Dermatologic Aspects of Actinomycosis

In 1845, the surgeon Bernhard von Langenbeck together with the physician Antoinne Lembert described the first cases of human actinomycosis. Surgeons of the time considered it submandibular adenitis, while the dermatologists thought it was syphilis.[1] The term "actinomycosis" (from the Greek aktino and mykos translating to "ray-fungus") was given by the botanist and mycologist Carl Otto Harz. It derived from the characteristic filamentous, branching morphology of the organisms resembling fungal hyphae. The specimens evaluated by Harz represented material submitted by the pathologist Otto Bolliger, who had found the disease in jaws of cattle in 1877.[2] In 1878, the surgeon James A Israel demonstrated one of the species as a human infectious pathogen.[3, 4]

Actinomycosis is a chronic, slowly progressing, granulomatous infectious disease caused by human-associated Actinomyces species. It is well known that it represents an endogenous infection. The causative agents are inhabitants of mucosal surfaces and skin, gaining access by disruption of the epithelial barrier via trauma, surgical procedures, or foreign bodies.[5, 6, 7] Although actinomycosis is considered an uncommon disease, its true prevalence is not available.[5, 8, 9] Its clinical presentation includes features such as abscess formation, dense fibrotic tissue reaction, and draining sinus tracts.[6] The infection is usually classified according to the affected body site as orocervicofacial (50-65%), thoracic (15-30%), and abdominopelvic (20%). Less frequent sites of presentation include the central nervous (2-3%) and musculoskeletal (rare) systems, and a disseminated form (rare).[6, 7, 10, 11] Cutaneous actinomycosis is generally a secondary process to deeper tissue infection, spreading by direct extension or by hematogenous means.[5, 12, 13] It usually begins as an inflammatory soft-tissue mass/abscess, which may or may not develop fistulous tracts with draining sites.

Owing to the slowly progressing and indolent nature of the condition, in association to early nonspecific symptoms (ie, edema, low-grade fever, weight loss), initiation of medical care is occasionally delayed.[7] Additionally, the clinical and radiologic findings of actinomycosis are varied and may represent a challenge, owing to overlapping characteristics with other inflammatory, infectious, and neoplastic entities.[6] The diagnosis is established by microbiologic isolation of Actinomyces, in the appropriate clinical setting. Currently, 16S rRNA gene sequence analysis and MALDI-TOF mass spectrometry are both precise diagnostic methods adopted by multiple laboratories.[14, 15, 16]

The treatment of actinomycosis may require high-dose, prolonged antibiotic therapy, and, occasionally, an interventional procedure such as collection drainage or surgical excision/resection.[7, 8]

Actinomycosis is a bacterial infection that spreads by direct extension and, rarely, hematogenously.[3, 5, 12, 13]  Actinomyces are found as commensal flora of human mucosae and skin, giving origin to foci of infection as a result of disruption of the epithelial surfaces secondary to trauma, surgical procedures, or foreign bodies.[5, 6, 7] Their pathogenicity is low, but little is known about their mechanism of infection. It has been speculated they may have the ability to evade the host's immune system. Additionally, since Actinomyces are frequently isolated from polymicrobial infections (75-95%), it has been presumed that interactions with other microorganisms contribute and synergistically enhance the pathogenic process.[5, 17]

See the image below.

Photomicrograph of gram-positive organisms in actinomycosis, which may be confused with those causing a mycotic infection (hematoxylin and eosin, original magnification X40).

The genus Actinomyces belongs to the family Actinomycetaceae, order Actinomycetales, and phyla Actinobacteria. It is currently composed of 54 validly published species.[18] These are anaerobic or microaerophilic, nonsporulating, nonmotile, gram-positive bacilli with filamentous and branching histopathological structures.[19] More than half of Actinomyces species have been associated with human infections, with Actinomyces israelii being the leading agent causing actinomycosis. Additional species associated with classic actinomycosis include Actinomyces gerencseriae and Actinomyces graevenitzii. A wide range of the published species are increasingly emerging as infectious agents at many body sites.[5] Detailed characterization of Actinomyces at nonoral human body sites is infrequent.[5]

Actinomyces is one of the predominant genera in the human oral microbiome, with at least 19 species currently identified as part of it.[20] Some of these play a central role in early biofilm formation. The total biomass of Actinomyces do not differ between periodontally healthy and diseased subjects, although a relative focal decrease in their numbers has been described in diseased sites. In general, it is thought they do not play a pathogenic role in periodontitis.[5, 21, 22]

See the image below.

