Nocardiosis
I. What every physician needs to know.
Nocardiosis is an opportunistic disease caused by gram-positive aerobic actinomycetes of the genus Nocardia. It presents as an acute, subacute, or chronic infection with cutaneous, pulmonary, and disseminated forms. Nocardiosis affects mainly immunocompromised patients, such as those with acquired immunodeficiency syndrome (AIDS) or transplant recipients. Pulmonary disease is most common in immune-deficient patients, but can disseminate to virtually any organ.
Immunocompetent individuals usually present with primary cutaneous nocardiosis resulting from direct inoculation of the organism.
II. Diagnostic Confirmation: Are you sure your patient has Nocardiosis?
Patients with nocardiosis present with nonspecific symptoms. Gram stain, modified acid-fast (Kinyoun) stain, and specimen culture are the principal methods of diagnosis.
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A. History Part I: Pattern Recognition:
Nocardiosis appears worldwide and affects people between 20 and 60 years of age. Suspect nocardiosis in immunocompromised patients with acute, sub-acute, or chronic pneumonia, or in those with central nervous system or skin and soft tissue involvement.
B. History Part 2: Prevalence:
An estimated 500 to 1,000 new cases of nocardiosis appear every year in the United States, but incidence is likely rising with the increasing prevalence of impaired cell-mediated immunity. Invasive pulmonary infection, disseminated infection, and brain abscess comprise 80% of the cases; the remaining 20% present as cellulitis.
Nocardiosis is more frequent in patients with immune dysfunction, such as those with AIDS, hematologic and solid organ malignancies, liver cirrhosis, diabetes, alcoholism and chronic steroid use, as well as in organ and hematopoietic stem cell transplant recipients. As Nocardia species are ubiquitous soil organisms and are readily aerosolized with dust, the respiratory tract is the main portal of entry. Thus, structural lung abnormalities and bronchiectasis are risk factors for respiratory colonization. Agricultural work can lead to direct inoculation and primary infection of the skin and subcutaneous tissue.
C. History Part 3: Competing diagnoses that can mimic Nocardiosis.
Nocardiosis can present with a myriad of symptoms that mimic other disease processes. Likewise, co-infections with other members of the fungal genus which are also ubiquitous in nature, such as can also occur especially in immunocompromised patients.
Sporotrichosis or other fungal infections can mimic primary cutaneous nocardiosis. Bacterial lung abscesses, tuberculosis, aspergillosis, and other opportunistic fungal infections present similarly to pulmonary nocardiosis. Disseminated nocardiosis should be distinguished from actinomycosis, tuberculosis, fungal infections and malignancies affecting the lungs, the skin, and the brain by biopsy and culture.
D. Physical Examination Findings.
Pulmonary and disseminated nocardiosis symptoms are nonspecific and include fatigue, fever, chills, productive cough, dyspnea, pleuritic chest pain, and weight loss. Those with cutaneous nocardiosis can present with cellulitis, pustules, pyoderma, paronychia, ulcerations, and localized abscesses. Patients with nocardiosis invading the central nervous system (CNS) may have headache, lethargy, confusion, seizures, or focal neurological deficits.
E. What diagnostic tests should be performed?
Collect sputum, bronchoalveolar lavage, or other respiratory specimens if pulmonary nocardiosis is suspected. Obtain skin biopsies to evaluate for cutaneous nocardiosis. Aspirations from fluid collections, cerebrospinal fluid (CSF), and biopsy material for disseminated nocardiosis should be obtained and sent for culture.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Staining with modified acid-fast stain and gram stain can provide a rapid presumptive diagnosis while awaiting culture results. Nocardia species are in the family of aerobic actinomycetes and present as gram-positive branching filamentous rods that produce fungus-like colonies in culture. Samples may be repeated if initial specimens are negative but there is high suspicion for nocardiosis. Nocardiae normally appear within 2 to 7 days on routine media, but slow-growing strains may require up to 2 weeks of incubation to appear. Once the microorganism has been isolated, the species should be identified by biochemical reaction or molecular techniques as different species have different resistance profiles. The majority of cases are caused by the Nocardia asteroides complex (>50% of invasive infections).
Lumbar puncture of the CSF in patient with a brain abscess due to Nocardia will reveal elevated protein, low glucose, and elevated neutrophils, consistent with a bacterial meningitis. Blood cultures should be obtained when pulmonary or disseminated nocardiosis is suspected.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
In pulmonary nocardiosis, nodular images and cavities are frequently seen in the chest radiograph and computed tomography (CT) scan. In patients with disseminated nocardiosis, brain imaging, either CT or magnetic resonance imaging (MRI), should be performed to exclude neurologic involvement. See Figure 1 and Figure 2.
Figure 1.
Figure 2.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
None
III. Default Management.
Management of nocardiosis involves antimicrobial therapy in conjunction with surgical debridement/drainage when appropriate, as well as improvement of immune function when possible. Therapy is dependant on the severity and localization of the infection, host immune status, potential drug interactions, and the Nocardia species involved. Obtain specimen for culture. Empiric treatment with antibiotics should be initiated while awaiting final speciation and susceptibility results. The mainstay of treatment has been sulfonamides.
