Chapter 28: Actinomyces and Nocardia

Actinomyces and Nocardia are gram-positive rods characterized by filamentous, tree-like branching growth, which has caused them to be confused with fungi in the past. They are opportunists that can sometimes produce indolent, slowly progressive diseases. A related genus, Streptomyces, is of medical importance as a producer of many antibiotics, but it rarely causes infections. Important differential features of these groups and of the mycobacteria to which they are related are shown in Table 28–1.

BACTERIOLOGY

Actinomyces are typically elongated gram-positive rods that branch at acute angles (Figure 28–1). They are gram-positive bacilli that grow slowly (4-10 days) under microaerophilic or strictly anaerobic conditions. In pus and tissues, the most characteristic form is the sulfur granule (Figure 28–2). This yellow-orange granule, named for its gross resemblance to a grain of sulfur, is a microcolony of intertwined branching Actinomyces filaments solidified with elements of tissue exudate.

Species of Actinomyces are distinguished on the basis of biochemical reactions, cultural features, and cell wall composition. Most human actinomycosis is caused by Actinomyces israelii, but other species (Actinomyces naeslundii, Actinomyces viscosus, Actinomyces odontolyticus, Actinomyces meyeri) have been isolated from typical actinomycotic lesions. Another group of Actinomyces species have been associated with dental and periodontal infections (see Chapter 41).

ACTINOMYCOSIS

Actinomyces are normal inhabitants of some areas of the gastrointestinal tract of humans and animals from the oropharynx to the lower bowel. These species are highly adapted to mucosal surfaces and do not produce disease unless they transgress the epithelial barrier under conditions that produce a sufficiently low oxygen tension for their multiplication (Figure 28–3). Such conditions usually involve mechanical disruption of the mucosa with necrosis of deeper, normally sterile tissues (eg, following tooth extraction). Once initiated, growth occurs in microcolonies in the tissues and extends without regard to anatomic boundaries. The lesion is composed of inflammatory sinuses, which ultimately discharge to the surface. As the lesion enlarges, it becomes firm and indurated. Sulfur granules are present within the pus, but are not numerous. Free Actinomyces or small branching units are rarely seen, although contaminating gram-negative rods are common. As with other anaerobic infections, most cases are polymicrobial involving other flora from the mucosal site of origin.

Human cases of actinomycosis provide little evidence of immunity to Actinomyces. Once established, infections typically become chronic and resolve only with the aid of antimicrobial therapy. Antibodies can be detected in the course of infection, but seem to reflect the antigenic stimulation of the ongoing infection rather than immunity. Infections with Actinomyces are endogenous, and case-to-case transmission does not appear to occur.

ACTINOMYCOSIS: CLINICAL ASPECTS

MANIFESTATIONS

Actinomycosis exists in several forms that differ according to the original site and circumstances of tissue invasion. Infection of the cervicofacial area, the most common site of actinomycosis (Figure 28–4), is usually related to poor dental hygiene, tooth extraction, or some other trauma to the mouth or jaw. Lesions in the submandibular region and the angle of the jaw give the face a swollen, indurated appearance.

Thoracic and abdominal actinomycosis are rare and follow aspiration or traumatic (including surgical) introduction of infected material leading to erosion through the pleura, chest, or abdominal wall. Diagnosis is usually delayed, because only vague or nonspecific symptoms are produced until a vital organ is eroded or obstructed. The firm, fibrous masses are often initially mistaken for a malignancy. Pelvic involvement as an extension from other sites also occurs occasionally. It is particularly difficult to distinguish from other inflammatory conditions or malignancies. A more localized chronic endometritis, due to Actinomyces, is associated with the use of intrauterine contraceptive devices.

DIAGNOSIS

A clinical diagnosis of actinomycosis is based on the nature of the lesion, the slowly progressive course, and a history of trauma or of a condition predisposing to mucosal invasion by Actinomyces. The etiologic diagnosis can be difficult to establish with certainty. Although the lesions may be extensive, the organisms in pus may be few and concentrated in sulfur granule microcolonies deep in the indurated tissue. The diagnosis is further complicated by heavy colonization of the moist draining sinuses with other bacteria, usually gram-negative rods. This contamination not only causes confusion regarding the etiology but interferes with isolation of the slow-growing anaerobic Actinomyces. Material for direct smear and culture should include as much pus as possible to increase the chance of collecting the diagnostic sulfur granules.

