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CLINICAL MICROBIOLOGY REVIEWS, Jan. 2009, p. 46–64 Vol. 22, No. 10893-8512/09/$08.00�0 doi:10.1128/CMR.00028-08Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Microbiology of Odontogenic Bacteremia: beyond EndocarditisN. B. Parahitiyawa,1 L. J. Jin,2 W. K. Leung,2 W. C. Yam,3 and L. P. Samaranayake1*
Oral Bio-Sciences1 and Periodontology,2 Faculty of Dentistry, and Department of Microbiology,3
Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
INTRODUCTION .........................................................................................................................................................46Bacterial Entry into the Bloodstream....................................................................................................................47
OBJECTIVES ................................................................................................................................................................47Search Strategy .........................................................................................................................................................47
HISTORICAL PERSPECTIVES.................................................................................................................................48TRIGGERING FACTORS IN ODONTOGENIC BACTEREMIA .........................................................................49
Chewing ......................................................................................................................................................................49Personal Oral Hygiene Measures...........................................................................................................................55Periodontal Procedures............................................................................................................................................55Tooth Extraction .......................................................................................................................................................55Orthodontic Procedures...........................................................................................................................................56Endodontic Procedures ............................................................................................................................................56Miscellaneous Oral Procedures ..............................................................................................................................56
TEMPORAL NATURE OF ODONTOGENIC BACTEREMIA..............................................................................56SYSTEMIC OR END ORGAN INFECTIONS WITH ORAL BACTERIA ...........................................................57
CNS.............................................................................................................................................................................57Skeletal Infections.....................................................................................................................................................57Respiratory Infections ..............................................................................................................................................57Septicemia..................................................................................................................................................................57Infections in Pregnancy............................................................................................................................................59
DIAGNOSING THE SOURCE OF BACTEREMIA.................................................................................................59BACTERIAL DIVERSITY IN ODONTOGENIC BACTEREMIA..........................................................................60CONCLUDING REMARKS........................................................................................................................................60REFERENCES ..............................................................................................................................................................61
INTRODUCTION
Recent advances in bacterial identification methods, partic-ularly culture independent approaches such as 16S rRNA genesequencing, have shown that oral niches are inhabited by morethan 6 billion bacteria representing in excess of 700 speciesbelonging to at least nine different phyla (1, 33, 36, 70, 96).Since some 30 to 40% of the bacteria normally residing in thehuman mouth remain to be identified, the 16S rRNA sequenc-ing approach also provides a tool to arbitrarily estimate thediversity of these organisms (24). The bacterial flora of themouth, like most other resident floras of the human body, suchas those of the skin and the gut, exhibits commensalism, asurvival mechanism that benefits the microbes without harm-ing the host. Yet these largely innocuous commensal residentsof the human body have the propensity to become pathogenicin the event of translocation to a different niche (58).
Oral commensals, particularly those residing in periodontalniches, commonly exist in the form of biofilm communities oneither nonshedding surfaces, such as the teeth or prostheses, orshedding surfaces, such as the epithelial linings of gingivalcrevices or periodontal pockets. A feature that is unique to theoral bacterial biofilm, particularly the subgingival plaque bio-
film, is its close proximity to a highly vascularized milieu (90).This environment is different from other sites where bacteriacommonly reside in the human body. For example, the ingressof cutaneous flora into the circulation is prevented by therelatively thick and impermeable keratinized layers of the skin,while the mucosal flora of the gastrointestinal and genitouri-nary tracts is commandeered by the rich submucosal lymphat-ics, which keep microorganisms under constant check. Theircovering epithelia are continuously shed at a quick rate, deny-ing prolonged colonization by the bacterial flora. Althoughinnate defense by polymorphonuclear neutrophils is highly de-veloped at the dentogingival junction and backed up by ahighly organized lymphatic system, the oral biofilms, if leftundisturbed, can establish themselves permanently on non-shedding tooth surfaces subjacent to the dentogingival junc-tion. Under these circumstances, any disruption of the naturalintegrity between the biofilm and the subgingival epithelium,which is at most about 10 cell layers thick, could lead to abacteremic state (Fig. 1) (116).
All too often, in common inflammatory conditions such asgingivitis and chronic periodontitis, which are precipitated bythe buildup of plaque biofilms, the periodontal vasculatureproliferates and dilates, providing an even greater surface areathat facilitates the entry of microorganisms into the blood-stream. Often, these bacteremias are short-lived and transient,with the highest intensity limited to the first 30 min after atrigger episode, as discussed in the following sections (Fig. 2).
* Corresponding author. Mailing address: Oral Bio-Sciences, Fac-ulty of Dentistry, The University of Hong Kong, Hong Kong SAR.Phone: (852) 2859 0342. Fax: (852) 2547 6257. E-mail: [email protected].
46
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On occasions, this may lead to seeding of organisms in differ-ent target organs, resulting in subclinical, acute, or chronicinfections. Bacterial endocarditis is a well-known complicationof such bacteremias of odontogenic origin and has been amatter of great concern for dentists, cardiologists, and micro-biologists alike for many a decade. The literature and guide-lines on the prevention and management of bacteremia ofodontogenic origin have been under constant review, particu-larly with regard to prophylactic antibiotics and dental proce-dures, with differing opinions expressed on both sides of theAtlantic, particularly in recent months (51, 108, 143). Yet thereare a number of other organs and body sites that may beaffected by focal bacteremic spread from the oral cavity.Hence, the focus of this review is on issues that are unrelatedto the connectivity between bacterial endocarditis and odon-togenic bacteremias, with emphasis on other local and systemicmorbidities due to such bacteremias.
Bacterial Entry into the Bloodstream
Based on the current evidence, it is likely that bacteriagain entry into the bloodstream from oral niches through anumber of mechanisms and a variety of portals. First, andmost commonly, when there is tissue trauma induced byprocedures such as periodontal probing, scaling, instrumen-tation beyond the root apex, and tooth extractions, a break-age in capillaries and other small blood vessels that arelocated in the vicinity of the plaque biofilms may lead tospillage of bacteria into the systemic circulation (Fig. 1).Obviously, a higher microbial load would facilitate suchdissemination, as it is known that individuals with poor oralhygiene are at a higher risk of developing bacteremias dur-ing oral manipulative procedures (48). Second, innate mi-crobial factors may play a role in the latter phenomenon, asonly a few species are detected in experimental bacteremiasdespite the multitude of diverse bacteria residing within the
periodontal biofilm. Species that are commonly found in thebloodstream have virulence attributes that could be linked tovascular invasion (Table 1). Of particular note are attributessuch as endothelial adhesion of Streptococcus spp., degradationof intercellular matrices by Porphyromonas gingivalis, and im-pedance of phagocytic activity by Aggregatibacter actinomyce-temcomitans and Fusobacterium nucleatum.
OBJECTIVES
The focus of this review is threefold. The first aim is toevaluate the evidence base on triggering mechanisms and un-derlying predisposing factors that lead to odontogenic bacte-remias, the second aim is to determine the diversity and fre-quency of causative bacterial species in relation to various oralmanipulative procedures, and the final aim is to assess the roleof odontogenic bacteremia as a causative factor in systemic andend organ infections other than endocardial infections. Wehave particularly focused on systemic or end organ affectionsother than bacterial endocarditis, primarily because the patho-genesis of endocarditis secondary to odontogenic bacteremiahas been reviewed extensively elsewhere (for a recent review,see reference 40).
Search Strategy
We searched the PubMed database for articles on bacte-remia in human subjects, limiting the search to articles pub-lished in English. In order to elicit the events that lead tobacteremia of oral origin, the search query was worded“bacteremia,” coupled with “procedure” and the Booleanoperator “and.” Bacterial diversity in the mouth was studiedby analyzing the records cited in the database that hadadopted the rRNA sequence-based phylogenetic approach,while diversity of oral bacteremias was appraised by com-bining the search for “bacterial genera” with the term “bac-
FIG. 1. Possible routes of bacterial entry from teeth into the systemic circulation. Pathway 1, entry via the root canal (RC) or fromperiapical lesions (PA) into the alveolar blood vessels (AW); pathway 2, entry from the periodontium, where bacteria in the gingival crevices(GC) translocate to the capillaries (C) in the gingival connective tissues, possibly through the junctional epithelium (JE). E, enamel; D,dentine; L, periodontal ligament; and AB, alveolar bone. (Panels i and ii are modified from reference 116 with permission from Elsevier.Panel iii is courtesy of Lu Qian [Oral Bio-Sciences, Faculty of Dentistry].) Note that the junctional epithelium was detached from the enameldue to processing for microscopy.
