Nocardia species are saprophytic aerobic actinomycetes and are common worldwide in soil, where they contribute to the decay of organic matter. More than 50 species have been identified, mostly on the basis of 16S rRNA gene sequences. More than 30 species have been associated with human disease. Until recently, isolates from the majority of cases of pneumonia and systemic disease were identified as Nocardia asteroides, but human disease involving N. asteroides proper is actually rare. Nocardiae are relatively inactive in standard biochemical tests, and speciation is difficult or impossible without molecular phylogenetic techniques. Most clinical laboratories cannot speciate isolates accurately and may identify them simply as N. asteroides or Nocardia species.
Nine species or species complexes are most commonly associated with human disease (Table 162-1). Most systemic disease involves N. cyriacigeorgica, N. farcinica, N. pseudobrasiliensis, and species in the N. transvalensis and N. nova complexes. N. brasiliensis is usually associated with disease limited to the skin. Actinomycetoma—an indolent, slowly progressive disease of skin and underlying tissues with nodular swellings and draining sinuses—is often associated with N. brasiliensis, N. otitidiscaviarum, N. transvalensis complex strains, or other actinomycetes.
Nocardiosis occurs worldwide. The annual incidence has been estimated on three continents (North America, Europe, and Australia) and is ∼0.375 cases per 100,000 persons. The disease is more common among adults than among children and among males than among females. Nearly all cases are sporadic, but outbreaks have been associated with contamination of the hospital environment, solutions, or drug injection equipment. Person-to-person spread is not well documented. There is no known seasonality.
More than 90% of cases of pulmonary or disseminated disease occur in people with a host defense defect. Most have deficient cell-mediated immunity, especially that associated with lymphoma, transplantation, glucocorticoid therapy, or AIDS. The incidence is ∼140-fold greater among patients with AIDS and ∼340-fold greater among bone marrow transplant recipients than in general populations. In AIDS, nocardiosis usually affects persons with <250 CD4+ T lymphocytes/μL. Nocardiosis has also been associated with pulmonary alveolar proteinosis, tuberculosis and other mycobacterial diseases, chronic granulomatous disease, interleukin 12 deficiency, and treatment with monoclonal antibodies to tumor necrosis factor. Any child with nocardiosis and no known cause of immunosuppression should undergo tests to determine the adequacy of the phagocytic respiratory burst.
Cases of actinomycetoma occur mainly in tropical and subtropical regions, especially those of Mexico, Central and South America, Africa, and India. The most important risk factor is frequent contact with soil or vegetable matter, especially in laborers.
Pathology and Pathogenesis
Pneumonia and disseminated disease are both thought to follow inhalation of fragmented bacterial mycelia. The characteristic histologic feature of nocardiosis is an abscess with extensive neutrophil infiltration and prominent necrosis. Granulation tissue usually surrounds the lesions, but extensive fibrosis or encapsulation is uncommon.
Actinomycetoma is characterized by suppurative inflammation with sinus tract formation. Granules—microcolonies composed of dense masses of bacterial filaments extending radially from a central core—are occasionally observed in histologic preparations. They are frequently found in discharges from lesions of actinomycetoma but almost never in discharges from lesions in other forms of nocardiosis. Infrequently, nocardiae and other indolent pathogens, including fungi or mycobacteria, are isolated from the same patient.
Nocardiae have evolved a number of properties that enable them to survive within phagocytes, including neutralization of oxidants, prevention of phagosome-lysosome fusion, and prevention of phagosome acidification. Neutrophils phagocytose the organisms and limit their growth but do not kill them efficiently. Cell-mediated immunity is important for definitive control and elimination of nocardiae.
Respiratory Tract Disease
Pneumonia, the most common form of nocardial disease in the respiratory tract, is typically subacute; symptoms have usually been present for days or weeks at presentation. The onset is occasionally more acute in immunosuppressed patients. Cough is prominent and produces small amounts of thick, purulent sputum that is not malodorous. Fever, anorexia, weight loss, and malaise are common; dyspnea, pleuritic pain, and hemoptysis are less common. Remissions and exacerbations over several weeks are frequent. Roentgenographic patterns vary, but some are highly suggestive of nocardial pneumonia. Infiltrates vary in size and are typically dense. Single or multiple nodules are common (Figs. 162-1 and 162-2), sometimes suggesting tumors or metastases. Infiltrates and nodules tend to cavitate (Fig. 162-2). Empyema is present in one-quarter of cases.
