Actinomycosis STATE-OF-THE-ART CLINICAL ARTICLE Raymond A. Smego, Jr., and Ginamarie Foglia

Actinomycosis STATE-OF-THE-ART CLINICAL ARTICLE Raymond A. Smego, Jr., and Ginamarie Foglia

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STATE-OF-THE-ART CLINICAL ARTICLE
Actinomycosis
Raymond A. Smego, Jr., and Ginamarie Foglia
Etiology
Of the 14 Actinomyces species, six may cause disease in
humans, including the faculatively anaerobic A. israelii,
A. naeslundii, A. odontolyticus, A. viscosus, A. meyeri, and
A. gerencseriae [1]. In a recent review of anaerobic bacteria, it
was reported that in addition to the aforementioned pathogenic
species, some CDC (Centers for Disease Control and Prevention) coryneform bacteria have now been assigned to the
genus Actinomyces [2]. CDC group 1 coryneform bacteria
(A. neuii) and CDC coryneform group E (A. radingae and
A. turicensis) were the Actinomyces strains most commonly
isolated at one laboratory during a 4.5-year period [3]. CDC
coryneform group 2 bacteria (A. bernardiae) and A. pyogenes
have recently been placed in the genus Arcanobacterium [4].
Actinomyces are fastidious bacteria that require cultures enriched with brain-heart infusion media, may be aided in growth
by an atmosphere of 6% – 10% ambient CO2 , and grow best at
377C. Colonies may appear after 3 – 7 days of incubation, but
for adequate detection of slow growth, cultures should be observed for £21 days. Characteristically, Actinomyces species
Received 15 December 1997; revised 12 January 1998.
Reprints or correspondence: Dr. R. A. Smego, Jr., Department of Infectious
Diseases and Clinical Microbiology, University of the Witwatersrand, Medical
School — Room 3T02, 7 York Road, Johannesburg 2193, Republic of South
Africa.
Clinical Infectious Diseases 1998;26:1255–63
q 1998 by the Infectious Diseases Society of America. All rights reserved.
1058–4838/98/2606–0001$03.00
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appear as ‘‘molar-tooth’’ colonies on agar or as ‘‘breadcrumb’’ colonies suspended in broth media. Differentiation of
the species is difficult, requiring assessment of several metabolic capabilities.
Bacteria of the related species Propionibacterium propionicus (formerly Arachnia propionica and Actinomyces propionicus) may produce actinomycosis-like disease; however,
P. propionicus differs from Actinomyces species by the presence of aminopimelic acid in its cell wall, the formation of
propionic acid as the major intermediate metabolite from glucose, and the tendency to form spheroplasts as cultures age.
Nocardia species are morphologically indistinguishable from
Actinomyces species on gram staining and also clinically resemble Actinomyces in that they produce chronic infections of the
lung and CNS. However, Nocardia species are aerobic in
growth, and some strains are partially acid fast.
Other bacteria are frequently isolated from clinical specimens containing Actinomyces. Actinobacillus actinomycetemcomitans, Eikenella corrodens, and species of Fusobacterium,
Bacteroides, Capnocytophaga, Staphylococcus, Streptococcus,
and Enterococcus have commonly been isolated in various
combinations, depending on the site of infection [5 – 7]. In
fact, A. actinomycetemcomitans is associated with Actinomyces
species in £30% of noncerebral lesions [8].
Epidemiology
Human actinomycosis was first described in 1878 by Israel
[9], who along with Wolfe [10] first isolated the causative agent
in culture and defined the organism’s anaerobic nature. In early
reports of infections caused by filamentous gram-positive organisms, no distinction was made between disease caused by
actinomyces and nocardias. It was not until 1943 that these
genera were clearly differentiated by Waksman and Henrici,
enabling separation of the diseases they caused [11].
The pathogenic Actinomyces species do not exist freely in
nature but are commensals and normal inhabitants of the oropharynx, gastrointestinal tract, and female genital tract in humans. Hence, humans are themselves the natural reservoir of
the Actinomyces species that cause actinomycosis. No external
environmental reservoir such as soil or straw has been documented. There is no person-to-person transmission of the patho-
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Actinomycosis is a chronic disease characterized by abscess
formation, tissue fibrosis, and draining sinuses. It is caused
by non-spore-forming, anaerobic or microaerophilic bacterial
species of the genus Actinomyces, order Actinomycetales. Actinomyces species and the closely related Nocardia species,
which were once believed to be fungi because of their
branching filaments, are now classified as higher prokaryotic
bacteria. The Actinomyces species are gram-positive, pleomorphic, and diphtheroidal, or more commonly, delicately filamentous. The cervicofacial, thoracic, and abdominopelvic
regions and the CNS are most commonly involved in actinomycosis.
