Actinomycosis

Etiology

Actinomyces were initially classified as fungi because of their branching morphology. The organisms measure approximately 2 to 30 μm in length and 0.3 to 0.5 μm in width. Actinomyces species often mimic malignancy in intraabdominal infections.[5] Actinomyces normally colonize the human mouth, urogenital tract, and gastrointestinal tract. As commensal organisms, Actinomyces can be difficult to distinguish from true infection.[6][7][8] More than 30 species have been identified, with A israelii being the most frequently reported in human infections.[9][10]

Infection commonly occurs when mucosal or epithelial barriers are disrupted, allowing the organism to invade normally sterile tissue. The most common risk factors include poor dental hygiene, oral surgery, maxillofacial trauma, local tissue inflammation, and diabetes.[11] Thoracic actinomycosis can occur in patients with alcohol use disorder and seizure disorders. Pulmonary infection usually develops as a complication of aspiration. Rarely, disease can result from a human bite. Cervicofacial infection typically occurs after oral cavity surgery in patients with poor oral hygiene. Pelvic actinomycosis is associated with intrauterine device use. Abdominal actinomycosis has been reported after abdominal surgery, most commonly after appendectomy.[12]

Epidemiology

The incidence of actinomycosis is higher in male populations, with an overall male-to-female ratio of approximately 3:1. However, the ratio may be narrower for certain disease sites, such as the central nervous system.[13] The most commonly affected age group is 20 to 60 years, with peak incidence between 40 and 50 years. Prolonged intrauterine device use is associated with increased incidence in female individuals. Actinomycosis has a higher prevalence in populations with low socioeconomic status. No racial predilection has been identified.

Immunosuppression, which may arise from HIV infection, steroid use, treatment with biologic agents like infliximab, organ transplantation, and chemotherapy for hematologic malignancies, also increases the risk of infection. Recent data from cancer center cohorts further highlight radiation therapy and gastrointestinal or genitourinary surgery as significant risk factors for invasive disease. Although uncommon, skin and soft tissue involvement can follow direct skin injury. Hematogenous spread is exceptionally rare.

Pathophysiology

As Actinomyces is a normal component of host flora, the organism has limited virulence and invades deeper tissues primarily after tissue injury and disruption of the normal mucosal barrier. Infection is usually polymicrobial, with up to 5 to 10 additional bacterial species present. Companion bacteria facilitate infection by inhibiting host defenses, reducing oxygen tension, or producing toxins that promote Actinomyces inoculation.[14]

Following mucosal barrier disruption and establishment of infection, the host initiates an intense inflammatory response characterized by suppurative and granulomatous inflammation. The infection does not respect tissue planes and spreads contiguously. This pattern results in the formation of draining sinus tracts, small yellow clumps known as sulfur granules, and potentially extensive tissue fibrosis.[15]

Approximately 60% of infections are cervicofacial and described as “lumpy jaw syndrome.”[16] Predisposing risk factors for cervicofacial infection include infection involving erupting teeth, dental caries, gingivitis, dental extraction, diabetes, alcohol use disorder, malnutrition, and malignancy. Additional risk factors include HIV infection, solid organ transplantation involving the lungs or kidneys, the use of biologic agents like infliximab, and acute lymphoblastic leukemia treated with chemotherapy.

Pulmonary infections primarily result from aspiration of oral and gastrointestinal secretions. Risk factors include the conditions described above and chronic lung diseases that cause tissue destruction and disrupt normal mucosal defenses, such as chronic obstructive pulmonary disease, bronchiectasis, tuberculosis, and silicosis. Pulmonary disease can result from direct or indirect extension of cervicofacial infection. Actinomyces can spread from the lungs to the mediastinum and pleura. Bronchial and laryngeal infections are rare.[17] Vocal cord infection may mimic malignancy.

The genitourinary tract is the second most frequent site of Actinomyces infection. Prolonged intrauterine device use is the primary risk factor.[18] Abdominal actinomycosis most commonly involves the appendix, cecum, and colon and can mimic malignancy. Abdominal surgery is the most significant risk factor.[19] Skin and soft tissue actinomycosis is rare but can occur after skin injury. Hematogenous dissemination is extremely rare.[20]

Growing evidence from recent histopathological studies implicates Actinomyces species in the pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) and osteoradionecrosis (ORN). A 2022 study using targeted histological evaluation identified Actinomyces colonization in a significant proportion of MRONJ bone specimens. However, whether Actinomyces species contribute causally or represent secondary colonization of necrotic tissue remains debated. Histologic staining for Actinomyces species is now considered a common finding in MRONJ lesions.[21]

Histopathology

Gram staining of infected tissue or purulent material is a useful adjunct and, in some cases, more sensitive than culture, which may be negative in approximately 50% of cases. The high rate of negative culture results is attributed to prior antibiotic therapy, polymicrobial infection with competing organisms that inhibit growth, failure to maintain anaerobic conditions during specimen transport and culture, or short incubation periods.[22]

