Nahed Abdel-Haq and Ashir Kumar
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
Nocardiosis is an uncommon gram-positive infection with protean clinical manifestations.1Nocardia asteroides is the most common species that causes human disease. Other species that are associated with human disease include N brasiliensis, N farcinica, N otitidiscaviarum, N nova, and N transvalensis.3Nocardia species can be skin contaminants and respiratory tract saprophytes. Nocardia species are ubiquitous in the environment and can be found in soil, water, and decaying organic material. Infections with Nocardia appear to be more prevalent in the southwestern United States. Possible explanations include the facilitation and dispersal of Nocardia by the dusty, dry, and windy conditions in these areas.5N brasiliensis is most frequently found in tropical and subtropical areas. In the United States, N brasiliensis is prevalent in the southeastern and southwestern states.6 Most systemic diseases in humans are caused by N asteroides. N farcinica has been reported to cause more severe disease and disseminated infections than other species.7 Human beings acquire pulmonary infections by inhaling contaminated dust particles from environmental sources, whereas traumatic inoculation through the skin is responsible for subcutaneous disease.5
The immune response to Nocardia is both humoral and cellular.3,10 The neutrophils inhibit the spread of infection; however, the cell-mediated immune response is vital in preventing dissemination.11Nocardiamay persist in neutrophils and macrophages by production of enzymes that inactivate the myeloperoxidase system.12 Nocardiosis produces suppurative necrosis and abscess formation typical of pyogenic infection. In contrast to the pronounced tissue fibrosis seen in actinomycosis, nocardiosis seldom provokes more than a loose wall of granulation tissue. This absence of encapsulation accounts for the tendency of this organism to disseminate from its initial pulmonary focus. Sulfur granules are not formed by this organism except in the skin in the lymphocutaneous or mycetoma syndromes.
Although typically considered as an opportunistic infection, Nocardia can cause various clinical syndromes in immunocompetent patients.13-15 The most characteristic features of Nocardia are its ability to disseminate to any organ and its tendency for relapse despite appropriate antibiotic treatment. Pulmonary infection is the most common manifestation of nocardial disease.16 It occurs mostly in immunocompromised patients. Hematogenous dissemination particularly involves the nervous system and soft tissues.
N asteroides is the etiologic agent most often isolated from pulmonary lesions.
There are no specific signs or symptoms that distinguish Nocardia from other infections.1 Symptoms of pulmonary nocardiosis may resemble other chronic lung infections, with a tendency for remissions and exacerbations. Fever, night sweats, malaise, productive cough, pleuritic pain, anorexia, and weight loss are frequent. Radiologic findings include single or multiple nodules. Cavitation is a common finding. Lesions may appear as a localized infiltrate, a solitary lung abscess, necrotizing pneumonia, or progressive nodular fibrosis.3,21 Empyema, which can form sinus tracts to the chest wall resembling actinomycosis, may be seen. Local extension of lung lesions may cause mediastinitis or pericarditis.22,23N asteroides is the etiologic agent most often isolated from pulmonary lesions. The differential diagnosis includes tuberculosis; actinomycosis; fungal infections, especially Aspergillus; Rhodococcus equi (in HIV-infected patients); and tumor. In high-risk patients, the diagnosis should be suspected when soft tissue swellings or abscesses and/or central nervous system (CNS) mass lesions develop in conjunction with a current or chronic pulmonary infection.
Hematogenous dissemination occurs in 30% of patients with pulmonary diseases. Metastatic subcutaneous abscesses are common with pulmonary disease, as are hepatic and renal lesions. Although extrapulmonary nocardiosis usually occurs with concomitant lung lesions, some patients may present solely with extrapulmonary disease. CNS involvement occurs in 20% of patients with Nocardia infections and 44% of patients with disseminated disease.3Affected patients most frequently present with discrete brain lesions or abscesses. Brain lesions may be single or multiple.26 Fever and leukocytosis may be absent in patients with nocardial CNS disease mimicking a noninfectious etiology such as malignancy.3 The clinical progression of CNS disease is rapid in patients with underlying immune disorders. Normal hosts, in contrast, develop a more insidious and indolent disease process.3 Because Nocardiacommonly causes metastatic brain lesions, especially in immunocompromised patients, brain imaging should be done in those who have had Nocardia isolated from other sites. Similarly, nocardiosis should always be suspected in any patient who presents with a brain lesion and has concurrent or recent lung findings.20
Primary cutaneous disease occurs mainly in immunocompetent hosts. Clinical manifestations include ulcerations, wound infection, pyoderma, superficial cellulitis, subcutaneous abscesses, and lymphocutaneous infections. Mycetoma or Madura foot is a localized and slowly progressive chronic infection of the skin that may extend to involve the subcutaneous tissues and bone, usually involving the foot. It is characterized by swelling and sinus tracts that drain purulent material that may occasionally contain sulfur granules. Evidence of systemic disease such as fever or malaise is lacking; local pain is rare. Most cases are due to N brasiliensis.35 Walking barefoot predisposes for this condition in endemic areas due to repeated trauma and inoculation of Nocardia from contaminated soil. Nocardial mycetoma occurs endemically in the tropics.
