Actinomyces/Actinomycosis

Actinomyces is an anaerobic, gram-positive, branching, filamentous rod. Actinomyces israelii is the most common species involved in human disease. The organism is commonly found as part of the normal flora in the oral cavity, gastrointestinal tract, and reproductive tract. The disease is caused when the organism is displaced even by minor trauma or procedure, allowing the organism to move beyond the mucosal barrier. Reaching areas of low oxygen leads to the organism’s multiplication. Actinomyces is associated with cervicofacial infection, which forms draining sinus tracts. Actinomyces can also affect the thoracic, abdominal, and pelvic areas. Drainage or infected tissue may have the characteristic yellow sulfur granules associated with Actinomyces. Management is with long-term penicillin and surgery, if needed.

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Classification

Microbiology flowchart gram-positive bacteria classification

Gram-positive bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview:
Most bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview can be classified according to a lab procedure called Gram staining.
Bacteria with cell walls that have a thick layer of peptidoglycan retain the crystal violet stain utilized in Gram staining but are not affected by the safranin counterstain. These bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview appear as purple-blue on the stain, indicating that they are gram positive. The bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview can be further classified according to morphology (branching filaments, bacilli, and cocci in clusters or chains) and their ability to grow in the presence of oxygen (aerobic versus anaerobic). The cocci can also be further identified. Staphylococci can be narrowed down on the basis of the presence of the enzyme coagulase and on their sensitivity to the antibiotic novobiocin. Streptococci are grown on blood agar and classified on the basis of which form of hemolysis they employ (α, β, or γ). Streptococci are further narrowed on the basis of their response to the pyrrolidonyl-β-naphthylamide (PYR) test, their sensitivity to specific antimicrobials (optochin and bacitracin), and their ability to grow on sodium chloride (NaCl) media.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics

Actinomyces

  • General characteristics:
    • Structure: branching, filamentous rods/bacilli
    • Gram stain: gram-positive
    • Other stain(s): not acid-fast
    • Spore formation: non-spore–forming (differentiates Actinomyces from fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview)
    • Oxygen requirement: anaerobe
  • Culture medium: same as for other anaerobes
  • Actinomycosis (disease-caused): 
    • Chronic suppurative and granulomatous infection
    • Associated with abscess formation with interconnecting sinus tracts
    • Sulfur granules:
      • Characteristic finding 
      • Microcolonies of the bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview with yellow color (no sulfur) and peripheral clubs
      • Found embedded in tissue elements

Clinically relevant species

  • A. israelii (most common)
  • A. gerencseriae
  • A. naeslundii
  • A. viscosus
  • A. odontolyticus
  • A. meyeri
Actinomyces naeslundii

Histopathological changes of brain abscess Brain abscess Brain abscess is a life-threatening condition that involves the collection of pus in the brain parenchyma caused by infection from bacteria, fungi, parasites, or protozoa. The most common presentation is headache, fever with chills, seizures, and neurological deficits. Brain Abscess due to A. naeslundii bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview (in silver stain). Branching bacilli are noted.

Image: “Actinomyces naeslundii 01” by CDC/Dr. Lucille Georg. License: Public Domain

Epidemiology

  • Men > women
  • Higher prevalence in low socioeconomic areas and in those with poor dental hygiene
  • Use of intrauterine device (IUD) has increased incidence in women.

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Pathogenesis

Reservoir and transmission

Reservoir:

  • Normal flora of:
    • Oral cavity
    • Reproductive tract
    • Gastrointestinal (GI) tract

Transmission:

  • Trauma displaces the organism.
  • Breaching the mucosal barrier and moving to areas with low oxygen (anaerobic environment) facilitate its multiplication.

Risk factors

  • Poor oral hygiene 
  • Gingivitis
  • Dental surgery
  • Dental trauma
  • IUD use
  • Alcoholism
  • Malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries
  • Malignancy and related local tissue damage (from the disease or from radiation treatment)
  • Diabetes
  • Osteonecrosis of the jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint due to bisphosphonates Bisphosphonates Bisphosphonates are pyrophosphate analogs most well-known for treating osteoporosis by preventing bone loss. Bisphosphonates end in the suffix "-dronate" or "-dronic acid" (e.g., alendronate, risedronate, pamidronate) and bind to hydroxyapatite crystals in bone, inhibiting osteoclast-induced bone resorption. Bisphosphonates

