Pediatric Nocardiosis 

Updated: Aug 14, 2018
Author: Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP; Chief Editor: Russell W Steele, MD 

Overview

Background

Nocardia are weakly gram-positive, filamentous bacteria found worldwide in soils. Human disease from this microbe was first described by Eppinger in 1890, after bovine disease was described by Nocard in 1888. Pathogenic Nocardia are members of the family Nocardiaceae, the aerobic actinomycetes. Nocardia asteroides is the principal cause of systemic nocardiosis in the United States. Nocardia pseudobrasiliensis,Nocardia otitidis-caviarum (formerly Nocardia caviae), Nocardia farcinica,Nocardia nova, and Nocardia transvalensis have also been rarely associated with human systemic disease.[1]

A recent report of infections with Nocardia carnea, Nocardia elegans, Nocardia paucivorans, Nocardia puris, and Nocardia takedensis has come from Japan.[2] Nocardia brasiliensis is a common cause of localized chronic mycetoma. A total of approximately 30 strains of Nocardia have been associated with human disease.

Two newly described species have been associated with disease in humans: Nocardia abscessus, from soft-tissue abscesses,[3] and Nocardia africana, from respiratory secretions of patients with pneumonia in the Sudan.[4] Most recently, Nocardia ignorata, a new agent of human nocardiosis, was isolated from respiratory specimens in Europe and soil samples from Kuwait.[5] Case reports of Nocardia cyriacigeorgica occurring in the United States have been published, with several infections being retrospectively identified from stored samples.

Molecular DNA hybridization techniques (usually involving the 16S ribosomal RNA [rRNA]) have better characterized the Nocardia species; this identification is useful in identifying antibiotic resistance patterns. Several of the species mentioned above (N nova, Nfarcinica, Nabscessus, N cyriacigeorgica) had been considered as N asteroides isolates in some reports.[6]

Nocardiosis is an acute, subacute, or chronic suppurative infection caused by Nocardia. It has a pronounced tendency to remission and exacerbation. Infections are localized or disseminated. Localized cutaneous or lymphocutaneous infections usually occur after contamination of an abrasion, resulting in cutaneous or lymphocutaneous abscess. In children with immunocompetence, systemic spread from the primary skin site is extremely rare.

Disseminated and fulminant disease mainly occurs in immunocompromised hosts (among persons with deficient cell-mediated immunity) with underlying illnesses, such as chronic granulomatous disease or human immunodeficiency virus (HIV) infection, and in children undergoing cytotoxic chemotherapy, bone marrow transplantation, or prolonged glucocorticoid treatment.

Nocardiosis has also been associated with pulmonary alveolar proteinosis, tuberculosis and other mycobacterial diseases, and interleukin 12 deficiency. Inhalation of the free-living organism is the likely route of infection. The primary disease occurs in the pulmonary system and may mimic tuberculous, staphylococcal, or mycotic infections. Hematogenous dissemination may occur to all organs of the body. The brain, kidneys, and liver are the most common metastatic sites.

Interestingly, Nocardia species have been found to produce effective antibacterial agents, including one agent (nargencin) that shows promise against methicillin resistant Staphylococcus aureus.[7] Nocardia lactamdurans has also been found to produce a cephamycin under the right conditions.[8]

Pathophysiology

Introduction of N asteroides via the respiratory tract results in pulmonary lesions that most often manifest as multiple abscesses. Nocardia abscesses are characteristically confluent, with little evidence of encapsulation, which probably accounts for the ready dissemination from the initial pulmonary focus. This organism also evades the host's bactericidal mechanisms. Host neutrophil mobilization can inhibit Nocardia but does not kill them. Cell-mediated immunity triggered by activated macrophages and the induction of a T-cell population capable of direct lymphocyte-mediated cytotoxicity are necessary to kill Nocardia. Infection progresses after the initial inhibition by neutrophils unless antimicrobial therapy or cytotoxic lymphocytes take over.

Nocardia exhibit specific organ tropisms. Log-phase cells of Nocardia, which contain specific cell wall mycolic acids, are more virulent and may influence the ability of nocardiae to localize in certain tissues, such as the brain. Nocardial metastasis manifests as multiple abscesses without granules in different organs. In patients with poor neutrophil activity or impaired cell-mediated immunity, fulminant pulmonary or systemic nocardiosis is an uncommon but opportunistic infection. It is curable but has a high mortality rate (exceeding 50% in some reports), probably because of delayed diagnosis and treatment. A high index of suspicion, followed by aggressive diagnosis and treatment, is necessary for optimal results.

