Endodontic Topics 2003, 6, 78–95
Printed in Denmark. All rights reserved
Copyright r Blackwell Munksgaard
ENDODONTIC TOPICS 2003
Periapical Actinomycosis and
infection with Propionibacterium
Propionicum
JOSE´ F. SIQUEIRA JR
Introduction
Apical periodontitis is an inflammatory disease of
microbial etiology (1, 2). It is formed in response to
intra-radicular infection and comprises an effective
barrier against spreading of the infection to the alveolar
bone and to other body sites. In most situations, apical
periodontitis lesions are free of microorganisms.
However, in specific circumstances, the inflamed
periapical tissues can be invaded by microorganisms,
resulting in extra-radicular infection. The most common form of extra-radicular infection is the acute
periapical abscess, characterized by purulent inflammation in the periapical tissues in response to the egress of
virulent bacteria from the root canal (3). There is,
however, another form of extra-radicular infection
which, unlike the acute abscess, is usually characterized
by the absence of overt symptoms. This condition
consists of establishment of microorganisms in the
periapical tissues, either by their adherence to the apical
root surface in the form of biofilm-like structures (4) or
within the body of the inflammatory lesion, usually as
cohesive colonies (5). Those extra-radicular microorganisms have been regarded as one of the etiologies
of persistence of apical periodontitis in spite of
endodontic treatment (4–6).
It can be assumed that the extra-radicular infection
may be dependent on, or independent of the root canal
infection (Fig. 1). For example, the acute periapical
abscess – the most common form of extra-radicular
infection – is clearly dependent on the intra-radicular
infection; once the intra-radicular infection is properly
treated and drainage of pus is achieved, the extra-
78
radicular infection subsides. Thus, extra-radicular
infections are commonly supported by the intraradicular infection and, except for abscesses, extraradicular infection is a rather rare occurrence (3).
Recent studies using culture (7–9) or molecular
methods (10, 11) for microbial identification have
reported the extra-radicular occurrence of a complex
microbiota associated with post-treatment apical periodontitis, which did not respond favorably to the root
canal therapy. Anaerobic bacteria have been reported to
be the dominant microorganisms in several of those
lesions (7–11). Although those studies did not evaluate
the bacteriological conditions of the apical part of the
root canal, it is entirely possible that such extraradicular infections were in fact supported by intracanal microorganisms. This may be another example of
extra-radicular infection that is dependent on the
presence of an intra-radicular infection.
In fact, the aforementioned findings are very intriguing, as most of the detected species are usually oral
opportunistic pathogens that are unlikely to survive in
a hostile environment such as the inflamed periapical
tissues (3). The following questions arise: Were
bacteria actually present within the periapical tissues?
If so, were they truly established in the inflamed
periapical tissues or was their presence only transient
before elimination by host defenses? Can a mixed
infection composed of several species become established in the periapical lesions in a relatively high
percentage of cases? If most of the apical periodontitis
lesions involve extra-radicular infection, can the nonsurgical (orthograde) endodontic therapy result
in a high healing rate? Can we non-surgically treat an
Periapical Actinomycosis
Fig. 1. Extra-radicular infections can be dependent on
(A) or independent of (B) the intra-radicular infection. In
the former, eradication of the intra-radicular infection
usually results in healing of the periapical lesion. In the
latter, periapical inflammation can be sustained, even after
thorough elimination of the intra-raticular infection.
extra-radicular infection? Further research is still
required before these questions can be answered with
a degree of confidence.
In most teeth associated with apical periodontitis,
infection is restricted to the root canal. Most of the
microbial species that infect the root canal are
opportunistic pathogens (3) that do not have the
ability to survive host defense mechanisms in the
periapical tissues. Rare exceptions are those microbial
species or even strains within a species that possess
strategies to survive and thus to infect vital tissues. Such
microorganisms must be able to invade tissues,
scavenge nutrients, and evade the host defense
mechanisms (3). If all these requirements are materialized, an extra-radicular infection may develop.
A few oral microorganisms have the ability to
overcome host defense mechanisms, thrive in the
inflamed periapical tissues and, as a consequence,
induce an extra-radicular infection. Several species of
putative oral pathogens have been detected in posttreatment apical periodontitis lesions (7, 10, 11). Some
of them possess an apparatus of virulence that
theoretically can allow them to invade and to survive
in a hostile environment, such as the periapical lesion
(3). However, their involvement in an extra-radicular
infectious process independent of the intra-radicular
infection is not certain.
There are a few conditions in which the extraradicular infection may actually occur, persist even after
successful eradication of the intra-radicular infection,
and hence be the exclusive etiology of post-treatment
disease. In this case, the extra-radicular infection is
conceivably independent of the intra-radicular infection. So far, evidence suggests that the main bacterial
species implicated in exclusively extra-radicular infections are the members of the genus Actinomyces and the
species Propionibacterium propionicum (formerly designated Arachnia propionica), in a pathologic entity
named periapical actinomycosis (12–15). Given the
widely recognized role of these bacteria in causation of
post-treatment disease, this review will focus on their
involvement with different types of endodontic infections, with special emphasis placed on their association
with periapical actinomycosis. The mechanisms of
pathogenicity of Actinomyces species and P. propionicum that can play a role in the etiology of periapical
actinomycosis, as well as the therapeutic measures to
manage this disease, will also be discussed.
Actinomycosis
The term ‘actinomycosis’ was introduced by Israel, in
1878 (16), in his accurate description of a cervicofacial
and thoracic case of the disease. Additional clinical
descriptions followed along with the isolation of
Actinomyces israelii by Bujwid in 1889 (17). This
species was then well described by Wolff and Israel, in
1891 (18).
The causative agents of this slowly progressive
infection are Gram-positive bacteria of the genera
Actinomyces and Propionibacterium, which are normal
inhabitants of the oral cavity, colon and vagina (19–21).
A. israelii is by far the species most commonly involved
in causation of actinomycosis, but less common causes
of the disease include Actinomyces naeslundii genospecies 1 and 2, Actinomyces odontolyticus, Actinomyces
meyeri, Actinomyces gerencseriae, and P. propionicum
(19, 20).
