Infectious Diseases

Nocardia species

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Nocardia species are thin, aerobic, gram-positive bacilli that form branching filaments. The bacteria stain irregularly and appear beaded on Gram stain. The speciation of Nocardia has been problematic. The original classification was based on the ability to use specific nutrients and to decompose substrates such as adenine, casein, urea, gelatin, and xanthine. However, gene sequencing and deoxyribonucleic acid (DNA)-DNA hybridization have now defined the true taxonomy. The species called Nocardia asteroides was previously reported to be the most common cause of human disease. However, the majority of these bacteria were misidentified by today’s standards. The number of species causing human disease is large and includes N. abscessus, N. brevicatena/paucivorans complex, N. nova complex, N. transvalensis complex, N. farcinica, N. cyriacigeorgica, N. otitidiscaviarum, N veterana, N. brasiliensis, and N. pseudobrasiliensis.

What is the best treatment?

  • Sulfonamides remain the treatment of choice for pulmonary and cutaneous disease. Trimethoprim/sulfamethoxazole given orally at a dose of 160/800 mg (one double strength) three times a day is the most commonly used adult regimen.

  • For disseminated and/or central nervous system (CNS) Nocardia infection combination therapy is recommended:

    • Trimethoprim/sulfamethoxazole at the above doses, amikacin (10 mg/kg/day in divided dose), and either ceftriaxone (2 g twice a day) or imipenem (500 mg every 6 hours) is one of the preferred empiric regimens.

    • For patients failing trimethoprim/sulfamethoxazole therapy, imipenem with or without amikacin has been shown to be effective.

    • Patients with disseminated or CNS disease treated with sulfonamides alone have a less than 50% survival rate.

    • One of the most common species to cause disseminated disease, N. farcinica, is also one of the most common Nocardia species to be resistant to sulfonamides. In these more serious conditions, combination therapy is generally recommended. The exact regimen should be guided by antibiotic susceptibility testing.

  • Linezolid 600 mg twice a day has been used successfully in a small number of CNS infections. However, prolonged therapy with this agent can lead to bone marrow toxicity and irreversible peripheral neuropathy, and warrants weekly monitoring of the peripheral cell counts and careful attention to any symptoms suggesting neuropathy.

  • Moxifloxacin (400 mg orally per day recommended) has been shown to have activity against several strains of Nocardia, including N. farcinica and N. brasiliensis, and these agents may prove to be useful in patients who cannot tolerate sulfonamides, however relapse has been reported.

  • Minocycline (100 mg orally twice a day) or amoxicillin/clavulanate (875/125 mg orally twice a day) are other potentially effective alternative treatments for Nocardia infection.

  • The duration of therapy is 6 to 12 months in the immunocompromised host and 4 to 6 months in the normal host in order to prevent relapse. Nocardia is intracellular and has slow rates of bacterial growth making eradication of the organism difficult, and explaining its tendency to relapse.

  • Surgical drainage—in addition to antibiotics, patients with brain abscess or subcutaneous abscesses will require surgical drainage for cure.

How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology-

    • Nocardia species are ubiquitous, and primarily originate in soil. Despite being found throughout the environment, they rarely cause symptomatic infection in humans. Because nocardiosis is not a reportable disease, the frequency of this disease is unknown. However, the annual incidence has been estimated to be approximately 0.4 cases per 100,000 population.

  • Infection control and prevention issues-

    • Nocardia has not been shown to spread from person to person and no isolation precautions are required.

    • Because of the rarity of this infection, even among immunocompromised patients, no specific prophylaxis is recommended. However, the practice of giving patients trimethoprim/sulfamethoxazole to prevent pneumocystis has the potential to also prevent many cases of Nocardia infection. However, it is important to keep in mind that trimethoprim/sulfamethoxazole prophylaxis does not always protect against Nocardia infection.

    • No vaccine is available.

What host factors protect against this infection?

  • In addition to neutrophils and macrophages, cell-mediated and humoral immunity play roles in protecting the host against Nocardia invasion, explaining the wide range of immunocompromised patients that are at increased risk for contracting nocardiosis.