VOL. 22, 2009 ODONTOGENIC BACTEREMIA BEYOND ENDOCARDITIS 47
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teremia.” On all occasions, records were sorted according torelevance, and if it was deemed necessary, references citedin a given record were further analyzed. In total, 170 cita-tions were derived for the search “bacteremia and proce-dure.” By relevance, 6 citations in relation to physiologicaland personal hygiene activities, 13 regarding periodontalprocedures, 19 regarding different modalities of tooth ex-tractions, 5 regarding orthodontic appliances, 3 regardingendodontic procedures, and 5 regarding miscellaneous pro-cedures were further appraised. In relation to systemic af-fections consequent to odontogenic bacteremia, 27 citationswere evaluated based on relevance.
HISTORICAL PERSPECTIVES
The link between dental procedures and resultant bactere-mias has been under scrutiny for more than half a century.Some early work dates back to the 1930s, when it was foundthat the extent of gum disease has a confounding effect on thedevelopment of bacteremia following dental extractions. Inone of the earliest reports, in 1939, Elliot (41) noted in anarticle to the Royal Society of Medicine in the United King-dom that the incidence of postextraction bacteremia due tostreptococci was increased when the condition of the periodon-tal health declined from minimally detectable gum disease to
FIG. 2. Chart indicating the time course distribution of the incidence of odontogenic bacteremias from 50 studies reported in the literature.The lowest and highest incidences reported at a given time point are annotated in the chart, with the percentage shown in bold. (Note that at timepoint A the sampling was done during the intervention or immediately thereafter.)
48 PARAHITIYAWA ET AL. CLIN. MICROBIOL. REV.
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moderate and marked periodontitis. Furthermore, the inten-sity of the bacteremia was also observed to be highest amongsubjects with periodontal disease (41). In subsequent studies,the decline in incidence and the efficacy of antimicrobials, suchas sulfanilamide, that were in use during the period in reducingbacteremias were evaluated, and the higher incidence of viri-dans group streptococcal bacteremias was reported (10). In1954, Cobe evaluated the degree of dental and periodontaltrauma that resulted in bacteremia in a cohort of 1,350 subjectsassigned to five groups based on operative or surgical proce-dure. His findings in this landmark study indicated the highestincidence of bacteremia with periodontal cleaning (40%), fol-lowed by exodontia (tooth extraction) (35%), brushing (24%),and hard mastication (chewing hard candy) (17%) (25). Themore “innovative” approach of other early investigators, whoinoculated hapless subjects with bacteria and lytic enzymes toevaluate the degree of bacteremia, cannot even be contem-plated in the present-day context of medical ethics (17, 25)!Nevertheless, these studies helped to highlight the significanceand importance of the gingival crevice as a portal of bacterialentry into the bloodstream.
TRIGGERING FACTORS INODONTOGENIC BACTEREMIA
Any disruption of the finely and harmoniously balanced bac-terial biofilm within the gingival tissue niche leads to dissem-ination of organisms into the bloodstream (116). Not only oralprocedures such as periodontal probing, scaling, root planing,and tooth extractions but also routine oral hygiene activitiessuch as brushing, flossing, and other physiological phenomena,such as chewing, can be assumed to be disruptive to the deli-cate anatomical and functional barrier between the oral bio-film and the host tissues. For these reasons, it can be antici-pated that the presence of inflammation in situations such asperiodontitis, gingivitis, pulpal or root canal infections, or oral
trauma by poorly fabricated appliances poses an increased riskof bacteremia, especially following mechanical manipulationsof the oral cavity.
The literature reveals a vast number of studies on the factorstriggering odontogenic bacteremia, varying from prospectivecontrolled studies to clinical trials and case reports. As de-scribed in detail below, these fall essentially into bacteremiasrelated to the following: chewing, personal oral hygiene mea-sures such as toothbrushing, periodontal procedures such asscaling and root planing, tooth extractions, insertion of orth-odontic appliances, endodontic procedures, and miscellaneousprocedures such as sialography (Table 2).
Chewing
The normal physiological act of chewing has marked indi-vidual variations, making it one of the most difficult aspects tocontrol in an experimental setting. Despite the theoretical pos-sibility that in susceptible individuals chewing could give rise toa bacteremic state, the data available in the literature so far areinconclusive. In one of the earlier studies of odontogenic bac-teremia, it was shown that 17% of the subjects who chewedhard candy (hard mastication) developed bacteremia, whilenone was detected with gentle mastication (25). Similar resultswere observed in a later study where postchewing bacteremiawas detected in 20% of subjects who had evidence of periodon-tal inflammation, while none was detected in periodontallyhealthy subjects and subjects with gingivitis (i.e., superficialinflammation of the gums but not the deep periodontal tissues)(48). However, Murphy and coworkers (89) showed in a con-trolled study that chewing failed to seed detectable numbers ofbacterial species into the bloodstream at different time inter-vals, irrespective of periodontal health status. Interestingly, ina parallel approach, Geerts et al. (49) noted significantly raisedlevels of bacterial endotoxins in subjects with chronic peri-odontitis, as assessed by the Limulus amoebocyte lysate assay.
TABLE 1. Major bacterial species recovered from odontogenic bacteremias and putative virulence factors thought to facilitate theirentry and survival in blood
Organism Factor, function, and/or characteristic Reference
Streptococcus mutans Ability to switch peripheral blood monocytes to dendritic cells which exhibit largenumbers of adhesion molecules, such as ICAM-1, ICAM-2, and LFA-1,contributing to adhesion to the injured endothelium and to fibrinogen in bloodclots
52
Porphyromonas gingivalis Cysteine proteinase (gingipain); degrades extracellular matrix proteins, such aslaminin, fibronectin, and type IV collagen
6
Abiotrophia defectiva Strains associated with endocarditis in humans show a higher fibronectin-bindingability than that of related species
122
Aggregatibacter actinomycetemcomitansand Fusobacterium nucleatum
Inhibits binding of chemotactic peptides to neutrophils 136
A. actinomycetemcomitans EmaA (extracellular matrix protein adhesin A); forms antenna-like protrusionsassociated with the surface and mediates adhesion to collagen
115
Streptococcus intermedius Hyaluronidase and chondroitin sulfate depolymerase break the ground substancein connective tissues, facilitating spread
123
Streptococcus anginosus Binds to the endothelium, the basement membrane, and collagen 4Streptococcus sanguis Platelet aggregation-associated protein; enhances platelet accumulation 52Porphyromonas gingivalis Porin-like activity of the outer membrane molecules (probably
lipopolysaccharide) can depolarize neutrophils and immobilizepolymorphonuclear leukocyte responses
91
Viridans streptococci Secreted factors could increase the production of interleukin-8, which isparticularly important in lung pathology, such as acute respiratory distresssyndrome (ARDS)
125
VOL. 22, 2009 ODONTOGENIC BACTEREMIA BEYOND ENDOCARDITIS 49
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vera
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ost
atis
tical
lysi
gnifi
cant
diffe
renc
ein
irri
gatio
nw
ithw
ater
and
chlo
rhex
idin
e
No
data
avai
labl
eon
the
exac
tid
entifi
catio
nof
the
isol
ates
;the
maj
ority
ofth
eis
olat
esw
ere
facu
ltativ
egr
am-p
ositi
veco
cci
Chl
orhe
xidi
neir
riga
tion
does
not
redu
ceth
ein
cide
nce
ofba
cter
emia
Effe
cts
ofin
trao
pera
tive
and
preo
pera
tive
irri
gatio
nw
ithPr
osol
-chl
orhe
xidi
ne(1
993,
Alli
son
�5�)
12su
bjec
tsin
who
mno
dent
alth
erap
yha
dbe
enst
arte
dB
asel
ine,
with
in1
min
ofsc
alin
gof
each
quad
rant
,and
10m
inaf
ter
the
who
lepr
oced
ure
(15
ml)
Aer
obic
and
anae
robi
ccu
lture
sin
Bac
tec
cultu
rebo
ttle
sPl
aceb
ori
nse,
9/12
patie
nts;
Pros
ol-c
hlor
hexi
dine
(tes
t),3
/12
patie
nts
36po
sitiv
ecu
lture
s,13
ofw
hich
wer
evi
rida
nsgr
oup
stre
ptoc
occi
Initi
alan
dco
ntin
uous
use
ofch
lorh
exid
ine
redu
ces
the
inci
denc
eof
bact
erem
ia
Subg
ingi
vali
rrig
atio
nan
dri
nsin
gw
ithan
antis
eptic
mou
thri
nse
(199
6,F
ine
�46�
)
18su
bjec
tsw
how
ere
cons
ider
edba
cter
emia
pron
ein
the
initi
alas
sess
men
t
Bas
elin
ean
dpo
stsc
alin
gw
ithpl
aceb
oan
dan
tisep
tic(1
0m
l)