Pathophysiology

  • The bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview take advantage of the mucosal break, invading neighboring tissues.
  • Once Actinomyces infection is established, inflammatory response follows (suppurative and granulomatous). 
  • Infection spreads by creating sinuses that contain sulfur granules; these may drain into the surface. 
  • Infections occur near the usual reservoir.
  • Pulmonary infections occur, from direct extension of the oropharyngeal source or by aspiration of oral and GI secretions.
Pathogenesis of actinomyces

Pathogenesis of Actinomyces
When there is a breakdown of the mucosal barrier, Actinomyces from the oropharynx (which goes to respiratory areas), GI tract, and reproductive tract cause infection and spread to contiguous tissues while creating sinus tracts.

Image by Lecturio.

Clinical Presentation

Cervicofacial disease

  • Most common presentation
  • Oral/facial abscesses in the jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint (“lumpy jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint”), draining through sinus tracts 
  • Commonly affects the maxilla, cheek, and lower jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint
  • Forms characteristic yellow sulfur granules in pus or tissues:
    • Resemble grains of sand
    • Bacterial microcolonies
  • May extend to other tissues, bones, and lymph nodes
  • Manifestations:
    • Trismus and difficulty chewing
    • Pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain occurs with compression of neighboring structures.
  • Often associated with dental caries, extractions, or jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint trauma

Thoracic actinomycosis

  • Transmission: 
    • Aspiration of oropharyngeal secretions
    • Introduction of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview via esophageal injury
    • Direct extension from neck or abdomen
    • Hematogenous spread
  • Presents as subacute pulmonary infection: fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, cough with sputum
  • Lung parenchyma: may have cavitations, which can form sinus tracts
  • These tracts can go through the chest wall Chest wall The chest wall consists of skin, fat, muscles, bones, and cartilage. The bony structure of the chest wall is composed of the ribs, sternum, and thoracic vertebrae. The chest wall serves as armor for the vital intrathoracic organs and provides the stability necessary for the movement of the shoulders and arms. Chest Wall or invade the ribs.

Abdominal actinomycosis

  • From a ruptured appendix/bowel or an ulcer
  • Patient may have had prior abdominal surgery.
  • Presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, change in bowel habits, abdominal pain, weight loss
  • Extension can affect any intraabdominal organ.

Pelvic actinomycosis

  • In patients with an IUD
  • May present as lower abdominal pain and vaginal discharge
  • May cause pelvic abscesses

Diagnosis and Management

Diagnosis

  • Culture: 
    • Culture media and techniques: same as for other anaerobes 
    • Prolonged incubation (sometimes takes 7–21 days to appear)
    • Specimen(s): 
      • Pus (from draining sinuses)
      • Sputum
      • Specimens of tissue (with yellow-orange, microscopic sulfur granules)
    • In some cases, Actinomyces is seen on Pap smear.
      • If symptomatic of infection: IUD is removed and sent for culture.
      • If without symptoms: Patient is educated on symptoms to watch for and IUD is left in place.
  • Microscopic examination of sulfur granule: composed of tissue elements and branching actinomycotic filaments (club-shaped at the periphery)
  • Imaging studies:
    • Computed tomography (CT) scan of the abdomen: shows site and extent of the disease in abdominal infection
    • CT of the chest:
      • Evaluates thoracic infection
      • Shows mass with central areas of low attenuation and ring-like rim enhancement 
      • Cavities also may be seen.
    • Pelvic ultrasound: 
      • Obtained when patients present with symptoms of pelvic inflammatory disease Pelvic inflammatory disease Pelvic inflammatory disease (PID) is defined as a polymicrobial infection of the upper female reproductive system. The disease can affect the uterus, fallopian tubes, ovaries, and adjacent structures. Pelvic inflammatory disease is closely linked with sexually transmitted diseases, most commonly caused by Chlamydia trachomatis, Neisseria gonorrhoeae, and Gardnerella vaginalis. Pelvic Inflammatory Disease
      • Look for abscess
Osteonecrosis of the jaw associated with actinomyces

Osteonecrosis of the jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint associated with Actinomyces
(a) Hematoxylin and eosin staining of an aggregate composed of filaments, so-called sulfur granules (#). These granules macroscopically appear as yellow granules surrounded by neutrophilic granulocytes (*) and a necrotic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones trabecula (+, magnification x 100).
(b) The granules (#) stain periodic-acid Schiff (PAS)–positive (magnification x 200).
(c) High magnification elucidates the filamentous structure (#, sun-ray morphology) of the organisms (magnification x 400).
(d) Typical growth pattern of Actinomyces spp. in microbiological culture.

