Nocardiosis

Background

Nocardiosis is an acute, subacute, or chronic infectious disease that occurs in cutaneous, pulmonary, and disseminated forms. Primary cutaneous nocardiosis manifests as cutaneous infection (cellulitis or abscess), lymphocutaneous infection (sporotrichoid nocardiosis), or subcutaneous infection (actinomycetoma). Pleuropulmonary nocardiosis manifests as an acute, subacute, or chronic pneumonitis, usually in immunocompromised hosts, although isolated cases have been reported in immunocompetent hosts. Disseminated nocardiosis may involve any organ; lesions in the brain or meninges are most common.

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Pathophysiology

Members of the genus Nocardia are aerobic actinomycetes that are ubiquitous saprophytes in soil, decaying organic matter, and fresh and salt water. Over 100 species of the genus Nocardia have been identified, more than half of which have been described during the last decade.

The taxonomy has been challenging and likely remains in evolution.^{[1, 2]} Most human infections are due to members of the formerly called Nocardia asteroides complex. N asteroides complex was later separated into Nocardia abscessus, Nocardia brevicatena-paucivorans complex , Nocardia nova complex, Nocardia transvalensis complex, Nocardia farcinica, Nocardia asteroides sensu stricto, and Nocardia cyriacigeorgica; however, use of the term " N asteroides complex" is currently outdated because of the heterogenous group of organisms it includes. Nocardia species also cause infections in animals, including bovine mastitis and sporotrichoid nocardiosis in horses.

When observed microscopically, either in Gram-stained smears of clinical specimens or cultures or on histopathology in tissues, Nocardia organisms are branching, beaded, filamentous, gram-positive bacteria with a characteristic morphology to a trained observer. See the image below.

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High-power microscopic appearance of Nocardia. Image courtesy of CDC.

Nocardia are typically weakly acid-fast after traditional staining and positive on modified acid-fast staining, but this is not invariable.

The cutaneous, lymphocutaneous, and subcutaneous forms of nocardiosis arise from local traumatic inoculation. These infections are not necessarily associated with immunocompromised host states, but dissemination from these sites of inoculation is more likely in immunocompromised hosts, particularly those with impaired cell-mediated immunity. Pleuropulmonary nocardiosis presumably arises from inhalation exposure. Disseminated nocardiosis results from hematogenous dissemination, usually from a pulmonary focus. Most persons with disseminated nocardiosis have underlying immunocompromising disease or are receiving immunosuppressive therapy.

Nocardiosis produces suppurative necrosis with frequent abscess formation at sites of infection. See the image below.

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Photomicrograph of tissue biopsy stained with Gomori methenamine silver demonstrating acute inflammatory response and organisms compatible with Nocard....

Disease manifestations of nocardiosis are determined by strain characteristics, inoculation site, tissue tropism, ability to survive initial neutrophilic leukocyte phagocytic attack, and the nature of the immune response. T-cell–mediated immunity is the principal protective immune response to nocardiosis.^[3] Therefore, nocardiosis is most problematic in individuals with impaired T-cell–mediated immunity.^[2]

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Epidemiology

Frequency

United States

The estimated incidence of nocardiosis in the United States is 500-1000 cases per year.^[4]

Clusters of nocardiosis have been described in hospitalized patients, related to contaminated fomites from construction or contaminated hands of staff.

International

No reliable estimates on the international frequency of nocardiosis are available.

Mortality/Morbidity

Nocardiosis has a variable prognosis, depending on the site of infection, extent of infection, and underlying host factors.^[5]

Cure rates with appropriate therapy are approximately 100% in skin and soft-tissue infections.

Ninety percent of pleuropulmonary infections can be cured with appropriate therapy.

The cure rate in disseminated nocardiosis falls to 63%, while only half of patients with brain abscess can be cured with therapy.^[6]

Race

Nocardiosis has no apparent racial predilection.

Sex

Nocardiosis is more common in males than in females, with a male-to-female ratio of 3:1. This difference may be related to exposure frequency rather than a gender difference in susceptibility.

Age

All ages are susceptible to nocardiosis. The mean age at diagnosis is in the fourth decade of life.

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Patient Education

Patients with nocardiosis must be educated about the need for protracted antimicrobial therapy.

Patients with nocardiosis should be informed of the potential adverse effects of protracted antimicrobial therapy and which circumstances require reporting to their physician promptly.