Photomicrograph of a characteristic sulfur granule of actinomycosis (hematoxylin and eosin, original magnification X10).

Frequency

Actinomycosis occurs worldwide, although it is a rare infection. Little is known about its epidemiology, and the limited existing knowledge derives mostly from case reports and case series. Based on this information, Actinomyces affects people of all ages, without predilection for a particular race. Of note, a higher rate of infection has been seen among males, hypothesized (by circumstantial evidence) to be related to increased trauma or poorer dental hygiene.[19, 23] Some cases have been linked to specific conditions such as corticosteroid use, osteoradionecrosis or bisphosphonate-related osteonecrosis, leukemia, renal failure, congenital immunodeficiencies, and human immunodeficiency virus infection.[5, 19, 24, 25] While Actinomyces affect immunocompromised patients, most cases have been reported in immunocompetent individuals.[7, 8] Risk factors associated with orocervicofacial actinomycosis include, in addition to poor dental hygiene, smoking and heavy alcohol use.

Race

Actinomycosis has no race predilection.

Sex

Actinomycosis has a male predominance, with an approximate ratio of 3:1.[26]

Age

Actinomycosis affects subjects of all ages, although pediatric cases are less frequent.[5]

Actinomycosis is known for its slow progression and indolent nature.[7] Source control with antibiotic therapy and surgical interventions, as pertinent, are the mainstay of treatment. Prompt recognition of uncontrolled or advanced infection is critical to avoid the additional morbidity from radical and extensive surgeries.[27]

A detailed clinical history is critical as in any other pathologic entity. Diagnostic consideration of actinomycosis is reasonable under the following circumstances[6] :

• The timeline of the clinical manifestations demonstrate chronicity of the event, in association with a firm masslike lesion with extensive compromise of tissue planes.
• Drainage of an abscess by a sinus tract.
• Temporary improvement after a course of antibiotic therapy, followed by relapsed disease, and recurrences

Presentations

Most cases of actinomycosis present in the orocervicofacial region (50-65%); the majority of them are of odontogenic origin. Invasive dental procedures and tooth extractions facilitate the access of Actinomyces to deeper tissues. Early diagnosis of infection is challenging owing to the nonspecific and inconsistent signs and symptoms at this stage, such as edema, cough, occasional pain, and low-grade fever. Less frequently, a soft-tissue mass or abscess is present in the acute to subacute phases.[6, 19] As the infection evolves, the lesion extends within the soft tissues, growing as a fibrotic mass, spreading and dissecting through tissue planes, and forming sinus tracts, which may drain to the skin's surface.[6] Skin discoloration may be seen in the acute phase.[3] Cutaneous inflammatory changes in association with the draining sites are common. Up to 75% of cases drain yellow, purulent material from these sites, known as sulfur granules, which are strongly suggestive of, but nonspecific for, actinomycosis. Other entities such as nocardiosis and various fungal infections may manifest with the production of identical material.[3, 28]

Actinomycosis of the thoracic region (10-30%) may be secondary to the extension of local infections or hematogenous spread, or due to aspiration of oropharyngeal secretions.[8] It may manifest as an endobronchial infection, nodule/mass, pneumonia, pleural effusion, or, less commonly, with mediastinitis.[19] As mentioned, the infectious process by Actinomyces characteristically extends throughout different tissue planes despite anatomic barriers. Cases of thoracic actinomycosis presenting as empyema necessitans have been described.[29, 30]

