Objectives

1. Understand the epidemiologic characteristics of pulmonary nocardial infections.
2. Identify the microbiologic characteristics of Nocardia spp.
3. Identify the signs, symptoms, and radiologic features of Nocardia pulmonary infections.
4. Understand the appropriate diagnostic methods for Nocardia lung disease.
5. Appropriately use antimicrobial therapies for the treatment of Nocardia lung infections.

Key words

cavitary lung disease; Nocardia; pneumonia; pulmonary infections; skin infections

Nocardiosis is an invasive disease caused by members of the aerobic Actinomycete genus Nocardia, named after Edmond Nocard. Nocard described the isolation of an aerobic actinomycete in 1889 during a granulomatous disease outbreak in cattle. Two years later, Eppinger reported the first human case in a patient with pneumonia and a brain abscess.

Nocardia spp can cause pulmonary, skin, and soft tissue infections as well as disseminated disease.¹ Pulmonary nocardiosis, one of the most common manifestations, presents as an acute, subacute, or chronic condition following inhalation of mycelia fragments. Generalized spread throughout the body occurs subsequently in approximately one half of the cases. Nocardiosis includes other distinctive syndromes that follow inoculation through the skin or cornea, including cellulitis, lymphocutaneous syndrome (sporotrichoid), actinomycetoma (subcutaneous involvement), and keratitis.

Disseminated nocardial disease can occur in any organ but it is usually present in immunosuppressed patients with predominant involvement of both the meninges and brain tissue. An increasing number of Nocardia infections have been noted in the past 20 years as a result of the increasing numbers of immunocompromised hosts and improvement in laboratory identification techniques. This increase has also been associated with advances in organ transplantation and increases in HIV infections in the past two decades.

Epidemiology

Nocardia is found normally worldwide in soil and organic matter. According to physician surveys, there are approximately 500 to 1,000 cases a year in the United States (2 to 4 cases per 1 million people).² This incidence may represent an underestimation because Nocardia is not considered a reportable disease. The incidence has likely risen during the past two decades because of the concomitant increase in the population of immunosuppressed patients.

Nocardiosis is a disease that usually occurs in adults (90%), most of them men (2:1), with a pulmonary predilection (> 80% of the cases). Human-to-human or animal-to-human transmission has not been reported. Infection with Nocardia can occur in healthy individuals, but is more common in patients with the underlying conditions identified in Table 1.³ Since 1980, up to 10% of all Nocardia infections have occurred in patients with HIV infection or AIDS and in transplant recipients.^4,5 The incidence of Nocardia infections in transplant recipients has declined from 13% in 1976 to < 4% in two series reported in the 1990s, possibly as a result of the use of cyclosporine and aggressive prophylaxis for Pneumocystis carinii pneumonia.^2,6,7

Hospital-acquired outbreaks of invasive nocardiosis have occurred in patients with malignancies and also in transplant units, presumably arising from inhalation of contaminated dust or from hand transmission of contaminated fomites.¹ The use of new methodologies such as pulsed-gel electrophoresis and DNA fingerprinting have increased our knowledge of possible transmission and have helped to define the most likely sources of infection in different clusters or outbreaks. This technology has also added to the taxonomy of the Nocardia spp.⁸ Mycetomas are reported in both tropical and subtropical regions, especially in Central America, South America, and the southern parts of North America, Africa, and India. The microorganisms associated with mycetoma vary depending upon the geographical location. Mycetoma, colloquially known as “madura foot,” usually involves the lower extremities. The infection is acquired through inoculation from contaminated soil or plant products and is most often seen in the lower extremities, back, and neck.¹

