).
Bradley & Shaw (30) reviewed 235 cases of brain
abscess with regard to the time between the onset of
symptoms and hospitalization: 33% were hospital-
ized in less than 1week, 50% in 1week to 1 month,
14%in 1-3 months and 3.4% after 3 months. Grusz-
kiewiecz et al. (147)determined that 18%of 56 cases
sought hospitalization within 1 week of onset of
symptoms, 25%within 2 weeks, 14%within 3 weeks,
16%within 4 weeks, and 16%within 2 to 6 months.
Samson &nd Clark (289) estimated that 75% of pa-
tients with brain abscess seek hospitalization within
2 weeks of the onset of signs and symptoms. Accord-
ingly, 18% (147) to 33% (30) of brain abscess cases
seek diagnosis within 1week of symptom onset, and
73% (147)to 83% (30)have been hospitalized within
1 month.
The majority of clinical studies on brain abscesses
do not list the oral cavity as a suspected or proven
locus of the infection. However, 7 studies (34, 63,
147, 155, 276, 295, 314) do implicate a dental event
at an incidence of 28 of 410 cases (7%).In a worst-
case scenario with 7% of all brain abscesses caused
by dental manipulation and infection and with an
incidence of brain abscesses in the general popula-
tion of 1.3-12 per million population per year, the
oral cavity may be responsible for 0.09-0.84 cases of
brain abscess per million population per year. The
incidence becomes much lower by including studies
that list no relationship to dental treatment.
The incubation period (time from onset of bacter-
emia to onset of first symptoms) and time to hospi-
talization (timefrom onset of first symptoms to diag-
nosis) in brain abscess cases ascribed to dental treat-
ment and infections is critical to causation but can
be difficult to determine from existing literature. Ten
reasonably reliable cases of brain abscesses of dental
origin list a mean incubation period of 18 days, with
a range of 4-60 days (37, 64, 126, 172,224, 338). In a
single study with 8 reliable cases, the mean incuba-
tion period was 16 days with a range of 9-37 days
(159). In these 18 cases, the affected individuals
ranged in age from 6 to 66 years and the abscess was
located in the temporal lobe in 7 cases (37,64, 126,
159, 172,224, 338).In alleged dentally induced brain
abscesses, the time from onset of symptoms to hos-
pitalization was a mean 12 days with a range of 3-
49 days (37,64, 138, 141, 172, 176, 178,223,224, 322,
347). These data suggest that with an average in-
125

Pallasch & Slots
cubation period for a dentally induced brain abscess
of 16-18 days and an average time to hospitalization
of 12 days, the average time from onset of bacterem-
ia (dental manipulation) to hospitalization (diag-
nosis) is 30 days for dental manipulation and infec-
tion-induced brain abscesses.
It is apparent that antibiotic prophylaxis to “pre-
vent” brain abscesses in dental patients is fraught
with difficulties. In essence, 1million people would
have to receive ‘prophylactic’ antibiotics in an
attempt to save the theoretical less than 1person in
that million from the brain abscess. A correct guess
would have to be made in choosing the right anti-
biotic against the unknown causative organism. An
unfavorable risk-benefit ratio in prescribing anti-
biotic prophylaxis against brain abscesses also be-
comes a question of great concern. The mortality
rate from penicillin is at least 1per million and that
from orally induced brain abscess is less than 0.09-
0.84 per million, resulting in a net loss of life with
penicillin prophylaxis.
Orthopedic prosthetic joints
The issue of whether dental treatment- and/or oral
infection-induced bacteremia induce orthopedic
prosthesis infections and whether antibiotic prophy-
laxis might prevent such infections has never been
satisfactorily resolved.
Surveys of orthopedic surgeons indicate that the
vast majority favor antibiotic prophylaxis before
dental treatment (145, 174, 186, 303), even though
many orthopedic surgeons recognize that a relation-
ship between dentally induced bacteremia and pros-
thetic joint infections has not been established and
probably is of minimal importance (186). Most
studies on bacteremia-induced prosthetic joint in-
fections conclude that antibiotic prophylaxis is not
indicated for dental patients (1, 55, 60, 61, 73, 107,
117, 133, 169, 207, 228, 245, 2671, whereas a small
minority advocates such a practice (23, 65, 145, 235,
242). Advocates of antibiotic prophylaxis for dental
patients with prosthetic joints are concerned about
preventing a serious infection with a mortality rate
of up to 18%. This may be a valid concern, but:
“...the fear of a tragic complication following a pro-
portionately trivial procedure is not in itself justifi-
cation for irrational and excessive prophylactic ther-
apy” (228).The American Academy of Oral Medicine
(107) and the British Society for Antimicrobial
Chemotherapy (55) have concluded that antibiotic
prophylaxis is not routinely indicated for dental pa-
tients with prosthetic joints (107) and that the risk-
benefit ratio is unfavorable (55). The Council on
Dental Therapeutics of the American Dental Associ-
ation concluded that there is insufficient evidence to
recommend antibiotic prophylaxis (73).
The long incubation period for prosthetic joint in-
fections is a major impediment in establishing oral
treatment- and infection-induced bacteremia as a
cause of the disease. McGowan & Hendrey (228)de-
termined an incubation period ranging from 5 to 60
months (average 31 months), and Poss et al. (271)
from 4 to 104 months (average39 months). Maniloff
et al. (219) reported two cases of prosthetic joint in-
fection from C, perfringens and s. pneumoniae with
an incubation period of 10 and 7 months, respec-
tively. Case reports ascribing causation of prosthetic
joint infections to dental treatment often report in-
cubation periods of a few days to a few months and
then at times with organisms not likely to be of oral
origin, such as staphylococci (205, 282, 296, 332,
334). To link a prosthetic joint infection to a single
event (dental treatment) occurring amid months of
random cases of bacteremia and invasive events
(lacerations and systemic infections) associated with
daily living remains essentially impossible.
Gill & Mills (132) examined the incidence of bac-
terial contamination of prosthetic joint implant sites
before implant placement. Of 117 sites for implants,
15were contaminated with S. aureus,2 with S. epid-
ermidis, 2 with gram-negative rods and 2 with
streptococci. The degree of microbial contamination
of prosthetic joints before surgery has not been de-
termined.
The microbiology of late prosthetic joint infec-
tions (3months or later after placement) also creates
difficulties with purported dental causation. Table 4
lists the cumulative microbiological data from 281
isolates from 6 clinical studies of prosthetic joint in-
fections allegedly due to hematogenous bacterial
spread (19, 146,179, 181,239, 271).Two-thirds of the
prosthetic joint infections were due to staphylococci,
only 4.9% due to viridans streptococci of possibly
oral origin and 2.1% due to Peptostreptococcusspe-
cies. Oral organisms such as Actinobacillus,Prevotel-
la, Porphyromonas, Fusobacterium, and Veillonella
were conspicuously absent. About 84% of the in-
fecting organisms were gram-positive and 16%
gram-negative with many (staphylococci, gram-
negative bacilli) likely being resistant to penicillin V
and amoxicillin.
An animal model has been used to support the
causation of prosthetic joint infections by blood-
borne bacteria. Of 23 rabbits injected with 11.5Xlo8
colonies of staphylococci, 8 died almost immediately
126

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