Spre
adpl
atin
gaf
ter
mix
ing
with
thio
glyc
olat
ebr
oth
All
18pa
tient
sha
dae
robi
can
dan
aero
bic
bact
erem
iaN
osp
ecie
s-le
vel
iden
tifica
tion
was
men
tione
d
Inte
nsity
ofba
cter
emia
issi
gnifi
cant
lylo
wer
with
antis
eptic
50 PARAHITIYAWA ET AL. CLIN. MICROBIOL. REV.
on June 9, 2018 by guesthttp://cm
r.asm.org/
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nloaded from
Effe
cts
ofbl
eedi
ngse
veri
tyan
dex
tent
ofle
sion
sin
bact
erem
iaas
soci
ated
with
prob
ing
(199
7,D
aly
�27�
)
30su
bjec
tsat
the
begi
nnin
gof
trea
tmen
tfo
rpe
riod
ontit
isB
efor
ean
dim
med
iate
lyaf
ter
prob
ing
(20
ml)
Aut
omat
edcu
lture
s,st
anda
rdid
entifi
catio
nm
etho
ds43
45%
ofth
eis
olat
esw
ere
viri
dans
grou
pst
rept
ococ
ci
No
sign
ifica
ntco
rrel
atio
nsw
ere
foun
dbe
twee
nba
cter
emia
and
the
seve
rity
ofpe
riod
ontit
isor
exte
ntof
blee
ding
upon
prob
ing
Effe
cts
ofgi
ngiv
itis
and
peri
odon
titis
onpr
obin
g(2
001,
Dal
y�2
8�)
40(2
0pa
tient
sw
ithpe
riod
ontit
isan
d20
patie
nts
with
ging
iviti
s,ba
sed
prim
arily
onth
era
diog
raph
icev
iden
ce)
Prio
rto
and
afte
rpr
obin
g(2
0m
l)A
erob
ican
dan
aero
bic
auto
mat
edcu
lture
san
did
entifi
catio
nat
the
genu
sle
vel
Gin
givi
tispa
tient
s,10
;pe
riod
ontit
ispa
tient
s,40
4of
9ae
robi
c/fa
culta
tive
isol
ates
wer
est
rept
ococ
ci
Ris
kof
bact
erem
iais
high
erw
ithpe
riod
onta
linfl
amm
atio
nth
anw
ithgi
ngiv
itis
alon
e,as
note
dby
ahi
gher
odds
ratio
s
Effe
cts
ofpe
riod
onta
lpro
bing
(P),
brus
hing
(B),
and
scal
ing
(S)
(200
5,K
inan
e�6
8�)
30su
bjec
tsw
ithun
trea
ted
peri
odon
tald
isea
seat
the
com
men
cem
ent
oftr
eatm
ent
Bas
elin
e(B
L1
and
BL
2),
atpr
obin
g(P
),2
wk
late
r,at
brus
hing
(B),
atsc
alin
g(S
)(2
8m
l)
Aut
omat
edcu
lture
s,st
anda
rdid
entifi
catio
nm
etho
ds,1
6SPC
Rus
ing
bact
eria
lDN
Ain
bloo
d
Cul
ture
:BL
1,2;
P,6;
BL
2,0;
B,1
;S,4
;PC
R:B
L1,
3;P,
5;B
L2,
1;B
,4;S
,7
Am
ixtu
reof
orga
nism
s,w
here
Act
inom
yces
naes
lund
iian
dSt
rept
ococ
cus
spp.
wer
efo
und
inm
ore
than
two
subj
ects
No
spec
ies-
leve
lide
ntifi
catio
nw
asdo
neby
PCR
;in
gene
ral,
the
inci
denc
ew
aslo
wer
than
that
repo
rted
prev
ious
ly
Effe
cts
ofpo
vido
ne-io
dine
rins
e(t
est)
onba
cter
emia
indu
ced
byul
tras
onic
scal
ing
(200
7,C
herr
y�6
8�)
60pa
tient
sw
hoha
dpl
aque
-in
duce
dgi
ngiv
itis
atth
eco
mm
ence
men
tof
trea
tmen
t(3
0ea
chin
cont
rola
ndte
stgr
oups
)
Bef
ore
trea
tmen
t,30
san
d2
min
afte
rpr
oced
ure
(10
ml)
Lys
isce
ntri
fuga
tion
with
diffe
rent
iala
erob
ican
dan
aero
bic
cultu
res,
bioc
hem
ical
test
s
At
30s:
cont
rolg
roup
,13.
3;te
stgr
oup,
3.3;
at2
min
:co
ntro
lgro
up,3
0;te
stgr
oup,
6.7
Inco
ntro
ls,P
revo
tella
,A
ctin
omyc
es,a
ndSt
rept
ococ
cus;
inpo
vido
ne-io
dine
grou
p,E
nter
obac
teria
ceae
spp.
Rin
sing
with
povi
done
-iodi
neel
imin
ates
viri
dans
grou
pst
rept
ococ
ci
Effi
cacy
ofdi
ode
lase
rsin
redu
cing
bact
erem
iaas
soci
ated
with
ultr
ason
icsc
alin
g(2
007,
Ass
af�8
�)
22pa
tient
sw
ithpl
aque
-in
duce
dge
nera
lized
peri
odon
titis
atth
eco
mm
ence
men
tof
trea
tmen
t
For
cont
rolg
roup
,at
base
line,
3m
inaf
ter
initi
atio
nof
scal
ing,
and
30m
inla
ter;
for
test
grou
p,ju
stbe
fore
and
3m
inaf
ter
initi
atio
nof
scal
ing
(10
ml)
Aut
omat
edcu
lture
with
indi
cato
rsy
stem
Con
trol
grou
p,68
;dio
dela
ser
grou
p,36
Of
the
28po
sitiv
ecu
lture
s,61
%w
ere
stre
ptoc
occi
,w
hich
incl
uded
S.m
itis,
S.sa
livar
ius,
and
S.sa
ngui
s;ot
her
oral
spec
ies
incl
uded
Pre
vote
llaan
dC
apno
cyto
phag
a
Dio
dela
sers
wer
esh
own
tore
duce
the
inci
denc
ein
this
split
mou
thex
pt,b
utth
etim
ela
pse
betw
een
the
two
expe
rim
ents
allo
wed
apo
ssib
leca
rryo
ver
effe
ct
Iden
tity
ofpe
riod
onto
path
ogen
sin
bloo
daf
ter
scal
ing
and
root
plan
ning
(200
7,L
afau
rie
�71�
)
42(2
7w
ithge
nera
lized
seve
rech
roni
cpe
riod
ontit
isan
d15
with
gene
raliz
edag
gres
sive
peri
odon
titis
)
Bas
elin
ean
dim
med
iate
ly,1
5m
in,
and
30m
inaf
ter
the
proc
edur
e(5
ml)
Cul
ture
inR
uiz-
Cas
tane
dam
ediu
mfo
r15
days
,with
subc
ultu
res
atdi
ffere
ntin
terv
als
for
iden
tifica
tion
Hig
hest
inci
denc
e(a
t30
min
)fo
rge
nera
lized
aggr
essi
vepe
riod
ontit
is,
93.7
(14/
15pa
tient
s);t
hat
for
gene
raliz
edse
vere
chro
nic
peri
odon
titis
,74
.1(2
0/27
patie
nts)
(P�
0.05
)
Of
the
14di
ffere
ntsp
ecie
sis
olat
ed,P
.gin
giva
lisw
aspr
edom
inan
t,fo
llow
edby
(28.
6%)
Act
inom
yces
spp.