Microbiology

Nocardia is a genus of the family Nocardiaceae, order Actinomycetales. Nocardia asteroides is the most common pathogen that can cause pulmonary disease, followed by Nocardia brasiliensis.¹ It is a Gram-positive, partially acid-fast, aerobic organism that causes suppurative and granulomatous lesions in humans. A subgroup of aerobic nocardioform actinomycetes that causes human disease includes Mycobacterium, Corynebacterium, Rhodococcus, Gordona, and Tsukamurella. Although Nocardia was originally identified as a fungus owing to the presence of mycelia with true branching formation, it is now classified as a bacterium. Sometimes confused with Mycobacteria, it can be differentiated by the lack of chitin or cellulose within Nocardia’s cell wall and other biochemical properties. The bacilli divide by binary fission and then form branching filaments. They may ultimately then break up into bacillary or coccoid forms.⁹ The diseases associated with various Nocardia spp are listed in Table 2. N asteroides usually causes visceral infections, and N brasiliensis is usually responsible for direct inoculations to the skin with lymphangitic spread. N asteroides is a species complex including N asteroides sensu strictu, Nocardia farcinica, and Nocardia nova. Other human pathogens include Nocardia pseudobrasiliensis, Nocardia otitidis-caviarum (formerly Nocardia caviae), and Nocardia transvalensis. N farcinica is a virulent species that causes disseminated infection. N pseudobrasiliensis is similar to N brasiliensis but is more frequently related to invasive disease. N transvalensis is generally associated with actinomycetoma in otherwise healthy persons and with invasive disease in immunocompromised persons.^1,9

Pathogenesis

Acute Nocardia infections produce an acute pyogenic inflammatory reaction, with large number of small abscesses. There is also a cellular infiltration of neutrophils with giant cells and foam cells present. Activated lymphocytes are involved in the cellular response to a Nocardia infection. Histopathologic evaluation has shown extensive granulation tissue surrounding the lesions, and there is rarely fibrosis or encapsulation. Nocardia may also form sulfur granules as normally described in actinomycosis, which correspond to microcolonies that rarely cause discharge from the lesions. Some special features that facilitate the long survival of Nocardia in tissues include neutralization of oxidants, prevention of phagosome-lysosome fusion, and prevention of phagosome acidification. Neutrophils phagocytose Nocardia and limit growth but do not actually kill the organisms.¹⁰

Clinical Manifestations

As stated earlier, Nocardia infections usually occur in patients with predisposing factors, such as underlying pulmonary disease or systemic immunosuppression. In healthy individuals, the infection is commonly confined to the lung parenchyma. Pulmonary manifestations are the predominant clinical presentation in almost half of patients presenting with nocardiosis. Exacerbations and remissions can occur frequently over several weeks.

Pulmonary nocardiosis can be acute, subacute, or chronic. Symptoms are usually present for weeks to months before the patient presents to a physician. The most common pulmonary symptoms are cough, purulent sputum production, hemoptysis, chest pain, weight loss, and night sweats.¹¹

In severely immunosuppressed patients, Nocardia infection can have a clinical presentation similar to that of acute bacterial pneumonia. In addition, an acute infection can present as an isolated lung abscess or necrotizing pneumonia that can cavitate. Enlarged irregular pulmonary nodules that cavitate can cause empyema or complicated parapneumonic pleural effusions. Lymph nodes can also become involved, resulting in lymph node enlargement. The slow progression of the disease is usually masked by short courses of antimicrobial therapy prescribed by physicians for a nonresolving pneumonia before recognition of the diagnosis. The indolent progression of nocardiosis mimics other chronic granulomatous infections such as tuberculosis, endemic mycosis, or pulmonary malignancies. Radiographic findings vary and may include alveolar, interstitial, or reticulonodular infiltrates. Other radiographic changes that may be seen are the presence of pulmonary nodules, single or multiple masses, cavitary lesions, miliary lesions, or classic “fungus ball” appearance.^12-15 Chronic infection can present as small abscesses or chronic fibronodular disease. Such lesions may be confined to a single portion of the lungs or involve multiple lobes, mimicking miliary tuberculosis.¹⁶ Contiguous involvement of other organs may cause tracheitis, bronchitis, mediastinitis, endocarditis, or pericarditis. Chest wall invasion and sinus tract formation are rare as compared with actinomycosis.¹⁷ Airway colonization without active disease is possible and has been reported in a few cases.⁹