Abdominopelvic actinomycosis (20%) is usually the result of gastrointestinal tract mucosal disruption by perforation, trauma, or surgical intervention.[5, 8, 19] Pelvic disease has been associated with the use of intrauterine contraceptive devices, although most women, despite the presence of Actinomyces infection, are asymptomatic.[31, 32] Abdominopelvic disease may start as an abdominal focus extending to the pelvic region, or vice versa.[10]

Other possible but uncommon sites of infection by Actinomyces include the central nervous and musculoskeletal systems, and its disseminated form.[5, 8, 33]

Findings

Actinomycosis may present as a phlegmon, abscess, firm mass, or a draining sinus in any of the regions of presentation. The clinical findings are variable and may resemble other inflammatory, infectious, and/or neoplastic lesions. Imaging, tissue sampling, and microbiologic correlation are advised to prompt early, accurate diagnosis and treatment.[6]

Actinomycosis can result in extensive regional tissue invasion and markedly morbid functional and structural compromise of organs and systems. Skin defects and scarred tissue may require resective and reconstructive surgical interventions.

High clinical suspicion of actinomycosis should be followed by concurrent histological and microbiological evaluation of tissue, diagnostic imaging, and antibiotic treatment. Surgical interventions may be required depending on tissue extension and severity of disease.

Collection, transport, and storage of specimens

Specimens suitable for culturing Actinomyces include aseptically collected peripheral blood, tissue, aspirates, and fluids (eg, cerebrospinal, synovial, pleural). Collections from mucocutaneous sites are challenging owing to the risk of contamination with commensal microbiota in the vicinity. The use of swabs is discouraged. Anaerobic transportation techniques should be used to carry and deliver the specimens to the laboratory.[34]

Direct examination

Microscopic examination for the diagnosis of actinomycosis has been a major tool for years. Evaluation of sulfur granules (not present in all infections) revealing a mass of gram-positive, branching filaments is suggestive, although not pathognomonic, of the disease.[34]

Culture findings in actinomycosis

Actinomyces usually produce small, relatively nondescript, clear-to-white colonies. Some species show a characteristic morphology described as "molar tooth" appearance.[34]

Cultures may reveal a polymicrobial isolate, including anaerobic streptococci, fusiform bacilli, Haemophilus species, and gram-negative bacilli. Obtaining individual susceptibilities in this scenario is discouraged as it may not be clinically helpful. The susceptibility of bacteria should be determined when a given organism is isolated in pure culture or is predominant.[34]

Performing cultures for actinomycosis

Appropriate culture media, including sheep's blood agar and Brucella agar at 37°C, should be used. Most Actinomyces are aerotolerant, although anaerobic culture incubation is recommended for optimal recovery. The media may be examined after 24 hours of incubation in an anaerobic chamber; however, waiting for 48 hours is advised.[34]

Initial characterization of the isolate involves aerotolerance (growth in air vs air plus 5% carbon dioxide), gross morphology, hemolysis, pigmentation, and fluorescence under long-wave ultraviolet illumination (365-nm wavelength). Additional rapid tests for initial grouping include catalase production, nitrate reduction, and motility. Biochemical testing had been historically used for the phenotypic characterization and speciation, but it is particularly unreliable for the identification of many Actinomyces. The assessment of Gram stain morphology from the colonies usually shows gram-positive bacilli/rods (nonbranching). The filamentous, branching morphology is mostly seen in histological samples. Most Actinomyces are aerotolerant and catalase and urease negative, and the majority show no pigment production.[34]

Speciation may be pursued by larger laboratories where MALDI-TOF mass spectrometry is available. An additional tool to obtain specific and accurate answers up to the species level is the use of 16S rRNA gene sequencing.[14, 15, 16]

Susceptibility testing methods and breakpoints for anaerobes, such as Actinomyces, are based on minimum inhibitory concentrations; disk diffusion is not acceptable for this organisms.

Hematologic study results in actinomycosis

Hematologic studies may reflect the infectious/inflammatory process, with an elevated white blood cell count and an increase in positive acute-phase response proteins. Owing to the chronic nature of the infection, it is not uncommon to see associated anemia.