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History

Clinical manifestations of nocardiosis depend on the site of infection.^{[7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]}

Primary cutaneous nocardiosis may present as cutaneous infection, lymphocutaneous infection, or subcutaneous infection. Cutaneous nocardiosis generally manifests as either cellulitis or, more likely, single or multiple nontender erythematous nodule(s) at the site of traumatic inoculation. These nodules occasionally drain purulent material. Lymphocutaneous nocardiosis manifests as similar lesions accompanied by ascending regional lymphadenopathy. The lymphadenopathy may also occasionally drain purulent material. N brasiliensis is the most common cause of progressive cutaneous and lymphocutaneous (sporotrichoid) disease.

Nocardial species can cause mycetoma, a chronic, swollen, purulence-draining, subcutaneous infection of the extremities, typically encountered in tropical areas of the world, but also has been reported from the southern United States, Central and South Americas, and Australia. It is usually ascribed to N brasiliensis.^{[17, 20]}

Postoperative wound infections due to Nocardia species are rare, but case clusters of nosocomial transmission have been described.

Traumatic inoculation nocardial arthritis has occurred but is rare. This presents as a subacute or chronic monarthritis, typically involving the knee.

Traumatic inoculation or postoperative nocardial keratitis has been well described in Asia and travelers returning from Asia.

Traumatic inoculation nocardial endophthalmitis has also occurred in rare instances.

Pulmonary disease is the predominant clinical finding in most patients with nocardiosis.^{[10, 18]} Pulmonary nocardiosis may be acute, subacute, or chronic. Clinical manifestations include inflammatory endobronchial masses or localized or diffuse pneumonias, which may be accompanied by cavitation, abscess formation, pleural effusion, or empyema. Symptoms in patients with nocardiosis are indistinguishable from those in patients with similar pulmonary infections of other microbial etiology. Cough with sputum production and fever are the dominant symptoms. At least 40% of patients with disseminated nocardiosis have pulmonary infection; therefore, the clinical presentation may be dominated by the pulmonary symptoms.

Patients with nocardiosis may present with deep abscess at any site, particularly in the lower extremities or the CNS. In patients with extra-CNS abscesses, fever and local symptoms predominate. Up to 25% of reported nocardiosis cases (other than those involving mycetoma) involve the CNS. When occurring in isolation, CNS nocardiosis manifests as a slowly progressive mass lesion, with a host of specific neurologic findings related to the specific location of the abscess. CNS nocardiosis is detected in up to 44% of disseminated nocardial infections.^[21] In two thirds of patients with CNS nocardiosis, clinical findings indicate abscess with or without meningitis, including fever, headache, stiff neck, and/or altered mental status.

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Physical

The physical findings of nocardiosis also vary based on the site of infection.

Patients with primary cutaneous nocardiosis present with cellulitis, cutaneous nodules, nodules with ascending lymphadenopathy, or with a mycetoma that is clinically indistinguishable from similar infections due to other pathogens.

Patients with pulmonary nocardiosis present with findings of pulmonary consolidation with or without evidence of pleural effusions.

The presentation of disseminated nocardiosis depends on the sites of infection. Pulmonary findings frequently predominate. Local findings associated with metastatic abscesses may be present at almost any site but are typically in the lower extremities. The combination of pneumonia and lower-extremity abscess is particularly suggestive of nocardiosis, although this is not seen exclusively in nocardiosis. Patients with brain abscess may present with altered mental status, personality changes, or various localizing neurologic findings. Patients with meningitis present with fever, altered consciousness, and meningismus.

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Causes

Pulmonary and disseminated nocardiosis are clearly associated with immunocompromising conditions, with approximately 60% of cases of nocardiosis other than mycetoma occurring in individuals with some compromise of host defense systems. Conditions associated with an increased risk of pulmonary and disseminated nocardiosis include the following:

• Chronic pulmonary disease: Although pulmonary nocardiosis has been described in association with various chronic pulmonary diseases, patients with pulmonary alveolar proteinosis are at particular risk.
• Alcoholism
• Cirrhosis
• Lymphoreticular malignancy
• Solid-organ transplantation^[22]
• Bone marrow or stem cell transplantation, particularly allogeneic transplantation with subsequent graft versus host disease
• Long-term corticosteroid use or Cushing syndrome
• Systemic lupus erythematosus
• Systemic vasculitis
• Ulcerative colitis
• Sarcoidosis
• Renal failure
• Whipple disease
• Hypogammaglobulinemia
• Treatment with anti–tumor necrosis factor antibody
• HIV infection and AIDS: Nocardiosis in individuals with advanced HIV disease usually presents as a relentlessly progressive infiltrative pulmonary infection. The median CD4 count in patients infected with HIV who develop nocardiosis is approximately 50 cells/µL.^[15]

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Laboratory Studies

The diagnosis of nocardiosis is established with culture of the causative organism from the infection site(s). Because nocardiae grow slower than common bacteria, the microbiology laboratory should always be notified when nocardiosis is clinically suspected. This is particularly true when sputum is the submitted specimen. Respiratory secretions, skin biopsy samples, and aspirates from abscesses are the most common specimens from which Nocardia species are identified. Direct smears or histopathologic stains of these specimens can be highly suspicious, as noted above. Nocardia species can usually be isolated in 3-5 days.