Nocardial pneumonia. A dense infiltrate with a possible cavity and several nodules are apparent in the right lung.
Nocardial pneumonia. A CT scan shows bilateral nodules, with cavitation in the nodule in the left lung.
Nocardiosis may spread directly from the lungs to adjacent tissues. Pericarditis, mediastinitis, and the superior vena cava syndrome have all been reported. Nocardial laryngitis, tracheitis, bronchitis, and sinusitis are much less common than pneumonia. In the major airways, disease often presents as a nodular or granulomatous mass. Nocardiae are sometimes isolated from respiratory secretions of persons without apparent nocardial disease, usually individuals who have underlying lung or airway abnormalities.
In half of all cases of pulmonary nocardiosis, disease appears outside the lungs. In one-fifth of cases of disseminated disease, lung disease is not apparent. The most common site of dissemination is the brain. Other common sites include the skin and supporting structures, kidneys, bone, and muscle, but almost any organ can be involved. Peritonitis has been reported in patients undergoing peritoneal dialysis. Nocardiae have been recovered from blood in a few cases of pneumonia, disseminated disease, or central venous catheter infection. Nocardial endocarditis occurs rarely and can affect either native or prosthetic valves.
The typical manifestation of extrapulmonary dissemination is a subacute abscess. A minority of abscesses outside the lungs or central nervous system (CNS) form fistulas and discharge small amounts of pus. In CNS infections, brain abscesses are usually supratentorial, are often multiloculated, and may be single or multiple (Fig. 162-3). Brain abscesses tend to burrow into the ventricles or extend out into the subarachnoid space. The symptoms and signs are somewhat more indolent than those of other types of bacterial brain abscess. Meningitis is uncommon and is usually due to spread from a nearby brain abscess. Nocardiae are not easily recovered from cerebrospinal fluid (CSF).
Nocardial abscesses in the right occipital lobe.
Disease Following Transcutaneous Inoculation
Disease that follows transcutaneous nocardial inoculation usually takes one of three forms: cellulitis, lymphocutaneous syndrome, or actinomycetoma.
Cellulitis generally begins 1–3 weeks after a recognized breach of the skin, often with soil contamination. Subacute cellulitis, with pain, swelling, erythema, and warmth, develops over days to weeks. The lesions are usually firm and not fluctuant. Disease may progress to involve underlying muscles, tendons, bones, or joints. Dissemination is rare. N. brasiliensis and species in the N. otitidiscaviarum complex are most common in cellulitis cases.
Lymphocutaneous disease usually begins as a pyodermatous nodule at the site of inoculation, with central ulceration and purulent or honey-colored drainage. Subcutaneous nodules often appear along lymphatics that drain the primary lesion. Most cases of nocardial lymphocutaneous syndrome are associated with N. brasiliensis. Similar disease occurs with other pathogens, most notably Sporothrix schenckii (sporotrichosis, Chap. 206).
Actinomycetoma (Fig. 162-4) usually begins with a nodular swelling, sometimes at a site of local trauma. Lesions typically develop on the feet or hands but may involve the posterior part of the neck, the upper back, the head, and other sites. The nodule eventually breaks down, and a fistula appears, typically followed by others. The fistulas tend to come and go, with new ones forming as old ones disappear. The discharge is serous or purulent, may be bloody, and often contains 0.1- to 2-mm white granules consisting of masses of mycelia. The lesions spread slowly along fascial planes to involve adjacent areas of skin, subcutaneous tissue, and bone. Over months or years, there may be extensive deformation of the affected part. Lesions involving soft tissues are only mildly painful; those affecting bones or joints are more so. Systemic symptoms are absent or minimal. Infection rarely disseminates from actinomycetoma, and lesions on the hands and feet usually cause only local disability. Lesions on the head, neck, and trunk can invade locally to involve deep organs, with consequent severe disability or death.
Common features of nocardial actinomycetoma include swelling, multiple sinus tracts, and involvement of the foot. (Image provided by Amor Khachemoune and Ronald O. Perelman, New York University School of Medicine.)
Nocardia species are uncommon causes of subacute keratitis, usually following eye trauma. Nocardial endophthalmitis can develop after eye surgery. In one series, nocardiae accounted for more than half of culture-proved cases of endophthalmitis after cataract surgery. Endophthalmitis can also occur during disseminated disease. Nocardial infection of lachrymal glands has been reported.