  • The risk of symptomatic Nocardia infection is greatly increased (the incidence is estimated to be >1,000-fold higher) in individuals who are immunocompromised, including patients who are receiving immunosuppressive agents following bone marrow or solid organ transplant, and patients with acquired immunodeficiency syndrome (AIDS). Corticosteroids are the immunosuppressants most frequently associated with nocardiosis; however, cases have also have been reported in patients receiving anti-tumor necrosis factor-α antibody (infliximab), as well as other immunosuppressants.

  • Other risk groups include patients with cancer, Cushing disease, chronic granulomatous disease, and dysgammaglobulinemia.

  • Patients with chronic pulmonary disorders, particularly alveolar proteinosis, are also more susceptible to this infection.

  • In approximately one third of patients with nocardiosis no predisposing condition can be identified.

  • The histopathology typically reveals a robust acute inflammatory response with degraded neutrophils and fibrin. Localized areas of necrosis are commonly seen and discrete abscesses without significant capsular formation often form in the skin, lungs, and brain. A granulomatous reaction surrounding the regions of acute inflammation may be seen; however, true granuloma, are not found.

What are the clinical manifestations of infection with this organism?

Nocardiosis has no pathognomonic characteristics, and delays in diagnosis are common. Failure of a pulmonary or skin infection to respond to conventional antibiotic therapy should raise the possibility of a Nocardia species infection. Nocardiosis should always be considered in the immunocompromised patient.

  • Pulmonary infection—approximately two thirds of patients with nocardiosis present with pulmonary infection.

    • The infection is usually subacute in onset, mimicking a fungal or mycobacterial infection, and is most commonly misdiagnosed as tuberculosis. Acute onset of pneumonia has occasionally been reported in the immunocompromised host.

    • Common complaints are:

      • persistent cough producing purulent sputum

      • fever

      • anorexia and weight loss

    • Pleuritic chest pain and dyspnea are less common.

    • Hemoptysis is rare, but can develop in patients with large cavitary lesions.

  • CNS infection—approximately 5% of patients with a Nocardia infection suffer CNS involvement.

    • Multilocular brain abscess is the most common CNS manifestation and is usually the consequence of transient bacterial dissemination from the lung. Lesions can occur in any region of the brain, and symptoms depend on location.

    • Headache is the usual initial complaint and it is frequently localized to the site of the abscess.

    • The patient may present with neurological deficits as well as seizures.

    • In AIDS patients, a brain abscess is often accompanied by an abnormal chest X-ray, while in other patients abnormalities in chest X-ray are not always present.

    • The infection mimics other diseases including:

      • metastatic lung carcinoma. The combined findings of a lung nodule on chest X-ray and a ring-enhancing CNS lesion are often mistaken for metastatic lung carcinoma

      • disseminated aspergillosis or toxoplasmosis. When the immunocompromised host presents with both a lung and CNS focus disseminated aspergillosis and toxoplasmosis should also be considered

    • Meningitis is a less common CNS manifestation, and is often associated with brain abscess (40% of meningitis cases). Cerebrospinal fluid cultures are often negative and these patients fail to fully respond to empiric antibiotic therapy.

  • Cutaneous infection—skin infection is usually caused by N. brasiliensis,

    • The infection usually follows a break in the skin that is contaminated by soil. It is reported in association with:

      • trauma

      • postoperative wounds

      • insect bites

      • thorn bush scratches

      • cat scratches

    • Initially a pustule or moderately erythematous, nonfluctuant nodule develops at the site of inoculation.

    • Lymphocutaneous or sporotrichoid disease: erythema can extend along the lymphatic system and is associated with tender lymphadenopathy.

      • This form of disease mimics other skin infections including:

        • cat scratch disease

        • tularemia

        • Mycobacterium marinum

        • sporotrichosis

      • Disseminated disease in the immunocompromised host may be manifest by multiple erythematous raised nodules and is an ominous finding. Organisms can also seed the eyes (primarily the retina), kidneys, bones, joints, and heart.

      • Mycetomas: in tropical regions of South and Central America Nocardia species can cause ulcerations and large tumor-like lesions called mycetomas that are usually found on the lower legs.

