Phyllis C. Tien SM MD
David A. Relman MD
Actinomycetes are variably acid-fast, gram-positive bacilli that are sometimes filamentous and branched. Originally thought to be fungi due to their hyphae-like appearance, they are now recognized as bacteria based on their cell wall components, reproduction by fission without sporulation or budding, inhibition by antibacterial agents, and molecular phylogenetic analysis. The actinomycete chromosomes contain a high content of guanosine and cytosine. The actinomycetes include the genera Mycobacterium and Corynebacterium, which are discussed in Chapter 61 and Chapter 62, respectively. The actinomycetes also include the genera Nocardia, Actinomyces, Rhodococcus, Tsukumurella, Gordona, Actinomadura, and Streptomyces, as well as the Whipple's disease bacillus Tropheryma whippelii. Of these, members of the genus Nocardia are the most significant from a clinical standpoint, followed by organisms from the genus Actinomyces. The other actinomycetes discussed in this chapter are less common causes of disease in humans.
Essentials of Diagnosis
Nocardiosis is chiefly an opportunistic infection and occurs especially in patients with lymphoma and leukemia and to a lesser extent in patients with solid tumors. It is becoming more frequently recognized in patients with AIDS (~ 10% of all nocardial infections since 1980), those receiving organ transplants (especially renal and heart), and those receiving therapy with cytotoxic agents. Underlying pulmonary conditions, such as chronic obstructive pulmonary disease and bronchiectasis, also predispose individuals to pulmonary nocardiosis. Children with chronic granulomatous disease are at elevated risk of developing this infection. One-third of patients with nocardiosis, however, have no apparent predisposing factor. The disease affects men approximately threefold as often as it affects women and most often affects men and women between the ages of 30 and 50 years.
Approximately 90% of nocardial infections in the United States are due to Nocardia asteroides (and the related species Nocardia farcinica and Nocardia nova, which together form the N asteroides complex). Other pathogenic species implicated in disease include Nocardia brasiliensis, Nocardia otitidiscaviarum, and Nocardia transvalensis. While infection with N asteroides is geographically widespread, most cases of N brasiliensis infection in the United States have originated in the southern regions of the United States, especially Texas, southern California, Oklahoma, and Florida. Cases have also been reported from North Carolina.
Neutrophils predominate in the early lesions, inhibiting nocardial cell growth, but not killing the organism. N asteroides has the ability to resist intracellular killing by inhibiting phagosome-lysosome fusion, decreasing lysosomal enzyme activity in macrophages, and neutralizing phagosomal acidification. It also resists the oxidative killing mechanism of phagocytes by producing a unique surface-associated and secreted superoxide dismutase.
As a result of this evasive bactericidal response, cell-mediated responses are required for eventual control of this disease. The host mounts a lymphocyte response and releases antibodies and/or lymphocyte signals enabling activated macrophages to kill Nocardia spp. When there is an inadequate cell-mediated immune response, a more indolent infection may ensue, because neutrophils alone are not sufficient to resolve infection.
Clinical Findings (See Box 63-1.)
Pulmonary nocardiosis comprises a constellation of protean and nonspecific findings. Symptoms and signs include fever, night sweats, anorexia, weight loss, productive cough with hemoptysis, and pleural pain. Initial pulmonary parenchymal disease may spread to adjacent lung tissue, progress to form one or more pulmonary abscesses, and spread to pleural surfaces or to distant sites, such as the skin and the brain. Nocardiosis must be suspected when soft-tissue and/or CNS disease develops in conjunction with chronic or subacute pulmonary disease.
Radiographic findings are also variable but most frequently include localized infiltrates, irregular nodules, pleural effusions, and hilar adenopathy. Less common findings include masses, miliary lesions, diffuse alveolar and interstitial infiltrates, and calcified granulomatous lesions suggestive of fungal infection or tuberculosis.
Other respiratory tract manifestations include tracheitis, bronchitis, and pleuropulmonary fistula. Mediastinitis with superior vena cava syndrome and sinusitis have also been reported.
Lesions can be found in any anatomic site of the CNS and are often loculated with satellite extensions. CNS nocardiosis is associated with high morbidity and mortality if prompt antimicrobial therapy is not initiated. In compromised hosts, infection is more rapidly progressive and associated with increased mortality.
