Nocardia/Nocardiosis

Nocardia is a branching, filamentous, gram-positive bacilli. It is partially acid fast due to the presence of mycolic acids in the cell wall. Nocardia is a ubiquitous soil organism that most commonly affects immunocompromised patients. Nocardia is transmitted via inhalation of aerosolized bacteria or less commonly, via direct contact with wounds. Nocardia causes opportunistic infections, primarily pulmonary infections (pneumonia, abscess, or cavitary lesions), which may spread to form brain abscesses. In immunocompetent patients, Nocardia can cause a cutaneous infection. Treatment for nocardiosis is with trimethoprim–sulfamethoxazole and/or surgical intervention as indicated.

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Classification

Microbiology flowchart gram-positive bacteria classification

Gram-positive bacteria:
Most bacteria can be classified according to a lab procedure called Gram staining.
Bacteria with cell walls that have a thick layer of peptidoglycan retain the crystal violet stain utilized in Gram staining but are not affected by the safranin counterstain. These bacteria appear as purple-blue on the stain, indicating that they are gram positive. The bacteria can be further classified according to morphology (branching filaments, bacilli, and cocci in clusters or chains) and their ability to grow in the presence of oxygen (aerobic versus anaerobic). The cocci can also be further identified. Staphylococci can be narrowed down on the basis of the presence of the enzyme coagulase and on their sensitivity to the antibiotic novobiocin. Streptococci are grown on blood agar and classified on the basis of which form of hemolysis they employ (α, β, or γ). Streptococci are further narrowed on the basis of their response to the pyrrolidonyl-β-naphthylamide (PYR) test, their sensitivity to specific antimicrobials (optochin and bacitracin), and their ability to grow on sodium chloride (NaCl) media.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics

Nocardia

  • General characteristics:
    • Structure:
      • Branching, filamentous rods
      • Filaments fragment readily into coccobacillary forms.
    • Gram stain: gram positive
    • Other stain(s): weakly acid fast due to mycolic acids in the cell wall
    • Enzyme produced: urease positive, catalase positive
    • Spore formation: non-spore forming
    • Oxygen requirement: obligate aerobe
  • Culture medium: grows on most ordinary laboratory media (such as blood agar) 
  • Nocardiosis (disease caused):
    • Frequently an opportunistic infection, manifesting as a pulmonary or disseminated disease.
    • Localized disease occurs, and usually presents as a cutaneous syndrome.
Stain nocardia species

This slide with gram-positive aerobic Nocardia asteroides reveals chains of bacteria among aerial mycelia.

Image by Lecturio.

Clinically relevant species

  • Nocardia asteroides (N. asteroides) has been divided based antimicrobial susceptibility patterns:
    • N. abscessus complex
    • N. brevicatena-paucivorans complex
    • N. nova complex
    • N. transvalensis complex
    • N. farcinica
    • N. cyriacigeorgica
  • Nocardia brasiliensis (N. brasiliensis)

Epidemiology

  • Incidence of nocardiosis: 500–1,000 cases per year in the United States
  • Infection affects men > women
  • All ages are susceptible to infection.

Related videos

Pathogenesis

Reservoir and transmission

  • Reservoir(s): soil, decaying organic matter, water
  • Transmission:
    • Inhalation:
      • Primary route of exposure
      • Mainly with N. asteroides, causing pulmonary disease
    • Environmental exposure through trauma or wound contamination:
      • Mainly with N. brasiliensis 
      • Infections affect the skin and lymph nodes.

Virulence

  • Mechanisms of Nocardia spp:
    • Resistance to phagocytosis: when bacterial growth is in log phase
    • Resistance to hydrolysis: If phagocytosis occurs, the fusion of the phagosome and lysosome is stopped.
    • Resistance to antimicrobial action of neutrophils:
      • Superoxide dismutase from the cell surface
      • Increased catalase 
  • N. farcinica:
    • More virulent than other species
    • With antimicrobial resistance
    • Associated with disseminated infection
  • L forms:
    • Microbial variants without a structurally intact cell wall
    • Found to persist in animal models (in cerebrospinal fluid)
    • Believed to be related to relapse or development of neurologic signs even after treatment

Disease process

  • Nocardia is introduced after a local injury to the skin and infection occurs:
    • In immunocompetent patients: remains localized
    • In immunocompromised patients: with potential to spread to other organs
  • Pleuropulmonary nocardiosis: 
    • Infection follows after inhalation of contaminated aerosolized droplets. 
    • Majority of patients are immunocompromised.
Pathogenesis of Nocardia

Pathogenesis of Nocardia:
Left: Inhaled organisms colonize the oropharynx and are passively aspirated into the lower airways, resulting in necrosis and abscess formation (in immunocompromised patients).
Right: Environmental exposure and contamination of wounds lead to wound infections or granulomatous lesions.

