Are You Confident of the Diagnosis?
What you should be alert for in the history
Nocardiosis is an opportunistic infection that can manifest in three forms: cutaneous, pulmonary, or disseminated disease. Nocardia has been called one of the “great imitators” because it can present in multiple forms, affect any organ, and cause a variety of signs and symptoms that overlap with other diseases. Thus, diagnosis is difficult and requires a high degree of clinical suspicion and careful diagnostic work-up.
Because it is a rare and predominately opportunistic infection, the first step to diagnosis is being alert to potential risk factors in a patient’s history. Consider nocardiosis in the differential for any immunocompromised patient with fevers, chills, night sweats, skin lesions and pulmonary or neurologic symptoms. Also consider nocardia in any individual with symptoms of a superficial or systemic infection that cannot be explained by another organism, cannot be identified by routine work-up, and is not responding to standard antimicrobial therapy. Have a high suspicion of nocardiosis in HIV or AIDS patients, who have up to a 340-fold higher incidence compared to the general population.
Other commonly affected individuals are solid organ transplant patients, stem cell/bone marrow transplant patients, and patients on chronic corticosteroids or immunosuppressives. Even if a patient is unaware of any history of immunosuppression, always inquire further about possible conditions associated with altered immunity or conditions requiring immunosuppressives. Does the patient have a history of chronic lung disease, alcoholism, cirrhosis, malignancies (especially hematologic), Cushing syndrome, systemic lupus erythematosus, ulcerative colitis or Crohn’s disease, sarcoidosis, renal failure, Whipple disease, hypogammaglobulinemia, chronic granulomatous disease, or diabetes mellitus?
Nocardiosis predominantly affects immunocompromised individuals, but up to 30% of infections can occur in normal hosts. However, in normal hosts, the disease is often localized and will commonly have a clear antecedent event. Be alert to posttraumatic infections that appear unusually indurated, ulcerate, develop purulent sinus tracts, or are refractory to routine antimicrobials. Historical clues that should raise suspicion of nocardia include jaw trauma with subsequent abscess formation, agricultural-associated wounds, trauma occurring in soil or near decaying material, and exposure to aerosolized dirt. Has the patient been in a wooded area recently, spent time in barns or walking through fresh water? Has the patient traveled anywhere recently? Nocardia is endemic in some tropical areas. Also be alert to any recent surgeries, especially head/neck, which could innoculate the bacteria.
Characteristic findings on physical examination
Cutaneous nocardiosis manifests in four forms: primary cutaneous, lymphocutaneous, cutaneous from a disseminated infection or mycetoma. Clinical findings vary among forms. Overall, fever is common and generalized lymphadenopathy is rare. Primary cutaneous nocardiosis may present with pustules, erythematous nodules, abscesses, ulcerations, cellulitis, or pyoderma (Figure 1). Nocardia cellulitis characteristically appears as a sharply demarcated, deeply erythematous indurated plaque similar to that of erysipelas.
Lymphocutaneous nocardiosis may mimic sporotrichosis, causing painful ulcerative nodules at the site of innoculation and ascending regional lymphadenopathy. Nocardia mycetoma occurs with subcutaneous infections and appears as a painless erythematous chronically swollen extremity. The associated triad of tumefaction, sinus tract formation, and drainage of sulfur granules should alert the clinician to the presence of a mycetoma. Less common types of superficial infections include paronychias, endophthalmitis, keratitis, and wound infections.
Expected results of diagnostic studies
The principal method of diagnosis is by identification of Nocardia species from the site of infection. Superficial smears, tissue samples, and abscess aspiration are the most common methods of detection. Nocardia organisms can be visualized by gram staining, Gomori methenamine silver stain, or modified Kinyoun acid-fast staining. The characteristic histologic appearance is an irregularly-shaped, filamentous, branching organism surrounded by neutrophils.
Nocardia species are aerobic, weakly acid fast and weakly gram-positive. Nocardia mycetomas are associated with expression of white-to-yellow sulfur granules, which are also classically seen with actinomyces infection. Nocardia species can be detected with most routine bacterial cultures, but cultures can take up to 2-4 weeks to grow. Simultaneous smears and cultures of multiple sites should be submitted to increase the detection rate. A biopsy of the affected tissue will demonstrate a dense predominately neutrophilic, mixed inflammatory infiltrate with a background of granulation tissue, fibrosis, and granulomas.
When a deep infection is present, site-specific local radiographs, computed tomography (CT) scans, or magnetic resonance imaging scans (MRIs) may be needed to determine the extent of underlying involvement.
To be confident of a diagnosis of nocardiosis, be certain that the bacterial isolate is not a colonizer or contaminant. Nocardia species commonly colonize the respiratory tract, especially in patients with anatomical or functional defects. Positive cultures have been shown to demonstrate a real infection in only 62.5% of patients with cystic fibrosis or bronchiectasis.
Nocardia may be thought of as a diagnosis of exclusion with a wide differential diagnosis. Often it is not considered or detected until all other infectious, neoplastic, or inflammatory conditions are ruled out by routine work-up, or the patient continues to progress despite appropriate therapy. In general alternative diagnoses can be ruled out by culture, histology, serology, clinical history, and disease course.