Sulfur granules crushed and stained show a dense, gram-positive center with individual branching rods at the periphery (Figure 28–2). Granules should also be selected for culture, because material randomly taken from a draining sinus usually grows only superficial contaminants. Culture media and techniques are the same as those used for other anaerobes. Incubation must be prolonged, because some strains require 7 days or more to appear. Identification requires a variety of biochemical tests to differentiate Actinomyces from Propionibacteria (anaerobic diphtheroids), which may show a tendency to form short branches.

Biopsies for culture and histopathology are useful, but it may be necessary to examine many sections and pieces of tissue before sulfur granule colonies of Actinomyces are found. The morphology of the sulfur granule in tissue is quite characteristic with routine hematoxylin and eosin (H&E) or histologic Gram staining. With the histologic H&E stain, the edge of the granule shows amorphous eosinophilic “clubs” formed from the tissue elements and containing the branching actinomycotic filaments.

TREATMENT

Penicillin G is the treatment of choice for actinomycosis, although a number of other antimicrobics (ampicillin, doxycycline, erythromycin, and clindamycin) are active in vitro and have shown clinical effectiveness. Metronidazole is not active. High doses of penicillin must be used and therapy prolonged for up to 6 weeks or longer before any response is seen. The initial treatment course is usually followed with an oral penicillin for 6 to 12 months. Although slow, response to therapy is often striking given the degree of fibrosis and deformity caused by the infection. Because detection of the causative organism is difficult, many patients are treated empirically as a therapeutic trial based on clinical findings alone.

BACTERIOLOGY

Nocardia species are gram-positive, rod-shaped bacteria related to mycobacteria and like them abundant mycolic acids are present in their cell wall. They show true branching both in culture and in stains from clinical lesions. The microscopic morphology is similar to that of Actinomyces, although Nocardia tend to fragment more readily and are found as shorter branched units throughout the lesion rather than concentrated in a few colonies or granules. Many strains of Nocardia take the Gram stain poorly, appearing “beaded” with alternating gram-positive and gram-negative sections of the same filament (Figure 28–5A and B). The species most common in human infection (Nocardia asteroides and Nocardia brasiliensis) are weakly acid-fast.

In contrast to Actinomyces, Nocardia species are strict aerobes. Growth typically appears on ordinary laboratory medium (blood agar) after 2 to 3 days incubation in air. Colonies initially have a dry, wrinkled, chalk-like appearance, are adherent to the agar, and eventually develop white to orange pigment. Speciation involves uncommon tests such as the decomposition of amino acids and casein.

NOCARDIOSIS

EPIDEMIOLOGY

Nocardia species are ubiquitous in the environment, particularly in soil. In fact, fully developed colonies of Nocardia give off the aroma of wet dirt. The organisms have been isolated in small numbers from the respiratory tract of healthy persons, but are not considered members of the microbiota. The pulmonary form of disease follows inhalation of aerosolized bacteria, and the cutaneous form follows injection by a thorn prick or similar accident (Figure 28–3). Most pulmonary cases occur in patients with compromised immune systems due to underlying disease or the use of immunosuppressive therapy. Transplant patients have been a prominent representative of the latter group. There is no case-to-case transmission.

PATHOGENESIS

Factors leading to disease after inhalation of Nocardia are poorly understood. Neutrophils are prominent in nocardial lesions, but appear to be relatively ineffective. The bacteria have the ability to resist the microbicidal actions of phagocytes and may be related to the disruption of phagosome acidification or resistance to the oxidative burst. No specific virulence factors are known. The primary lesions in the lung show acute inflammation, with suppuration and destruction of parenchyma. Multiple, confluent abscesses may occur. Unlike Actinomyces infections, there is little tendency toward fibrosis and localization. Dissemination to distant organs, particularly the brain, may occur. In the central nervous system (CNS), multifocal abscesses are often produced.