  • Septic Arthritis – this is a rare complication, only 34 cases being reported in the literature.

      • Hematogenous spread is most common and usually seen in immunocompromised hosts.

      • Local spread can occur in normal hosts.

      • Prolonged therapy is required, median duration being 24 weeks for hematogenous cases and 12 weeks for cutaneous inoculation cases.

      • Management is complex and should include input from specialists in rheumatology, infectious diseases and surgery.

How should I identify the organism?

  • Invasive procedures are generally required for specific diagnosis. For pulmonary infection, bronchoscopy with transbronchial biopsy or skinny needle biopsy is recommended. For brain abscess computed tomography (CT) guided needle aspirate is the diagnostic procedure of choice.

  • Gram stain or Brown-Brenn stains reveal gram-positive beaded branching forms. The morphology is identical to Actinomyces, however the high lipid content of its cell wall often renders Nocardia modified acid-fast positive, while Actinomyces spp. are modified acid-fast negative. However, acid fastness may be variable when staining Nocardia colonies from cultures, and is unreliable for direct clinical samples.

  • Isolation of the organism on culture provides a definitive diagnosis for needle aspirate samples from brain abscess, and a presumptive diagnosis when grown from respiratory and cutaneous samples.

    • Nocardia grow best under aerobic conditions with 5 to 10% carbon dioxide.

    • The organism grows slowly on blood agar, taking 3 to 5 days to form colonies.

      • This allows other organisms to overgrow.

      • Selective media should be used when Nocardia is suspected. Notify the clinical laboratory and they will then know to use selective media and prolonged incubation.

    • 16S ribosomal ribonucleic acid (rRNA) gene sequencing can allow rapid species identification.

    • MALDI-TOF diagnosis is becoming available and was associated with a 94% accuracy for identification to the species level on a set of 164 isolates.

    • Increasing numbers of Nocardia have been shown to be resistant to sulfonamides. Therefore, antibiotic susceptibility testing should always be performed to guide the choice of antibiotics.

How does this organism cause disease?

  • Most Nocardia species gain entry to the host via the respiratory tract or less commonly by skin inoculation.

  • Important virulence factors:

    • Superoxide dismutase—invading bacteria elicit a neutrophil response that inhibits, but does not kill the organism. The bacteria are phagocytosed by neutrophils and macrophages and become enclosed in a membrane bound phagolysosome. In this closed environment neutrophils and macrophages are able to kill many species of bacteria by synthesizing superoxide and hydrogen peroxide. However, Nocardia are able to survive in this hostile environment by producing superoxide dismutase, an enzyme that inactivates these toxic oxygen by-products.

    • Mycolic acid, also called cord factor, inhibits the fusion of lysosomes with the phagolysosomal compartment, preventing toxic proteases and other antibacterial products from reaching the intracellular bacteria.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Microbiology and antibiotic sensitivity

Lowman, W, Aithma, N. "Antimicrobial susceptibility testing and profiling of Nocardia species and other aerobic actinomycetes from South Africa: comparative evaluation of broth microdilution versus the Etest". J Clin Microbiol. vol. 48. 2010. pp. 4534-40.

(Drug susceptibility patterns demonstrated limited concordance with species identification. The Etest is not an acceptable alternative to the reference method of broth microdilution for antimicrobial susceptibility testing.)

Uhde, KB, Pathak, S, McCullum, I. "Antimicrobial-resistant nocardia isolates, United States, 1995-2004". Clin Infect Dis. vol. 51. 2010. pp. 1445-8.

(The species most commonly identified were N. nova (28%), N. brasiliensis (14%), and N. farcinica (14%). Of 765 isolates submitted, 61% were resistant to sulfamethoxazole and 42% were resistant to trimethoprim/sulfamethoxazole.)

Brown-Elliott, BA, Brown, JM, Conville, PS, Wallace, RJ. "Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy". Clin Microbiol Rev. vol. 19. 2006. pp. 259-82.

(Reviews taxonomy, 16S rRNA gene sequencing, antibiotic sensitivities, and treatment.)