Actinomycosis is a chronic, granulomatous infectious
disease characterized by suppuration, abscess formation
and draining sinus tracts, which erupt to the skin or
mucosal surfaces and drain pus containing ‘sulfur
granules’ (small colonies of bacteria) (19, 21). The
clinical forms of actinomycosis that account for most of
these infections in humans are as follows, in decreasing
order of prevalence: (1) cervicofacial, (2) abdominal,
(3) thoracic, and (4) cerebral forms (19, 21, 22). The
cervicofacial form is the most common form of the
disease. It is characterized by a slowly evolving
induration in the mandibular–preauricular region,
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often accompanied by sinus tracts to the skin that
discharge typical ‘sulfur granules’ (21). Sometimes it
may take the form of acute abscesses (21). The majority
of cases have been observed in patients with poor oral
hygiene and/or a history of invasive dental procedures
or trauma. Pulverer et al. (23) evaluated microbiological and selected clinical data derived from 1997
culture-positive cases of human cervicofacial actinomycoses examined during 1972–1999; they reported that
causative actinomycetes belonged to at least nine
different species, among which A. israelii and A.
gerencseriae predominated. The highest incidence was
found in female patients aged 11–40 years and in male
patients aged 21–50 years. Periapical actinomycosis is a
form of cervicofacial actinomycosis, but signs and
symptoms are usually different (see discussion below).
The abdominal and the thoracic forms are presumably
due to aspiration and swallowing of bacteria from the
oral cavity (24).
The basic microscopic picture in actinomycosis is
suppurative, but it can vary from an acute abscess to a
chronic lesion in which proliferating connective tissue
is commonly seen (19). In tissues, Actinomyces species
grow in microscopic or macroscopic clusters, which
may reach diameters of up to 3–4 mm (19). Clusters
sometimes exude from soft tissues through sinus tracts,
and because of their yellowish appearance, they are
commonly referred to as ‘sulfur granules’, even though
there is no clear evidence that they contain sulfur at all
(25). In fact, such clusters or granules consist of a
central mass of intertwined branching bacterial filaments, held together by an extra-cellular matrix, with
the peripheral radiating clubs. Microscopically, the
granules give the appearance of rays projecting out
from a central mass of filaments, which gave origin to
the name Actinomyces or ‘ray fungus’ (19). Granules are
very likely to be formed in response to host defenses
and can provide the bacteria with protection against
phagocytosis or other immunological mechanisms (19,
20).
It should be pointed out that not all cases in which
granules are observed in the purulent exudate should
be indiscriminately diagnosed as actinomycosis. This is
because other bacteria also can form aggregates with
similar appearance (19). Apparently, this observation is
also true for periapical actinomycosis. Sunde et al. (25)
reported the occurrence of ‘sulfur granules’ in nine
refractory periapical lesions and found bacteria in seven.
Actinomyces species occurred in five granules and a wide
80
spectrum of other bacterial species was detected in
addition to Actinomyces. Many of the ‘sulfur granules’
were calcified and the source for mineralization may
have been the inflammatory exudate and/or the activity of extra-radicular bacteria (25). Although ‘sulfur
granules’ have long been considered as suggestive of
actinomycosis, that study (25) confirmed that other
species can form aggregates that are similar to those
formed by Actinomyces species and P. propionicum.
Therefore, the mere observation of the presence of
‘sulfur granules’ does not represent sufficient information for the diagnosis of periapical actinomycosis.
It has been suggested that the demonstration of
typical ray fungus patterns, or actinomycotic rosettes in
tissue sections is sufficient to establish a diagnosis of
actinomycosis (26). Although this is really widely
accepted, an irrefutable diagnosis is only achieved after
the bacterial species involved are properly identified by
culture-dependent or -independent approaches.
Actinomyces species
The genus Actinomyces encompasses a heterogeneous
group of non-acid fast, non-motile, non-spore forming, obligately anaerobic and facultatively anaerobic,
Gram-positive rods. Early classification of Actinomyces
was complicated by their histological resemblance to
fungi (Actinomyces 5 ray fungus), which occurred due
to the radial appearance of filaments in the granules
found in actinomycotic lesions. Actinomyces cells are
0.4–1 mm wide, short (1.5–5 mm long) or longer (5–
50 mm long). They can be straight, curved, branched or
pleomorphic, and they can occur singly, in pairs,
clusters or short chains. Most of the species are
facultative anaerobes, while some are obligate anaerobes. Actinomyces species are fermentative, generally
utilizing carbohydrates to produce formic, acetic, lactic
and succinic acids (20, 27).
Recent taxonomic changes have taken place in the
genus Actinomyces and new species have been proposed. Strains originally classified as A. israelii serotype
II have been designated as a separate species, A.
gerencseriae, based on comparisons of 16S rRNA
sequences (28). A. gerencseriae is a common but minor
component of the microbiota of the healthy gingival
crevice. Johnson et al. (28) proposed subdivision of A.
naeslundii into three new genospecies: (1) genospecies
1 included A. naeslundii serotype I; (2) genospecies 2
Periapical Actinomycosis
included A. naeslundii serotypes II and III, and human
strains of Actinomyces viscosus; and (3) genospecies 3
comprised Actinomyces WVA 963. A previously unknown bacterium isolated from infected root canals was
classified as A. radicidentis based on both phylogenetic
and phenotypic evidence (29). Cells of this new species
are coccoid, Gram-positive, facultatively anaerobic,
non-motile, and catalase positive.