The characteristic finding of actinomycosis is the presence of yellow sulfur granules, which consist primarily of mycelial fragments surrounded by a calcium phosphate matrix (Splendore-Hoeppli phenomenon) that prevents phagocytosis and promotes immune evasion (see Image. Sulfur Granules). The classic microscopic finding is suppurative granulomatous inflammation surrounding sulfur granules, with filamentous gram-positive bacteria visible within the granules. The optimal specimens include tissue biopsy or purulent material from the infected site. Clinicians should communicate suspicion of actinomycosis to microbiologists or pathologists to facilitate prolonged anaerobic incubation and optimize organism recovery.[23] Immunofluorescence has poor sensitivity but high specificity and may confirm the diagnosis.[24]

History and Physical

The clinical presentation depends on the site of infection and varies accordingly. A detailed history, including assessment of risk factors, is essential.[25][26][27]

Cervicofacial Disease

Cervicofacial actinomycosis is the most common form, accounting for approximately 50% of infections. The mandible is the most frequently affected site (53.6%), followed by the cheek (16.4%), chin (13.3%), submaxillary ramus and angle (10.7%), and maxilla (5.7%).[28] The most common presentation is a progressive, painless, indurated mass with or without reddish or bluish discoloration of the overlying skin. The mass eventually progresses to multiple abscesses with sinus tract formation that drain yellow sulfur granules (see Image. Actinomycosis Sinus Tract). Patients may report a history of oral procedures or injury. Difficulty chewing and trismus can occur during chronic stages of infection. Lymphadenopathy is not associated with the disease process.

Genitourinary Presentation

A history of long-term copper intrauterine device (IUD) use is common, with increased duration appearing to confer the greatest risk. IUD-associated pelvic actinomycosis accounts for approximately 3% of all cases. Symptoms often mimic those of gynecologic tumors, including malignant and benign neoplasms. Presentations may include lower abdominal pain, constipation, and vaginal discharge. Fever is uncommon unless infection spreads to the peritoneum.[29]

Gastrointestinal Involvement

Patients may have a history of abdominal surgery, particularly appendectomy, viscus perforation, or fishbone ingestion. Infection may occur in the esophagus, appendix, cecum, or colon, with clinical presentation varying by site. Esophageal disease most commonly presents with dysphagia. Involvement of other gastrointestinal sites is associated with nonspecific symptoms, including low-grade fever, weight loss, fatigue, nausea, vomiting, changes in bowel habits, and abdominal pain with or without a palpable mass. Rarely, Actinomyces infection affects the liver and biliary tract, causing right upper quadrant pain and jaundice (see Image. Liver Actinomycosis).

Pulmonary Localization

Pulmonary actinomycosis can present as an acute-to-subacute infection. However, diagnostic challenges mean most cases are diagnosed during the chronic phase. Initial symptoms are often nonspecific and include low-grade fever and weight loss. Clinical manifestations can mimic those of other chronic pulmonary infections and malignancy. The most common symptoms include chronic productive cough with or without hemoptysis, dyspnea, and chest pain. Pulmonary parenchymal infection can cavitate and form sinus tracts, which are a pathognomonic finding.[30] Extensive disease in immunocompromised individuals can result in severe hypoxemia, respiratory failure, and acute respiratory distress syndrome.

Evaluation

A complete blood count may demonstrate leukocytosis with neutrophilia. Nonspecific inflammatory markers, including C-reactive protein and erythrocyte sedimentation rate, are elevated.[31][32][33] The gold-standard diagnostic test is tissue biopsy culture, with anaerobic pus cultures that demonstrate sulfur granules.[34] Swabs from infected sites should be avoided. Cultures may yield false-negative results. 

However, Gram staining can demonstrate branched, beaded, gram-positive filamentous rods with sulfur granules, supporting a preliminary diagnosis. For microscopic examination, granules should be crushed between 2 slides and stained with Gram stain or hematoxylin and eosin to identify the organism. Filamentous bacterial aggregates are readily visualized on hematoxylin and eosin staining and highlighted by Gram (Brown-Hopps or Brown-Brenn) stains. Gram staining may also demonstrate gram-positive filamentous branching bacteria. Serologic tests are not useful for diagnosis. Imaging findings depend on the site of infection and can mimic those of malignancies or other chronic infections, including nocardiosis and tuberculosis.

Cervicofacial Actinomycosis

Imaging findings are nonspecific and do not contribute to the diagnosis, but can help assess the extent of soft-tissue and bone involvement. Dental radiographs are useful for evaluating apical abscesses. Computed tomography (CT) and magnetic resonance imaging (MRI) may demonstrate osteolysis in chronic infection.

