ACTINOMYCETES

Actinomycetes are a large, diverse group of gram-positive bacilli with a tendency to form chains or filaments. They are related to the corynebacteria and mycobacteria as well as the streptomycetes. As the bacilli grow, the cells remain together after division to form elongated chains of bacteria (1 m in width) with occasional branches. The extent of this process varies in different taxa. It is rudimentary in some actinomycetesthe chains are short, break apart after formation, and resemble diphtheroids; others develop extensive substrate or aerial filaments (or both); and either may produce spores or fragment into coccobacillary forms. Most are saprophytes that live in soil, but members of this group of bacteria are responsible for three human infections: actinomycosis, nocardiosis, and actinomycetoma.

ACTINOMYCOSIS
Actinomycosis is a chronic suppurative and granulomatous infection that produces pyogenic lesions with interconnecting sinus tracts that contain granules composed of microcolonies of the bacteria embedded in tissue elements. The etiologic agents are several closely related members of the normal flora of the mouth and gastrointestinal tract. Most cases are due to Actinomyces israelii, Actinomyces naeslundii , and related anaerobic or facultative bacteria. Based on the site of involvement, the three common forms are cervicofacial, thoracic, and abdominal actinomycosis. Regardless of site, infection is initiated by trauma that introduces these endogenous bacteria into the mucosa. Often, in addition to the primary agent of actinomycosis, there are concomitant bacteria present. Some of these are relatively fastidious gram-negative bacilli such as Actinobacillus actinomycetemcomitans,

Haemophilus aphrophilus, Eikenella corrodens , and capnocytophaga species. Occasionally,

staphylococci, streptococci, or enteric gram-negative bacilli are found.

Morphology & Identification

Most strains of A israelii and the other agents of actinomycosis are facultative anaerobes that grow best in an atmosphere with increased carbon dioxide. On enriched medium, such as brain-heart infusion agar, young colonies (2448 hours) produce gram-positive substrate filaments that fragment into short chains, diphtheroids, and coccobacilli. After a week, these spider colonies develop into white, heaped-up molar tooth colonies. In thioglycolate broth, A israelii grows below the surface in compact colonies. Species are identified based on cell wall chemotype and biochemical reactions. The sulfur granules found in tissue are yellowish in appearance, up to 1 mm in size, and are composed of macrophages, other tissue cells, fibrin, and the bacteria. Eosinophilic club-shaped enlargements of the bacterial cells often project from the periphery of the granule.

Pathogenesis & Pathology

Regardless of the body site, the natural history is similar. The bacteria bridge the mucosal or epithelial surface of the mouth, respiratory tract, or lower gastrointestinal tractassociated with dental caries, gingivitis, surgical complication, or trauma. Aspiration may lead to pulmonary infection. The organisms grow in an anaerobic niche, induce a mixed inflammatory response, and spread with the formation of sinuses, which contain the granules and may drain to the surface. The infection causes swelling and may spread to neighboring organs, including the bones. There is often superinfection with other endogenous bacteria.

Clinical Findings
Cervicofacial disease presents as a swollen, erythematous process in the jaw area. With progression, the mass becomes fluctuant, producing draining fistulas. The disease will extend to contiguous tissue, bone, and lymph nodes of the head and neck. The symptoms of thoracic actinomycosis resemble those of a subacute pulmonary infection: mild fever, cough, and purulent sputum. Eventually, lung tissue is destroyed, sinus tracts may erupt to the chest wall, and invasion of the ribs may occur. Abdominal actinomycosis often follows a ruptured appendix or an ulcer. In the peritoneal cavity, the pathology is the same, but any of several organs may be involved, including the kidneys, vertebrae, and liver. Genital actinomycosis is a rare occurrence in women that results from colonization of an intrauterine device with subsequent invasion.

Diagnostic Laboratory Tests

Pus from draining sinuses, sputum, or specimens of tissue are examined for the presence of sulfur granules. The granules are hard, lobulated, and composed of tissue and bacterial filaments, which are club-shaped at the periphery. Specimens are cultured in thioglycolate broth and on brain-heart infusion blood agar plates, which are incubated anaerobically or under elevated carbon dioxide conditions. Growth is examined for typical morphology and biochemical reactions. The main agents of actinomycosis are catalase-negative, whereas most other actinomycetes are catalase-positive. Surface lesions may also contain other bacterial species.

