BASICS
DESCRIPTION
- A rare infectious disease caused by Nocardia sp. bacteria
- No pathognomonic presentation
- Nocardiosis can be acute, subacute, or chronic, and involve multiple systems:
- Pulmonary (>70% overall, 39% only lung)
- Disseminated: ≥2 sites (32% overall)
- Cutaneous (~8%)
- CNS (20% overall, 44% of disseminated, 9% brain only)
- Patients are typically immunocompromised or have chronic pulmonary or systemic disease.
- Less commonly, Nocardia can infect the eye, heart valves, bone, and any other organ system.
EPIDEMIOLOGY
- Overall: 0.4/100,000 cases/person-years
- >60% are immunocompromised.
- All ages are susceptible; mean age at diagnosis is in 4th decade of life.
- Male > female (3:1)
- ~500 to 1,000 clinically evident cases/year in United States; not a reportable disease
- HIV/AIDS: 53/100,000 cases/person-years
- Bone marrow transplant recipients: 128/100,000 cases/person-years
- Solid-organ transplant recipients: 1,122/100,000 cases/person-years
ETIOLOGY AND PATHOPHYSIOLOGY
- Nocardia sp. are aerobic gram-positive branching rods found worldwide in soil, decaying plants, fresh and salt water.
- >80 species, >30 cause human disease.
- Nocardia asteroides complex causes the majority of symptomatic infections and includes Nocardia abscessus, Nocardia cyriacigeorgica, Nocardia farcinica and Nocardia nova.
- Nocardia enters through inhalation (e.g., contaminated dust), traumatic skin inoculation and ingestion.
- Nocardiosis of the skin has four patterns: primary cutaneous, lymphocutaneous, cutaneous secondary to disseminated spread, and mycetoma.
- Pulmonary, CNS, and other organ system infection with Nocardia is typically suppurative, often leading to abscess formation.
- Incubation period: days to weeks
- Pathologic Nocardia sp. have several intrinsic means of overcoming host immune responses.
RISK FACTORS
- Most cases occur in immunocompromised hosts, particularly those with impaired cell-mediated immunity. Other chronic diseases (e.g., DM, COPD) may predispose individuals to nocardiosis.
- Farm workers and other immunocompetent individuals may develop pulmonary, cutaneous, and disseminated disease after appropriate exposure.
- Nocardiosis can be severe and fatal in immunocompromised patients; immunologically normal people rarely develop severe disease.
- Immunocompromised children are also at risk.
COMMONLY ASSOCIATED CONDITIONS
- Chronic pulmonary disease
- Hematologic and other malignancies
- Bone marrow and solid-organ transplantation
- Chronic corticosteroid therapy
- Autoimmune diseases
- Tumor necrosis factor therapy
- Kidney failure
- Cirrhosis and alcoholism
- Hypogammaglobulinemia
- HIV/AIDS
- Diabetes mellitus
- TB and other granulomatous disease
DIAGNOSIS
HISTORY
- Diagnosis requires a high index of clinical suspicion
- Symptoms vary by site of infection. Pulmonary CNS and cutaneous symptoms are most frequently infected:
- Headache, anorexia, weight loss, pleuritic chest pain, dyspnea, malaise, cough, confusion, pain
- Nocardiosis produces suppurative necrosis and abscess formation at sites of infection
- Disseminated disease may involve any organ (with corresponding symptoms): CNS, pulmonary, and skin are the most commonly involved.
PHYSICAL EXAM
- Pulmonary nocardiosis
- Fever
- Hemoptysis
- Tachypnea
- Rales
- CNS nocardiosis
- Can be clinically silent in the immunocompetent
- Fever
- Meningismus
- Seizures
- Focal neurologic signs
- Primary cutaneous nocardiosis
- Ulcerations
- Cellulitis
- Skin nodules
- Abscesses
- Lymphocutaneous nocardiosis
- Spread of primary cutaneous nocardiosis to include regional lymphangitis
- Nocardial mycetoma
- Painless nodule at inoculation site
- May become large complex inflammatory nodule
- Local induration
- Cutaneous nocardiosis from disseminated spread
- Identical to primary cutaneous and/or lymphocutaneous infections
- Disseminated nocardiosis
- Two noncontiguous sites of infection
- Symptoms corresponding to those sites (e.g., pulmonary, CNS, eye, bone, etc.)