Localized cutaneous nocardiosis presents as pustules, abscesses, or cellulitis, all of which are usually self-limited. These lesions mimic those of cutaneous Streptococcus or Staphylococcus infection. Nocardia infections tend to be more indolent, however. Frequently, infection spreads to regional lymph nodes, which then suppurate. The resulting lymphocutaneous syndrome is referred to as the sporotrichoid form of cutaneous nocardiosis because it is difficult to distinguish from infection with the fungus Sporothrix schenckii. Thus, an appropriate laboratory diagnostic workup is required for a definitive diagnosis.
Mycetoma is a separate, distinct manifestation of cutaneous and subcutaneous nocardial infection. Other organisms can cause mycetomas, but Nocardiaspecies appear to be the most common cause in the United States. Mycetoma is a chronic, localized, slowly progressive subcutaneous infection that can eventually invade the fascia, muscle, and bone if left untreated. It usually starts as a painless nodule after traumatic inoculation. It may become purulent and necrotic, and suppurate with formation of draining sinus tracts containing granules. Granules are conglomerations of the causal organism whose size, color, and degree of hardness vary by microbial species. Mycetoma is the only clinical form of nocardiosis regularly associated with the presence of such granules. The granules tend to be white, unlike the granules of Actinomyces spp., which are yellow and hence named “sulfur granules.”
Mycetomas can be caused by a number of actinomycetes, in which case they are properly termed actinomycetomas as a group, or they can be caused by fungi, in which case they are referred to as eumycetomas. Microorganisms known to cause actinomycetomas include N brasiliensis, Actinomadura madurae, Actinomadura pelletieri, Streptomyces somaliensis, and, less commonly, N asteroides, N otitidiscaviarum, Nocardiopsis dassonvillei, and N transvalensis. In North America, South America, Mexico, and Australia, N brasiliensis is the chief cause of actinomycetomas, whereas in Africa, it is S somaliensis. Mycetomas tend to be well-delineated infections. Actinomycetomas most often affect persons who live in warm, rural environments. The most common site of infection is the foot, but infections in the leg, arm, hand, face, and neck are also seen.
BOX 63-1 Nocardiosis in Adults and Children
A Gram stain that shows thin, delicate, variably gram-positive, irregularly stained or beaded branching filaments is suggestive of nocardiosis. The diagnosis must be confirmed by culture. Currently, there is no reliable serodiagnostic test.
This normally elusive organism can usually be detected in pus or abscess drainage from a fistula, which should be submitted in a sterile tube or syringe. Fibers from sterile cotton swabs can interfere with the interpretation of smears, so the use of swabs should be discouraged. Surgical tissues and biopsy material from lung, skin, or brain should be kept moist during transport. When examining sputum specimens, early-morning expectorated samples should be collected on 3 separate days. Single smears and cultures are positive in only one-third of cases, so multiple specimens are encouraged.
Nocardia spp. grow readily on most of the media used for bacterial, fungal, and mycobacterial growth. Their growth can be enhanced if they are incubated at between 32 and 35°C in the presence of 5–10% carbon dioxide. They are slow growing, so the laboratory should be alerted when Nocardia infection is suspected. Colonies from pure cultures form within 48–72 h, but, with complex specimens such as respiratory samples, other more rapidly growing bacteria can easily obscure small Nocardia colonies. To enhance recovery and inhibit bacterial and fungal overgrowth, a variety of selective media have been used including paraffin agar and buffered charcoal-yeast extract medium (originally designed to isolate Legionella species).
After recovery of a Nocardia isolate, biochemical tests to determine the ability of the isolate to decompose casein, xanthine, hypoxanthine, and tyrosine are performed to distinguish the different Nocardia species. Additional biochemical tests are often necessary for further speciation. Gas chromatography and high-performance liquid chromatography (HPLC) analyses of the mycolic acid composition of nocardiae provide a more rapid technique to distinguish the different species. However, the results must be interpreted cautiously, because the type of culture medium, incubation temperature, and other factors can alter mycolic acid composition. A more rapid and accurate approach to identify different species may be polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.
Clinically, pulmonary nocardiosis must be distinguished from other bacterial infections such as mycoplasma infections, actinomycosis, tuberculosis, and fungal infections and carcinomas.
Sulfonamides have been the mainstay of therapy for Nocardia infections since the first report of a cure in 1944. Prior to the 1940s, infections with Nocardiaspp. were almost always fatal. Today the combination of trimethoprim and sulfamethoxazole (TMP-SMX) is generally the drug of choice despite inadequate in vitro data regarding synergy with this drug combination (Box 63-2). Between 90 and 95% of pulmonary infections with susceptible strains of N asteroidesrespond favorably to treatment. Oral or intravenous TMP-SMX is recommended for adults with normal renal function. Sulfonamide levels should be followed initially to ensure that a serum level of between 100 and 150 mg/dL is achieved. Levels should be drawn 2 h after oral ingestion of the drug.
