Chapter 276. Nocardiosis

Nocardiosis is an uncommon gram-positive infection with protean clinical manifestations. It is caused by a soilborne aerobic actinomycete of the family Nocardiaceae and is acquired mostly through the respiratory tract.1 Members of the family Nocardiaceae reproduce by fragmenting into bacillary and coccoid elements but are distinguished by filamentous growth with true branching.2 These organisms appear as gram-positive branching filaments and are weakly acid-fast.2Nocardia species grow readily on simple media as pigmented colonies due to rudimentary aerial mycelia.

Epidemiology and Pathophysiology

The genus Nocardia contains at least 50 species that were characterized by phenotypic and molecular methods.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. They are ubiquitous in the environment and can be found worldwide as saprophytes in soil, water, and decaying organic material, including vegetation and animal deposits.4 Some species may be more prevalent than others in certain geographic areas with specific climates. 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 There is no evidence for airborne, animal-to-person or person-to-person spread. Nosocomial outbreaks have been linked to environmental sources.8 Dust contaminating air systems in the operating rooms or the transplant units has been suggested as the source.9 About 15% of all patients with nocardiosis are children.

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.11Nocardia may 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.

Clinical Manifestations

Nocardia can cause both localized and disseminated infections in humans. 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 Disease

Pulmonary infection is the most common manifestation of nocardial disease (usually N asteroides) and occurs in 80% of affected patients.16 It occurs mostly in immunocompromised patients with frequent dissemination and death. Hematogenous dissemination particularly involves the nervous system and soft tissues. Pulmonary nocardiasis may occur in some patients with underlying chronic disease such as brochiectasis.17

N asteroides is the etiologic agent most often isolated from pulmonary lesions. Over one half of the patients with pulmonary disease due to Nocardia species are immunocompromised hosts. There is an increased risk of nocardiosis in patients with alveolar proteinosis and chronic granulomatous disease.18,19

Lung involvement may be acute, subacute or chronic. 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.20 Radiologic findings include single or multiple nodules that often look smooth and round. Cavitation of these lesions 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. 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.24

Most children with pulmonary nocardiosis are immunocompromised due to, for example, underlying chronic granulomatous disease, steroid therapy, acute leukemia, Hodgkin's disease, or transplantation. In immunocompromised patients the infection may be fulminant.25

Extrapulmonary Disease

Hematogenous dissemination occurs in 30% of patients with pulmonary diseases. Metastatic subcutaneous abscesses are common with pulmonary disease, as are hepatic and renal lesions. CNS involvement occurs in 20% of patients with Nocardia infections and 44% of patients with disseminated disease.3 Affected patients most frequently present with discrete brain lesions or abscesses. Brain lesions may be single or multiple.26 Less frequently, Nocardia meningitis occurs, often with concomitant parenchymal involvement.20 The cerebrospinal fluid typically shows neutrophilic pleocytosis, hypoglycorrhachia, and elevated protein.27 Patients with CNS involvement may develop signs of increased intracranial pressure such as headache, confusion, and altered mental status. Seizures are common in patients with brain abscess. 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 Nocardia commonly 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. N brasiliensis is responsible for the majority (80%) of these infections.28,29N otitidiscaviarum has been identified with increasing frequency as it causes mycetomas and the lymphocutaneous syndrome.30 Common sites of involvement include the face in children and the lower extremities in adults. Clinical manifestations include ulcerations, wound infection, pyoderma, superficial cellulitis, subcutaneous abscesses, and lymphocutaneous infections. Primary cutaneous infections should be distinguished from hematogenous dissemination.28

Superficial skin infections due to Nocardia often occur in immunocompetent individuals and follow local trauma and subsequent environmental, often soil, wound contamination. Gardening and farming are common predisposing factors in adults. Nocardial postoperative sternal wound infections have also been reported.31 Skin infections with Nocardia may also follow a cat scratch or a bite by a tick or insect.32,33