Blood cultures are positive for Nocardia organisms in a minority of patients, but they always should be obtained when pulmonary or disseminated nocardiosis is suspected.

Immunodominant antigens of Nocardia species have been identified and used in serological assays. However, no serologic technique or molecular technique is yet available for routine clinical use. Similarly, nucleic acid amplification assays have been described but are not available for routine clinical use.

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Imaging Studies

Plain chest radiography and, often, CT chest scanning are useful in evaluating pulmonary nocardiosis and in monitoring the course of the infection. However, no characteristic radiographic findings have been described. Radiographic findings may include irregular nodules (which may cavitate), reticulonodular or diffuse alveolar pulmonary infiltrates, lung abscess formation, and pleural effusion. See the images below.

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Plain chest radiograph in a patient with nocardiosis. Image courtesy of Applied Radiology, Anderson Publishing, LTD.

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Chest CT scan in a patient with pleuropulmonary nocardiosis. Image courtesy of Applied Radiology, Anderson Publishing, LTD.

All patients with nocardiosis, except those with mycetoma, should undergo brain imaging with either CT scanning or MRI (likely preferred). Intracranial abscess is the most common abnormality found. Spread of intracranial abscesses to contiguous structures is particularly suggestive of nocardiosis. See the image below.

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Brain CT scan in a patient with nocardial brain abscess. Image courtesy of Applied Radiology, Anderson Publishing, LTD.

Localized symptoms other than pulmonary or CNS should be evaluated with appropriate site-specific imaging.

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Other Tests

If meningitis is suspected, cerebrospinal fluid (CSF) should be obtained for analysis unless this is contraindicated by mass effect on brain imaging. Nocardial meningitis typically results in findings typical of bacterial meningitis (ie, neutrophilic pleocytosis, hypoglycorrhachia, and an elevated CSF protein level).

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Procedures

Biopsy of skin lesions or aspiration of deep abscesses may be required for diagnosis of nocardiosis.

Similarly, in patients with pulmonary nocardiosis, bronchoalveolar lavage and/or transbronchial lung biopsy may be required if the microbial etiology is not definitively established based on examination and culture of expectorated sputum.

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Histologic Findings

Suppurative infection with organisms of characteristic morphology and staining attributes is the typical histopathologic finding in nocardiosis. Granulomatous infection is occasionally encountered.

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Medical Care

Protracted specific antimicrobial therapy is the mainstay of medical care for nocardiosis. Therapy is generally recommended for at least 6 months.^[1]

In patients who require immunosuppressive therapy, such therapy can generally be continued while appropriate specific therapy for nocardiosis is administered.

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Surgical Care

For lesions outside the CNS, surgical management is the same as standard recommendations for other infections; that is, localized abscesses generally require prompt surgical therapy.

In patients with nocardial brain abscesses, surgery should be performed if the lesions are large, if they are readily accessible, or if they progress beyond 2 weeks of antimicrobial therapy.^[11]

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Consultations

An infectious diseases specialist is recommended for coordinating protracted antimicrobial therapy. Depending on the infection site(s), consultation with a pulmonologist, thoracic surgeon, general surgeon, and/or neurosurgeon may be appropriate.

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Diet

No specific dietary recommendations are warranted.

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Activity

Activity can be as tolerated by the patient.

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Prevention

Although not clearly established, prophylactic therapy for Pneumocystis jiroveci pneumonia (PCP) with TMP-SMX in patients with AIDS whose CD4 count is less than 200 cells/µL probably decreases the likelihood of nocardiosis. (For an excellent discussion of PCP prophylaxis, see the Medscape Reference article Preventing Opportunistic Infections in Patients With HIV.) Similarly, TMP-SMX prophylaxis in solid-organ transplant or hematopoietic stem cell transplant recipients may decrease the likelihood of nocardiosis. However, prophylaxis is not fully effective in either circumstance.

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Inpatient & Outpatient Medications

Antimicrobial therapy for pulmonary or disseminated nocardiosis should be continued for 6-12 months and at least 1 month following resolution of all evidence of infection. These patients require at least 12 months of monitoring after the completion of therapy to detect possible late relapses.

Follow-up radiographic studies should be obtained to monitor treatment.