Pulmonary Actinomycosis

Imaging findings of actinomycosis are nonspecific. Acute disease can resemble other forms of pneumonia. Chronic disease can present as a pulmonary mass or cavitary lesion. Actinomycosis should be considered in patients with a pulmonary mass suggestive of malignancy. Tuberculosis is an important consideration in the differential diagnosis, particularly in cavitary lesions. CT findings vary, depending on disease duration and may include consolidation, cavitation, pleural effusion, lymph node enlargement, atelectasis, and ground-glass opacification.

The gold-standard diagnostic approach is histological examination and bacterial culture of biopsy specimens obtained via bronchoscopy, CT-guided biopsy, or video-assisted thoracoscopic surgery (VATS). Bronchoscopy is performed by a pulmonologist, CT-guided biopsy by an interventional radiologist, and video-assisted thoracoscopic surgery by a thoracic surgeon. Anaerobic cultures of pleural fluid rarely yield the organism. Sputum cultures are not useful unless cavitary disease is present.

Gastrointestinal Actinomycosis

Imaging findings of actinomycosis are nonspecific and vary with the site of infection and the chronicity of the disease. Chronic disease may demonstrate enterocutaneous fistulas with multiple abdominal abscesses on CT. Culture of infected tissue is the preferred diagnostic test.

Genitourinary Actinomycosis

CT may demonstrate a pelvic mass measuring 6 to 7 cm with a cystic component. Lymphadenopathy occurs in approximately 50% of cases. A tubo-ovarian abscess is highly suggestive of actinomycosis. Bladder actinomycosis can mimic bladder carcinoma, with findings including bladder wall thickening and hematuria.

Pus samples may be obtained after removal of the IUD. Colonization must be distinguished from infection. Tissue biopsy should be obtained in patients presenting with pelvic masses to exclude malignancy.

Treatment / Management

Most cases of actinomycosis may be managed with antibiotic administration, with surgery serving as an adjunctive treatment.[35] Medical management typically involves penicillin G as the first-line agent, administered intravenously at high doses initially, followed by stepdown therapy with oral penicillin V or amoxicillin after 2 to 6 weeks. Long oral amoxicillin treatment courses may be used as stepdown therapy. Amoxicillin may also be used as the primary agent in mild cases. Ceftriaxone has activity against Actinomyces and may be administered as an alternative. Cephalexin has no activity against the organism and should not be used.(A1)

For patients with penicillin allergy, alternative agents include clindamycin and macrolides, such as erythromycin, clarithromycin, or azithromycin. Tetracyclines, such as doxycycline, as well as carbapenems, are also reasonable options. Metronidazole has no activity against Actinomyces and should not be used for actinomycosis. In polymicrobial infections, agents targeting copathogens, such as amoxicillin-clavulanate, may be added. However, the primary regimen should include a β-lactam agent with activity against Actinomyces.

Antimicrobial susceptibility testing is not routinely indicated because of predictable susceptibility patterns, although resistance profiles vary among species.[36] Treatment typically lasts 6 to 12 months, with a minimum of 8 weeks even in favorable cases. Therapy duration may be shortened after surgical resection of the infected site.[37] Surgical management depends on the site and extent of disease and typically involves incision and drainage of abscesses, decompression of closed spaces, and excision of sinus tracts. Treatment response may be monitored with serial imaging.(B3)

Differential Diagnosis

The differential diagnosis depends on the site of infection. Actinomycosis is a slowly progressive condition that can mimic benign and malignant tumors, nocardiosis, and tuberculosis. Differential diagnoses for cervicofacial actinomycosis include brain abscess, dental abscess, and osteomyelitis. Pulmonary actinomycosis should be differentiated from lung abscess, pulmonary tuberculosis, pulmonary sarcoidosis, fungal pneumonia, and aspiration pneumonia. Gastrointestinal actinomycosis should be distinguished from appendicitis, diverticulosis, and Crohn disease. Pelvic inflammatory disease is an important consideration in the differential diagnosis of genitourinary actinomycosis.

Prognosis

Prolonged antibiotic treatment is usually required, and the prognosis is excellent. Improved oral hygiene, widespread antibiotic availability, and advances in surgical techniques have contributed to better clinical outcomes and lower mortality. Extensive or complicated disease often requires both antibiotic therapy and surgery. Morbidity is high in these cases, and death may occur. The addition of surgery to antimicrobial treatment is independently associated with improved outcomes.

Complications

Complications of actinomycosis include abscess formation and local or distant spread of infection. Osteomyelitis may involve the ribs, vertebrae, and mandible.[38] Nervous system complications include meningitis, brain abscess, actinomycetoma, cranial infection, epidural infection, subdural infection, and spinal epidural infection (see Image. Brain Actinomycosis). Dissemination occurs in up to 20% of cases and can involve the lungs, abdomen, and other sites, resulting in a case fatality rate of approximately 11% and persistent disability in about 22% of cases (see Image. Right Leg Actinomycosis). Additional complications include hepatic actinomycosis and endocarditis.[39] Endocarditis can cause perforation of the coronary cusps, resulting in cardiac failure.