The radiologic findings of actinomycosis are variable and depend on the primary site involved by the infection, extension, and duration of disease. Different diagnostic imaging tools such as radiography, axial computed tomography (preferably contrast-enhanced), and magnetic resonance imaging are routinely used to evaluate these lesions, according to their location.

In orocervicofacial disease, it is not uncommon to see an actinomycotic lesion as a mass with focal necrosis and cysts, with relatively homogeneous enhancement (the latter most likely due to abundant granulation tissue and fibrosis). Although the infectious process may evolve to compromise the bone, causing osteomyelitis in the adjacent mandible or maxilla, such a finding is not commonly seen. Maxillary involvement (less frequent) usually presents with a soft mass and underlying osteomyelitis, with cutaneous or maxillary sinus fistulas. Facial actinomycosis can spread into the neck, and even the mediastinum and thorax, ignoring fascial planes. Regional reactive lymphadenopathy in association with the infectious process is rare.[6]

Actinomycosis of the thoracic region may cause bronchopulmonary, pleural, chest wall, and/or mediastinal involvement (rare). Some of the imaging findings include chronic segmental airspace consolidation with necrotic areas showing peripheral enhancement, often accompanied by adjacent pleural thickening. Pleural thickening and effusion may be seen in association with parenchymal disease in more than half of cases. Transdiaphragmatic infection (from thorax to abdomen, and vice versa) has been described.[6]

Abdominopelvic actinomycosis preferentially involves the ileocecal region of the bowel, extending to surrounding structures across fascial and connective-tissue planes. There is concentric bowel wall thickening, with an adjacent mass and prominent inflammatory infiltration, with dense and extensive fibrosis. The ovary and fallopian tubes are the most commonly affected structures in pelvic actinomycosis.[6]

Musculoskeletal, central nervous system, and other less common sites are rarely compromised by Actinomyces. In the presence of radiologic findings consistent with granulomatous, markedly fibrotic, and focally necrotic lesions extending aggressively through different planes of tissue, actinomycosis should be considered as a differential diagnosis.

The treatment of actinomycosis may require extended antibiotic therapy and surgical interventions as pertinent. Medications should be adjusted based on individual patient needs. Actinomyces species are in general susceptible to penicillin and other beta-lactam antibiotics, as well as to most agents used to treat infections by gram-positive anaerobic rods. Susceptibility to clindamycin is variable, with resistance varying from 17-33%.[34] Metronidazole and aminoglycosides are ineffective against these species.[3]

If the actinomycosis is recognized early, cervicofacial infection has a good prognosis with the use of antibiotics alone. In the treatment of actinomycosis, tetracyclines are as effective as penicillin. Intravenous or intramuscular benzylpenicillin at a dose of 20 million IU/day is not uncommon. Oral amoxicillin is recommended at a dose of 2-4 g/day. Patients should be treated for a minimum of 3 months, preferably extending the treatment 2-3 weeks after symptoms have subsided.[3] Medication adjustments based on individual minimum inhibitory concentrations (MICs) may be required. Differences in MICs among Actinomyces species are known, with Actinomyces  europaeus and Actinomyces turicensis being the most resistant.[5]

Surgical management in actinomycosis has consisted of various treatment modalities, including excision of sinus tracts, drainage of the abscess cavities, removal of bulky infected masses, and irrigation and curettage of the osteomyelitic bony lesions.[35]

The Infectious Diseases Society of America and the American Society for Microbiology have updated guidelines on microbiologic diagnosis of infectious diseases: A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiology.[36]

The goals of pharmacotherapy in the treatment of actinomycosis are to eradicate the infection, reduce morbidity, and prevent complications.

Penicillin G (Pfizerpen)

Penicillin G interferes with the synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. Prolonged therapy, including longer than 1 year, may be necessary.

Penicillin VK (Beepen-VK, Betapen-VK, Pen-Vee K, Robicillin VK, Veetids)

Penicillin VK interferes with the synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. It has better GI absorption than penicillin G.