Treatment
Prolonged administration (612 months) of a penicillin is effective in many cases. Clindamycin or erythromycin is effective in penicillin-allergic patients. However, drugs may penetrate the abscesses poorly, and some of the tissue destruction may be irreversible. Surgical excision and drainage may also be required.

Epidemiology
Because A israelii and the related agents of actinomycosis are endogenous members of the bacterial flora, they cannot be eliminated. Some individuals with recurrent infections are given prophylactic penicillin, especially prior to dental procedures.

NOCARDIOSIS
Nocardiosis is caused by infection with Nocardia asteroides complex or, less frequently, Nocardia

brasiliensis or Nocardia otitidiscaviarum , and only rarely by other species of nocardia. The Nocardia asteroides complex includes Nocardia abscessus, Nocardia farcinia, Nocardia nova, and others. The
importance of the complex is that its members tend to have variable antimicrobial susceptibility, which can influence treatment. The pathogenic nocardiae, like many nonpathogenic species of nocardia, are found worldwide in soil and water. Nocardiosis is initiated by inhalation of these bacteria. The usual presentation is as a subacute to chronic pulmonary infection that may disseminate to other organs, usually the brain or skin. Nocardiae are not transmitted from person to person.

Morphology & Identification

Nocardia species are aerobic and grow on a variety of media. Over the course of several days to a week or more, they develop heaped, irregular, waxy colonies. Strains vary in their pigmentation from white to orange to red. These bacteria are gram-positive, catalase-positive, and partially acid-fast bacilli. They produce urease and can digest paraffin. Nocardiae form extensive branching substrates and aerial filaments that fragment after formation, breaking into coccobacillary cells. The cell walls contain mycolic acids. They are considered to be weakly acid-fast, but if they are stained with the routine acid-fast reagent (carbol-fuchsin) but decolorized with 14% sulfuric acid instead of the stronger acid-alcohol decolorant, most isolates will stain acid-fast. The species of nocardia are identified by routine physiologic tests.

Pathogenesis & Clinical Findings

In most cases, nocardiosis is an opportunistic infection associated with several risk factors, most of which impair the cell-mediated immune responses: cortico steroidtreatment, immunosuppression, organ transplantation, AIDS, tuberculosis, and alcoholism. Nocardiosis begins as chronic lobar pneumonia, and a variety of symptoms may occur, including fever, weight loss, and chest pain. The clinical manifestations are not distinctive and mimic tuberculosis and other infections. Pulmonary consolidations may develop, but granuloma formation and caseation are rare. The usual pathologic process is abscess formation. Spread from the lung often involves the central nervous system, where abscesses develop in the brain, leading to a variety of clinical presentations. Some patients have subclinical lung involvement and present with brain lesions. Dissemination may also occur to the skin, kidney, or elsewhere.

Diagnostic Laboratory Tests

Specimens consist of sputum, pus, spinal fluid, and biopsy material. Gram-stained smears reveal grampositive bacilli, coccobacillary cells, and branching filaments. With the modified acid-fast stain, most isolates will be acid-fast. Nocardia species grow on most laboratory media. Serologic tests are unreliable at present.

Treatment
The treatment of choice is trimethoprim-sulfamethoxazole. If patients fail to respond, a number of other antibiotics have been used with success, such as amikacin, imipenem, and cefotaxime. Surgical drainage or resection may be required.

ACTINOMYCETOMA
Mycetoma (Madura foot) is a localized, slowly progressive, chronic infection that begins in subcutaneous tissue and spreads to adjacent tissues. It is destructive and often painless. In many cases the cause is a soil fungus that has been implanted into the subcutaneous tissue by minor trauma. An actinomycetoma is a mycetoma caused by filamentous branching bacteria. The actinomycetoma granule is composed of tissue elements and gram-positive bacilli and bacillary chains or filaments (1 m in diameter). The most common causes of actinomycetoma are Nocardia brasiliensis, Streptomyces somaliensis, and

Actinomadura madurae. N brasiliensis may be acid-fast. These and other pathogenic actinomycetes
are differentiated by biochemical tests and chromatographic analysis of cell wall components. Actinomycetomas respond well to various combinations of streptomycin, trimethoprim-sulfamethoxazole, and dapsone if therapy is begun early before extensive damage has occurred.