The first step in diagnosis is examination of sputum or pus for crooked, branching, beaded, gram-positive filaments 1 μm wide and up to 50 μm long (Fig. 162-5). Most nocardiae are acid-fast in direct smears if a weak acid is used for decolorization (e.g., in the modified Kinyoun, Ziehl-Neelsen, and Fite-Faraco methods). The organisms often take up silver stains. Recovery from specimens containing a mixed flora can be improved with selective media (colistin–nalidixic acid agar, modified Thayer-Martin agar, or buffered charcoal–yeast extract agar). Nocardiae grow well on most fungal and mycobacterial media, but procedures used for decontamination of specimens for mycobacterial culture can kill nocardiae and thus should not be used when these organisms are suspected. Nocardiae grow relatively slowly; colonies may take up to 2 weeks to appear and may not develop their characteristic appearance—white, yellow, or orange, with aerial mycelia and delicate, dichotomously branched substrate mycelia—for up to 4 weeks. Several blood culture systems support nocardial growth, although nocardiae may not be detected for up to 2 weeks. The growth of nocardiae is so different from that of more common pathogens that the laboratory should be alerted when nocardiosis is suspected in order to maximize the likelihood of isolation.
Gram-stained sputum from a patient with nocardial pneumonia. (Image provided by Charles Cartwright and Susan Nelson, Hennepin County Medical Center, Minneapolis, MN.)
In nocardial pneumonia, sputum smears are often negative. Unless the diagnosis can be made in smear-negative cases by sampling lesions in more accessible sites, bronchoscopy or lung aspiration is usually necessary. To evaluate the possibility of dissemination in patients with nocardial pneumonia, a careful history should be obtained and a thorough physical examination performed. Suggestive symptoms or signs should be pursued with further diagnostic tests. CT or MRI of the head, with and without contrast material, should be undertaken if signs or symptoms suggest brain involvement. Some authorities recommend brain imaging in all cases of pulmonary or disseminated disease. When clinically indicated, CSF or urine should be concentrated and then cultured. Actinomycetoma, eumycetoma (cases involving fungi; Chap. 206), and botryomycosis (cases involving cocci or bacilli, often Staphylococcus aureus) are difficult to distinguish clinically but are readily distinguished with microbiologic testing. Granules should be sought in any discharge. Suspect particles should be washed in saline, examined microscopically, and cultured. Granules in actinomycetoma cases are usually white, pale yellow, pink, or red. Viewed microscopically, they consist of tight masses of fine filaments (0.5–1 mm wide) radiating outward from a central core. Granules from eumycetoma cases are white, yellow, brown, black, or green. Under the microscope, they appear as masses of broader filaments (2–5 mm wide) encased in a matrix. Granules of botryomycosis consist of loose masses of cocci or bacilli. Organisms can also be seen in wound discharge or histologic specimens. The most reliable way to differentiate among the various organisms associated with mycetoma is by culture.
Isolation of nocardiae from sputum or blood occasionally represents colonization, transient infection, or contamination. In typical cases of respiratory tract colonization, Gram-stained specimens are negative and cultures are only intermittently positive. A positive sputum culture in an immunosuppressed patient usually reflects disease. When nocardiae are isolated from sputum of an immunocompetent patient without apparent nocardial disease, the patient should be observed carefully without treatment. A patient with a host-defense defect that increases the risk of nocardiosis should usually receive antimicrobial treatment.
The Clinical Laboratory Standards Institute has approved a broth dilution antimicrobial susceptibility test protocol for use with human nocardial isolates. Procedures differ from those used with common human bacterial pathogens, and most clinical laboratories will not be sufficiently experienced with Nocardia to produce reliable results. Because nocardiosis is uncommon, data on the relation between susceptibility test results for specific drugs and clinical outcomes in patients treated with these drugs are meager. Empirical therapy with the drugs discussed below is recommended for newly diagnosed cases. When possible, and especially in severe cases or cases that do not improve promptly with empirical therapy, clinicians should arrange for susceptibility tests at a laboratory with experience in nocardial microbiology, such as the Mycobacteria/Nocardia Laboratory at the University of Texas Health Science Center (11937 US Highway 271, Tyler, TX 75708-3154; phone, 903-877-7685; fax, 903-877-7652).