From the Department of Infectious Diseases and Clinical Microbiology,
University of the Witwatersrand, and the South African Institute for
Medical Research, Johannesburg, Republic of South Africa; and the
Section of Infectious Diseases, Robert C. Byrd Health Sciences Center,
West Virginia University, Morgantown, West Virginia, USA
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Smego and Foglia
genic Actinomyces species [12, 13]. Actinomycosis in cattle,
horses, and other animals is caused by other species, usually
Actinomyces bovis [14, 15].
Pathogenesis and Pathology
Manifestations
Cervicofacial Actinomycosis
The face and neck are the most common sites of actinomycosis. The frequency of this location among cases of actinomyco-
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sis ranges from 11% [26] to 97% [27], with a mean frequency
of 55% [19]. Actinomyces species are normally present in high
concentrations in the tonsillar crypts and gingivodental crevices, and many actinomyces infections are odontogenic in origin. In addition to poor dentition and recent dental manipulation, chronic tonsillitis, otitis, and mastoiditis are important
risk factors for these infections. External trauma may result in
the introduction of Actinomyces species into head and neck
tissues. Cervicofacial actinomycosis may take the form of
acute, painful pyogenic abscesses or indolent disease that resembles the lumpy jaw caused by A. bovis in cattle [14]. The
latter process may evolve into a painless indurated mass in the
face or neck, often accompanied by one or more draining sinus
tracts that discharge sulfur granules. Lesions are frequently
located at the angle of the jaw or in the submandibular region.
Cervicofacial actinomycosis may extend to the underlying
mandible or facial bones, leading to the development of periostitis or osteomyelitis.
Thoracic Actinomycosis
Thoracic actinomycosis may involve the lungs, pleura, mediastinum, or chest wall. Routes of infection include aspiration
of oropharyngeal secretions or gastric contents; direct extension
of cervicofacial infection into the mediastinum, along the deep
fascial planes of the neck; transdiaphragmatic or retroperitoneal
spread from the abdomen; or rarely, hematogenous dissemination. Infection in the lung usually leads to the development of
chronic pneumonia with or without associated pleural effusion
[28]; however, an endobronchial mass [29] in the presence or
absence of a foreign body may at times develop. The clinical
picture of thoracic actinomycosis most often mimics that of
tuberculosis or malignancy, with findings of cough, low-grade
fever, weight loss, and chest pain [30, 31].
Chest radiographs may reveal infiltrates suggestive of aspiration pneumonitis, fibronodular and cavitary parenchymal disease, or a mass in the lung (figure 1). Contiguous extension
from a chronic pulmonary focus may lead to empyema; vicinal
destruction of the ribs, sternum [32], or shoulder girdle;
involvement of the chest-wall muscles and soft tissues; and the
formation of sinus tracts extending to the skin. Involvement of
mediastinal structures rarely leads to obstruction of the superior
vena cava, formation of a tracheoesophageal fistula, vertebral
or paravertebral extension, or the development of pericarditis
or myocarditis [33, 34].
Although the presence of sulfur granules in sputum or drainage from a fistula in the chest wall is characteristic of actinomycosis, definitive diagnosis is often delayed until thoracotomy is
performed to exclude the diagnosis of bronchogenic carcinoma.
The presence of Actinomyces species in cultures of bronchopulmonary secretions or even tissue specimens can be misleading
because actinomycosis may coexist with lung cancer and tuberculosis [35].
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Four clinical forms of actinomycosis, i.e., cervicofacial, thoracic, abdominopelvic, and cerebral, account for the majority
of infections in humans. Actinomycosis usually occurs in immunocompetent persons but may occur in persons with diminished host defenses. In a previously cited study [3], several
patients with abscesses, diabetic foot ulcers, cellulitis, and bacteremia due to A. neuii were immunosuppressed. Bacteria isolated from gingival crevices and tonsillar crypts of healthy
persons [16] and from dental caries in otherwise asymptomatic
persons [17] were initially classified as A. bovis but are now
recognized as the Actinomyces species that are potential human
pathogens. As saprophytes, Actinomyces species are generally
of low pathogenicity and cause disease only in the setting of
antecedent tissue injury.