Extrapulmonary infections can occur by inoculation through the skin or the eyes. Infection from transcutaneous inoculation usually takes one of four forms: cellulitis, lymphocutaneous syndrome (sporotrichoid), mycetoma, or keratitis. About 50% of the cases of pulmonary nocardiosis present outside of the lungs. Nocardia often disseminates hematogenously, especially to the CNS. It most commonly presents as one or more multiloculated brain abscesses. Clinical features include headache, nausea, vomiting, mental status changes, and focal neurologic signs. Tissue diagnosis of a cerebral mass in the presence of pulmonary nocardiosis is not always necessary, but should be considered in immunocompromised patients to rule out other serious pathogens with similar clinical presentations. Meningitis can be a complication of the CNS involvement.¹⁸ Dissemination to almost every organ has been reported, including the kidneys, spleen, liver, thyroid, adrenal glands, prostate, and rarely even bone. The differential diagnosis of pulmonary and extrapulmonary nocardiosis is extensive and is reviewed in Table 3.^9,19

Diagnosis

The best diagnostic method for the isolation of Nocardia is from blood, sputum, tissue, or some other types of body fluids. Nocardia spp are difficult to isolate, and require good sample collection from a fistula or an abscess. The microbiology laboratory should always be notified about clinical suspicions of Nocardia infections because the growth of Nocardia spp may take several days to weeks, even though the usual culture growth time is 3 to 5 days. Culture plates should be held for 4 to 6 weeks before one can be sure of a negative result.^20,21

On Gram stain, the organism has delicate, Gram-positive, irregularly staining, beaded, branching filaments that can fragment easily and can look like Gram-positive coccobacillus forms. The organisms are partially acid-fast and exhibit standard discoloration with 1% sulfuric acid (Kinyoun method). They must therefore be identified under oil immersion because of their extremely fine nocardial filaments (0.5 to 1.0 µm in diameter). Nocardia does not stain in hematoxylin-eosin or by the periodic acid-Schiff technique, and the organism will be missed unless special tissue stains are used. Expectorated sputum may or may not yield positive smears or cultures in established pulmonary infection. Various invasive procedures for obtaining specimens, including bronchoscopic biopsy, percutaneous lung aspiration, and open lung biopsy, may be necessary to make a definitive diagnosis. In culture, colonies have colors varying from white to pink to orange, and have a characteristic tarry odor. Species identification can be accomplished with a variety of biochemical tests and is always recommended. Biochemically, Nocardia spp reduce both urea and nitrate and are fermentative of carbohydrates. Different species can also be differentiated by their ability to decompose casein, tyrosine, xanthine, and hypoxanthine. Molecular biology techniques can aid in speciation and taxonomic classification, and eventually these techniques may become the identification methods of choice.^8,22,23

Serology and skin tests have previously been unreliable; more promising results have been described recently, but the techniques remain experimental.⁹ Susceptibility testing for Nocardia spp is a difficult area.²⁴ In vitro antimicrobial susceptibility testing for Nocardia spp has not shown a clear correlation with in vivo response, but it has been suggested as a useful tool for individual cases. The use of antimicrobial susceptibility testing is recommended in patients with clinical failure or patients who discontinue therapy because of intolerance. It can be also be used to guide therapy with more rapid bactericidal or combination agents in patients who have progressive infection, have highly resistant pathogens, or require high concentrations in the tissue during therapy (such as patients with CNS involvement).

Treatment

Medical therapy with specific antimicrobial agents is the recommended therapeutic option in patients with nocardiosis. The optimal duration for therapy is not clear, but most authors often recommend 6 to 12 months of treatment at a minimum.²⁵ Treating the underlying condition might also be helpful in certain patients with immunosuppression. Continuation of the immunosuppressive therapy should not be interrupted while appropriate specific anti-Nocardia therapy is administered. Several different therapeutic alternatives are available for patients with nocardiosis, but no randomized, controlled trials have yet defined the best approach. Most of the data available are extracted from case series and case reports showing variable success.

