Agents of Actinomycosis

Etiologic Agents

Actinomycosis is most commonly caused by the gram-positive higher bacterium Actinomyces israelii . Additional species that are established but are less common causes of actinomycosis include Actinomyces naeslundii, Actinomyces viscosus, Actinomyces odontolyticus, Actinomyces gerencseriae , Actinomyces graevenitzii, and Actinomyces meyeri , which has been increasingly described in some studies. Pseudopropionibacterium propionicum (formerly Propionibacterium propionicum and Arachnia propionica ) has been described as a cause of actinomycosis, but most reports primarily describe this pathogen as causing lacrimal canaliculitis and endodontic infections.

Until recently, classification of Actinomyces spp. was based on differences in the results of phenotypic testing (see “ Diagnosis ” later). However, advances in microbiologic taxonomy, using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry and genotypic methods such as comparative 16S ribosomal RNA (rRNA) or sequencing of alternative genes, have led to the identification of many new Actinomyces species from both human and animal specimens. Many A. naeslundii isolates are now reclassified as Actinomyces oris. These methods have also led to the reclassification of certain Actinomyces species as Trueperella (Arcanobacterium), Actinotignum (Actinobaculum), or Cellulomonas. Presently, 47 species and 2 subspecies have been recognized. Twenty-five species have caused infections in humans, although the “classic” syndrome of actinomycosis has been variably described. Actinomyces europaeus, Actinomyces neuii, Actinomyces radingae, Actinomyces turicensis, Actinomyces georgiae, Actinomyces urogenitalis, Actinomyces funkei, Actinomyces hongkongensis, Actinomyces houstonensis, Actinomyces massiliensis, Actinomyces timonensis, and Actinomyces cardiffensis are capable of causing a variety of human infections. A. neuii most commonly has been reported to cause endovascular infection and abscesses. Trueperella (Arcanobacterium) pyogenes and Trueperella (Arcanobacterium) bernardiae are additional causes of human infection.

When an adequate bacteriologic evaluation is performed, most if not all actinomycotic infections are polymicrobial in nature. Aggregatibacter (Actinobacillus) actinomycetemcomitans, Eikenella corrodens, Fusobacterium, Bacteroides, Capnocytophaga, Staphylococcus, Streptococcus, and Enterobacteriaceae have been isolated in various combinations, depending on the site of the infection. The contribution of these additional isolates to the pathogenesis of actinomycosis is difficult to assess; however, it seems reasonable to consider them as being potential copathogens when one is designing therapeutic regimens.

Epidemiology

The agents of actinomycosis have been clearly established as members of the endogenous flora of mucous membranes. The frequency of oral cavity colonization with Actinomyces is nearly 100% by 2 years of age. It is also often cultured from the gastrointestinal tract, bronchi, and female genital tract. It has never been cultured from nature, and there are no documented cases of person-to-person transmission. Although the normal habitats for the more recently identified Actinomyces spp. have not been optimally defined, data available to date suggest that these species are also members of the endogenous oral, gastrointestinal, and genital flora. Possible transmission via a lamb bite has been described in a single report.

Actinomycosis has no geographic boundaries. Infection may occur in individuals of all ages. The peak incidence of actinomycosis is reported to be from 30 to 60 years, with cases in individuals younger than 10 and older than 60 years being less frequent. Nearly all series have reported males to be infected more frequently than females, at a ratio of approximately 3 : 1. Plausible but unproven explanations for this discordance include poorer dental hygiene and increased oral trauma in males.

Studies on the occurrence of actinomycosis estimated a yearly incidence of 1 : 100,000 in the Netherlands and Germany in the 1960s and 1 : 300,000 in the Cleveland area during the 1970s, making this disease uncommon but not rare. Its frequency has undoubtedly diminished since the preantibiotic era, when this disease was not only common but more malignant in nature. Improved dental hygiene and early antimicrobial treatment of infections before the development of a characteristic classic actinomycotic syndrome are likely contributing factors. However, individuals or populations that do not have access to dental or medical care, or both; prolonged use of an intrauterine contraceptive device (IUCD) (see “ Pelvic Disease ” later); and bisphosphonate use (see “ Oral-Cervicofacial Disease ” later) are associated with higher risk. Furthermore, many unrecognized cases probably occur, especially oral-cervicofacial disease, owing to early successful empirical therapy.