and
Mic
rom
onas
mic
ros
No
sign
ifica
ntdi
ffere
nce
inin
cide
nce
was
seen
betw
een
chro
nic
peri
odon
titis
and
aggr
essi
vepe
riod
ontit
is
Den
tale
xtra
ctio
nsIn
cide
nce,
natu
re,a
ndan
tibio
ticse
nsiti
vity
ofan
aero
bic
bact
eria
isol
ated
inpo
stex
trac
tion
bact
erem
ia(1
966,
Kha
irat
�66�
)
100
subj
ects
unde
rgoi
ngde
ntal
extr
actio
ns,i
rres
pect
ive
ofpe
riod
onta
lhea
lthst
atus
Pre-
and
post
proc
edur
e(3
0m
l)D
iffer
entia
laer
obic
and
anae
robi
cbr
oth
and
pour
plat
ecu
lture
s,w
ithan
dw
ithou
tC
O2
Post
extr
actio
n,64
155
stra
ins;
46w
ere
stri
ctan
aero
bes,
44of
the
isol
ates
wer
evi
rida
nsgr
oup
stre
ptoc
occi
Peri
odon
talh
ealth
stat
usha
sno
influ
ence
onth
eca
usat
ion
ofpo
stex
trac
tion
bact
erem
ia,a
ndth
ene
edfo
rus
eof
corr
ect
anae
robi
ccu
lture
sw
ashi
ghlig
hted
Effe
cts
ofpo
vido
ne-io
dine
irri
gatio
non
post
extr
actio
nba
cter
emia
(197
1,Sc
opp
�121
�)
64tr
eate
dw
ithpo
vido
ne-
iodi
ne,3
0tr
eate
dw
ithpl
aceb
o
Bas
elin
e,3
min
afte
rde
ntal
extr
actio
n(u
nkno
wn
vol)
Con
vent
iona
lcul
ture
and
stan
dard
iden
tifica
tion
test
sPo
vido
ne-io
dine
grou
p,28
;pl
aceb
ogr
oup,
56Id
entit
ies
ofis
olat
esw
ere
not
men
tione
dR
educ
tion
orno
grow
thin
ging
ival
cultu
res
was
obse
rved
inth
epo
vido
ne-io
dine
grou
pE
ffect
sof
topi
cala
pplic
atio
nof
antis
eptic
spr
ior
toex
trac
tion
(197
8,Sw
eet
�127
�)
100
patie
nts
divi
ded
into
four
grou
ps(n
oan
tisep
tics,
chlo
ram
ine
T,c
hlor
amin
eT
with
elec
tric
brus
h,or
irri
gatio
nw
ithL
ugol
’sso
lutio
n)
Bas
elin
e,5
min
afte
ran
tisep
tic,1
min
,30
min
,1h,
and
6h
afte
rex
trac
tions
Prim
ary
and
diffe
rent
ial
cultu
re,m
orph
olog
y,ch
rom
atog
raph
y,L
imul
usam
oebo
cyte
lysa
tete
stfo
ren
doto
xin
Con
trol
grou
p,84
;ch
lora
min
eT
rins
egr
oup,
48;b
rush
ing
with
chlo
ram
ine
T,4
8;ir
riga
tion
with
Lug
ol’s
solu
tion,
80
290
posi
tive
cultu
res,
amon
gw
hich
29w
ere
�-h
emol
ytic
orno
nhem
olyt
icSt
rept
ococ
cus
spp.
;of
the
300
Lim
ulus
test
s,7
wer
epo
sitiv
e
One
stud
yw
here
the
dura
tion
ofba
cter
emia
has
been
stud
ied
beyo
nd1
h;re
sults
for
the
inci
denc
eof
bact
erem
iaat
6h
are
not
show
n
Effi
cacy
ofpo
vido
ne-io
dine
and
chlo
rhex
idin
ein
post
extr
actio
nba
cter
emia
(198
4,M
acfa
rlan
e�8
4�)
60pa
tient
sun
derg
oing
unco
mpl
icat
edde
ntal
extr
actio
nsun
der
loca
lan
esth
esia
(pla
cebo
grou
p,20
patie
nts;
chlo
rhex
idin
egr
oup,
20pa
tient
s;po
vido
ne-
iodi
negr
oup,
20pa
tient
s)
Imm
edia
tely
prio
rto
and
30s
afte
rex
trac
tion
(10
ml)
Incu
batio
nin
thio
glyc
olat
ebr
oth
and
biph
asic
med
ia,
with
subs
eque
ntae
robi
can
dan
aero
bic
cultu
res
and
stan
dard
iden
tifica
tion
met
hods
Plac
ebo
grou
p,16
/20
patie
nts;
chlo
rhex
idin
egr
oup,
5/20
patie
nts;
povi
done
-iodi
negr
oup,
8/20
patie
nts
Of
46po
sitiv
ecu
lture
s,39
wer
est
rept
ococ
ci,
incl
udin
gei
ght
Stre
ptoc
occu
ssa
ngui
sst
rain
san
dsi
xS.
mut
ans
stra
ins
Ant
imic
robi
alse
nsiti
vity
test
sre
veal
edth
atal
l46
isol
ates
wer
ese
nsiti
vefo
ram
pici
llin,
ceph
alor
idin
e,an
dva
ncom
ycin
Con
tinue
don
follo
win
gpa
ge
VOL. 22, 2009 ODONTOGENIC BACTEREMIA BEYOND ENDOCARDITIS 51
on June 9, 2018 by guesthttp://cm
r.asm.org/
Dow
nloaded from
TA
BL
E2—
Con
tinue
d
Proc
edur
est
udie
dan
dpa
ram
eter
sun
der
inve
stig
atio
n(y
r,au
thor
�ref
eren
ce�)
No.
and
desc
ript
ion
ofsu
bjec
tsSa
mpl
ing
time
(vol
)C
ultu
rem
etho
d/id
entifi
catio
nte
chni
que
Inci
denc
e(%
)
Inte
nsity
(no.
ofco
loni
es),
dive
rsity
(no.
ofsp
ecie
s),
and/
orpr
edom
inan
tsp
ecie
s
Rem
arks
Effe
ctof
mac
rolid
ean
tibio
tics
inpo
stex
trac
tion
bact
erem
ia(1
991,
Can
nell
�18�
)
60(p
lace
bogr
oup,
20pa
tient
s;er
ythr
omyc
ingr
oup,
20pa
tient
s;jo
sam
ycin
grou
p,20
patie
nts)
Prio
rto
prop
hyla
xis
and
2m
inaf
ter
extr
actio
n(2
0m
l)
Con
vent
iona
laer
obic
and
anae
robi
ccu
lture
s,w
ithid
entifi
catio
nof
pres
umpt
ive
stre
ptoc
occi
byA
PIsy
stem
Plac
ebo
grou
p,65
;er
ythr
omyc
ingr
oup,
60;
josa
myc
ingr
oup,
70(n
otst
atis
tical
lysi
gnifi
cant
)
No
data
avai
labl
eon
the
num
ber
ofis
olat
esid
entifi
ed
No
sign
ifica
ntef
fect
sof
thes
etw
om
acro
lide
antib
iotic
sin
redu
cing
post
extr
actio
nba
cter
emia
wer
ese
enE
ffect
sof
povi
done
-iodi
ne,
hydr
ogen
pero
xide
,and
chlo
rhex
idin
eon
post
extr
actio
nba
cter
emia
(199
2,Y
amal
ik�1
44�)
80pa
tient
sw
ithm
ediu
m-
degr
eeor
alhy
gien
ein
dice
s(p
lace
bogr
oup,
20pa
tient
s;hy
drog
enpe
roxi
degr
oup,
20pa
tient
s;po
vido
ne-io
dine
grou
p,20
patie
nts;
chlo
rhex
idin
egr
oup,
20pa
tient
s
Pre-
and
post
proc
edur
e(1
0m
l)C
onve
ntio
nalc
ultu
rean
dst
anda
rdid
entifi
catio
nte
sts
Plac
ebo
grou
p,70
;hy
drog
enpe
roxi
degr
oup,
50;p
ovid
one-
iodi
negr
oup,
35;c
hlor
hexi
dine
grou
p,40
Of
61is
olat
esin
all
grou
ps,1
6w
ere
viri
dans
grou
pst
rept
ococ
ci
Use
ofan
tisep
tics
alon
eis
not
enou
ghto
elim
inat
eba
cter
emia
,des
pite
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432
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nce
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edur
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and
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ifica
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161
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rent
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mos
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9.9%
ofth
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stud
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orth
odon
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emto
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ifica
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and
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VOL. 22, 2009 ODONTOGENIC BACTEREMIA BEYOND ENDOCARDITIS 53
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eit
alto
geth
er
54 PARAHITIYAWA ET AL. CLIN. MICROBIOL. REV.
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Whether this is a sequel of odontogenic bacteremia or endo-toxemia from the inflamed periodontal niches remains to bedetermined.
Personal Oral Hygiene Measures
The effect of routine personal oral hygiene measures on thedevelopment of bacteremia is also difficult to evaluate. There-fore, procedures such as toothbrushing, flossing, and toothpicking and their relationship to bacteremia have been evalu-ated under controlled conditions, although in reality such ex-ercises could be deemed rather artificial. Nevertheless, Fornerand coworkers (48) found that toothbrushing did not causesignificant bacteremia of oral origin in either healthy subjectsor those with gingivitis, as no positive blood cultures werefound in their controlled clinical trial of 60 subjects. Althoughthe latter findings need to be confirmed by further work, thesedata indicate that mild gingivitis may not cause bacteremiaduring oral manipulation. Also, in another study of 30 healthymilitary recruits, it was shown that the true incidence of bac-teremia was zero after brushing with soft-bristled tooth-brushes. Of the 180 aerobic and anaerobic cultures that wereanalyzed, only 3 yielded detectable growth, and even thesewere identified as Propionibacterium acnes, a well-known skincontaminant of blood cultures (56). In early studies, detectablelevels of bacteremia ranging from 17 to 44% were noted fol-lowing toothbrushing in healthy subjects when brushing wasperformed by the investigator (25, 120). Thus, it appears that atleast in adults with a healthy periodontium, brushing is not asignificant factor contributing to systemic bacterial dissemina-tion from the mouth.