Epidemiology

Frequency

United States

Nocardiosis is sporadic and person-to-person spread is not well documented. Rare outbreaks have been associated with contamination of the hospital environment. Incidence estimates vary in immunocompromised populations. In patients who undergo renal transplant, the incidence rate is 0-20%. In patients who undergo bone marrow transplant, the incidence rate is 0.3%, and in patients with systemic lupus erythematosus, the incidence rate is 2.8%.

Higher rates of infection are observed in the hotter, drier states, perhaps because of easier entry of infectious organisms into the lungs from dust blown into the air.

International

Nocardiosis occurs sporadically worldwide.

Mortality/Morbidity

Death occurs from sepsis, overwhelming pneumonia, or brain abscess, rather than the untreated underlying disease. Mortality is increased in patients with acute infection and in those with disseminated disease involving 2 or more contiguous organs or the CNS. Mortality is also increased in patients taking corticosteroids or antineoplastic agents.

Race

No racial predilection is known.

Age

No age predilection is recognized.

 

Presentation

History

See the list below:

  • Generalized nocardiosis

    • In patients with cutaneous disease, elicit history of trauma at the site of mycetoma (eg, scrape from thorn), firm subcutaneous abscesses (eg, cat scratch, insect bite, open cut), and/or cervical adenitis (eg, dental injury). Signs of infection tracking along lymph node chains or a draining sinus may be present.

    • Slowly progressive joint swelling and pain, with or without fever, may occur, resulting in Nocardia septic arthritis if the trauma was deep (eg, puncture from rooster's claw).

    • The pulmonary course begins with nonspecific complaints, including fever (night sweats), malaise, chest or abdominal pain (may be sudden onset), persistent cough (rarely hemoptysis), and anorexia.

  • Disseminated nocardiosis

    • If dissemination occurs from a pulmonary infection, a constellation of acute and chronic symptoms develops, ranging from headache to obtundation (CNS), pyuria (kidneys), and right upper abdominal pain (liver). CNS infection may have no signs or symptoms or may present with focal neurological deficits, seizures, and coma.

    • Children at risk for nocardiosis as an opportunistic infection include patients with the following:

      • Lymphoreticular neoplasms

      • Chronic pulmonary disorders (most notably alveolar proteinosis)

      • Prolonged corticosteroid usage

      • Systemic lupus erythematosus

      • Severe asthma

      • Chronic granulomatous disease

      • Children with acquired immune deficiency syndrome (AIDS)

    • Patients undergoing transplant for the following are at risk:

      • Renal

      • Cardiac

      • Liver

      • Bone marrow

Physical

See the list below:

  • Subcutaneous abscesses are palpable at the site of trauma and generally feel firmer than fluctuant. Contiguous lymph nodes may indicate infection tracking along lymphatics.

  • A lung examination may reveal diffuse or localized abnormal breath sounds.

  • Mild-to-severe respiratory distress that progresses to respiratory failure may occur.

  • Disseminated miliary appearance can occur with diffuse organ abscesses that mimic miliary tuberculosis.

  • Clinical manifestations may include the following:

    • Bronchopneumonia

    • Lobar pneumonia

    • Necrotizing pneumonia

    • Persistent meningitis

    • Cerebral abscesses

    • Peritonitis

    • Intra-abdominal abscesses

    • Hematogenous endophthalmitis

    • Sinusitis

    • Endocarditis

    • Aortitis

    • Mediastinitis

    • Pyelonephritic abscesses

    • Septic arthritis

Causes

See the list below:

  • Nocardia are usually found in soil and dust, and infection results from inoculation of a wound or inhalation. Person-to-person transmission has not been reported, and Nocardia are not commensal in humans or animals.

  • Nosocomial cases have been reported. In some cases, N asteroides were detected in the dust and air of the hospital unit.

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • Gram staining is indicated in nocardiosis.

    • Directly examine clinical materials (eg, sputum, bronchoalveolar lavage, cerebral spinal fluid, pus) by Gram stains and acid-fast stains (modified Ziehl-Neelsen stains). Delicately branched, weakly gram-positive, variably acid-fast bacilli with tendency to fragment are indicative of Nocardia.