The clinical manifestations of nocardial skin infections may be indistinguishable from common bacterial infections such as Staphylococcus aureus and group A streptococcus. Cellulitis often presents subacutely with swelling, warmth, and erythema; local drainage is unusual. Rarely, the lesion may disseminate locally to involve the muscle, bone, or joint.1 Lymphocutaneous syndrome is a subcutaneous nodule or abscess with lymphangitis and regional lymphadenopathy. The primary lesion is characterized by ulceration and purulence (pyoderma). Lymphocutaneous infection, particularly by N brasiliensis, resembles sporotrichosis and may be associated with traumatic injury.34

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. 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

Bacteremia due to Nocardia has been reported mainly in cancer patients, including children with implanted vascular ports for chemotherapy.36 The clinical course of these central venous catheter infections is usually benign, and most patients respond to catheter removal and systemic antibiotic therapy.36

Ocular nocardiosis is uncommon. Infection may develop in healthy people following minor trauma to the eye or may follow eye surgery.37 Other risk factors include corneal lens implants and topical corticosteroids.38 It may also occur as part of disseminated disease in immunocompromised patients.37 Eye involvement includes keratitis, iritis, uveitis, choroiditis, retinal abscess, and retinal detachment.1Nocardia endophthalmitis may follow either hematogenous spread or cataract surgery or trauma and is associated with poor visual outcome.39,40

Nocardia peritonitis may occur in patients undergoing continuous ambulatory peritoneal dialysis without any other obvious risk factors. Nocardia synovitis is another uncommon infection that occurs as a complication of disseminated disease in immunocompromised patients. Other rare complications of Nocardia include peritonitis, synovitis, osteomyelitis, peritonsillar abscess, ventriculitis associated with a ventriculoperitoneal shunt, and cervicofacial infection resembling actinomycosis.25,41

Diagnosis

An invasive procedure such as tissue biopsy is often required to establish the diagnosis of nocardiosis.24 The most common samples that are submitted for diagnosis of nocardiosis are bronchial washings, bronchoalveolar lavage, and sputum, as well as samples from abscesses, tissues, and cerebrospinal fluid. The initial microscopic inspection should include detection of the presence or absence of granules. If present, the granules should be washed, crushed, and microscopically examined. Granules are most commonly seen in N brasiliensis infections. However, they may be present in other Nocardia species infections and in actinomycosis.1

If Nocardia is suspected in a clinical specimen, the laboratory needs to be notified to optimize recognition and recovery of the organism. 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 the typical delicate, weakly gram positive, irregularly stained and beaded branching filaments surrounded by acute inflammatory cells.1 Many Nocardia species are acid-fast.2 Retention of carbol-fuchsin in a modified acid-fast stain that decolorizes with 1% sulfuric acid instead of acid alcohol will differentiate Nocardia from Actinomyces. Nocardia is usually seen as partially acid-fast filamentous bacilli; both acid-fast and non–acid-fast organisms are present.1 Biopsy material should be stained by the Brown-Brenn (tissue Gram stain) and modified Fite (tissue acid-fast) stains. The diagnosis is confirmed by culture. Blood agar is a satisfactory isolation medium, but growth in liquid media produces a dry, waxy surface pellicle similar to mycobacteria and may aid in visualizing branching filaments.2 On slide culture, Nocardia shows hyphae branching at right angles and secondary branching. Nocardia species grow poorly on many inhibitory media used for fungal isolation and can be inhibited by many antibiotics. However, recovery of the pathogen can be increased by using selective media. 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. Nocardia speciation is done using a battery of biochemical tests.42 Because different Nocardia species vary in their antibiotic resistance patterns, it is essential to send these isolates to a reference laboratory for precise speciation and susceptibility testing.20

Routine serology is not available. A number of serologic assays have been evaluated in the diagnosis of nocardiosis. Early immunodiffusion assays lacked sensitivity and specificity.43,44 Subsequently, immunoblot and enzyme-linked immunosorbent assays that detect antibodies to specific high-molecular-weight proteins of Nocardia have been developed.45 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 However, these tests are not routinely available in clinical laboratories.