Image: “The association of medication-related osteonecrosis of the jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint with Actinomyces spp. infection” by Scientific Reports. License: CC BY 4.0

Management

  • Prolonged penicillin treatment 
    • Mild disease: 2–6 months
    • Severe disease: 6–12 months
  • Alternatives for penicillin-allergic patients: clindamycin or erythromycin
  • Surgical incision and drainage may be required.
  • Removal of IUD 

Comparison

Two clinically relevant gram-positive, branching, filamentous rods that must be distinguished:

Differentiating factors Actinomyces Nocardia Nocardia Nocardia is a branching, filamentous, gram-positive bacilli. It is partially acid fast due to the presence of mycolic acids in the cell wall. Nocardia is a ubiquitous soil organism that most commonly affects immunocompromised patients. Nocardia is transmitted via inhalation of aerosolized bacteria or less commonly, via direct contact with wounds. Nocardia/Nocardiosis
Oxygen requirement Anaerobic Aerobic
Acid-fast stain Not acid-fast Acid-fast (partially)
Reservoir/habitat Normal oral, GI, and reproductive flora Found in soil, water, decaying organic matter
Infections caused
  • Orofacial abscesses, associated with dental caries or facial trauma
  • Sinus tracts
  • Pelvic inflammatory disease
  • Pulmonary infection in immunocompromised patients (can spread hematogenously and cause brain abscesses)
  • Cutaneous lesions in immunocompetent patients
Management Penicillin Trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim-sulfamethoxazole

Mnemonic:

 SNAP (Sulfonamides-Nocardia, ActinomycesPenicillin)

Differential Diagnosis

  • Appendicitis Appendicitis Appendicitis is the acute inflammation of the vermiform appendix and the most common abdominal surgical emergency globally. The condition has a lifetime risk of 8%. Characteristic features include periumbilical abdominal pain that migrates to the right lower quadrant, fever, anorexia, nausea, and vomiting. Appendicitis: presents with abdominal pain and tenderness, mostly in the right lower quadrant. Computed tomography scan can help diagnose appendicitis. Abdominal actinomycosis can occur if appendicitis is complicated with rupture.
  • Odontogenic abscess/infection: arises after dental extraction or from an infected tooth. Infections are often polymicrobial; most common bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview are Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus viridians, Peptostreptococcus, and Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus. Culture will differentiate the organisms.
  • Pelvic inflammatory disease: the more common bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview involved in this disease are Chlamydia Chlamydia Chlamydiae are obligate intracellular gram-negative bacteria. They lack a peptidoglycan layer and are best visualized using Giemsa stain. The family of Chlamydiaceae comprises 3 pathogens that can infect humans: Chlamydia trachomatis, Chlamydia psittaci, and Chlamydia pneumoniae. Chlamydia trachomatis and Neisseria Neisseria Neisseria is a genus of bacteria commonly present on mucosal surfaces. Several species exist, but only 2 are pathogenic to humans: N. gonorrhoeae and N. meningitidis. Neisseria species are non-motile, gram-negative diplococci most commonly isolated on modified Thayer-Martin (MTM) agar. Neisseria gonorrhoeae. Infections from both organisms are sexually transmitted. Actinomycosis is often associated with IUD use.

References

  1. Riedel S, Hobden JA, et al (Eds.) (2019). Infections caused by anaerobic bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview. In Jawetz, Melnick, & Adelberg’s Medical Microbiology (28th ed.) McGraw-Hill. 
  2. Russo TA. (2018). Actinomycosis. In Jameson J, Fauci AS, et al (Eds.), Harrison’s Principles of Internal Medicine (20th ed.) McGraw-Hill.
  3. Ryan KJ (Ed.) (2017). Actinomyces and nocardia. In Sherris Medical Microbiology (7th ed.) McGraw-Hill.
  4. Sharma S, Hashmi M, Valentino D. (2020). Actinomycosis. StatPearls. Retrieved Nov 25, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK482151/
  5. Valour F, Sénéchal A, et al (2014). Actinomycosis: etiology, clinical features, diagnosis, treatment, and management. Infect Drug Resist, 7, 183–197. https://dx.doi.org/10.2147%2FIDR.S39601

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