    • Use methenamine-silver stains for demonstrating the organisms in tissue specimens.

    • Inoculate clinical material, including blood specimens, on brain-heart infusion media or Sabouraud agar without antibiotics. N asteroides and N braziliensis are obligate aerobes, thermophilic, and slow growing. Colonies take 1-2 weeks to develop and are usually waxy then chalky in appearance.

  • Serological diagnosis is not readily available.

  • Cultures typically grow within 3-5 days on blood or chocolate agar, but cultures from normally sterile sites should be maintained for 3 weeks in a liquid medium.

  • Case reports of positive testing for beta-D-glucan with nocardial infections have been published,[9, 10] but it isn't always clear whether concomitant infection with a fungus or Pneumocystis was ruled out. In some cases PCP or a candidal infection were discovered shortly after the Nocardia diagnosis, both of which would produce elevated beta-D-glucan levels.

Imaging Studies

See the list below:

  • Generalized infections

    • Chest radiographic findings vary and include fluffy infiltrates, scattered nodules, and confluent lobar infiltrates progressing to complete consolidation and cavitation.

    • Chest CT scanning may be necessary to visualize the extent of disease and to rule out empyema.[11, 12]

    • CT scanning with contrast or MRI may be necessary to visualize cerebral abscesses.

  • Disseminated nocardiosis

    • Perform CT scanning with contrast or MRI to rule out cerebral abscesses. Because of the high incidence of spread to the brain, all patients with pulmonary nocardiosis should have a neuroimaging study, even in the absence of CNS symptoms. Lesions should show ring-enhancement with contrast and fluid-attenuated inversion recovery (FLAIR). Early lesions, or those present during treatment with steroids, may not enhance and may mimic infarction.

    • Use 2-dimensional echocardiography to rule out vegetations.

    • Perform abdominal and/or pelvic sonography and CT scanning to rule out intra-abdominal, hepatic, splenic, or renal abscesses.

Procedures

See the list below:

  • A bronchoalveolar lavage is recommended in immunocompromised individuals in whom nocardiosis is suspected because mortality can exceed 50% without rapid diagnosis and treatment.

 

Treatment

Medical Care

See the list below:

  • Sulfa-based therapy is recommended for nocardiosis. Trimethoprim-sulfamethoxazole (Bactrim) or a sulfonamide (sulfadiazine), given intravenously in high doses, is the treatment of choice.[13]

  • Linezolid has a growing literature in support of its use in combination and even monotherapy for treatment of Nocardia infections. It has good CNS penetration, is available in an oral form, and is the only antibiotic known to be active against all strains of Nocardia.

  • Additional concurrent therapy with an aminoglycoside (amikacin, gentamicin) plus ceftriaxone benefits patients with fulminant disease.

  • Other medications for the pediatric age group include extended-spectrum cephalosporins, imipenem/meropenem, ampicillin, and amoxicillin-clavulanate. Tetracycline derivatives used in treatment include minocycline or doxycycline (in a child >8 y with sulfa hypersensitivity).

  • Patients who are immunocompetent with lymphocutaneous disease are usually treated for 6-12 weeks. Therapy includes incision and drainage of abscesses. Patients with immunocompromising conditions are treated for at least 3 months after clinical cure (usually up to 1 y of therapy).

  • Closely monitor patients with AIDS and CNS disease; relapse can occur years after therapy.

Surgical Care

See the list below:

  • Surgical therapy to drain abscesses is usually helpful (and potentially diagnostic); however, brain abscesses may respond to antimicrobial treatment without surgery. The risks of an invasive neurosurgical procedure should be balanced against the benefits of a diagnostic biopsy or potentially therapeutic drainage.

Consultations

See the list below:

  • A multidisciplinary team in a pediatric ICU setting should manage fulminant nocardiosis.

  • Consultation with a pediatric infectious diseases specialist is also recommended.

  • Neurosurgery or interventional radiology may need to be consulted to obtain biopsies.