Skin infections follow direct inoculation of Nocardia. This mechanism is usually associated with some kind of outdoor activity and with relatively minor trauma. The species is usually N brasiliensis, which produces a superficial pustule at the site of inoculation. If Nocardia gain access to the subcutaneous tissues, lesions resembling actinomycosis may be produced, complete with draining sinuses and sulfur granules.

IMMUNITY

There is evidence that effective T-cell–mediated immunity is dominant in host defense against Nocardia infection. Increased resistance to experimental Nocardia infection in animals has been mediated by cytokine-activated macrophages, and activated macrophages have enhanced capacity to kill Nocardia that they have engulfed. Patients with impaired cell-mediated immune responses are at greatest risk for nocardiosis. There is little evidence for effective humoral immune responses.

NOCARDIOSIS: CLINICAL ASPECTS

MANIFESTATIONS

Pulmonary infection is usually a confluent bronchopneumonia that may be acute, chronic, or relapsing. Production of cavities and extension to the pleura are common. Symptoms are those of any bronchopneumonia, including cough, dyspnea, and fever. The clinical signs of brain abscess depend on its exact location and size; the neurologic picture can be particularly confusing when multiple lesions are present.

The combination of current or recent pneumonia and focal CNS signs is suggestive of Nocardia infection. The cutaneous syndrome typically involves a pustule, fever, and tender lymphadenitis in the regional lymph nodes.

DIAGNOSIS

The diagnosis of Nocardia infection is much easier than that of actinomycosis, because the organisms are present in greater numbers and distributed more evenly throughout the lesions. Filaments of gram-positive rods with primary and secondary branches can usually be found in sputum and are readily demonstrated in direct aspirates from skin or other purulent sites. Demonstration of acid-fastness, when combined with other observations, is diagnostic of Nocardia (Figure 28–5). The acid-fastness of Nocardia species is not as strong as that of mycobacteria. Like Mycobacterium leprae the staining method thus uses a decolorizing agent weaker than that used for the classic AFB stains. Culture of Nocardia is not difficult because the organisms grow on blood agar. It is still important to alert the laboratory to the possibility of nocardiosis, because the slow growth of Nocardia could cause it to be overgrown by the respiratory flora commonly found in sputum specimens. Due to competition from local microbiota the yield from respiratory specimens may be improved by the use of selective media developed for other pathogens. These include buffered charcoal yeast extract (BCYE, Legionella) and Thayer-Martin agar (Neisseria gonorrhoeae). Specific identification can take weeks due to the unconventional tests involved. Nucleic acid amplification methods have been developed but are not widely available.

TREATMENT

For decades Nocardia infection has been one of the few indications for systemic use of sulfonamides alone or combined with trimethoprim. Recent surveys indicate an increase in resistance to sulfonamides including the Trimethoprim–sulfamethoxazole combination. Technical difficulties in susceptibility testing have hampered the rational selection and study of other antimicrobials. Although most Nocardia strains are relatively resistant to penicillin, some of the newer β-lactams (imipenem, meropenem, cefotaxime) have been effective, as have minocycline, doxycycline, erythromycin, and amikacin. Antituberculous agents and antifungal agents such as amphotericin B have no activity against Nocardia.

Rhodococcus is a genus of aerobic actinomycetes with characteristics similar to those of Nocardia. Morphologically the rods vary from cocci to long, curved, clubbed forms. Some strains are acid-fast. Rhodococcus has recently been recognized as an opportunistic pathogen causing an aggressive pneumonia in severely immunocompromised patients, particularly those with AIDS. The organisms are found in the soil. One species, Rhodococcus equi, has an association with horses where it also causes pneumonia in foals. This species is a facultative intracellular pathogen of macrophages with features somewhat similar to those of Legionella and Listeria. Optimal treatment is unknown, although erythromycin, aminoglycosides, and some β-lactams show in vitro activity.