The portal of entry of Actinomyces species is typically a
break in the mucosa of the gastrointestinal tract, anywhere from
the mouth to the rectum; such a break may occur as a result
of a dental procedure, overt or covert dental sepsis, bacterial
suppuration, diverticulitis, appendicitis, surgery, or trauma
[18 – 20]. The newly classified A. radingae – A. turicensis complex has been recovered from a variety of infections including
otitis, pleural empyema, infected decubitus ulcers, perianal abscesses, and diabetic foot ulcers [21, 22]. Aspiration of oropharyngeal or gastrointestinal secretions into the respiratory tract
and the presence of intrauterine-intravaginal devices are also
important risk factors for actinomycosis [23]. Implantation of
Actinomyces species into damaged tissue eventually leads to
the development of chronic, indurated, suppurative infections,
often with draining sinuses and fibrosis.
In tissues, infecting Actinomyces species grow in microscopic or macroscopic clusters of tangled filaments that are
surrounded by polymorphonuclear neutrophils. Subacute or
chronic inflammation with granulation tissue, extensive fibrosis, and sinus tracts is present in the surrounding tissues, but
giant cells and caseation necrosis are generally not seen. When
grossly visible, clusters exude from soft tissues through sinus
tracts, are pale yellow in color, and are called sulfur granules
[24]. Sulfur granules are not unique to actinomycosis. They
occur in cases of nocardiosis, chromomycosis, eumycetoma,
and botryomycosis. The causative organisms can be recognized
by their particular morphological features and cultural characteristics. The absence of sulfur granules from any lesion, however, does not exclude the diagnosis of actinomycosis; cultureproven cases of actinomycotic cerebral lesions have lacked this
feature [25].
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Actinomycosis
Hematogenous dissemination of Actinomyces species may
result from thoracic disease but is extremely rare with other
forms of actinomycosis. Virtually any organ or tissue may be
infected, and the prognosis is more serious for patients with
thoracic disease than for those with the other forms of actinomycosis.
Abdominal and Pelvic Actinomycosis
Actinomyces species are frequently part of the normal flora
of the gastrointestinal and female genital tracts. Abdominal
actinomycosis usually occurs following penetrating trauma,
perforation of the gut (e.g., the colon or appendix), or surgical
manipulation of the gastrointestinal tract [36]. Abdominal actinomycosis may be the most indolent and latent of all of the
clinical forms of the disease; diagnosis may be delayed months
to years after the inciting event. There is a predilection for
involvement of the ileocecal region of the gut; thus, chronic
abdominal actinomycosis may be confused with intestinal tuberculosis, ameboma, chronic appendicitis, regional enteritis,
and carcinoma of the cecum [37, 38]. The disease may localize
or spread extensively without conforming to fascial and connective tissue planes or vascular channels.
Anorectal disease is not uncommon, and may present as
rectal stricture, perirectal or ischiorectal abscess, or recurrent
draining sinuses and fistulae. The primary site may be an anal
crypt, or there may be direct extension from an intra-abdominal
focus of infection. Gastric and perigastric, hepatic, splenic, and
renal involvement are uncommon forms of abdominal actinomycosis. Actinomyces species may reach these viscera through
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direct extension from the bowel or an intra-abdominal or intrathoracic site or via seeding through the portal vein or systemic
circulation [39].
Abdominal actinomycosis may spread into the pelvis. Alternatively, primary involvement of pelvic structures may arise
in association with preceding colonization and infection of intrauterine devices (IUDs) [23]. Similar to intestinal infection,
pelvic actinomycosis is typically insidious in its course and
easily confused with other inflammatory or malignant pelvic
disorders. Nonspecific symptoms of this form of the disease
(lower-quadrant abdominal pain and weight loss) and lowgrade fever (or no fever) may persist for months to years.