Nocardia species are ubiquitous in the environment and may contaminate cultures. Thus, the isolation of Nocardia in culture should always be correlated with the clinical setting, particularly in relation to the signs and symptoms and the presence of underlying immunodeficiency.1 Colonization, without disease, of the respiratory tract may occur in patients with bronchiectasis, such as those with cystic fibrosis.49

Treatment

A sulfonamide-containing regimen such as trimethoprim-sulfamethoxazole or a sulfonamide alone, are the most effective and best-studied drugs for the treatment of nocardiosis and are considered the drugs of choice.50,51 Sulfisoxazole (150 mg/kg every 4–6 hours) has been used. The recommended maintenance serum or plasma level of the sulfonamide is 100 to 150 μg/ml.20 Sulfadiazine is less soluble in urine than other sulfonamides and may cause oliguria, azotemia, and crystalluria and thus should be avoided.52 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. Other agents with potential clinical usefulness include amikacin, cefotaxime, ceftriaxone, amoxicillin-clavulanate, and imipenem.2 Treatment should be continued for 6 to 12 months in immunocompromised patients.53N farcinica may be more virulent than other species and is associated with increased resistance to antimicrobials, including third-generation cephalosporins, ampicillin, and aminoglycosides other than amikacin. It remains, however, susceptible to sulfamethoxazole, ciprofloxacin, amikacin, and imipenem.7 These factors should be taken into consideration during treatment of N farcinica infections. The optimal antibiotic treatment for patients with nocardiosis is still uncertain.

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 amoxicillin-clavulanate. 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. Fluoroquinolones are not approved for use in children younger than 18 years of age.

Patients with corneal keratitis may be treated with oral trimethoprim-sulfamethoxazole. Monotherapy with topical amikacin may also be effective.56

Linezolid, an oxazolidinone antibiotic, has recently been shown to have excellent in vitro activity against all clinically significant Nocardia species. It has been successfully used to treat patients with nocardiosis, including those who failed therapy with other antibiotics.57 However, linezolid use for more than 4 weeks is associated with hematologic toxicity; this may limit the use of linezolid for nocardiosis.58

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

Drainage of empyema and mediastinal fluid collections is essential for good outcome.23 Localized pleuropulmonary disease usually does not require surgery. Drainage of abscesses is required in patients who fail to respond to antibiotic therapy; however, antimicrobial treatment of brain abscesses without surgery has been successful in some cases.59

Because immunosuppressive therapy predisposes patients to nocardiosis, lowering the doses of these medications or stopping them, if possible, may be helpful during the course of treatment.60 In transplant patients, treatment of nocardiosis can also be hampered by the adverse pharmacological interaction of cyclosporine and sulfonamides, causing nephrotoxicity.61 Metastatic lesions have appeared after the completion of an otherwise effective course of sulfonamides, so careful long-term follow-up is mandatory.62 Some authorities suggest indefinite suppressive therapy for patients with nocardiosis whose immunosuppressive status cannot be reversed, such as transplant recipients.63 It has been shown that patients who receive trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis have decreased incidence of Nocardia infections.64 In fact, nocardiosis as a complication of AIDS may be underreported owing to the common use of trimethoprim-sulfamethoxazole as prophylaxis and treatment of Pneumocystis pneumonia.62 Sulfonamide-containing regimens resulted in higher survival rates among infected renal transplant patients compared with nonsulfonamide regimens.50 Trimethoprim-sulfamethoxazole. Despite the efficacy of sulfonamides in nocardiosis, invasive infections have been reported in immunocompromised patients receiving trimethoprim-sulfamethoxazole prophylaxis.65

Outcome

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