- Unusual Nocardia infections and presentations:
- Keratoconjunctivitis associated with contact lenses, penetrating eye injury or surgery
- Peritonitis in patients on peritoneal dialysis
- Pericarditis and cardiac tamponade
- Hematogenous endophthalmitis
- Prosthetic joint infections
- Natural/prosthetic valve endocarditis
- Male genitourinary tract
- Intravascular access device related infections
DIFFERENTIAL DIAGNOSIS
- Pulmonary nocardiosis
- Other symptomatic pulmonary infections: bacterial (typical or atypical pneumonias), mycobacterial (e.g., TB), fungal (e.g., Aspergillus)
- Malignancy, primary or metastatic
- CNS nocardiosis
- Other symptomatic CNS infections: bacterial abscesses-meningitis, fungal (e.g., Coccidioides), parasitic (e.g., cysticercosis)
- Malignancy, primary or metastatic
- Cutaneous nocardiosis
- Multiple skin infections can mirror Nocardia: fungal (e.g., Sporothrix), several non-TB mycobacteria, bacterial (e.g., Francisella tularensis), parasitic (e.g., Leishmania)
- Can be clinically insignificant and overlooked
- Disseminated nocardiosis
- Infectious processes and malignancies that can impact multiple organ systems
Initial Tests (lab, imaging)
- Microscopic examination of purulent fluid, with Gram stain showing fine, filamentous, branching gram-positive rods (similar to Actinomyces); same appearance on modified partial acid-fast staining (Actinomyces do not acid-fast stain)
- Culture, speciation, and sensitivity help guide therapy.
- Notify laboratory if suspicious for nocardiosis because Nocardia grows very slowly (2 to 3 weeks) and may require use of selective media.
- Blood cultures for patients with endovascular devices; maintain specimens 2 to 4 weeks. Alert lab and culture under appropriate conditions.
- Radiography
- CXR findings include pulmonary or mediastinal masses, nodules, cavities, infiltrates, pleural effusions.
- MRI or CT if CNS symptoms, in all immunocompromised patients, and in immunocompetent people with pulmonary or disseminated infections
Follow-Up Tests & Special Considerations
- Consult a reference laboratory, including the CDC 's Special Bacteriology Reference Laboratory (SBRL), 1-800-CDC-INFO (232-4636).
- US or MRI may be required to assess extent of complex mycetomas, abscesses, and focal-disseminated infections.
Diagnostic Procedures/Other
- Invasive procedures may be required for specimen analysis, to improve culture yield, for speciation and antibiotic sensitivity.
- Polymerase chain reaction (PCR) offers rapid, accurate Nocardia testing but is only available in select labs.
TREATMENT
GENERAL MEASURES
- Consider infectious disease consultation.
- Modify treatment based on sensitivity results.
MEDICATION
First Line
- CNS/disseminated nocardiosis (1,2)[B]
- Trimethoprim-sulfamethoxazole 15 mg/kg/day TMP IV divided in 2 to 4 doses; plus,
- Imipenem 500 mg IV q6h; ‚ ±,
- Amikacin 7.5 mg/kg IV q12h
- After bacterial sensitivity results and/or 3 to 6 weeks of improvement, may change to oral therapy for immunocompetent patients: trimethoprim-sulfamethoxazole 10mg/kg/day of trimethoprim component in 2 to 3 divided doses or minocycline 100 to 200 mg PO BID and/or amoxicillin-clavulanate 500 mg PO TID or 875 mg PO BID; total duration 3 to 6 months and at least 1 month beyond resolution
- For immunocompromised patients, two drug therapy for 12 months and at least 1 month beyond resolution, including one sulfa-based antibiotic; consideration for lifelong suppressive therapy with trimethoprim-sulfamethoxazole
- Pulmonary (only) nocardiosis (1,2)[B]
- Trimethoprim-sulfamethoxazole 15 mg/kg/day TMP IV divided in 2 to 4 doses; plus,
- Imipenem 500 mg IV q6h
- After bacterial antibiotic sensitivity results and/or 3 to 6 weeks of improvement, may change to oral for immunocompetent patients trimethoprim-sulfamethoxazole 10 mg/kg/day in 2 to 3 divided doses or minocycline 100 to 200 mg PO BID or amoxicillin-clavulanate 500 mg PO TID or 875 mg PO BID; total duration 3 to 6 months and at least 1 month beyond resolution
- For immunocompromised patients, two drug therapy for 6 to 12 months and at least 1 month beyond resolution, including one sulfa-based antibiotic
- For treatment of CNS, pulmonary, and disseminated nocardiosis trimethoprim-sulfamethoxazole or sulfadiazine are the mainstay of treatment with a recommended sulfonamide level at 100 to 150 Ž ¼g/mL 2 hours after dosing; many experts recommend desensitization therapy if allergic to sulfa (1,2)[B].
- Cutaneous (only) nocardiosis
- Trimethoprim-sulfamethoxazole 5 to 10 mg/kg/day TMP component IV or PO divided in 2 to 4 doses; total duration 3 months and at least 1 month beyond resolution; for immunocompromised, 6 months with at least 1 month beyond resolution (1,2)[B]
- Empiric therapy for acutely ill patients should be ceftriaxone 2 g IV q12h or meropenem 1 to 2 g IV q8h + amikacin 7.5 to 15 mg/kg IV q12h, with an IV sulfonamide considered in critically or acutely ill patients (1,2)[B].