Girard, V, Mailler, S, Polsinelli, S. "Routine identification of Nocardia species by MALDI-TOF mass spectrometry". Diagn Microbiol Infect Dis. October 2016.

(MALDI-TOF MS demonstrated a 94% accuracy in identifying Nocardia species from a collection of 164 species and identification details will be available in the next release of VITEK MS update [IVD Version 3.0].)

Clinical manifestations

Chaussade, H, Lebeaux, D, Gras, G. "Nocardia Arthritis: 3 Cases and Literature Review". Medicine (Baltimore). vol. 94. 2015. pp. e1671.

(A rare complication, contracted by hematogenous spread in immunocompromised and by cutaneous spread in immunocompetent patients. Management is complicated and is best managed with help from rheumatology, infectious disease and surgical experts.)

Coussement, J, Lebeaux, D, van Delden, C. "Nocardia Infection in Solid Organ Transplant Recipients: A Multicenter European Case-control Study". Clin Infect Dis. vol. 63. 2016. pp. 338-45.

(117 cases reported, 5 risk factors were identified: high calcineurin inhibitor trough levels, use of tacrolimus, corticosteroid dose, patient age and length of stay in the intensive care unit after SOT.)

Dodiuk-Gad, R, Cohen, E, Ziv, M. "Cutaneous nocardiosis: report of two cases and review of the literature". Int J Dermatol. vol. 49. 2010. pp. 1380-5.

(Two case reports of a localized and a disseminated case of cutaneous Nocardia infection.)

Lederman, ER, Crum, NF. "A case series and focused review of nocardiosis: clinical and microbiologic aspects". Medicine (Baltimore). vol. 83. 2004. pp. 300-13.

(Report of five cases of nocardiosis representing various aspects of this "great imitator": 1) pneumonia in the setting of underlying malignancy, 2) chronic pneumonia with drug-resistant organism, 3) bacteremia and empyema with chronic hematologic malignancy, 4) primary cutaneous disease, and 5) sternal wound infection. Summarizes the English literature from 1966 to 2003.)

Li, S, Song, X, Zhao, Y. "Clinical Analysis of Pulmonary Nocardiosis in Patients With Autoimmune Disease". Medicine (Baltimore). vol. 94. 2015. pp. e1561.

(24 cases of patients with autoimmune disorders and pulmonary nocardiosis. Air-space opacities and nodules were the most common chest imaging features. Disseminated nocardiosis with lung and skin involvement was the most common clinical presentation.)

Minero, MV, Marín, M, Cercenado, E, Rabadán, PM, Bouza, E, Muñoz, P. "Nocardiosis at the turn of the century". Medicine (Baltimore). vol. 88. 2009. pp. 250-61.

(A comprehensive series of cases from a single hospital that, as compared with reviews of individual case reports, more accurately reflects the organ distribution of Nocardia infection, the common clinical manifestations, treatment, and outcome.)

Rafiei, N, Peri, AM, Righi, E, Harris, P, Paterson, DL. "Central nervous system nocardiosis in Queensland: A report of 20 cases and review of the literature". Medicine (Baltimore). vol. 95. 2016. pp. e5255.

(20 cases reported from Queensland. Overall, 35% or 7 patients died within 1 year, and 6 were attributed to N farcinica. Half of the patients were immunocompromised hosts, with corticosteroid administration being the most common risk factor.)

Imaging

Cianfoni, A, Calandrelli, R, De Bonis, P, Pompucci, A, Lauriola, L, Colosimo, C. "Nocardia brain abscess mimicking high-grade necrotic tumor on perfusion MRI". J Clin Neurosci. vol. 17. 2010. pp. 1080-2.

(Perfusion magnetic resonance imaging has been helpful in differentiating brain abscess from tumor. A case of Nocardia brain abscess is reported whose diffusion characteristics were identical to necrotic tumor.)

Kanne, JP, Yandow, DR, Mohammed, TL, Meyer, CA. "CT findings of pulmonary nocardiosis". AJR Am J Roentgenol. vol. 197. 2011. pp. W266-72.

(Common CT findings include lung consolidation and nodules and masses. Cavitation may occur. Chest wall involvement develops in a small number of patients.)
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