Follow-up laboratory studies are required to monitor for adverse effects of prolonged antimicrobial therapy.

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Medication Summary

General treatment guidelines for nocardiosis are hindered by (1) lack of controlled clinical trials of therapy; (2) difficult, and, in the past, poorly standardized in vitro susceptibility testing leading to widely disparate reports of in vitro antimicrobial susceptibility^{[23, 24]} ; (3) lack of firm data on correlation of in vitro susceptibility with in vivo therapeutic efficacy; and (4) the changing taxonomy of Nocardia species. Therapy should likely be guided by in vitro susceptibility testing at a specialized laboratory experienced at testing Nocardia strains.

Sulfonamides have long been the first-line antimicrobial therapy for nocardiosis. Among the sulfonamides, sulfadiazine is generally preferred because of its CNS and CSF penetration. Although not convincingly demonstrated superior, trimethoprim-sulfamethoxazole (TMP-SMZ) is considered the therapy of choice by most authorities. Divided doses of 5-10 mg/kg/d of the trimethoprim component should be administered to produce sulfonamide levels of 100-150 mcg/mL; such levels should possibly be confirmed in individuals with severe disease.

Additional or alternative parenteral therapies include carbapenems (imipenem or meropenem, but not ertapenem), third-generation cephalosporins (cefotaxime or ceftriaxone), and amikacin, alone or in combination. Imipenem plus amikacin may be the preferred regimen in sulfonamide-allergic individuals. Linezolid in vitro activity and in vivo efficacy has been reported.^[25] Tigecycline also has reported activity in vitro.^[1]

For most serious Nocardia infections, combination therapy has been recommended.^[1] Combination therapy should be continued until clinical improvement occurs and confirmation of in vitro drug susceptibility has been acquired.

Alternative oral therapies include minocycline and amoxicillin/clavulanate, in addition to linezolid. These may be used initially in mild-to-moderately severe disease or as sequential therapy after an induction course of parenteral therapy. Modern fluoroquinolones often have demonstrable in vitro activity against Nocardia species but have failed therapeutically.

Duration of treatment is generally prolonged to minimize risk of disease relapse. Immunocompetent patients with non-CNS nocardiosis may be successfully treated with 6-12 months of antimicrobial therapy. Immunosuppressed patients and those with CNS disease should receive 12 months of therapy or longer if escalation of immunosuppression takes place (such as graft or organ rejections). In For patients on chronic steroid or cytotoxic therapy, prolonged maintenance of anti-nocardial therapy may be indicated. Appropriate clinical monitoring should be conducted during protracted antimicrobial therapy.^[1]

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Sulfadiazine (Microsulfon)

• Dosing, Interactions, etc.

Clinical Context:  Exerts its bacteriostatic action by competitive antagonism of paraaminobenzoic acid (PABA). Microorganisms that require exogenous folic acid and do not synthesize folic acid are not susceptible to the action of sulfonamides. In difficult cases, may be important to document peak serum levels (2 h after PO dose are 100-150 mg/L).

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Trimethoprim-sulfamethoxazole (Bactrim, Septra)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

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Meropenem (Merrem IV)

• Dosing, Interactions, etc.

Clinical Context:  Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell-wall synthesis. Effective against most gram-positive and gram-negative bacteria. Has slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared to imipenem.

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Cefotaxime (Claforan)

Clinical Context:  Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms. Arrests bacterial cell wall synthesis, which in turn inhibits bacterial growth.

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Ceftriaxone (Rocephin)

• Dosing, Interactions, etc.

Clinical Context:  Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.

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Amikacin (Amikin)

• Dosing, Interactions, etc.

Clinical Context:  For gram-negative bacterial coverage of infections resistant to gentamicin and tobramycin. Effective against Pseudomonas aeruginosa.

Irreversibly binds to 30S subunit of bacterial ribosomes and blocks recognition step in protein synthesis, which causes growth inhibition. Use patient's IBW for dosage calculation.

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Minocycline (Minocin)

• Dosing, Interactions, etc.

Clinical Context:  Treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible Chlamydia, Rickettsia, and Mycoplasma.

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Amoxicillin and clavulanate (Augmentin)

• Dosing, Interactions, etc.

Clinical Context:  Drug combination treats bacteria resistant to beta-lactam antibiotics. In children >3 mo, base dosing protocol on amoxicillin content. Because of different amoxicillin/clavulanic acid ratios in 250-mg tab (250/125) vs 250-mg chewable tab (250/62.5), do not use 250-mg tab until child weighs >40 kg.

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Linezolid (Zyvox)

• Dosing, Interactions, etc.

Clinical Context:  Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process. Bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Used as alternative in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci.

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Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

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