On the other hand, subjects wearing orthodontic appliancesdemonstrated bacteremias of odontogenic origin followingtoothbrushing, with an incidence of 25% (119). For children,there is some evidence to indicate that bacteremias ensue upontoothbrushing performed under general anesthesia and naso-tracheal intubation. Furthermore, the incidence was higherwhen electric sonicating toothbrushes rather than conventionaltooth brushes were used (12). The latter finding on bacteremiaunder general anesthesia needs to be interpreted cautiously, asprolonged intubation in itself causes bacteremia and the mag-nitude of bacteremia in terms of incidence and diversity in-creases with the duration of the intubation (93).
With regard to dental flossing, a procedure that could me-chanically disturb the periodontal plaque biofilms, bacteremiawas associated with sporadic flossing, while no significant bac-teremia was detected with daily flossing, even in subjects withgingivitis (19). However, due to the paucity of data and giventhe fact that flossing is an oral hygiene measure widely advo-cated for those with gingivitis and periodontitis, prospectiverandomized controlled studies with larger numbers of subjectsare necessary to arrive at a definitive conclusion.
Periodontal Procedures
Various degrees of bacterial dissemination are associatedwith periodontal probing (27, 28), scaling (22, 68), root plan-ing, and subgingival irrigation (5, 77, 106, 141). The presenceof inflammation in the periodontal site is an important con-tributory factor to bacterial dissemination, as shown by the
increased incidence of bacteremia in subjects with periodonti-tis compared to those with gingivitis (where the degree ofinflammation is considered less severe) and those with healthyperiodontium (48). For instance, the incidence of bacteremiavaries from 5 to 75% for subjects with periodontitis, as op-posed to 5 to 20% for subjects with gingivitis (27, 48). Despitethe foregoing, the inflammation associated with gingivitis canbe less than that with periodontitis, but not always. In verysevere cases of gingivitis, the intensity and inflammation can beequal to or exceed that associated with some cases of peri-odontitis. In addition, there is no uniform agreement on apositive association between various indices used to measurethe degree of periodontal inflammation, such as the presenceof bleeding upon probing, gingival index, and plaque index,and systemic bacterial dissemination (Table 2).
Subgingival irrigation with antiseptics such as chlorhexidineprior to scaling and root planing is practiced by some dentalsurgeons. Waki and his group (141) found no significant de-cline in the incidence of bacteremia due to this supplementaryprocedure, nor was there a significant relationship with thequality of the irrigation fluid used, whether sterile water, cleanwater, or antiseptics (77, 106). However, there is some evi-dence that the bacteremic incidence does drop with continuousand regular rinsing with chlorhexidine or povidone-iodine ir-rigation of gingival sulci (5, 102).
In laboratory microbiological terms, although there is nosignificant influence on reducing the incidence of bacteremia,some workers found the intensity of bacteremia, measured bythe number of CFU per milliliter, to be significantly lowerwhen antiseptic mouth rinses were used prior to ultrasonicscaling (46). Taken together, the foregoing data imply thatwhen periodontal procedures are performed on individualswith poor oral hygiene (as indicated by increased plaque indi-ces), there is a higher risk of developing a bacteremia.
As for methods that reduce the incidence and intensity ofbacteremia during periodontal manipulations, promising re-sults have been shown with the use of a diode laser as anadjunct to ultrasonic scaling, and this could be attributed to thelesser degree of tissue trauma inflicted. In addition, lasers mayalso possess a degree of antibacterial activity (8). However,large-scale and well-controlled studies are necessary to confirmthe latter finding.
Tooth Extraction
Tooth extraction, or exodontia, and associated tissue traumacause bacteremia, and this is by far the most-studied oralsurgical procedure evaluated to assess odontogenic bactere-mias. According to a number of studies, the incidence of bac-teremia ranges from 13 to 96%, depending on the evaluatedtime intervals as well as other experimental variables studied(Table 2). It has been shown that bacteremias can follow sim-ple dental extractions as well as extractions of impacted teeththat entail minor surgical intervention (76, 103, 109, 110, 132,137, 140). In such circumstances, the bacteremic incidenceappears to be influenced positively by the presence of gingivi-tis, periodontitis, and other odontogenic infections, such asdentoalveolar abscesses, suggesting a direct relationship be-tween an increased bacterial biofilm burden and bacteremia(15, 26, 128, 132). Other contributory factors for the phenom-
VOL. 22, 2009 ODONTOGENIC BACTEREMIA BEYOND ENDOCARDITIS 55
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enon are the extent and duration of the surgical period and themagnitude of blood loss (92). When surgical incisions weremade to facilitate the extraction of teeth, particularly impactedthird molars, with subsequent insertion of sutures, nearly 10%of individuals had a bacteremia following the removal ofsutures, and the incidence was not reduced by the use of preop-erative antiseptic rinses (16).
Despite the fact that intubation is associated with bactere-mia (93), no significant change in bacteremic incidence wasobserved when extractions were performed under general an-esthesia (128). In addition, there is no apparent change in theincidence of bacteremia with increased numbers of teeth ex-tracted or the use of mucoperiosteal elevators (103, 111, 133).Similarly, pre- and perioperative administration of antimicro-bial agents, such as clindamycin, erythromycin, josamycin, andcefaclor, appears to have no significant effect in reducing theincidence of bacteremia (18, 53, 54). Similar results have beenobserved with the use of perioperative topical antibiotic appli-cations (137).
Only a few procedures related to exodontia appear to reducesurgical bacteremias, and these include preoperative adminis-tration of antimicrobial agents, such as amoxicillin, cefuroxime,and moxifloxacin, that significantly reduce the incidenceof such bacteremias (39, 140). Moreover, broad-spectrumdegerming rinses, such as povidone-iodine, chloramine-T, andchlorhexidine, have been shown to reduce the incidence ofbacteremia when administered as a rinse or irrigation prior tothe extraction procedure or instrumentation, and povidone-iodine was shown to be the most potent in reducing theincidence (84, 121, 127, 144).
Orthodontic Procedures
Insertion of fixed orthodontic appliances involves manipu-lation of the oral tissues, particularly the teeth and the gingi-vae, and this may lead to systemic bacterial dissemination.However, the evidence to date shows that significant bactere-mia is associated only with the insertion of separators thatmechanically push teeth apart with significant force to createspace for unerupted teeth (83). Other orthodontic procedures,such as taking alginate impressions, banding, debonding, re-moval of fixed appliances, and gold chain adjustments, appearto produce no significant bacteremia (42, 43, 83, 113).
Endodontic Procedures
It is highly likely that endodontic procedures that entailinstrumentation of pulp chambers of either single or multipleroot canals of teeth with reamers and broaches may introducebacteria into the periapical vasculature of the teeth, with con-sequent bacteremic episodes. One important determinant ofthe onset of bacteremia in such situations appears to be thedegree of tissue trauma caused by the instrumentation. Notsurprisingly, therefore, the incidence of bacteremia was report-edly higher when the reamers reached beyond the confines ofthe root canal than in atraumatic endodontic procedures (11,30, 31).
Miscellaneous Oral Procedures
Apart from the routine therapeutic and preventive dentalprocedures such as extractions and periodontal surgery dis-cussed above, elective esthetic procedures, such as tooth pol-ishing and whitening, which are now very popular and whichare known to induce gingival epithelial abrasion and trauma,have not been shown to produce bacteremia (59). There is,however, a paucity of literature in this area and a need forlarge-scale controlled clinical trials.
Sialography, a procedure commonly carried out by special-ists in oral medicine for imaging of the major salivary glands,entails injection of radio-opaque dyes into the ductal system ofthe glands. Bacteremias of streptococcal origin have been ob-served by some workers during different stages of such proce-dures (72). One reason for this could be the translocation ofmucosal flora into the salivary duct system due to the pressureof the injecting dye.
Dentoalveolar abscesses are known to induce inflammationand vascular proliferation essentially at the periapical region ofthe tooth. Bacteremias have been reported when the purulentcontent of such lesions was drained by simple incisions. How-ever, needle aspiration of pus prior to incision and drainage ofthe abscess was shown to reduce or totally eliminate the bac-terial dissemination, possibly by reduction of the pressure in-side the abscess before the surgical manipulation of the tissues(47).
To conclude, then, with reference to all of the dental treat-ment procedures discussed above, it appears that the followingtwo major parameters dictate bacteremic episodes: first, andmost importantly, the degree of inflammation present at thesite, which is often directly related to the microbial load of thebiofilm, as seen in generalized aggressive periodontitis (7, 29,94); and second, the amount of tissue trauma that is inflicted.As for measures to eradicate odontogenic bacteremia, no sin-gle method (either topical or systemic antimicrobials ordegerming antiseptic agents) has been effective, despite thefact that some measures may reduce the incidence significantlyrelative to others.