Although Actinomyces species have been found to be
etiologic agents in infections in diverse body sites,
including some forms of actinomycosis, eye infections,
abscesses in different sites as well as respiratory, genital
and urinary tract infections (30), most species are
normal inhabitants of the oral cavity (Table 1). A.
odontolyticus and A. naeslundii genospecies 1 and 2 are
the primary Actinomyces species in infants’ mouths as
well as in early dental plaque (31, 32). Actinomyces
georgiae, A. gerencseriae, A. israelii, A. naeslundii and
A. meyeri have been found in gingival crevices of
Table 1. Species of the genus Actinomyces found in
humans
Oral
A. georgiae
A. gerencseriae
A. graevenitzii
A. israelii
A. meyeri
A. naeslundii genospecies 1
A. naeslundii genospecies 2 (A. viscosus)
A. odontolyticus
A. radicidentis
Non-oral
A. europaeus
A. funkei
A. houstonensis
periodontally healthy and diseased individuals (33, 34).
Actinomyces graevenitzii has been found in infants’
saliva (31). It has been demonstrated that oral
Actinomyces species colonize hard tissues (supra- and
sub-gingival plaque) at far higher proportions than soft
tissues (33). In general, Actinomyces species are usually
isolated from supra-gingival and sub-gingival plaque,
tonsils, dentinal and root surface caries, periodontal
pockets and infected root canals (33, 35–37).
P. propionicum
P. propionicum was formerly assigned to the genus
Actinomyces, then transferred to the genus Arachnia
and from there to Propionibacterium on the basis of
sequence homology of ribosomal RNA (38, 39).
Further analysis of its fatty acid pattern supported
transfer of this species to the genus Propionibacterium
(40). Cells are non-motile and may appear as irregular
rods, 0.2–0.3 mm in diameter and 3–5 mm in length,
which may or may not be branched, often with swollen
or clubbed ends. They can also occur as branching
filaments, 5–20 mm in length. Occasionally large round
cells may be observed (5 mm in diameter). P. propionicum is facultatively anaerobic, but best growth is
attained under anaerobic conditions. Propionic and
acetic acids are the major end products of the anaerobic
fermentation of glucose. CO2 and lesser amounts of
lactic and succinic acids are also produced (38).
P. propionicum is a normal inhabitant of the human
oral cavity, and can be involved in several oral diseases.
In addition, this species has been reported to occur in
cases of tympanomastoiditis (41), vertebral osteomyelitis (42), epidural abscess (43), lacrimal canaliculitis
(44, 45), brain abscess (46), pulmonary infection in
patients with hairy cell leukemia (47), and actinomycosis (38, 48). P. propionicum may produce disease
clinically indistinguishable from that caused by Actinomyces species (43, 48). Like Actinomyces species, P.
propionicum is known to be able to flourish in host
tissues for long periods of time without causing
symptoms.
A. neuii
A. radingae
A. turicensis
A. urogenitalis
Association with primary intraradicular infections
Actinomyces species are normal inhabitants of the oral
cavity and their occurrence in endodontic infections is
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thereby not surprising. In fact, they are arguably one of
the first colonizers of the exposed pulp, given their high
prevalence in carious dentin (49). In one study (49)
Actinomyces species along with species from the genera
Eubacterium and Propionibacterium were found to
have invaded the pulps of six out of nine teeth with deep
dentinal lesions even before pulpal exposure occurred.
Primary intra-radicular infections are caused by
microorganisms that initially colonize the necrotic pulp
tissue (3). Several studies, using different approaches
for microbial identification, have reported that Actinomyces species can take part in the microbiota associated
with primary intra-radicular infections, irrespective of
whether symptoms are present or not (1, 50–71)
(Table 2). Reported prevalence figures for Actinomyces
species can reach up to half of the examined cases (71).
Commonly detected species have been A. israelii, A.
naeslundii genospecies 1 and 2, A. odontolyticus, A.
meyeri, and A. gerencseriae (36, 50–71). Siqueira and
Roˆc¸as (52) reported a very low prevalence of the
recently described A. radicidentis in primary endodontic infections. This species was detected in one tooth
associated with chronic apical periodontitis and in
another tooth associated with acute apical periodontitis. In general, A. radicidentis was found in 4% of
the samples taken from primary endodontic infections.
Actinomyces species can be found in the apical
segment in about 30% of infected root canals (53).
They have also been reported to participate in the
microbiota associated with acute periapical abscesses.
Sundqvist et al. (54) investigated the microbiota of 72
root canals, 17 of which were associated with periapical
abscesses and purulent drainage through the canal.
Actinomyces species were found in six of the abscessed
teeth, usually in combination with other bacteria,
except for one tooth in which the root canal contained
only A. israelii and A. naeslundii. Siqueira et al. (51)
investigated the prevalence of Actinomyces species in
abscessed cases using the checkerboard DNA–DNA
hybridization method and found A. gerencseriae in 15%
of the cases, A. israelii in 7% and A. odontolyticus in 4%.
In general, the presence of Actinomyces genus was
positively associated with abscesses, but no such
correlation could be established for any particular
species. Khemaleelakul et al. (70) isolated A. naeslundii
in 18% and A. odontolyticus in 12% of the cases of
abscess/cellulitis of endodontic origin. By using a PCR
assay, Xia and Baumgartner (71) found Actinomyces
species in 46% of abscesses and 30% of cellulitis cases.
82
Most studies using culture identification procedures
have revealed the presence of P. propionicum in primary
endodontic infections. The prevalence of such occurrence has been reported to range from 3% to 31% of
teeth with apical periodontitis (1, 54, 56, 58, 60, 61,
65, 66, 69). Recently, Siqueira and Roˆc¸as (52) devised a
nested PCR assay to detect P. propionicum in endodontic infections associated with different forms of
apical periodontitis, and found this species in 36% of the
cases (29% of the teeth with chronic periapical lesions,
in 50% of the teeth with acute apical periodontitis, and
in 37% of the teeth with acute periapical abscesses).
Cumulatively, all these findings suggest that Actinomyces species and P. propionicum have the ability to
colonize the necrotic pulp and participate in a mixed
microbial consortium that can be involved in causation
of different forms of periapical diseases.
Association with post-treatment
disease
In addition to being frequently found in teeth with
primary endodontic infections, Actinomyces species and
P. propionicum have also been found in association with
post-treatment disease. They have been reported to
occur either in persistent/secondary intra-radicular
infection, or as the exclusive etiology of extra-radicular
infection, diagnosed as periapical actinomycosis.