Sulfonamides are the drugs of choice (Tables 162-1 and 162-2). The combination of sulfamethoxazole (SMX) and trimethoprim (TMP) is probably equivalent to a sulfonamide alone; some authorities believe that the combination may in fact be more effective, but it also poses a modestly greater risk of hematologic toxicity. At the outset, 10–20 mg of TMP per kg and 50–100 mg of SMX per kg are given each day in two divided doses. Later, daily doses can be decreased to as little as 5 mg/kg and 25 mg/kg, respectively. In persons with sulfonamide allergies, desensitization usually allows continuation of therapy with these effective and inexpensive drugs.
Table 162-2 Treatment Duration for Nocardiosis |Favorite Table|Download (.pdf)
Table 162-2 Treatment Duration for Nocardiosis
|Pulmonary or systemic|
|Intact host defenses||6–12 months|
|Deficient host defenses||12 monthsa|
|CNS disease||12 monthsb|
|Cellulitis, lymphocutaneous syndrome||2 months|
|Osteomyelitis, arthritis, laryngitis, sinusitis||4 months|
|Actinomycetoma||6–12 months after clinical cure|
Topical: until apparent cure
Systemic: until 2–4 months after apparent cure
Clinical experience with other oral drugs is limited. Minocycline (100–200 mg twice a day) is often effective; other tetracyclines are usually less effective. Linezolid is active against all species in vitro and has been effective in a few clinical cases, but adverse effects are common with long-term use. Tigecycline appears to be active in vitro against some species, but no relevant clinical experience has been reported. Amoxicillin (875 mg) combined with clavulanic acid (125 mg), given twice a day, has been effective in some cases but should be avoided in cases involving strains of the N. nova complex, in which clavulanate induces β-lactamase production. Among quinolones, ciprofloxacin has been studied most often, but moxifloxacin and gemifloxacin now appear to be more active.
Amikacin, the best-established parenteral drug except in cases involving the N. transvalensis complex, is given in doses of 5–7.5 mg/kg every 12 h or 15 mg/kg every 24 h. Serum drug levels should be monitored during prolonged therapy in patients with diminished renal function and in the elderly. Cefotaxime, ceftriaxone, and imipenem are usually effective except as indicated in Table 162-1.
Patients with severe disease are initially treated with a combination including TMP-SMX, amikacin, and ceftriaxone or imipenem. Clinical improvement is usually noticeable after 1–2 weeks of therapy but may take longer, especially with CNS disease. After definite clinical improvement, therapy can be continued with a single drug (usually one that can be taken by mouth) in most cases. Some experts use two or more drugs for the entire course of therapy in some cases, but whether multiple drugs are better than a single agent is not known, and additional drugs increase the risk of toxicity. In patients with nocardiosis who need immunosuppressive therapy for an underlying disease or prevention of transplant rejection, immunosuppressive therapy should be continued.
Use of SMX and TMP in high-risk populations to prevent Pneumocystis disease or urinary tract infections appears to reduce but not eliminate the risk of nocardiosis. The incidence of nocardiosis is low enough that prophylaxis solely to prevent this disease is not recommended.
Surgical management of nocardial disease is similar to that of other bacterial diseases. Brain abscesses should be aspirated, drained, or excised if the diagnosis is unclear, if an abscess is large and accessible, or if an abscess fails to respond to chemotherapy. Small or inaccessible brain abscesses should be treated medically; clinical improvement should be noticeable within 1–2 weeks. Brain imaging should be repeated to document the resolution of lesions, although abatement on images often lags behind clinical improvement.
Antimicrobial therapy usually suffices for nocardial actinomycetoma. In deep or extensive cases, drainage or excision of heavily involved tissue may facilitate healing, but structure and function should be preserved whenever possible. Keratitis is treated with topical sulfonamide or amikacin drops plus a sulfonamide or an alternative drug given by mouth.
Nocardial infections tend to relapse (particularly in patients with chronic granulomatous disease), and long courses of antimicrobial therapy are necessary (Table 162-2). If disease is unusually extensive or if the response to therapy is slow, the recommendations in Table 162-2 should be exceeded.
With appropriate treatment, the mortality rate for pulmonary or disseminated nocardiosis outside the CNS should be <5%. CNS disease carries a higher mortality rate. Patients should be followed carefully for at least 6 months after therapy has ended.