Pathogenesis and Pathology

A pivotal step in the pathogenesis of actinomycosis is disruption of mucosal or epithelial barriers enabling entry of colonizing Actinomyces or related genera. Oral and cervicofacial disease is frequently associated with dental procedures, trauma, oral surgery, head and neck radiotherapy, or oncologic surgical procedures. Pulmonary infections often arise in the setting of aspiration, and abdominal infection is usually preceded by conditions that result in loss of mucosal integrity, such as surgery, diverticulitis, appendicitis, or foreign bodies (e.g., fish bones). Recognition of factors that enable bacterial entry into deep tissues, however, may be absent. The lack of such a history should not prevent consideration of this disease when the clinical circumstance is appropriate.

Other bacterial species concomitantly present have been designated as “companion organisms.” They may serve as copathogens by aiding in the inhibition of host defenses or by reducing oxygen tension. The difficulty in establishing an animal model of infection with Actinomyces alone and enhancement of infection by coinoculation of E. corrodens support the concept that additional organisms are important for the initiation of infection. Furthermore, coaggregation of Actinomyces and Streptococcus spp. results in increased resistance to phagocytosis and killing.

An acute inflammatory phase manifesting with a painful cellulitic reaction is occasionally observed with oral-cervicofacial disease or with soft tissue infection elsewhere in the body. The chronic phase of this disease is more often seen. “Classic” disease is characterized by a densely fibrotic lesion that undergoes slow, contiguous spread that ignores tissue planes. However, the factor(s) responsible for the unique pathogenesis of this disease remain undefined. Lesions usually appear as either single or multiple indurated swellings. Over time, central fluctuance and suppuration develop. The fibrous walls of the mass have been characteristically described as “wooden” and, in the absence of suppuration, have been frequently confused with neoplasms. This extensive fibrosis, which is one of the hallmarks of this disease, may be minimal, especially in pulmonary and central nervous system (CNS) lesions. Given time, sinus tracts will often extend from the abscess to either the skin or adjacent organs or bone, depending on the location of the lesion. Sinus tracts can spontaneously close and then reform. Overlying skin may assume a red to bluish hue. Lymphatic spread and associated lymphadenopathy are uncommon. Hematogenous dissemination can occur from local sites, which occasionally results in fulminant infection, although in the antibiotic era this clinical syndrome has become rare.

Microscopically, lesions have an outer zone of granulation, consisting of collagen fibers and fibroblasts. There is a central purulent loculation that contains neutrophils that surround the sulfur granules present. Granules are conglomerations of organisms and are virtually diagnostic of this disease. Bacterial biofilms may contribute to granule formation. One to six may be present per loculation, and they range from microscopic to macroscopic in size (see “ Diagnosis ” later). As many as 50 loculations may be present per lesion, and these loculations are separated by granulation tissue or foamy macrophages and may undergo coalescence. Lymphocytes and plasma cells are usually present, and eosinophils are seen in 15% of abscesses. Multinucleated giant cells are occasionally seen, primarily in pulmonary lesions, but they have also been described in disease elsewhere. Suppuration is a constant feature of active disease but may not be present in all areas of the lesion. Grains are usually surrounded by neutrophils and may be sporadic in biopsy tissue; additional sections may be required for them to be seen.

Foreign bodies appear to facilitate infection. This association has been most commonly observed with IUCDs and pelvic actinomycosis. Associations with actinomycosis and foreign material elsewhere are less strong. Aspirated, ingested, or implanted foreign bodies may contribute to pathogenesis via facilitating the growth and survival, and biofilm formation.

Cases of actinomycosis have been described in the settings of steroid use, anti–TNF-α agents, bisphosphonate treatment, radionecrosis, acute leukemia during chemotherapy, organ transplantation, common variable immunodeficiency, chronic granulomatous disease, and human immunodeficiency virus (HIV) infection. Ulcerative mucosal lesions (herpes simplex virus, cytomegalovirus, chemotherapy) and abnormalities in host defenses likely facilitated the development of actinomycosis in some HIV-associated cases; however, it remains unclear which arm(s) of the host defense are critical in preventing or controlling this infection and the degree to which the incidence of infection is increased in these settings.

Clinical Manifestations