Persistent and secondary intra-radicular
infection
Secondary intra-radicular infections are caused by
microorganisms that were not present in the primary
intra-radicular infection, but gained entry into the root
canal after some treatment intervention and succeeded
in colonizing this environment (3). Breach of asepsis
during treatment is one of the major causes of
secondary infections. Furthermore, secondary infections can occur after root canals had been filled, and
thereby can become a cause of post-treatment disease
(72).
Persistent intra-radicular infections are caused by
microorganisms that have survived the intra-canal
antimicrobial procedures associated with root canal
therapy. The microorganisms involved in persistent
infections can either be members of the primary
infection or of a secondary infection (3). Persistent
Periapical Actinomycosis
Table 2. Data from studies that reported the occurrence of Actinomyces species and Propionibacterium
propionicum in primary intra-radicular infections
Study
Identification method
Species
Prevalencen
Kantz & Henry (55)
Culture
A. israelii
4/16 (25%)
Actinomyces sp.w
Wittgow & Sabiston (56)
Culture
P. propionicum
Actinomyces sp.
Sundqvist (1)
Culture
Actinomyces sp.
1/16 (6%)
1/32 (3%)
1/32 (3%)
3/18 (17%)
A. naeslundii
2/18 (11%)
P. propionicum
2/18 (11%)
Zavistovski et al. (57)
Culture
A. israelii
1/10 (10%)
Sundqvist et al. (54)
Culture
A. meyeri
2/22 (9%)
Baumgartner & Falkler (53)
Sundqvist (58)
Wasfy et al. (59)
Sato et al. (60)
Culture
Culture
Culture
Culture
A. israelii
1/22 (5%)
A. odontolyticus
1/22 (5%)
A. naeslundii genospecies 2
1/22 (5%)
P. propionicum
1/22 (5%)
Actinomyces sp.
A. naeslundii
2/10 (20%)
A. israelii
1/10 (10%)
A. naeslundii genospecies 2
1/10 (10%)
A. israelii
Culture
7/65 (11%)
P. propionicum
5/65 (8%)
A. naeslundii
3/65 (5%)
A. odontolyticus
1/65 (2%)
A. meyeri
1/65 (2%)
A. naeslundii genospecies 2
1/65 (2%)
Actinomyces sp.
1/65 (2%)
A. naeslundii genospecies 2
9/78 (12%)
A. odontolyticus
8/78 (10%)
A. israelii
4/78 (5%)
A. meyeri
1/78 (1%)
P. propionicum
A. odontolyticus
Debelian et al. (61)
3/10 (30%)
P. propionicum
1/6 (17%)
1/6 (17%)
8/26 (31%)
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Table 2. Continued
Study
Brauner & Conrads (62)
Identification method
Culture
Species
A. israelii
A. naeslundii
2/26 (8%)
A. meyeri
1/26 (4%)
A. odontolyticus
1/26 (4%)
Actinomyces sp.
A. israelii
Weiger et al. (63)
Gomes et al. (64)
Le Goff et al. (65)
Culture
Culture
Culture
A. odontolyticus
Lana et al. (66)
Rolph et al. (67)
PCR
Culture
Culture
1/12 (8%)
A. israelii
4/40 (10%)
A. odontolyticus
4/40 (10%)
A. naeslundii genospecies 2
1/40 (3%)
A. odontolyticus
Actinomyces spp.
1/18 (6%)
5/15 (33%)
3/15 (20%)
A. naeslundii genospecies 2
1/15 (7%)
A. naeslundii
3/27 (11%)
A. meyeri
2/27 (7%)
P. propionicum
1/27 (4%)
A. naeslundii
A. israelii
Checkerboard DNA–DNA hybridization A. gerencseriae
84
3/18 (17%)
A. israelii
Siqueira et al. (51)
Culture
4/40 (10%)
A. meyeri
PCR
Khemaleelakul et al. (70)
1/12 (8%)
Actinomyces sp.
Siqueira et al. (68)
Culture
1/19 (5%)
1/12 (8%)
A. naeslundii genospecies 2
Peters et al. (69)
5/19 (26%)
A. meyeri
P. propionicum
Conrads et al. (50)
Prevalencen
5/26 (19%)
2/9 (22%)
1/9 (11%)
2/40 (5%)
4/27 (15%)
A. israelii
2/27 (7%)
A. odontolyticus
1/53 (2%)
A. odontolyticus
11/58 (19%)
A. meyeri
6/58 (10%)
Actinomyces sp.
3/58 (5%)
P. propionicum
2/58 (3%)
A. naeslundii
3/17 (18%)
Periapical Actinomycosis
Table 2. Continued
Study
Identification method
Species
A. odontolyticus
Prevalencen
2/17 (12%)
Xia & Baumgartner (71)
PCR
Actinomyces spp.
72/129 (56%)
A. naeslundii genospecies 2
42/131 (32%)
A. israelii
31/131 (24%)
A. naeslundii
11/131 (9%)
Siqueira & Roˆc¸as (52)
Nested PCR
P. propionicum
18/50 (36%)
A. radicidentis
2/50 (4%)
Number of cases positive for Actinomyces species or P. propionicum/number of cases positive for bacteria.
wNot identified to species level.
n
Table 3. Data from studies reporting the occurrence of Actinomyces species and Propionibacterium propionicum in
persistent intra-radicular infections
Study
Identification method
Species
Prevalencen
Molander et al. (73)
Culture
Actinomyces sp.w
2/68 (3%)
Sundqvist et al. (74)
Culture
A. israelii
3/24 (13%)
P. propionicum
1/24 (4%)
Cheung & Ho (78)
Culture
P. propionicum
1/12 (8%)
Hancock et al. (75)
Culture
Actinomyces sp.