TEMPORAL NATURE OFODONTOGENIC BACTEREMIA
It is generally accepted that odontogenic bacteremias aretransient in nature. Furthermore, it has been surmised that atleast in healthy individuals, the bacteria are scavenged fromthe bloodstream relatively quickly by the innate and adaptivedefense mechanisms (20, 100). Despite this general contention,some studies indicate that an episode of odontogenic bactere-mia could last as long as 60 min (39, 110, 132), and most studiesreport the presence of bacterial species in blood for up to 30min (Table 2; Fig. 2). This incidence profile can be observed inall forms of odontogenic bacteremias irrespective of the trig-gering factors, underlying predisposing conditions, or detec-tion methods. A schematic illustration compiled from the datain the literature on the relationship between the incidence ofbacteremia and the postprocedure time is given in Fig. 2. Fromthe cumulative data, it can be deduced that the bacteremicincidence peaks within the first few minutes and then graduallydeclines after 10 to 20 min. Furthermore, depending on the
56 PARAHITIYAWA ET AL. CLIN. MICROBIOL. REV.
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threshold sensitivity of the detection method, the total reduc-tion in the bacteremic load may vary from 10 to 90% at 30 sand from 2 to 20% at 60 min. It is important, however, that inspite of an initial steep fall, a few bacteria survive in thecirculation after a bacteremic challenge from the oral cavity.The role of these persisters and how they survive host defensesneed to be evaluated further, as they may well be the ones thatevade the initial host immune burst and have the propensity toseed target organs and cause systemic and distant infections(34, 73).
SYSTEMIC OR END ORGAN INFECTIONSWITH ORAL BACTERIA
The relationship between focal infection in the oral cavity,such as chronic periodontitis and gingivitis, and systemic dis-eases, including heart disease, diabetes, adverse pregnancyoutcomes, and stroke, has aroused much concern lately (104).Apart from the seeding infection as a direct consequence oftransient bacteremia, such oral-systemic interactions and out-comes could be due to other, indirect reasons, such as meta-static inflammation as a result of circulating macromolecularcomplexes and/or metastatic injury due to soluble toxins andbacterial lipopolysaccharide (50, 58, 74).
Although virtually any system or tissue can be affected bydisseminated infection from the oral niches, endocarditis is themost well known and highly evaluated such affection. As statedearlier, literature on the latter subject is vast and extensive, andwe make no attempt to review this aspect herein. Availabledata in the literature on other systemic and end organ infec-tions due to oral origin are summarized in Table 3.
CNS
The central nervous system (CNS), principally the brain andthe spinal cord, is encased in an anatomical and functionalcovering. Thus, circulation to the brain is dependent upon ameshwork of blood vessels in juxtaposition with specializedbrain cells known as the blood-brain barrier. Bacteria circulat-ing in the bloodstream could ingress into the CNS through theblood-brain barrier. In addition, because of anatomical prox-imity, organisms could directly ascend to the brain or the upperpart of the spinal cord from oral niches. For these reasons, it isapparent that the CNS could be a vulnerable relocation site fororal bacteria. In a review of cases of pyogenic infections in thebrain and the spinal cord, Ewald and coworkers (44) pointedout that predominant oral bacterial species, such as Fusobac-terium nucleatum, Veillonella, Streptococcus anginosus, Strepto-coccus oralis, and Actinomyces meyeri, could be detected inboth the primary lesions and either cerebrospinal fluid or theblood. In addition, most subjects demonstrated one or moreintraoral pathologies, such as periodontitis, gingivitis, caries, orperiapical osteitis. Arguably, these lesions could serve as theprimary infective focus for the dissemination and subsequentseeding of bacteria into an end organ site. For a majority ofepisodes, the absence of other detectable infective foci ledresearchers to conclude that the oral cavity, by default, is theprimary source of infection (57, 61, 63, 67, 86, 88, 114, 126,139). However, these studies, mainly case reports, suggest arelationship between pyogenic CNS infections and an oral or-
igin of bacteria such as Abiotrophia spp., Dalister pneumosintes,Streptococcus intermedius, S. oralis, Streptococcus constellatus,Fusobacterium spp., F. nucleatum, Aggregatibacter actinomyce-temcomitans, and Porphyromonas gingivalis (57, 61, 63, 67, 86,88, 114, 126, 139). These organisms are all members of the oralresident flora, particularly that of the subgingival niche. Inmost reports, there is concomitant circumstantial evidence ofpoor oral hygiene, periodontitis, dental abscesses, mucositiswith oral ulcerations, and the CNS lesions. Interestingly, in afew reports, phenotypic or genotypic homogeneity of the CNSand oral isolates was also traced (86, 139).
Skeletal Infections
As evident from the data presented in Table 3, odontogenicinfections of the bones and joints are not as frequent as CNSinfections. Yet there is clear evidence of oral bacteria causingmultiple discitis and sacroiliitis, prosthetic hip joint infections,acute osteomyelitis, and paraspinal abscesses (Table 3). Apartfrom the presence of chronic oral infections such as periodon-titis, recent invasive oral procedures, such as tooth extractionand ultrasonic scaling, have also been implicated as potentialtriggering factors for these infections. Common oral bacterialspecies such as Abiotrophia defectiva, Streptococcus intermedius,viridans group streptococci, Haemophilus aphrophilus, andHaemophilus paraphrophilus have all been implicated in suchinfections (37, 62, 75, 117, 142).
Respiratory Infections
Pulmonary infections consequential to odontogenic bactere-mia have been described, although this is controversial becauseit can always be argued that bacteria could translocate into thelungs through direct anatomical routes. However, involvementof more than one lung, the multiplicity of lesions, and thenature of the organisms favor an oral-hematogenous spread. Ithas therefore been argued that such episodes are a result ofspread from an oral niche due to the presence of poor oralhygiene or recent orogingival manipulation. Selenomonas spp.,viridans group streptococci, Streptococcus intermedius, andActinomyces odontolyticus have been implicated in acute respira-tory distress syndrome, infection of the postpneumonectomyspace, septic pulmonary embolism, and lung abscesses, respec-tively (13, 23, 38, 129). Interestingly, however, almost all sub-jects with such pulmonary infections were shown to have acompromised immune status due to advanced malignancies.
Septicemia
Similarly, there are many reports implicating odontogenicbacteremia as a causal factor for septicemia, particularly inindividuals with hematological malignancies (35, 64, 97, 98,105, 131, 138). In a recent study, even among otherwise healthysubjects, a majority of subjects with Leptotrichia buccalis sep-ticemia were shown to have some form of intraoral infectivefocus (135). Yet in a vast majority of these cases, the connec-tivity between the oral cavity and the systemic focus is tenuousand, at best, circumstantial.