BOX 63-2 Treatment of Nocardiosis
Intolerance of sulfonamides, especially in AIDS patients and in transplant patients, is reported frequently. Rash is a common adverse effect in these patients. TMP-SMX may enhance the nephrotoxicity of cyclosporin A in transplant recipients. Treatment failure has been reported in individuals with CNS infection and/or in immunocompromised individuals. Issues of patient compliance, microbial susceptibility, sequestered pus, and superinfection may have contributed to the poor outcome in these patients.
Other antimicrobial agents have shown in vitro activity against Nocardia spp. There are three oral agents other than sulfonamides which are useful in treating nocardiosis. Minocycline is the only tetracycline with excellent in vitro activity against the majority of pathogenic strains. Amoxicillin-clavulanate is effective, but certain species such as N nova, N otitidiscaviarum, and N transvalensis are resistant to this antibiotic. The fluoroquinolones such as ciprofloxacin and ofloxacin are less consistent in their activity against Nocardia spp., but penetrate most tissues well. Susceptibility studies should guide the choice of therapy.
Useful parenteral agents include imipenem, amikacin, and the third-generation cephalosporins. These drugs can be used alone or in combination with sulfonamides. Although good clinical responses have been achieved with imipenem, drug-induced seizures may deter use in individuals with brain abscesses. Amikacin has variable penetration of the CNS, but has been successfully used to treat CNS infection when the minimum inhibitory concentration (MIC) of the isolate was < 0.12 µg/mL. Third-generation cephalosporins have excellent CNS penetration and low toxicity.
The optimal duration of therapy and the indications for combination therapy remain uncertain, but long-term therapy is the rule, because relapse is common. In the nonimmunosuppressed individual, therapy for pulmonary and systemic nocardiosis should be continued for a minimum of 6–12 months. Complete resolution of primary cutaneous nocardiosis without bone involvement can be achieved with 2–4 months of therapy.
Immunosuppressed patients, regardless of their presentation, should receive a minimum of 12 months of therapy. Parenteral therapy may be necessary for only 3–6 weeks, depending on patient response. The use of immunosuppressive agents should be minimized, especially early in treatment of nocardiosis. Because high failure rates occur in patients with CNS disease and patients who are immunosuppressed, combination parenteral therapy with TMP-SMX and amikacin, imipenem, or a third-generation cephalosporin might be considered. Once a clinical response is achieved, the patient can be switched to single-agent therapy. Individuals with HIV coinfection should probably receive continuous suppressive therapy.
Prevention & Control
Because Nocardia spp. are ubiquitous and nocardiosis is sporadic and dependent on host factors, there are no effective prevention and control measures.
Essentials of Diagnosis
See earlier introductory comments.
Actinomyces infections are usually polymicrobial. Multiple other organisms, including Actinobacillus, Eikenella, Fusobacterium, Bacteroides, and Capnocytophaga spp., members of the Enterobacteriaceae, staphylococci, and streptococci, are usually present in various combinations. These organisms may exert a synergistic effect on the disease process by secreting collagenase and hyaluronidase and thus facilitating extension of the lesion. Actinomyces virulence factors are not well understood. Actinomyces fimbriae may play an important role in bacterial self- or coaggregation with other oral bacterial species.
Clinical Findings (See Box 63-3.)
There are three major clinical presentations and types of disease: cervicofacial (~ 50% of all cases), abdominal (~ 20%), and thoracic (~ 15%).
BOX 63-3 Actinomycosis in Adults and Children
“Sulfur granules” are hard, irregularly shaped yellow particles that range in size from 0.1 to 5 mm. Microscopically, they appear as masses of bacterial filaments that may be arranged in ray-like projections. Their presence is typical, but not unique to this disease. Other organisms such as Nocardia spp., Streptomyces spp., and staphylococci in botryomycosis may form similar granules. A definitive diagnosis is made by growing the organism from an appropriate specimen in anaerobic culture media.
Timely procurement of specimens before initiation of antimicrobial therapy and submission to the laboratory using anaerobic transport kits optimize recovery of the organism by culture. Tissue, pus, or sulfur granules are the specimens of choice, and swabs should be avoided because the cotton filaments may be confused on microscopy with the organism. Multiple specimens should be obtained because organisms may be scarce in pathology specimens.