8/33 (24%)
Rolph et al. (67)
Culture
A. israelii
1/9 (11%)
Pinheiro et al. (76)
Culture
A. naeslundii
4/51 (8%)
Siqueira & Roˆc¸as (52)
Nested PCR
A. odontolyticus
3/51 (6%)
A. naeslundii genospecies 2
3/51 (6%)
P. propionicum
1/51 (2%)
P. propionicum
7/12 (58%)
A. radicidentis
1/12 (8%)
n
Number of cases positive for Actinomyces species or P. propionicum/number of cases positive for bacteria.
wNot identified to species level.
intra-radicular infection has been deemed to be the
most common cause of post-treatment endodontic
disease (72). Most of the studies that investigated the
microbiota present in the filled root canals of teeth
associated with post-treatment apical periodontitis
have demonstrated the occurrence of Actinomyces
species in 3–24% of the teeth (67, 73–76) (Table 3).
Species reported to be present in these teeth include A.
israelii, A. naeslundii genospecies 1 and 2, A.
odontolyticus and A. radicidentis (67, 74–76).
Bo´rssen and Sundqvist (36) found Actinomyces
species in 10.6% of 235 root canal samples that had
positive bacterial cultures. Twenty-five Actinomyces
strains were isolated. Of these, 17 strains were derived
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from the root canals of teeth with necrotic pulps, five
from root-filled teeth, and three from teeth with vital
pulps. Twenty-three strains appeared in mixed cultures
and could be eliminated by means of conventional
endodontic treatment. Two A. israelii strains were in
pure cultures from teeth with post-treatment disease.
Immunofluorescence revealed that the A. israelii
strains had become established and had survived in
the periapical lesion (13).
A. radicidentis was first isolated in pure culture from
two endodontic patients who had shown persistent
signs and symptoms after conventional root canal treatment (29, 77). When this species was first described, it
was unknown whether it persisted from a primary
endodontic infection despite treatment, or was the
cause of secondary infection. Strains of A. radicidentis
exhibit relatively high tolerance to saturated calcium
hydroxide solution when compared with other bacterial
species commonly found in infected root canals (77).
Such resistance to calcium hydroxide may explain the
persistence of A. radicidentis during endodontic treatment. Indeed, in a recent study (52) using nested PCR,
A. radicidentis was detected in one out of 12 (8.3%)
root-filled teeth associated with post-treatment disease.
P. propionicum has also been isolated from root-filled
teeth associated with apical periodontitis, with the
reported prevalence ranging from 2% to 8% of the teeth
(74, 76, 78) (Table 3). Nonetheless, a recent study (52)
using nested PCR identified P. propionicum in over 50%
of the root canal samples obtained from teeth
associated with post-treatment disease. This was the
highest prevalence value reported for this bacterial
species in persistent intra-radicular infections and the
possible explanation for this finding was the higher
sensitivity and accuracy of the method used for
identification (52).
For a given bacterial species to be established in filled
root canals, it has to survive intra-canal antimicrobial
procedures or to invade the filled canal after treatment,
possibly as a result of coronal leakage (72). Whatever
the mechanism, the bacterial species surviving in filled
root canals should endure periods of nutrient deprivation (5, 72). How exactly Actinomyces species and P.
propionicum survive in root-filled teeth is still unknown, but their isolation from root-filled teeth
associated with apical periodontitis suggests that these
species can contribute to the etiology of post-treatment
disease by participating in a persistent or secondary
intra-radicular infection.
86
Extra-radicular infections – periapical
actinomycosis
As highlighted above, periapical actinomycosis is a
cervical form of human actinomycosis, and comprises
an extra-radicular infection that can be independent of
the bacteriological status of the root canal of the
affected tooth. In periapical actinomycosis, the causative bacteria may invade the periapical tissues and
establish an equilibrium with the host without inducing
acute inflammation with overt symptoms. Such equilibrium can be described as a situation in which neither
the bacteria nor the host defense mechanisms win the
battle. On the one hand, the bacteria cannot be
eliminated by the host defenses as a result of some
bacterial strategies to be discussed below. On the other
hand, the host succeeds in confining colonies to the
inflamed periapical tissues, preventing the spread of the
infection. However, persistent actinomycotic colonies
seem to be sufficient to sustain chronic inflammation
and the periapical disease process.
The majority of periapical actinomycosis cases have
been diagnosed based on the presence of ‘sulfur
granules’ and bacterial aggregates containing Grampositive branching rods in histologic sections obtained
through apical surgery or tooth extraction. Bacterial
aggregates may show central necrosis and club-shaped
extension of filaments, and are most often surrounded
by inflammatory cells (Fig. 2). In addition, there are
also several studies that have identified Actinomyces
species and P. propionicum in teeth associated with
post-treatment disease (7–11, 79, 80) (Table 4). In
most of these studies, however, there was no clear
diagnosis established of periapical actinomycosis.
It has been suggested that periapical actinomycosis
may be more prevalent than previously believed (14,
81). Reviewing the literature, Sakellariou (81) found
only 45 cases on record, including the one described in
that report. Most communications were in the form of
case reports (22, 81–86). As of 1996, several more
cases (87–89) have been reported.
Weir and Buck (90) reported on a case of periapical
actinomycosis and reviewed a series of 20 cases,
including their own. In their review, the average age
of the patients was 27.5 years, ranging from 10 to 64
years. Fifty eight percent of the patients were male and
the teeth most commonly affected were the maxillary
incisors. Many of these teeth were undergoing endodontic treatment or had treatment completed.
Periapical Actinomycosis
Fig. 2. Bacterial aggregate in an epithelialized periapical lesion, suggestive of actinomycosis. Inset, higher magnification
of the actinomycotic aggregate, which is surrounded by inflammatory cells (courtesy of Drs D. Ricucci and E.A. Pascon).
Sjo¨gren et al. (12) reported on a tooth with posttreatment disease, where the periapical tissue harbored
P. propionicum. This tooth healed completely after
apical surgery.
Happonen et al. (15) used immunocytochemical
methods for the demonstration of Actinomyces species
and P. propionicum in seven routine periapical specimens. Co-infection of P. propionicum and Actinomyces
species was found in four specimens, while P. propionicum occurred in five of the seven specimens. In
another study, Happonen (14) reported on 16
surgically treated cases that had immunocytochemically
verified periapical actinomycosis. A. israelii was detected in 13 biopsy specimens, P. propionicum in 10,
and A. naeslundii in six. More than one of these species
was present in nine specimens.