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TABLE 3. Summary table annotating the literature on systemic infections (apart from endocarditis) due to oral bacteria
Phylum, yr, and author(reference) Genus or species Systemic infection Putative oral source Diagnostic method Remarks/comments on
isolates
Firmicutes1985, Lindqvist (75) Viridans streptococci Hip arthroplasty
infectionAntecedent dental
proceduresCulture and biochemical
testsDetailed identification to
the species level notperformed
1990, Bisiaux-Salauze(13)
Selenomonas (S.artemidis and S.infelix)
Lung infections leadingto ARDS
Poor oral hygiene Culture and biochemicaltests with gaschromatography ofmetabolic productsand electronmicroscopy
Two cases; Selenomonasspp. are members of theoral commensal flora
1993, Christensen (23) Streptococcus intermedius Septic pulmonaryembolism
Recent history oftoothache
Culture and biochemicaltests
A predominant member ofthe oral commensal floraalso implicated inbacterial endocarditis
2000, Kaar (62) Streptococcus intermedius Infection of a revisiontotal hip arthroplasty
Supragingival cleaning�30 h before theonset of bacteremia
Culture and biochemicaltests
The bacteria might havedisseminated fromperiodontal plaquebiofilm
2000, Michelow (88) Abiotrophia spp. Cerebral abscess Severe mucositis withoral ulceration
Culture and biochemicaltests with RapIDANA II system
A definitive pathogenicrole within the oralcavity has not beendetermined for thisorganism
2002, Rousee (114) Dialister pneumosintes Brain abscess Gingivitis andperiodontitis
Phenotypiccharacterization and16S rRNA genesequencing
No evidence hitherto ofconcomitant systemicaffections
2004, Dietl (38) Viridans streptococci Infection ofpostpneumonectomyspace
Recent dental work(gum surgery)
Culture and biochemicaltests
Viridans group streptococciare commonly implicatedin endocarditis, but inthis case, they causedlung infection in a cancerpatient
2004, Marques daSilva (86)
Streptococcus constellatus Brain abscess Presence of deepperiodontal pockets,bleeding, toothmobility, andradiographic signs ofalveolar bone loss
Restriction fragmentlength polymorphismanalysis, ribotyping,and randomamplification ofcDNA ends showedidentical profiles withthe oral isolates
One of the few instanceswhere genetichomogeneity has beendetermined for blood/tissue and oral isolates
2005, Wilhelm (142) Abiotrophia defectiva Multiple discitis andsacroiliitis
Recent series of dentalsurgical procedures
Culture and biochemicaltests with 16S rRNAgene sequencing
Previously known asnutritionally variantstreptococci, thisorganism is increasinglyisolated fromimmunocompromisedpatients
2005, Kazanci (63) Streptococcus oralis Middle cerebral arterythrombosis
Dental abscess Culture and biochemicaltests
It is difficult to determinewhether the infection is aresult of local spread orhematogenousdissemination
2006, Detry (35) Solobacterium moorei Septicemia in a patientwith multiplemyeloma
Apical dental abscesses Cultures, biochemicaltests, andchromatography
This organism is alsoconsidered to beassociated with halitosis
Fusobacteria1985, Reig (105) Leptotrichia buccalis Septicemia (two cases) Oral mucosal
ulcerationCulture, biochemical
tests, GC content ofcellular organic acids
Both patients wereundergoingchemotherapy formalignancy
1999, Patel (97) Novel Leptotrichia spp. Septicemia Oral herpes simplexlesions
Culture, biochemicaltests, GC content ofcellular organic acids,and 16S rRNA genesequencing
The patient had acutemyeloid leukemia
2001, Tee (131) Leptotrichia trevisanii Septicemia Gingivitis, mucositis,and oral ulceration
Anaerobic culture,RapID ANA profiles,and 16S rRNA genesequencing
Infection in a patient withacute myeloid leukemia
2003, Heckmann (57) Fusobacterium nucleatum Multiple brain abscesses Poor oral hygiene Presence offusobacterial DNA inthe cerebrospinal fluid
F. nucleatum is a well-recognized periodontalpathogen
2006, Ulstrup (135) Leptotrichia buccalis Septicemia Periodontitis Culture and biochemicaltests
12/19 patients had orallesions
Continued on following page
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Infections in Pregnancy
Although a recent well-controlled randomized trial byMichalowicz and coworkers (87) found no association betweenperiodontal indices and pregnancy outcomes, there is increas-ing evidence to indicate that adverse pregnancy outcomes, suchas preterm birth and premature rupture of the membranes, areassociated with poor maternal oral health, particularly chronicperiodontitis (14, 69, 78, 79, 130). This could be due to a lowlevel of chronic bacteremia as well as to chronic inflammation,which upregulates the levels of cytokines and other inflamma-tory modulators.
Furthermore, periodontopathic bacteria could also be de-tected in placentas of pre-eclamptic women (9). Despite thefact that most infections of the gravid uterus, fetus, newborn,or postpartum uterus originate from the reproductive tract,records indicate at least one instance where oral bacterialspecies with identical genetic homogeneity were recoveredfrom both the in utero infection and the oral cavity (55). Giventhe well-known historical fact that the syphilitic spirocheteTreponema pallidum crosses the fetoplacental barrier, resultingin neonatal syphilis and associated dental abnormalities (e.g.,
mulberry molars and Hutchinson’s incisors), it is tempting tospeculate that oral bacteria, including the spirochete Trepo-nema microdentium and others, may affect the fetus, possiblythrough fetoplacental passage. Immunological studies havealso revealed higher levels of periodontopathogen-specific im-munoglobulin M in umbilical cord blood in babies born pre-term (14). Whether this is a result of fetoplacental bacterialpassage and dissemination or a generalized immune responsehas yet to be determined. Therefore, much more research iswarranted to establish a link between odontogenic bacteremiasand fetal and maternal health.
DIAGNOSING THE SOURCE OF BACTEREMIA
The traditional gold standard for the detection of bactere-mia is the use of in vitro cultures. For this purpose, liquid,solid, or biphasic culture media have been used with variousincubation periods (124). In clinical microbiology laboratories,automated blood culture systems such as the Bactec system arenow routinely used for this purpose (21). These automatedsystems enable the rapid recognition of bacterial growth by
TABLE 3—Continued
Phylum, yr, and author(reference) Genus or species Systemic infection Putative oral source Diagnostic method Remarks/comments on
isolates
2006, Khouzam (67) Fusobacterium spp. Brain abscess Poor oral hygiene, withnumerous cavitiesand gingivitis
Culture, biochemicaltests
Mixed microbial infectionwith Streptococcus spp.
2006, Ewald (44) Fusobacterium nucleatum Brain abscess in theright occipital lobe
One or more ofperiapical osteitis,caries in teeth,gingivitis, andretained tooth
Isolation of theorganism from thelesion through culture
Series of six cases;Streptococcus, Bacillus,and Actinomyces spp.were also isolated
Proteobacteria1993, Pedersen (98) Neisseria meningitidis Septicemia Recent tooth
extractionCulture and biochemical
testsAlthough the normal route
of infection is throughnasopharyngealcolonization, this case islikely to be odontogenic
1997, Roiz (112) Kingella kingae Septicemia Recent dentalprocedure
Culture and biochemicaltests
Well-known etiologicalagent of odontogenicendocarditis (i.e., theHACEK group)
1997, Samuel (117) Haemophilusparaphrophilus
Paraspinal abscess Recent periodontalsurgery
Specialized cultures Members of the HACEKgroup of organisms andoral commensals
1999, Dewire (37) Haemophilus aphrophilus Acute osteomyelitis ofthe humeral shaft
Recent dental cleaningand ultrasonicscaling
Culture and antibioticsensitivity tests
Members of the HACEKgroup of organisms andoral commensals; rarecause of bone infections
2004, Iida (61) Porphyromonas gingivalis Brain abscess Presence of toothinfection
Recovery of theorganism from thecerebrospinal fluid
Well-confirmed etiologicalagent of periodontitis
2008, Pasqualini (95) Aggregatibacteraphrophilus
Spinal epidural abscesswith cervicalspondylodiscitis
Apical periodontitis Standard culturesbiochemical tests andAPI index
No underlying predisposingconditions exceptperiodontitis
2005, Stepanovic (126) Aggregatibacteractinomycetemcomitans
Brain abscess Poor dentition, poororal hygiene, withcariotic teeth
Culture and biochemicaltests
Previously known asActinomycesactinomycetemcomitans,associated with a numberof oral lesions
Actinobacteria2003, Takiguchi (129) Actinomyces
odontolyticusLung abscess Periodontitis Culture and biochemical
testsKnown oral pathogen
Bacteroidetes2003, Mantadakis (85) Capnocytophaga
gingivalisSepticemia Dental caries and
gingivitisQuantitative culture by
lysis centrifugationAcute lymphoblastic
leukemia
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emitting fluorescence or a color change of the sample. Oncegrowth is detected, aliquots are subcultured onto different agarmedia for further definitive identification of the offending or-ganism(s). These automated methods are rapid, yet quantifi-cation of bacteremia is difficult, and for this purpose, the lysisfiltration method is generally used. Briefly, lysis filtration in-volves treatment of a defined volume of blood with a mediumthat can digest the cellular contents and filtering through amembrane of defined pore size to capture the bacteria. Themembrane is then inoculated in a growth medium to evaluatebacterial growth. The data yielded are quantitative and thusare more sensitive than those obtained with conventional andautomated culture techniques (82, 145).
Once cultured, the bacteria are usually identified using phe-notypic characteristics, such as the presence or absence ofmetabolic pathways, alterations in metabolic pathways, the uti-lization of substrates, and end product profiles. These tests areminiaturized and packaged into standardized, commerciallyavailable kits that allow comparison of the activity profile in-dices (e.g., API tests). One drawback of these identificationmethods is that they are exclusively dependent on the growthof the organism in either a liquid or solid culture medium.Given the fact that a large number of oral bacterial species arenow known to be extremely slow growing or uncultivable, thevalue of standard culture methods and growth-dependentidentification profiling has recently been questioned (3). As apartial solution to this problem, molecular probe-based iden-tification methods are used and are gaining popularity (45, 99).Unfortunately, though, most of the latter methods are alsodependent upon the successful isolation of the bacterial spe-cies in the primary culture. The latest approaches in detectingbloodstream infections, such as PCR–single-strand conforma-tion polymorphism and direct amplification and sequencing ofthe 16S rRNA genes, which do not rely on in vitro culture,appear to be the solution to this impasse (101, 134). Neverthe-less, such approaches have yet to be used and validated inprospective trials of experimental odontogenic bacteremias.