For primary cutaneous nocardiosis, treat with Trimethoprim/Sulfamethoxazole (TMP/SMX) or Trimethoprim (TMP) and a fluoroquinolone if there is a concern for a deep infection. For patients with serious disease, central nervous system involvement, and/or disseminated infection, a 3-drug regimen comprising of TMP/SMX, amikacin, and either ceftriaxone or imipenem may be used. Patients should be initially started on parenteral antibiotics. For serious infections, at least 2 weeks of initial intravenous antibiotics is recommended and can be switched to oral therapy with clinical improvement. Consider surgical treatment for deep abscesses.
A. Immediate management.
Supportive care, obtain specimens for gram staining and culture.
B. Physical Examination Tips to Guide Management.
As previously discussed, physical exam findings in nocardiosis are nonspecific. Look for signs of clinical improvement with appropriate treatment of the infection.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
Due to the prolonged treatment course for nocardiosis, monitor for side effects associated with TMP-SMX, including gastrointestinal symptoms, skin rashes, renal impairment, hepatotoxicity, and bone marrow suppression. Evaluate skin for development of rash, obtain urinalysis if concern for urolithiasis, and monitor complete blood count (CBC), blood urea ntirogran/creatinine, liver function tests to monitor for possible side effects of antibiotic therapy.
Given the expansion of taxonomy of Nocardia species in recent years and new susceptibilities in patients with suboptimal response to standard therapy, consider 16S sequencing to identify the appropriate isolate and test for susceptibility and possible TMP-SMX resistance, as well as the role for other antibiotics such as Linezolid.
D. Long-term management.
Primary cutaneous nocardiosis should be treated for 1 to 3 months. Mycetoma requires even more prolonged therapy. Patients with pulmonary and disseminated nocardiosis without central nervous system involvement should be treated for at least 6 months. Those with central nervous system involvement should be treated for at least 9 to 12 months. Antimicrobial therapy should be continued at least 1 month following resolution of evidence of infection. Human immunodeficiency virus (HIV) patients with low CD4 counts and transplanted patients should be provided secondary prophylaxis with an active oral agent until immune status improves.
In the event of hematogenous spread, a patient may develop long term persistent nocardiosis and may require up to 24 months of antibiotic therapy.
E. Common Pitfalls and Side-Effects of Management.
As there is no definitive evidence of person-to-person transmission of Nocardia infection, respiratory or contact isolation is not recommended. As the disease has a tendency to recur, antibiotic doses and levels must be monitored to ensure optimal concentrations.
See Table I for antibiotic recommendations.
Table I.
| Primary cutaneous nocardiosis | Pulmonary nocardiosis | Disseminated nocardiosis | |
| Suggested initial treatment | TMP/SMXTMP/SMX + fluoroquinolone | TMP/SMXTMP/SMX+ ceftriaxoneTMP/SMX+ moxifloxacinImipenem+ amikacin | Imipenem+ amikacinTMP/SMX+ imepenem + amikacinTMP/SMX+ ceftriaxone + amikacin |
| Doses | 10mg/kg/d of TMPaCiprofloxacin500-750 mg bidMoxifloxacin400 mg qd | 10-20mg/kg/d of TMPa10-20mg/kg/d of TMPa + 2,000 mg qd10-20mg/kg/d of TMPa + 400 mg qd500mg qid + 15 mg/kg/d qd | 500mg qid + 15 mg/kg/d qd10-20mg/kg/d of TMPa + 500 mg qd + 15 mg/kg/d qd10-20mg/kg/d of TMPa + 2,000 mg qd + 15 mg/kg/d qd |
| Mainside effects | Rash, bone marrow suppression, urinary lithiasis | Rash, bone marrow suppression, urinary lithiasis, renal toxicity, hypersensitivity | Rash, bone marrow suppression, urinary lithiasis, renal toxicity, hypersensitivity |
| Comments | Afluoroquinolone must be considered for deep infections, especially mycetoma. | TMP/SMXmonotherapy only in immunocompetent patients with mild disease. Combination therapy is preferred in the immunocompromised. | Linezolidcould replace any of the proposed drugs. At least 2 weeks of initial IV treatmentis recommended. Surgical treatment must be considered for deep abscesses. |
TMP/SMXtrimethoprim-sulfamethoxazole; qd once a day; bid twice a day; qid four timesa day
aDivided into three doses
Ambrosioni et al. Infection.2010 Apr;38(2):89-97
IV. Management with Co-Morbidities.
A. Renal Insufficiency.
Monitor renal function if treating with TMP/SMX.
B. Liver Insufficiency.
Monitor liver function tests if treating with TMP/SMX.
C. Systolic and Diastolic Heart Failure.
No change in standard management.
D. Coronary Artery Disease or Peripheral Vascular Disease.
No change in standard management.
E. Diabetes or other Endocrine issues.
No change in standard management.
F. Malignancy.
Refer to immunosuppression section.