Sulfonamide remains the initial treatment and the mainstay of therapy for Nocardia infection.⁹ We have had clinical experience with sulfonamides that include trimethoprim-sulfamethoxazole, sulfisoxazole, and sulfadiazine. Patients usually respond well to sulfonamides, with rapid clinical improvement about 1 week after initiation of therapy and antibiotic levels revealing excellent tissue penetration. Sulfonamides inhibit N asteroides, a species that commonly infects immunosuppressed patients. These antibiotics are well tolerated, but high doses may be necessary. The occurrence of adverse effects or bacterial resistance may limit the use of the sulfonamides.²⁶

Wallace et al²⁷reported that 19% of 200 clinical isolates of Nocardia spp were resistant to both cefotaxime and cefamandole. This susceptibility pattern is very characteristic and distinguishes N farcinica from N asteroides. N farcinica shows a clear cephalosporin resistance in > 70% of the isolates, and for this reason susceptibility testing should be ordered to direct appropriate antimicrobial therapy selection.²⁷

Several other antibiotic treatments have been reported to be successful, but tetracycline derivatives (eg, minocycline), aminoglycosides, and carbapenems (imipenem-cilastatin, meropenem) have been the safest and most effective treatment alternatives. The use of alternative antibiotics is also effective in patients with underlying immunosuppression, including transplant recipients or patients with HIV/AIDS. We have limited experience with alternative agents such as amoxicillin-clavulanate, cycloserine, ampicillin, chloramphenicol, or a combination of ampicillin and erythromycin, which have shown to be possibly effective in treating patients with Nocardia infections in some reports (Tables 4 and 5). There is also limited experience with newer agents such as piperacillintazobactam and linezolid, but promising results have been reported in patients with nocardiosis.^28,29 In 1988, Wallace and coworkers^24,30 performed antimicrobial susceptibility testing for several agents used against N asteroides. They found varying susceptibility rates: for amikacin, 95%; imipenem, 88%; ceftriaxone, 82%; cefotaxime, 82%; sulfonamides, 100%; minocycline, 100%; and amoxicillin, 40%.^24,30 Vancomycin has not been shown to have in vivo or in vitro activity against Nocardia spp.

Because Nocardia infections are susceptible to relapses, long-term therapy is recommended. The optimal duration of therapy varies depending on several factors, such as immunosuppression, severity of illness, clinical course, antimicrobial susceptibility, medication tolerability, and location of the infection. In nonimmunosuppressed patients, the duration of therapy should be ≥ 6 months; a longer course of ≥ 1 year is required in those immunosuppressed patients who have disseminated disease or CNS involvement.

Surgical therapy is recommended in patients who have localized abscesses that require surgical drainage, and may be needed in patients with CNS involvement. Mamelak et al³¹ recommended medical treatment in patients with a brain abscess diameter < 2 cm. For patients who have brain abscesses > 2 cm in diameter or experience clinical deterioration despite medical therapy, stereotactic aspiration therapy can be used to confirm the diagnosis and may also be used to decompress the lesion.

Summary

Nocardiosis refers to the disease caused by a filamentous, aerobic, Gram-positive rod, with branching chains on microscopic evaluation, included in the aerobic actinomycete genus Nocardia. Nocardiosis is usually associated with pulmonary, skin, soft tissue, and disseminated disease in immunosuppressed patients. Pulmonary nocardiosis can present as an acute, subacute, or chronic condition with many different clinical presentations. Localized Nocardia disease includes other distinctive syndromes that follow inoculation of the organism through the skin or cornea, including cellulitis, lymphocutaneous syndrome (sporotrichoid), actinomycetoma (subcutaneous involvement), and keratitis. Disseminated nocardiosis can occur in any patient, but is usually present in immunosuppressed patients with predominant involvement of the meninges and brain tissue. The diagnosis of nocardiosis is made by microorganism identification using staining techniques or culture of tissue or body fluids. Biochemical identification is used to make the speciation possible, and antimicrobial susceptibility testing is recommended in order to guide therapy. Medical therapy with sulfonamides is the mainstay of management for Nocardia infections, although other antibiotics have also been reported to be effective. Nocardia infections should be suspected when pulmonary, skin, or disseminated disease occurs in immunosuppressed patients.

References

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