 

Medication

Antibiotics

Class Summary

The mainstay of nocardiosis therapy are sulfa-based antibiotics (eg, trimethoprim-sulfamethoxazole) given intravenously in high doses. Trimethoprim-sulfamethoxazole has shown less efficacy as a single agent in some AIDS-related nocardial infections. The single best regimen for treatment has not been established, and antibiotic resistance testing is recommended to tailor therapies to the specific strain infecting the patient. Trimethoprim-sulfamethoxazole, amikacin, and either ceftriaxone or imipenem are a reasonable combination of drugs for an initial empiric therapy prior to the results of susceptibility testing.

The use of linezolid to treat resistant or severe infection has been documented and shows promise.[14] Linezolid has been tested in vitro and has been shown to be the first antimicrobial agent to be active against all Nocardia species. It has good CNS penetration, does not require adjustment for renal or liver disease, has few drug interactions (especially with immunosuppressive medications), and has been shown to work as monotherapy against Nocardia. It is also available with excellent bioavailability in an oral form and may become a first-line therapy for Nocardia infection.

Trimethoprim-sulfamethoxazole (Bactrim, Septra)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Doses are based on the trimethoprim component.

Imipenem and cilastatin (Primaxin)

Therapy with this alternative agent often is used in combination with amikacin. For CNS nocardiosis, consider the related drug, meropenem, instead.

Amikacin (Amikin)

Used in conjunction with trimethoprim-sulfamethoxazole or imipenem-cilastatin. Peak therapeutic levels are 20-30 mg/L, and trough levels are 5-10 mg/L.

Minocycline (Dynacin, Minocin)

Another alternative drug both in PO and IV formulations for prolonged treatment. However, it is not recommended in children < 8 y.

Amoxicillin and clavulanate (Augmentin)

Aminopenicillin with a beta-lactamase inhibitor. Doses are based on the amoxicillin component. This drug is used as a follow-up treatment PO agent for prolonged therapy following IV treatment with imipenem or meropenem/amikacin. (See trimethoprim-sulfamethoxazole for suggested treatment duration.)

Ampicillin (Marcillin, Omnipen)

Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take PO medication.

Meropenem (Merrem IV)

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 bacteria and slightly decreased activity against staphylococci and streptococci compared to imipenem. Not recommended for children.

Doxycycline (Bio-Tab, Doryx, Vibramycin)

Inhibits protein synthesis and thus bacterial growth by binding to 30S and, possibly, 50S ribosomal subunits of susceptible bacteria.

Sulfadiazine (Microsulfon)

Exerts bacteriostatic action by competitive antagonism of para-aminobenzoic acid (PABA). Microorganisms that require exogenous folic acid and do not synthesize folic acid are not susceptible to the action of sulfonamides.

Linezolid (Zyvox)

A synthetic antibiotic of the oxazolidinone class, which prevents the formation of functional 70S initiation complex. This is essential for the bacterial protein translation process. Although it seems to be bacteriostatic against Nocardia (as it is with most bacteria except pneumococci), it does seem to be a very effective therapy even as a monotherapy.

 

Follow-up

Further Outpatient Care

See the list below:

  • Once patient is stable, continue prolonged antibiotic therapy on an outpatient basis.

  • An infectious diseases specialist should continue to monitor the patient to determine treatment progress and duration.

Further Inpatient Care

See the list below:

  • Fulminant or disseminated nocardiosis requires multidisciplinary intensive-care management.

  • Provide ongoing assessment for surgical debridement of nocardial abscesses.

  • Initiate intravenous antibiotic therapy immediately, during inpatient admission.

Transfer

See the list below:

  • In cases of fulminant disseminated nocardiosis, transfer patient to a facility with pediatric intensive care and subspecialty care.

Deterrence/Prevention

See the list below:

  • No specific recommendations for prophylaxis against Nocardia as an opportunistic pathogen in patients with immunocompromising conditions are known.

  • Bactrim prophylaxis is recommended for patients with AIDS, chronic granulomatous disease, and various malignancies but is usually used in the context of preventing Pneumocystis pneumonia.

  • The use of prophylaxis should not preclude testing, if the situation warrants, attenuate the symptoms and signs of infection. Case reports of drug-resistant Nocardia presenting in Bactrim-prophylaxed immunosuppressed patients have been presented.

Prognosis

See the list below:

  • Morbidity and mortality are high from fulminant nocardiosis. A high index of suspicion, followed by a rapid diagnosis and treatment, is warranted.

  • Intensive medical management (surgery, if necessary) and prolonged treatment leads to a cure.