Nair et al. (88) described three cases of ciliated
epithelium-lined periapical cysts and reported the
presence of typical ‘ray-fungus’ actinomycotic colonies
in the lumen of one of the lesions. Because the lesion
happened to be a periapical pocket cyst, the authors
suggested that Actinomyces cells could have advanced
from the infected root canal directly into the lumen of
the cyst.
Rush et al. (89) reported several cases of actinomycosis, including the periapical form of the disease. The
study was based on records of a diagnostic pathology
service. Fifty-six percent of the submitting clinicians
indicated a clinical impression of non-specific periapical
granuloma or cyst. Patient ages ranged from 13 to 86
years, with an average age of 59.8 years. The gender of
the patients was almost evenly distributed between
males and females. Distribution of cases per race was
reported as 73% Caucasian, 7% Hispanic, 3% African–
American and 17% unstated. Biopsy specimens were
more common in the maxilla (53% of the cases).
87
Siqueira
Table 4. Data from studies reporting the occurrence of Actinomyces species and Propionibacterium propionicum or
evidence of actinomycotic colonies in periapical lesions
Study
Identification method
Species
Prevalencen
Tronstad et al. (7)
Culture
A. israelii
1/8 (13%)
A. naeslundii genospecies 2
Iwu et al. (9)
Culture
A. naeslundii
A. naeslundii genospecies 2
Wayman et al. (79)
Culture
A. odontolyticus
A. meyeri
1/8 (13%)
5/16 (31%)
2/16 (13%)
1/24 (4%)
1/24 (4%)
Abou-Rass & Bogen (80)
Culture
Actinomyces sp.w
3/13 (23%)
Gatti et al. (10)
Checkerboard DNA-DNA
hybridization
A. naeslundii genospecies 2
16/20 (80% – IS)
A. naeslundii genospecies 2
A. odontolyicus
Sunde et al. (8)
Sunde et al. (11)
Culture
Checkerboard DNA–DNA
hybridization
Actinomyces sp.
16/16 (100% – SM)
5/16 (31% – SM)
2/15 (13% – IS)
A. naeslundii
1/15 (7% – IS)
A. odontolyticus
1/15 (7% – IS)
P. propionicum
1/15 (7% – SM)
A. naeslundii
16/17 (94% – IS)
A. naeslundii
4/17 (24% – SM)
A. israelii
16/17 (94% – IS)
A. israelii
14/17 (82% – SM)
A. naeslundii genospecies 2
16/17 (94% – IS)
A. naeslundii genospecies 2
14/17 (82% – SM)
A. odontolyticus
12/17 (71% – IS)
A. odontolyticus
9/17 (53% – SM)
A. gerencseriae
10/17 (59% – IS)
A. gerencseriae
7/17 (41% – SM)
Nair & Schroeder (26)
Light and transmission
electron microscopy
Actinomycotic colonies
2/45 (4%)
Sunde et al. (25)
Culture
A. naeslundii genospecies 2
7/36 (19%)
88
A. israelii
6/36 (17%)
A. naeslundii
5/36 (14%)
A. meyeri
3/36 (8%)
P. propionicum
2/36 (6%)
Periapical Actinomycosis
Table 4. Continued
Study
Identification method
Species
Actinomyces sp.
Hirshberg et al. (87)
Light microscopy
Actinomycotic colonies
Prevalencen
1/36 (3%)
17/963 (1.8%)
Number of cases positive for Actinomyces species, P. propionicum or actinomycotic colonies/number of cases evaluated.
wNot identified to species level.
IS, samples taken when an intra-sulcular incision was made; SM, samples taken when a sub-marginal incision was made.
n
While most cases of periapical actinomycosis have
been reported as isolated cases, data regarding the
actual frequency of periapical actinomycosis among
periapical lesions is still limited to a few studies (6, 26,
87).
Nair & Schroeder (26) examined 45 periapical
specimens using light and transmission electron microscopy and reported the occurrence of typical actinomycotic colonies in two lesions diagnosed as periapical
granuloma. In one specimen the colonies were
restricted to the apical root canal, while in the other a
typical actinomycotic colony was observed within the
body of the lesion. Polymorphonuclear leukocytes were
seen surrounding the colonies.
Bystro¨m et al. (6) followed the outcome of endodontic treatment in 79 teeth with apical periodontitis
for 2–5 years post-treatment. Only five teeth showed
little or no improvement after treatment. Of these, two
teeth were diagnosed as periapical actinomycosis.
Histological examination of periapical specimen obtained from one of the two teeth revealed a periapical
cyst with A. israelii and P. propionicum present. The
other tooth with periapical actinomycosis was clinically
diagnosed as a periapical abscess with A. israelii
present.
Hirshberg et al. (87) evaluated the incidence and
clinical outcome of lesions histologically diagnosed as
periapical actinomycosis. The study included 963
periapical biopsy specimens submitted for histologic examination and the diagnosis of periapical
actinomycosis was based on the presence of typical
branching colonies of filamentous bacteria staining
positive for periodic acid Schiff and Gram stain. They
reported the occurrence of actinomycotic colonies in
17 (1.8%) of the examined lesions. The maxilla was the
most frequently involved site (11 cases, 65%), with
equal distribution in the anterior and posterior areas.
Males were predominat (11 cases, 65%). Radiographi-
cally, most cases presented as radiolucent lesions with
well-defined borders. Of the cases diagnosed as
periapical actinomycosis, four lesions (24%) were true
periapical cysts and 11 (65%) were epithelialized
granulomas. One case was diagnosed as residual cyst
and another as periapical granuloma. The actinomycotic colonies presented as isolated masses of filamentous
bacteria with a central area of necrosis and radiating
filaments. Most colonies were surrounded by an
inflammatory infiltrate composed of polymorphonuclear neutrophils, lymphocytes and plasma cells.