If pelvic actinomycosis is secondary to intestinal infection,
the usual source is indolent ileocecal disease that extends to the
right adnexa in Ç80% of cases. The ovary is most commonly
affected, followed by the fallopian tubes, uterus, vulva, and
cervix. In contrast, endometrial actinomycosis with extension
to the ovaries is the usual form of actinomycosis that develops
in association with an IUD or pessary, septic abortion, or retained sutures. Subdiaphragmatic abscesses [40, 41], lung abscesses [42], and myocardial abscesses [43] and cutaneous fistulae [43 – 45] may also complicate pelvic actinomycosis.
CNS
Actinomycosis of the CNS may present as brain abscess,
meningitis or meningoencephalitis, subdural empyema, actinomycoma, and spinal and cranial epidural abscess [46 – 54].
Brain abscesses account for almost 75% of all CNS lesions.
Actinomycosis of the CNS is usually secondary to hematogenous spread from primary infection in the lung, abdomen, or
pelvis. However, extension from foci of infection in the ears,
paranasal sinuses, and cervicofacial regions may proceed
along connective tissue planes or through foramina at the base
of the skull, causing focal infection of the CNS or diffuse
basilar meningitis. In approximately one-third of cases, Actinomyces species are isolated as part of a mixed bacterial flora
that includes one or more species of aerobic or anaerobic
bacteria.
Actinomycotic cerebral abscesses are usually singular but
may be multiple; unilocular or multilocular; encapsulated or,
less frequently, unencapsulated. The interval from the onset
of symptoms to diagnosis is typically longer than that for
pyogenic brain abscesses [55]. There is a predilection for
involvement of the temporal and frontal lobes (figure 2) [56].
Cerebral actinomycosis may also be a component of disseminated disease that occurs in three or more noncontiguous body
sites.
Involvement of the meninges results in basilar meningitis.
The signs and symptoms mimic those of other chronic meningitides [57]. Because of the indolent nature of this form of
the infection, frequent lack of acute toxicity, and findings in
the CSF (e.g., mononuclear pleocytosis, an elevated protein
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Figure 1. Dense right-lower-lobe infiltrate in a patient with pulmonary actinomycosis secondary to aspiration.
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CID 1998;26 (June)
concentration, and normal or low glucose concentrations), the
disease is frequently misdiagnosed as tuberculous meningitis.
Actinomycomas may occur at various sites within the CNS,
i.e., as space-occupying lesions in the cerebral cortices, as
masses of the gasserian ganglion, or as lesions simulating tumors in the posterior fossa or third ventricle [51, 58 – 60]. Differential diagnoses include pyogenic infections, tuberculosis,
colloid or dermoid cysts, cholesteatomas, and aneurysms of
the basilar artery.
The clinical features of actinomycosis of the CNS are indistinguishable from those of pyogenic infections of intracranial
and spinal structures. For nonmeningitic infection, the signs
and symptoms are typically those of a space-occupying lesion,
with focal neurological defects and symptoms of increasing
intracranial pressure dominating the clinical picture. Specific
signs and symptoms are referable to the anatomic location of
the abscesses, empyema, or actinomycomas. Fever is present
in õ50% of cases; frequently, there may be little evidence
suggesting an infectious process, and the presence of a neoplasm may initially be suspected [56].
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Diagnosis
The diagnosis of actinomycosis is made most accurately by
isolating Actinomyces species in cultures of clinical specimens.
However, the demonstration of actinomycotic granules in exudates or in histological sections of tissues not connected to
hollow organs is strongly supportive of the diagnosis (figure
3) [61, 62]. Whether the sulfur granules are microscopic or
macroscopic, they consist of tangled filaments of Actinomyces
species, which becomes apparent on microscopic examination
of a gram-stained smear of a crushed granule. In tissue sections
stained with hematoxylin-eosin, sulfur granules are round or
oval basophilic masses with a radiating arrangement of eosinophilic terminal ‘‘clubs.’’ The granules may occur singly or in
loose aggregations. Actinomyces species are infrequently visible in sections stained with hematoxylin-eosin, however; visualization is facilitated by the use of special stains such as
Grocott-Gomori methenamine – silver nitrate stain, p-aminosalicylic acid, MacCallen-Goodpasture stain, or Brown-Brenn
stain.
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Figure 2. CT scan of the head of a patient with actinomycosis of the CNS. A, A large abscess in the left temporoparietal lobe (with rim
enhancement) and a smaller lesion in the right frontal lobe are apparent before treatment. B, Total resolution of the lesions is apparent 6
months after needle aspiration and treatment with chloramphenicol.