Whenever a bacterial species is isolated from a clinical bloodsample, the next issue that needs to be addressed is its origin.A vast number of studies on odontogenic bacteremias andsystemic infections of odontogenic origins are based on cir-cumstantial evidence that relates the oral organism and thoseof the infective focus. These include factors such as poor oralhygiene in the affected individual, a history of dental treatmentin the immediate past, or a traumatic event related to the oralcavity (Table 3). The veracity of these assumptions and thesignificance of the information can be ascertained only whenthe same phenotype is isolated, in particular when the isolatesfrom the two niches are genotypically identical. Phenotypicsimilarities between the isolates from the two sites have beendemonstrated by biochemical profiles, chromatographic evi-dence of cellular macromolecules, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of cellular proteins, andantibiotic sensitivity patterns (11, 31, 103). However, only a fewworkers have attempted to determine the genetic homogeneityof the isolates, despite the greater robustness of this method.For the latter purpose, pulsed-field gel electrophoresis ofgenomic DNA and ribotyping have commonly been used, al-though more recently, the use of 16S rRNA gene sequence
homogeneity and bioinformatics-based methods has shownpromising results in assessing clonality (30, 55, 64, 65, 86, 118).
Also notable is the fact that molecular sequence-based ap-proaches have higher sensitivities than do cultivation-basedapproaches. In addition, sequence-based detection methodsbased on universal 16S rRNA genes or other specific bacterialgene markers could be employed as markers of a treatmentresponse when cultures fail to show bacterial growth. Onedrawback of these rapid and sensitive molecular diagnosticmethods, however, is that they do not lend themselves to an-timicrobial sensitivity testing, as the organism cannot be phys-ically grown in culture. This information is important for cli-nicians, who rely on laboratory antimicrobial sensitivity tests toinitiate or modify treatment (107). In clinical terms, the mo-lecular typing methods to determine clonality should be con-sidered adjuncts in situations where the clinical presentation isatypical or when there is no or a poor response to antimicrobialtherapy.
BACTERIAL DIVERSITY INODONTOGENIC BACTEREMIA
As opposed to the more than 700 bacterial species thatinhabit the oral cavity, relatively fewer species have been iso-lated from blood cultures for odontogenic bacteremias. Asshown in Table 4, there are at least eight bacterial taxonomicfamilies that are represented in different oral niches. Of these,members of the family Firmicutes occupy the bulk of the mi-crobiome in terms of the numbers of genera and bacterialspecies (1, 36, 70). Phylogenetic studies of the oral microbiomehave shown that a large proportion of the oral bacteria com-prise the genus Streptococcus. This holds true for the isolates inexperimental odontogenic bacteremias as well (Table 2). In anumber of controlled clinical trials, streptococci were the pre-dominant organisms isolated, ranging from 40 to 65% of iso-lates (39, 48, 109, 110, 132, 140). Other genera of the Firmi-cutes family have been isolated from the bloodstream, to alesser extent than streptococci, and include species of theAbiotrophia, Dialister, Selenomonas, and Solobacterium genera,in descending order. The Fusobacteria family is the secondmost commonly isolated bacterial family from the bloodstreamand includes genera such as Leptotrichia and Fusobacteria,while other families, such as Actinobacteria, Synergistes, andBacteroidetes, are far less common. Finally, there are no data inthe literature describing the dissemination of either Spiro-chaetes or recently detected families, such as the Obsidian pooland TM7 bacteria, from the mouth in experimental odonto-genic bacteremias or systemic infections secondary to dentaltreatment procedures. The last two families are not known topossess any cultivable species thus far.
CONCLUDING REMARKS
On appraising the literature on odontogenic bacteremia, it isclear that a number of oral manipulative procedures can giverise to bacteremias of oral origin. The highest incidence ofbacteremia results from tooth extractions. Periodontal manip-ulations are also shown to produce a long-lasting (�30 min)bacteremia. This is probably a reflection of the bacterial loadand tissue trauma or associated inflammation at these niches.
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Other oral procedures are not as significant, at least for indi-viduals with healthy oral cavities. Routine oral hygiene mea-sures such as brushing or flossing are unlikely to cause a sig-nificant degree of bacteremia, but sporadic cleaning afteraccumulation of a heavy plaque load should be considered apotential risk factor for a bacteremic state.
As evident from Tables 2 and 3, bacteria of potential oralorigin detected in odontogenic bacteremias show some degreeof diversity, but to a much lesser extent than that of the oralcavity. It is probable that this lack of diversity of blood-bornebacterial species is due to (i) their virulence attributes thatfacilitate entry into the bloodstream, (ii) the rapid clearance ofthe bacteria by host defenses, and (iii) the low threshold of the
current detection methods used in clinical laboratories. How-ever, as in the oral niche, the predominant bacterial genusisolated from the blood is Streptococcus. More than half ofsystemic affections are of streptococcal etiology, indicating thatthe predominance of streptococci in the oral niche could be afactor in determining their entry into the bloodstream (136).
A vast majority of bacteremias have been detected by culti-vation and subsequent phenotypic characterization. Differentforms of aerobic and anaerobic culture methods have beenutilized. Comparison of different experimental bacteremiastudies is difficult because there is no uniform agreement be-tween timing of sampling, volume of blood drawn, and bacte-riological identification methods. However, irrespective of theculture method, a larger volume of blood drawn does notnecessarily concur with a higher incidence of bacteremia.Quantification of bacteria has often been done using lysis fil-tration of a defined volume of blood. Novel, more sensitivebacterial detection and identification methods, such as 16SrRNA gene sequencing, have not been used on a large scale.Strangely, though, the two studies that employed PCR of 16SrRNA genes showed lower incidences of bacteremia due tooral manipulations than that reported by culture techniques(68, 118). These differences could possibly be overcome byincreasing the template volume as well as the sample size.
Most of the bacteremias considered odontogenic in the lit-erature are based on circumstantial evidence. Hence, it is im-perative that future workers study the genetic relatedness oforganisms, rather than their phenotypes, in evaluating experi-mental odontogenic bacteremias.
Apart from bacterial endocarditis, there are a number ofother systemic affections caused by bacteria residing in the oralcavity. However, most of the records on such infections arepresented in the literature in the form of case reports or as asummary of a few cases. Since case reports are not the pre-ferred mode of editorial boards due to a lack of originality, itis safe to assume that a large number of these go unreported.
It is safe to conclude, then, that odontogenic bacteremias arelikely to cause systemic and end organ infections, but it is likelythat most such infections are occult and dealt with swiftly bybody defenses. The available data provide us only a glimpse ofthe reality, and much more work, using sophisticated sampling,detection, and analytical techniques, is required to draw firmconclusions. It is hoped that the availability of novel molecularand genomic tests will help to demystify the connection be-tween odontogenic bacteremia and end organ infections in thenot too distant future.
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TABLE 4. Bacterial families and genera that inhabit oral nichesa
Family Genus
Firmicutes ......................................................................AbiotrophiaAnaerococcusAnaeroglobusBulleidiaButyrivibrioCatonellaCentipedaDialisterEubacteriumFilifactorGemellaGranulicatellaJohnsonellaLactobacillusMegasphaeraMicromonasMogibacteriumPaenibacillusPeptococcusPeptostreptococcusSchwartziaSelenomonasSolobacteriumStaphylococcusStreptococcusVeillonella
Fusobacteria...................................................................LeptotrichiaFusobacterium
Actinobacteria................................................................ActinobaculumActinomycesAtopobiumCorynebacteriumRothia
Synergistes ......................................................................SynergistesSpirochaetes ...................................................................TreponemaProteobacteria ................................................................Kingella
LautropiaNeisseriaHaemophilusDesulfobulbusCardiobacteriumCampylobacter
TM7 ...............................................................................TM7 cloneBacteroidetes ..................................................................Capnocytophaga
PorphyromonasTannerellaPrevotellaBacteroides
a Data are from various studies. Note that apart from the domain Bacteria,members of the domain Archaea have also been isolated from different oralniches. However, their role in systemic infections has yet to be evaluated.
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AUTHOR’S CORRECTION
Microbiology of Odontogenic Bacteremia: beyond EndocarditisN. B. Parahitiyawa, L. J. Jin, W. K. Leung, W. C. Yam, and L. P. Samaranayake
Oral Bio-Sciences and Periodontology, Faculty of Dentistry, and Department of Microbiology, Li Ka Shing Faculty ofMedicine, The University of Hong Kong, Hong Kong SAR, China
Volume 22, no. 1, p. 46–64, 2009. Page 61: The Acknowledgments section was inadvertently omitted and should appear as shownbelow.
ACKNOWLEDGMENTS
We acknowledge financial support from the Hong Kong ResearchGrants Council (grant RGC HKU 7624/06M to L.P.S. and grantHKU7518/05M to L.J.J.) and the Strategic Research Theme on Infec-tion and Immunity of the University of Hong Kong.
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