On the basis of these few studies on the prevalence of
periapical actinomycosis, one can realize that the
percentage of apical periodontitis lesions infected by
Actinomyces species and/or P. propionicum is low.
However, their importance should not be underrated
since periapical actinomycosis is usually refractory to
conventional endodontic procedures and as such, it can
be one of the etiologies of post-treatment disease.
The bacterial source for periapical actinomycosis
is conceivably the intra-radicular infection. Since
Actinomyces species and P. propionicum are more
prevalent in intra-radicular than in extra-radicular
infections, it can be assumed that only a small
percentage of the cases in which these species are in
the root canal evolve into an extra-radicular infection.
Situations that can permit these bacteria to reach
periapical tissues and establish an extra-radicular
infection are likely to be the following: (1) apical
extrusion of debris during root canal instrumentation;
(2) direct advance from the infected root canal into the
lumen of the pocket cysts; or (3) previous participation
in acute periapical abscesses followed by persistence
after the acute response subsides. Moreover, the
virulence of the involved strains and the host resistance
to the infection appear to be important factors dictating
whether an extra-radicular infection will develop
or not.
89
Siqueira
Mechanisms of pathogenicity
Actinomyces species have a low pathogenicity (potential
to produce disease) in their normal habitats. However,
when normal mucosal barriers are disrupted by trauma,
surgery or preceding infection, these bacteria can
establish a chronic, pus-forming infection that can
spread unchecked through host tissues. Under specific
circumstances, an acute abscess can occur after invasion
of the host tissues by these bacteria.
Several studies have demonstrated the pathogenic
potential of Actinomyces species and P. propionicum in
animal models. Brown and von Lichtenberg (91)
evaluated the pathogenicity of A. israelii in mice and
observed a pattern of infection that was similar to the
course of other chronic infections. Initially, there was
an acute phase of growth and expansion of the lesions,
followed by a static period during which some animals
aborted the infection. In most cases, animals then
entered a prolonged chronic phase characterized by a
balance between aggression and defense, with slow
growth of the lesions. Behbehani and Jordan (92)
compared the pathogenicity of different species of
Actinomyces and of P. propionicum using a mouse
model. They reported that intraperitoneal injection of
strains of A. israelii, A. naeslundii genospecies 1 and 2,
and P. propionicum caused numerous abscesses in the
intestine, mesentery, liver, and at the site of injection.
A. odontolyticus did not cause any lesions. Differences
in pathogenicity among Actinomyces species were much
less pronounced during the initial acute stage of
the infection. A. naeslundii genospecies 1 and 2
(A. viscosus) produced acute lesions that resolved
after a few weeks. Abscesses caused by rough strains
of A. israelii and P. propionicum persisted and led to a
slowly progressive chronic infection. The other species
apparently lacked the virulence to survive the transitional phase of the infection from acute to chronic
stage. In an experimental study in mice, Siqueira et al.
(93) reported that a strain of A. naeslundii induced
abscess formation when inoculated subcutaneously in
pure culture or in association with Prevotella intermedia or with Prevotella nigrescens. Buchanan & Pine
(94) injected 16 mice intraperitoneally with two strains
of P. propionicum and observed that abscesses developed in all animals. Georg & Coleman (95) inoculated
mice with two strains of P. propionicum and reported
that lesions resembling those produced by A. israelii
occurred in all animals. Sumita et al. (96) packed A.
90
israelii cells in alginate gel particles and injected them
intraperitoneally into BALB/c mice. Actinomycotic
lesions were induced efficiently in nine out of 12 mice
after 3 or 9 weeks. Serum IgG levels against A. israelii
were significantly elevated, indicating the activation of
the animals’ humoral immunological response. The
researchers suggested that the bacteria might have
become resistant to phagocytosis.
Co-infection with other bacteria can play a role in
Actinomyces pathogenicity, by enhancing their virulence. In a study of experimental mixed infections (97),
A. israelii was a component of mixtures of bacteria that
produced abscesses but it was not essential for abscess
formation. In another study (98), A. meyeri grew better
in mixed cultures than alone. In addition, its presence
stimulated growth of non-protein-cleaving oral bacteria, most likely due to the ability of A. meyeri to degrade
serum proteins and thus to provide peptides for the
growth of amino acid-fermenting bacteria that cannot
cleave intact proteins by themselves. Their findings
indicated that protein-degrading A. meyeri might play
an important role in mixed oral infections, by providing
nutrients for growth of other species present in the
bacterial consortium.
Although the exact mechanism by which Actinomyces
species exert their pathogenicity has not been totally
clarified, there is some evidence that can help explain
infections caused by these microorganisms. Most
Actinomyces species are of low virulence and their mere
invasion into tissues does not usually suffice to establish
an infection. However, necrotic pulps do not offer
resistance to invasion by microorganisms, except for
selective pressures exerted by the environmental conditions, which are arguably adequate for most Actinomyces
species. Some Actinomyces species have fimbrial structures
that may play a role in bacterial coaggregation within the
root canal and can be important for bacterial survival in
the ecosystem. In addition, fimbriae would enable
Actinomyces cells to adhere to the root canal wall and to
dentinal debris forced out through the apical foramen
during treatment, and to cling to other bacteria or host
cells as they advance into the periapical tissues (99).