Image by Lecturio.

Host risk factors

  • Frequently the immunocompromised, particularly with impaired cell-mediated immunity:
    • Human immunodeficiency virus (HIV) syndrome: usually in patients with < 250 CD4+ T lymphocytes/μL
    • Transplant recipients 
    • Chronic glucocorticoid use
    • Chronic immunosuppression
    • Malignancy
  • Others:
    • Alcoholism
    • Diabetes
    • Chronic obstructive pulmonary disease
    • Inflammatory bowel disease

Clinical Presentation

Pulmonary nocardiosis

  • Predominant clinical presentation
  • Presents with fever, night sweats, dyspnea, weight loss, cough, chest pain, weight loss 
  • Seen mostly in the immunocompromised
  • Chest X-ray/computed tomography (CT) scan: infiltrates, cavitary lesions, abscess, or pleural effusion
  • May mimic tuberculosis but with negative purified protein derivative (PPD) test
COPD and Nocardia spp

Computed tomography (CT) scan imaging of the lung in a patient with chronic obstructive pulmonary disease and Nocardia infection:
A: right upper lobar consolidation
B: computed tomography images after 12 days, showing cavitary consolidation and ground glass opacity

Image: “COPD and Nocardia spp.” by the Department of Respiratory Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China. License: CC BY 4.0.

Disseminated nocardiosis

  • 2 or more non-contiguous sites are affected.
  • Infections may spread to the central nervous system (CNS), causing brain abscesses.
  • Slow-growing mass(es) causing headaches, fever, seizures, and neurologic deficits
  • Signs of meningitis may be present.
Disseminated central nervous system nocardiosis

Magnetic resonance imaging (MRI) with contrast showing multiple abscesses (arrows): The patient has disseminated CNS nocardiosis, with bilateral involvement of the brain. Multiple ring lesions with surrounding edema are shown.

Image: “45-year-old male” by the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China. License: CC BY 3.0.

Cutaneous nocardiosis

  • Commonly from N. brasiliensis
  • Occurs after trauma (gardening, surgery, animal bite)
  • Affects even the immunocompetent
  • Chronic, slowly progressing lesions
  • Presentation:
    • Primary cutaneous infection: 
      • Cellulitis or a single/multiple erythematous nodule(s) at the site of trauma
      • May drain purulent material
    • Lymphocutaneous nocardiosis: 
      • Cutaneous infection with lymphadenitis, possibly ulcerating and/or draining purulent material 
      • Similar to how Sporothrix schenckii infection presents (thus also called “sporotrichoid nocardiosis”)
    • Mycetoma: 
      • Progressive and chronic deep skin infection 
      • May extend to the fascia, muscle, and bone
      • May cause deformities and sinus tracts
      • May be a form of disseminated infection in immunocompromised patients
Nocardia brasiliensis Infection

Image of cutaneous nocardiosis: fluctuant, purulent, and crusted nodule noted in a patient receiving long-term immunosuppressive therapy. Tissue cultures revealed N. brasiliensis.

Image: “Lesional skin” by Alison M. Fernandes et al. License: CC BY 4.0.

Diagnosis and Management

Diagnosis

  • Culture: 
    • Grows on ordinary laboratory media after 3 to 5 days incubation in air
    • Specimens: sputum, pus, spinal fluid, or biopsy material
  • Microscopic examination: filamentous rods, with beading and branching morphology
  • Imaging studies are dictated by the clinical presentation:
    • Chest X-ray/CT scan of the chest: in pulmonary nocardiosis
    • CT scan of the brain/MRI: in patients with neurologic symptoms
Nocardia brain biopsy

Nocardia (white arrow) as found on a brain biopsy

Image: “Nocardia as found on a brain biopsy” by Doc James. License: Public domain, edited by Lecturio.