G. Immunosuppression (HIV, chronic steroids, etc.)
AIDS patients with CD4 <100 cells/microliter (cells/μL) are more likely to develop pulmonary and extrapulmonary disease. HIV patients with low CD4 count and transplanted patients should be given secondary prophylaxis with an oral agent until immune status improves. There is a high incidence of rash, fever, and neutropenia in AIDS patients associated with prolonged treatment regimens with TMP-SMX. Hepatotoxicity is also more frequently seen with AIDS patients. Hematogenous spread to the central nervous system is more common in immunocompromised hosts. Nocardiosis is rare within the first month after organ transplantation but can present after aggressive immunosuppression.
H. Primary Lung Disease (COPD, Asthma, ILD).
Underlying chronic structural lung disease is a risk factor for respiratory colonization by Norcardia species.
I. Gastrointestinal or Nutrition Issues.
No change in standard management.
J. Hematologic or Coagulation Issues.
Monitor CBC for bone marrow suppression if treating with TMP/SMX.
K. Dementia or Psychiatric Illness/Treatment.
No change in standard management.
L. Dermatologic issues:
Diffuse rash is a common adverse event associated with TMP-SMX use. Offending agent should be discontinued and alternative antibiotic options should be used.
V. Transitions of Care.
A. Sign-out considerations While Hospitalized.
No specific sign-out considerations for nocardiosis.
B. Anticipated Length of Stay.
Patients with nocardiosis often have higher comorbidity and disseminated disease requiring long term intravenous antibiotics for several weeks while awaiting susceptibility testing. Per several studies, mean length of stay is about 20 days.
C. When is the Patient Ready for Discharge.
Clinical improvement is usually seen within one week of initiating antimicrobial therapy. Patient is ready for discharge once baseline bloodwork (CBC, basic metabolic panel, liver function tests), specimens for culture, and central venous catheter access for parenteral antibiotics is established.
D. Arranging for Clinic Follow-up.
1. When should clinic follow up be arranged and with whom.
Follow up with primary care provider and infectious disease clinic.
2. What tests should be conducted prior to discharge to enable best clinic first visit.
Follow up radiographic studies should be obtained to monitor for resolution of infection. Following discontinuation of therapy, patients treated for cerebral nocardiosis should be monitored for relapse of disease with repeat CT or MRI imaging of the brain. Follow up laboratory studies should be obtained to monitor for adverse effects from antibiotic treatment.
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
See above.
E. Placement Considerations.
Patients will require prolonged antibiotic therapy.
F. Prognosis and Patient Counseling.
Patients should be counseled on the need for protracted antibiotic therapy and the potential adverse effects of antimicrobial therapy. Cure rates are almost 100% in appropriately treated skin and soft-tissue infections, 90% in pleuropulmonary disease, 63% in disseminated nocardiosis, and 50% in those with brain abscess. Patients with multiple brain abscesses have a higher mortality (41%), especially in the immunocompromised (55%). Organ transplant recipients can be cured with appropriate antimicrobial therapy even while on immunosuppressive agents if the diagnosis is made early and full-dose therapy is continued for an adequate time period.
VI. Patient Safety and Quality Measures.
A. Core Indicator Standards and Documentation.
None
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
Primary prophylaxis is generally not considered because of the overall low incidence of nocardiosis. However, prophylactic therapy for Pneumocystis jiroveci pneumonia (PCP) with TMP/SMX in AIDS patients with CD4 less than 200 cells/μL and in transplant patients appears to decrease the likelihood of nocardiosis.
De Clerk, F, Van Ryckeghem, F, Depuydt, P, Benoit, D, Druwe, P. “Dual disseminated infection with Ncardia farcinica and Mucor in a patient with systemic lupus erythematosus: a case report”. . vol. 8. 2014. pp. 376(While it is important not to miss Nocardia in clinical scenarios where other diagnoses such as malignancy are higher on the differential, it is also important not to miss co-infections. Multiple case reports have described co-infections with between Nocardia and fungal spp.)
Schlaberg, R, Fisher, M, Hanson, K. “Susceptibility profiles of Nocardia isolates based on current taxonomy”. . vol. 58. 2014. pp. 795-800. (There is increasing literature with evidence of resistance of Nocardia spp to TMP-SMX in the setting of new strains of Nocardia and new susceptibility patterns. For this reason, it is important for the physician to understand the need for further treatment in patients who may not be responding appropriately to standard therapy.)
Ozgenc, O, Avci, M, Ari, A, Celebi, I, Coskuner, S. “Long-term treatment of persistent disseminated Nocardia cyriacigeorgica infection”. . vol. 18 . 2014. pp. 556-560. (Though rare, it is important to recognize the need for prolonged treatment in patients with hematogenous spread of Nocardia leading to a persistent disseminated disease presentation.)
Ozgenc, O, Avci, M, Ari, A, Celebi, I, Coskuner, S. “Long-term treatment of persistent disseminated Nocardia cyriacigeorgica infection”. Braz J Infec Dis. vol. 18 . 2014. pp. 556-560. (The rash of TMP-SMX is very common and should still be mentioned in adverse events from use of this medication.)
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