Actinomyces species usually have a hydrophobic cell
surface character, which facilitates uptake by leukocytes. Figdor and Davies (100) investigated the
ultrastructure of A. israelii by electron microscopy
and reported that strains can have hair-like fimbriae
protruding through a thick surface coat. Thin sectioning revealed a Gram-positive cell wall surrounded by a
Periapical Actinomycosis
fuzzy outer coat. They suggest that both the fimbriaelike structures and the matrix of the outer coat
surrounding the bacteria can help the cells to aggregate
into cohesive colonies of tangled filaments. Moreover,
strains associated with post-treatment disease were
demonstrated to grow as intertwining filaments,
forming granulae within host tissues (99). It is believed
that the ability to form branching, filamentous microcolonies may be critical for the establishment of these
bacteria in the tissue. The size of bacterial aggregates is
important for phagocytosis to occur. The presence of a
hyaloid or hyaline layer in actinomycotic colonies may
provide protection against host defenses, and it may
also serve to embed the filamentous and branching
microorganisms in a cohesive mass (99). Thus, the
bacteria appear to be able to evade collectively host
defenses by building in host tissues cohesive colonies
consisting of large numbers of branching and filamentous bacteria enmeshed in a matrix of protein–
polysaccharide complex (99). Actinomycotic colonies
may live in equilibrium with host tissues without
necessarily inducing an acute response, but rather
maintaining a chronic periapical inflammation. Very
high numbers of Actinomyces cells are usually needed to
form persistent infections (92). The low pathogenicity
of these microorganisms and the consequent minimal
host response may be the reasons for the perpetuation
of the chronic periapical lesion.
Although P. propionicum is also recognized to be
pathogenic, its mechanisms of pathogenicity have yet
to be clarified. Figdor et al. (99) addressed the question
as to what allows P. propionicum to cause extraradicular infections by evaluating the ability of this
bacterium to induce experimental infections in guineapigs, its surface properties, as well as in vitro
phagocytosis and intracellular killing by polymorphonuclear leukocytes. Their results showed that P.
propionicum declined in number during the entire
period of infection and did not form colonies. P.
propionicum cells were hydrophobic, readily phagocytosed and efficiently killed by leukocytes. The authors
were not able to draw significant conclusions about the
mechanisms of pathogenicity of this bacterial species.
Clinical manifestation and treatment
The typical clinical manifestation of the cervicofacial
actinomycosis is characterized by the presence of
swelling, induration of soft tissues, multiple abscesses
and draining sinus tracts. If the clinician faces such
clinical picture, he/she should suspect actinomycosis
and look for the laboratory confirmation of the disease
in the pus collected from abscesses (81). However,
periapical actinomycosis is rather different as both the
clinical and radiographic manifestations are usually
indistinguishable from common apical periodontitis.
The occurrence of multiple sinus tracts may suggest but
is not a prerequisite for diagnosis of periapical
actinomycosis, since such has not been associated with
many reported cases (12, 23, 87). Some cases can
present a painless swelling (85). The mere occurrence
of persistent exudation and/or symptomatology, associated or not with persistent sinus tract, is not
exclusively indicative of periapical actinomycosis. Such
clinical picture can be caused by many etiological
factors, of which a persistent intra-radicular infection
(not necessarily containing Actinomyces species) is
arguably the most common one. Therefore, diagnosis
is usually achieved only after surgical removal of the
lesion, followed by histopathological and microbiological examination of the specimen (81).
Most forms of actinomycosis are usually treated with
systemic antibiotic therapy. Studies (20, 101) have
demonstrated that Actinomyces species and P. propionicum are commonly susceptible to the most widely
used antibiotics. Actinomyces species are usually highly
sensitive to the b-lactam antibiotics and have a high-tomoderate sensitivity to tetracyclines, macrolides, lincomycins and vancomycin (20). They are generally
resistant to aminoglycosides and metronidazole (20).
Holmberg et al. (101) tested the susceptibility to
several antibiotics of 46 reference strains and clinical
isolates of A. israelli and eight strains of P. propionicum,
using the agar dilution method in vitro. All strains were
susceptible to benzylpenicillin. Erythromycin, tetracycline, clindamycin and lincomycin possessed in vitro
activity at concentrations readily attainable in serum. In
vitro resistance to metronidazole was observed.
Prolonged systemic antibiotic therapy has been the
treatment of choice for all clinical forms of the disease
(21), except for periapical actinomycosis. As far as we
are aware, the vast majority of the reported cases of
periapical actinomycosis have been successfully treated
either by apical surgery or by extraction of the affected
tooth. In several reported cases, no systemic antibiotic
therapy was prescribed and healing was uneventful (6,
12, 14). Happonen (14) reported only one clear case of
91
Siqueira
persistent disease after apical surgery had been performed on 16 teeth with periapical actinomycosis. It
was concluded that a prolonged administration of
antibiotics, as generally recommended for actinomycotic infections elsewhere in the body, might be
unnecessary for the treatment of periapical actinomycosis (14). In reality, there appears to be no need for
prolonged use of systemic antibiotics provided the
infected periapical lesion is entirely removed during
surgery.
The use of systemically administered antibiotics alone
to treat periapical actinomycosis does not appear to be
an effective alternative to surgical procedures. First, as
already mentioned, the accurate diagnosis of periapical
actinomycosis is only possible after surgical removal of
the lesion. A question therefore arises – when should
one consider the prescription of antibiotics? Because
the incidence of periapical actinomycosis is rather low
when compared with other forms of apical periodontitis (where the primary cause of disease is usually
intra-radicular infection, not affected by systemic
antibiotics), and taking into account that periapical
actinomycosis is virtually impossible to diagnose based
only on clinical and radiographic findings, prescription
of antibiotics in all suspected cases is not warranted, and
would not guarantee healing. In addition, such
indiscriminate use would enhance the deleterious
effects of the abuse of antibiotics, such as selection of
resistant microorganisms. Finally, even if periapical
actinomycosis is suspected, there is no evidence as to
which antibiotic agent, dosage, and duration of therapy
is effective (if ever) in treating this disease.
Conclusions
Actinomyces species and P. propionicum can be found in
primary, persistent and secondary intra-radicular infections, as constituents of a polymicrobial consortium.
With regard to extra-radicular infection, however,
Actinomyces species and P. propionicum can be the
exclusive pathogens sustaining the post-treatment
disease process associated with root-filled teeth. The
latter may be characterized as an independent pathologic entity termed periapical actinomycosis. The
prevalence of periapical actinomycosis appears to be
low; therefore, it is one of several etiological factors of
post-treatment disease. Once periapical actinomycosis
is established, it can only be successfully treated by
92
apical surgery, including thorough curettage of the
periapical inflammatory lesion.
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