Second Line
- CNS/disseminated nocardiosis (1,2 and 3)[B]
- Linezolid 600 mg IV or PO q12h; plus
- Meropenem 1 to 2 g IV q8h
- Alternate for trimethoprim-sulfamethoxazole " “allergic: amikacin + imipenem 500 mg IV q6h or meropenem 1 to 2 g IV q8h or ceftriaxone 2 g IV q12h or cefotaxime 2 g IV q8h
- Pulmonary nocardiosis (1,2 and 3)[B]
- Alternate for trimethoprim-sulfamethoxazole " “allergic: amikacin + imipenem or meropenem or ceftriaxone or cefotaxime
- Alternate linezolid; + meropenem
- Cutaneous nocardiosis (1,2 and 3)[B])
- Sulfisoxazole 2 g PO BID, or minocycline 100 to 200 mg PO BID; total duration 3 months and at least 1 month beyond resolution; for immunocompromised, 6 months and at least 1 month beyond resolution; linezolid may be considered as an alternative.
ISSUES FOR REFERRAL
Consider early infectious disease consult for suspected or confirmed nocardiosis. ‚
SURGERY/OTHER PROCEDURES
Surgical or interventionist consultation may be needed to drain abscesses for laboratory specimen analysis and therapeutic drainage for larger abscesses and in individuals not responding to therapy (2)[B]. ‚
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Patients with symptomatic nocardiosis are often immunocompromised and require hospitalization.
- Patients with a mild to moderate presentation may not require hospitalization, especially if immunocompetent.
IV Fluids
Supportive care for nocardiosis may require IV fluids in the hospitalized patient. ‚
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Recovery after a variable period of convalescence; activity may be increased as patients improve. ‚
Patient Monitoring
Patients on high-dose sulfonamide therapy should have a serial CBC, up to every other week or as indicated; other assessments (kidney, liver) are based on patient comorbidities and response to therapy. ‚
DIET
No special restrictions required. ‚
PATIENT EDUCATION
- Not a contagious disease
- Patients may need long-term antibiotic therapy to treat nocardiosis and reduce the likelihood of relapse.
- Educate patients about adverse medication reactions.
PROGNOSIS
- Overall mortality is 7 " “44%.
- Approximately 10% of cases with uncomplicated pneumonia are fatal.
- The case fatality rate increases with overwhelming infection, disseminated disease, or brain abscess.
COMPLICATIONS
- Organ system deficits from the lasting effects of suppuration, tissue destruction, and mass effect
- Adverse reactions from long-term antimicrobial therapy
REFERENCES
11 Welsh ‚ O, Vera-Cabrera ‚ L, Salinas-Carmona ‚ MC. Current treatment for nocardia infections. Expert Opin Pharmacother. 2013;14(17):2387 " “2398.22 Wilson ‚ JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc. 2012;87(4):403 " “407.33 Shen ‚ Q, Zhou ‚ H, Li ‚ H, et al. Linezolid combined with trimethoprim-sulfamethoxazole therapy for the treatment of disseminated nocardiosis. J Med Microbiol. 2011;60(Pt 7):1043 " “1045.
ADDITIONAL READING
- Bargehr ‚ J, Flors ‚ L, Leiva-Salinas ‚ C, et al. Nocardiosis in solid-organ transplant recipients: spectrum of imaging findings. Clin Radiol. 2013;68(5):e266 " “e271.
- Brown-Elliott ‚ BA, Brown ‚ JM, Conville ‚ PS, et al. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol Rev. 2006;19(2):259 " “282.
- Corti ‚ ME, Villafa ƒ ±e-Fioti ‚ MF. Nocardiosis: a review. Int J Infect Dis. 2003;7(4):243 " “250.
- Filice ‚ GA. Nocardiosis in persons with human immunodeficiency virus infection, transplant recipients, and large, geographically defined populations. J Lab Clin Med. 2005;145(3):156 " “162.
- Mei-Zahav ‚ M, Livnat ‚ G, Bentur ‚ L, et al. The spectrum of nocardia lung disease in cystic fibrosis. Pediatr Infect Dis J. 2015:34(8):909 " “911.
- Saubolle ‚ MA, Sussland ‚ D. Nocardiosis: review of clinical and laboratory experience. J Clin Microbiol. 2003;41(10):4497 " “4501.
CODES
ICD10
- A43.9 Nocardiosis, unspecified
- A43.0 Pulmonary nocardiosis
- A43.1 Cutaneous nocardiosis
- A43.8 Other forms of nocardiosis
ICD9
- 039.9 Actinomycotic infection of unspecified site
- 039.1 Pulmonary actinomycotic infection
- 039.0 Cutaneous actinomycotic infection
- 039.8 Actinomycotic infection of other specified sites
SNOMED
- Nocardiosis (disorder)
- Pulmonary nocardiosis (disorder)
- Cutaneous nocardiosis
- Disseminated nocardiosis (disorder)
CLINICAL PEARLS
- The diagnosis of nocardiosis requires a high degree of clinical suspicion. Nocardiosis lacks a pathognomonic appearance and may present in a variety of ways.
- Immunocompromised patients have more severe manifestations of disease.
- Nocardiosis can progress and relapse despite appropriate therapy.
- Microscopic examination of purulent fluid should include Gram stain and modified partial acid-fast staining for preliminary diagnosis and to guide treatment.
- Treatment is based on location of disease and results of culture and sensitivity. Prolonged antibiotic therapy is typically required.