CID 1998;26 (June)
Actinomycosis
Histological diagnosis of actinomycosis is difficult because
many specimens contain only a few granules. For example, in
a study of 181 cases of actinomycosis in humans, only a single
granule was found in 25% of the lesions. Granules were not
detected in some cases in which the organisms were recovered
by culture [63]. Use of a species-specific fluorescein-conjugated monoclonal antibody technique permits rapid identification by direct staining of clinical materials, even after fixation
in formalin [64 – 70].
Increased awareness of actinomycosis is required in the differential diagnosis of any subacute or chronic inflammatory
lesion involving soft tissues or internal organs. Clinicians must
be knowledgeable in the proper techniques for collecting and
submitting specimens to optimize recovery of these fastidious
anaerobic bacteria.
Treatment and Prognosis
A specific diagnosis of actinomycosis, and, in particular,
differentiation of actinomycosis from nocardiosis, is crucial for
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successful therapy. Actinomyces species are susceptible in vitro
to several antimicrobials including penicillin G, chloramphenicol, the tetracyclines, erythromycin, clindamycin, imipenem,
streptomycin, and the cephalosporins [71 – 81]. Fluoroquinolones, aztreonam, fosfomycin, and other aminoglycosides generally have poor activity against Actinomyces species and
P. propionicus [78, 80]. The clinical experience with actinomycosis has been extensive and supports the use of penicillin G
as the drug of choice for all clinical forms of the disease. Mild
cervicofacial infections may be adequately managed with a 2month course of peroral penicillin V or one of the tetracyclines
(e.g., doxycycline, 100 mg given orally twice daily), without
surgical intervention [82].
For other more complicated forms of actinomycoses, parenteral penicillin G, 10 – 20 million U/d divided every 6 hours,
should be administered for 4 – 6 weeks, followed by oral penicillin V, 2 – 4 g/d divided every 6 hours, for 6 – 12 months [83].
For penicillin-allergic patients, a tetracycline, erythromycin,
clindamycin, and cephalosporins are suitable alternatives [77].
Chloramphenicol, given orally or intravenously in a dosage of
50 – 60 mg/(kgrd) divided every 6 hours, is probably the preferred agent for treating actinomycosis of the CNS in patients
who are allergic to the penicillins [82]. Risk factors significantly correlated with a poor outcome (death or relapse) for
patients with CNS actinomycosis include the onset of disease
ú2 months before presentation, lack of antibiotic therapy or
surgery, and the performance of needle aspiration drainage
rather than open drainage or excision [56].
In light of the potential for relapse of actinomycosis, prolonged antibiotic treatment is prudent; the exact duration of
therapy depends on the site and severity of disease. Prolonged
observation of patients after treatment is necessary to detect
recurrences.
Antimicrobial therapy need not be directed against secondary
organisms commonly identified concurrently with Actinomyces
species as part of a polymicrobial flora. Regimens that target
only Actinomyces species are usually curative [82].
A combined medical-surgical approach is frequently required for complicated disease involving the chest, abdomen,
pelvis, and CNS. Surgery is indicated for resection of necrotic
tissue, excision of sinus tracts, drainage of empyemas or abscesses, and curettage of bone. Although the performance of
surgery facilitates recovery, surgery is usually not curative by
itself [19, 20, 84 – 86].
Prevention
There are no specific measures for preventing actinomycosis;
however, maintenance of good personal orodental hygiene, and
in particular, removal of dental plaque, may reduce the density
if not the incidence of colonization and low-grade periodontal
infection with Actinomyces species. Furthermore, clinicians and
patients must be aware of the risk of actinomycosis when intrauterine and intravaginal devices are used.
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Figure 3. Gram stain of a sulfur granule from a patient with thoracic actinomycosis and a draining sinus of the chest wall (approximate magnification, 1600).
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The ‘‘Conflict-of-Interest Policy’’ of the Office of Continuing Medical Education, UCLA School of Medicine,
requires that faculty participating in a CME activity disclose to the audience any relationship with a pharmaceutical or equipment company which might pose a potential, apparent, or real conflict of interest with regard to
their contribution to the program. The author reports no
conflict of interest.
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