Management

  • Trimethoprim-sulfamethoxazole
  • Newer β-lactams (imipenem, meropenem, cefotaxime) may be effective.
  • Surgical drainage for abscess

Comparisons

Actinomyces and Nocardia

Table: Gram-positive, branching, filamentous rods that must be distinguished
Differentiating factorsActinomycesNocardia
Oxygen requirementAnaerobicAerobic
Acid-fast stainNot acid fastAcid fast (partially)
Reservoir/habitatNormal oral, gastrointestinal, and reproductive floraFound in soil, water, decaying organic matter
Infections caused
  • Orofacial abscesses, associated with dental caries or facial trauma
  • Sinus tracts
  • Pelvic inflammatory disease
  • Pulmonary infection in immunocompromised patients (can spread hematogenously and cause brain abscesses)
  • Cutaneous lesions in immunocompetent patients
ManagementTreatment with penicillinTreatment with trimethoprim-sulfamethoxazole
Treatment mnemonic: SNAP (sulfonamides-Nocardia, Actinomyces-penicillin)

Mycobacterium and Nocardia

Table: Acid-fast rods comparison
Differentiating factorsMycobacteriumNocardia
Oxygen requirementAerobicAerobic
Spore formationNon-spore formingNon-spore forming
Acid-fast stainAcid fastPartially acid fast
StructureStraight or slightly curved rodsBranching filamentous rods
PPD* testPPD* positivePPD* negative
*PPD: purified protein derivative

Differential Diagnosis

  • Sporotrichosis: infection caused by Sporothrix schenckii. Lymphocutaneous infection is the most common form and presents like cutaneous nocardiosis (inoculation of soil through the skin with erythematous, nodular lesion(s) along lymphatic channels). Culture of aspirated material helps distinguish the organisms.
  • Mycobacterial infection: pulmonary infection from Mycobacterium tuberculosis (M. tuberculosis) also presents with fever, night sweats, weight loss, cough, hemoptysis, and dyspnea. Both are acid-fast organisms, but Nocardia is only partially acid fast and is seen as a branching rod (resembling fungal hyphae). Recent infection with M. tuberculosis results in a positive PPD test.
  • Brain metastasis: Both brain metastasis and CNS nocardiosis present insidiously and imaging may show multiple lesions in one or both cerebral hemispheres. History helps in diagnosing these conditions; disseminated nocardiosis usually comes from a lung infection. Pulmonary investigation with imaging and cultures also help differentiate nocardiosis.

References

  1. Beaman, B., Black, C., Doughty, F., & Beaman, L. (1985) Role of superoxide dismutase and catalase as determinants of pathogenicity of Nocardia asteroides: importance in resistance to microbicidal activities of human polymorphonuclear neutrophils. Infect Immun. 1985 Jan;47(1):135-41. doi: 10.1128/IAI.47.1.135-141.
  2. Filice, G.A. (2018). Nocardiosis. In Jameson, J., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo, D.L., & Loscalzo, J. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. 
  3. Kurdgelashvili, G. (2018). Nocardiosis. Medscape. Retrieved 25 Nov 2020, from https://emedicine.medscape.com/article/224123-overview
  4. Long, S., Prober, C., & Fischer, M. (2018). Nocardia species. Principles and Practice of Pediatric Infectious Diseases. (5th ed, p. 812). Elsevier, Inc.
  5. Riedel, S., Hobden, J.A., Miller, S., Morse, S.A., Mietzner, T.A., Detrick, B., Mitchell, T.G., Sakanari, J.A., Hotez, P., & Mejia, R. (Eds.) (2019). Aerobic non–spore-forming gram-positive bacilli: Corynebacterium, Listeria, Erysipelothrix, Nocardia, and related pathogens. Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28e. McGraw-Hill. 
  6. Ryan, K.J. (Ed.) (2017). Actinomyces and Nocardia. Sherris Medical Microbiology, 7e. McGraw-Hill. 
  7. Spellman, D., Sexton, D., & Mitty, J. (2019). Microbiology, epidemiology and pathogenesis of nocardiosis. UpToDate. Retrieved 25 Nov 2020, from https://www.uptodate.com/contents/microbiology-epidemiology-and-pathogenesis-of-nocardiosis

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