Nocardia bacteremia is mostly associated with central venous catheter–related infections. Other rare complications of Nocardia include ocular disease, peritonitis (during peritoneal dialysis), synovitis, osteomyelitis, peritonsillar abscess, ventriculitis associated with a ventriculoperitoneal shunt, and cervicofacial infection resembling actinomycosis.25,41
The diagnosis of pulmonary nocardiosis in some cases may be established by sputum analysis and culture. However, because Nocardia can be a respiratory saprophyte, bronchoalveolar lavage or lung biopsy may be needed to confirm the diagnosis.
An invasive procedure such as tissue biopsy is often required to establish the diagnosis of nocardiosis.24 The most important diagnostic finding is appearance of the organisms on the gram-stained smear of the clinical specimen. This will reveal weakly gram-positive, irregularly stained and beaded branching filaments surrounded by acute inflammatory cells.1 Many Nocardia species are acid-fast.2 The diagnosis is confirmed by culture. Cultures from sterile sites will grow in 2 to 14 days.1 In mixed cultures from respiratory secretions rapidly growing bacteria may obscure small Nocardia colonies, and colonial characteristics sufficient to arouse suspicion often take 2 to 4 weeks to develop.3 Susceptibility testing should be conducted on all isolates from immunocompromised patients, patients with life-threatening illness or CNS involvement, and patients who are intolerant or not responding to initial treatment.
An experimental assay that detects antibody to a 55-kd Nocardia antigen is sensitive and specific; serum titers of greater than 1:256 are seen in 91% of patients, but these tests may be inadequate for diagnosing nocardiosis in patients with immunodeficiency.46
Molecular tests such as polymerase chain reaction (PCR), DNA probes, and DNA sequencing provide more accurate and rapid identification of Nocardia species but tests are not routinely available in clinical laboratories.1,47,48
A sulfonamide-containing regimen such as trimethoprim-sulfamethoxazole or a sulfonamide alone are considered the drugs of choice.50,51 Sulfisoxazole (150 mg/kg every 4–6 hours) has been used. Trimethoprim-sulfamethoxazole (15 mg/kg trimethoprim and 75 mg/kg sulfamethoxazole) is the most frequently used sulfonamide for nocardiosis, especially when intravenous treatment is desired.51 Patients unable to tolerate sulfonamides may receive minocycline, ampicillin, or erythromycin. The use of drugs other than sulfonamides should be supported by in vitro susceptibility testing.
The value of and need for combination therapy is debatable. However, most clinicians now administer combination drug therapy at least initially.20,54 Situations that favor this approach include CNS nocardiosis, overwhelming or disseminated disease, and nocardiosis in immunocompromised or HIV-infected patients. An empirical regimen consisting of trimethoprim-sulfamethoxazole, amikacin, and either ceftriaxone or imipenem has been used in such situations.20 Treatment is continued with two agents to which the organism is susceptible. Initial treatment should be given intravenously for at least 6 weeks or until the patient improves clinically.20,53 Patients who respond to the initial treatment and who do not have CNS disease may be switched to an oral antibiotic such as trimethoprim-sulfamethoxazole, minocycline, or amoxicillinclavulanate. Because of the high mortality and the possibility of CNS disease, a 2- or 3-drug combination is usually required for the first 6 to 12 months. All patients with CNS involvement as well as immunocompromised patients regardless of the site of diseases should be treated for a total duration of at least 1 year.20
Cutaneous Nocardia infections following inoculation injury in immunocompetent patients may be treated with a single oral agent. Trimethoprim-sulfamethoxazole and minocycline are the most commonly used antibiotics. Alternatively, amoxicillin-clavulanate, doxycycline, macrolides, fluoroquinolones, and linezolid may be used if susceptible in vitro.55 Patients with lymphocutaneous disease usually respond to a 6- to 12-week course of treatment. However, patients with mycetoma usually require treatment for 6 to 12 months. Tetracyclines are not used in children 8 years and younger because of potential dental staining.
Patients who do not show clinical improvement within the first 2 weeks of treatment should be carefully reevaluated. Poor response or progression of the disease indicates treatment failure. This may be due to drug resistance, the presence of an abscess that requires drainage, or poor tissue penetration of the antibiotic.20
The mortality of nocardiosis is still high (25–40%) despite specific therapy.66 Factors associated with poor outcome include underlying corticosteroid use, Cushing disease, the presence of dissemination involving two or more noncontiguous organs, CNS involvement, and fulminant disease at initial evaluation.66