Growth usually appears within 5–7 days but can take as long as 2–4 weeks, so the lab should be alerted if actinomycosis is suspected. Growth plate media containing 5% sheep blood or rabbit blood supplemented with hemin and vitamin K should be used. However, other types of media including anaerobic blood culture medium, enriched thioglycolate medium, and chopped meat-glucose medium will support the growth of these organisms. Plates should be incubated at 35 to 37°C in an anaerobic chamber. Often colonies are viewed first as “spiderlike” in appearance and mature to resemble a “molar tooth.” Biochemical tests are performed to distinguish the various species. There are no specific antibody or antigen detection tests.
Cervicofacial actinomycosis is often clinically misdiagnosed as a tumor, tuberculosis, or fungal infection. Actinomycosis often imitates a carcinoma, sarcoma, diverticular abscess, inflammatory bowel disease, or tuberculosis. Thoracic actinomycosis must be differentiated from other bacterial disease (tuberculosis and nocardiosis), systemic mycoses, and neoplastic disease.
Penicillin is the drug of choice for actinomycosis (Box 63-4). Prolonged therapy is necessary to achieve a cure and minimize relapse. Intravenous penicillin G for 2–6 weeks followed by oral penicillin for 6–12 months is a reasonable regimen. Treatment should extend beyond the resolution of measurable disease. Long-term therapy is necessary because of the amount of reactive fibrosis formed by infection. Relapse is common especially after a short course of empiric antibiotic therapy. For patients with penicillin allergies, tetracycline is the preferred agent. Minocycline erythromycin and clindamycin are also reasonable alternatives. In vitro susceptibility data suggest that oxacillin, dicloxacillin, cephalexin, metronidazole, and the aminoglycosides should be avoided.
BOX 63-4 Treatment of Actinomycosis
Prevention & Control
Currently, there are no recommended prevention and control measures. However, because of the association between intrauterine device (IUD) use and pelvic actinomycosis, women should consider alternative forms of contraception.
Species of the Rhodococcus genus have occasionally been implicated in human disease. Rhodococcus spp. differ from Nocardia spp. in that they do not produce aerial hyphae. Gordona and Tsukumurella, formerly classified in the Rhodococcus genus, are also rare causes of human disease. Rhodococcus equi, the species that is most commonly implicated in human disease, is found in soil and in the intestinal contents of grazing herbivore animals. Because most infections have been associated with immune system dysfunction, there has been an increase in reported cases of R equi infection since the onset of the HIV epidemic in the 1980s.
Pulmonary disease is the most common clinical manifestation of R equi infection, and occurs after inhalation of the organisms. Cutaneous infections, bacteremia, and catheter-associated sepsis have also been reported. Prolonged combination therapy with erythromycin or imipenem plus rifampin is currently the treatment of choice. Intestinal R equi disease may mimic Whipple's disease.
The disease that bears George Whipple's name affects primarily white, middle-aged males and causes arthralgias, abdominal pain, diarrhea, weight loss, fever, and lymphadenopathy. The causative agent, T whippelii, is an actinomycete that is difficult to cultivate in vitro. The gastrointestinal tract and its lymphatic drainage, the heart, and the CNS are the sites most commonly involved by this chronic, systemic disease. The diagnosis can be made by detection of numerous periodic acid-Schiff reagent (PAS)-positive macrophages within the intestinal lamina propria or by detection of the characteristic bacilli or their DNA within affected tissues or fluids, using electron microscopy or the polymerase chain reaction, respectively. Most patients respond to antibiotics; the recommended regimen consists of a combination of parenteral penicillin and streptomycin for 2 weeks, followed by ≥ 1 year of TMP-SMX. If untreated, the disease is fatal. Relapse within the CNS occurs in approximately one-third of patients, despite treatment.
The genus Streptomyces consists of a plethora of species of which most are considered saprophytes; they are found throughout the environment. Streptomyces spp. are primarily soil inhabitants. Three species, S somaliensis, Streptomyces paraguayensis, and Streptomyces anulatus, have been implicated in human disease, primarily in the formation of actinomycetomas. S somaliensis and S paraguayensis are rarely, if ever, found in the United States. They primarily inhabit Latin America, although S somaliensis is also known to cause disease in the arid regions of Africa and Arabia. S anulatus, on the other hand, has been associated with lung disease and sepsis, brain abscess, and panniculitis, as well as cervical lymphadenitis in an immunocompromised patient in the United States. Isolation of the streptomycetes should follow procedures used for the isolation of nocardiae. Colonies are usually glabrous or waxy and heaped. Definitive identification usually is extremely difficult. Streptomycin in combination with either dapsone or TMP-SMX has been suggested as treatment for infection with Streptomyces spp.
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