The differential diagnosis for cutaneous nocardiosis includes: (1) other bacterial causes of cellulitis, abscess, or ecthyma; (2) actinomycosis (this organism is anaerobic and forms thinner longer branching filaments); (3) deep fungal infections: sporotrichosis, histoplasmosis, blastomycosis, coccidiomycosis, aspergillus (differentiated by regional endemnicity and characteristic history); (6) leishmaniasis; (7) mycobacteria (cutaneous tuberculosis, Mycobacterium marinum, Mycobacterium avium complex); (8) other bacterial and fungal causes of mycetomas; (9) neoplasms (cutaneous lymphomas, non-Hodgkins lymphoma, glioblastoma multiforme [if ocular involvement]); (9) Kaposi’s sarcoma; (10) yaws
The differential for pulmonary or disseminated nocardiosis includes: (1) Mycobacterium tuberculosis; (2) deep fungal infections; (3) actinomycosis; (4) viral, bacterial, or fungal pneumonia/empyema (particularly Pneumocystis jiroveci pneumonia); (5) bacterial, fungal, or parasitic causes of cerebral abscesses.
Who is at Risk for Developing this Disease?
As Nocardia is a ubiquitous organism present in soil and water, every individual is exposed to the bacterium. However, disease occurs ony if the strain is able to evade the host’s immune defenses. Thus, any individual with altered immunity, particularly cell-mediated immunity, is at risk for nocardiosis. HIV and AIDS are the most common underlying conditions. The most common mode of transmission is inhalation of organisms suspended in dirt and dust. The organism can also be directly introduced into the blood stream or local tissues through puncture wounds or abrasions. The disease is found worldwide and is endemic in some tropical areas. It affects all ages and is more predominant in males.
What is the Cause of the Disease?
Nocardiosis is an opportunistic infectious disease caused by species of nocardia, a ubiquitous aerobic actinomycete found worldwide in soil, decaying organic material, and water. It is also found in oral flora. Thirty strains of Nocardia are pathogenic, with Nocardia asteroides being the most common cause of systemic disease in the United States.
Nocardia species are facultative intracellular pathogens that gain virulence through evading the host’s immune responses. Normal hosts can defend against nocardia infection via cell-mediated immunity triggered by activated macrophages and the induction of lymphocyte-mediated killing. Nocardia can cause disease only when these normal defense mechanisms are bypassed by either by immune suppression or by direct inoculation.
Systemic Implications and Complications
Nocardiosis commonly results in a multisystem illness, particularly in severely immunocompromised patients. Systemic involvement has been found in almost every organ.
Pleuropulmonary nocardiosis is the most common form of systemic nocardiosis. It characteristically presents as an acute, subacute, or chronic pneumonitis in immunocompromised hosts. However, there are rare reports of pulmonary disease in immunocompetent individuals. Patients present with fever, night sweats, productive cough, and pleuritic chest pain. The patient will appear to have pneumonia but the disease will be progressive and refractory to standard antibiotic therapy. With pulmonary symptoms, a chest radiograph or a CT should be performed and may demonstrate mulitple infiltrates, abscesses, cavitations, or effusions. Bronchoalveolar lavage or lung biopsy may be needed for diagnosis.
Disseminated nocardiosis is the most severe form and commonly involves widespread multi-organ abscesses. The skin, lungs, brain, and meninges are the most common locations of involvement. Patients may develop a high fever, multiple cavitating pulmonary infiltrates, cerebral abscesses, and subcutaneous abscesses. Lower extremity subcutaneous abscesses are the most common cutaneous finding in disseminated disease, however, patients may also present with widespread pustules, erythematous nodules, ulcerations or cellulitis which are commonly seen as isolated findings in cutaneous nocardiosis.
Nocardiosis with central nervous system (CNS) involvement is common and can present with headache, lethargy, confusion, seizures, or new neurological deficits. Neurological symptoms should prompt CNS imaging. Any intracranial abscess with signs of spreading to contiguous structures is highly suggestive of nocardiosis. Due to the high rate of CNS involvement, all patients with suspected nocardiosis, with the exception of mycetoma, should undergo a head CT or MRI. If meningeal signs are present, lumbar puncture should be performed and cerebral spinal fluid (CSF) analysis will be consistent with a bacterial meningitis.
Cardiac nocardiosis is less common, but can be found in patients with preexisting cardiac abnormalities and commonly presents as a subacute endocarditis after heart surgery. Natural and prosthetic heart valves can also be infected and damaged, leading to new onset murmurs or congestive heart failure. Blood cultures and echocardiography can be helpful with this diagnosis.
Treatment options are summarized in Table I.
|Primary Cutaneous Nocardiosis||Pulmonary Nocardiosis||Disseminated Nocardiosis|
|Topical Therapy||no role||no role||no role|
|First-Line Medical Therapy||
Trimethoprim/sulfamethoxazole [TMP/SMX] (10-15 mg/kg/day TMP and 50-75 mg/kg/day SMX every 6-12hrs orally)
amoxicillin/clavulante (500-875 mg every 8-12 hrs orally) or ampicillin (.5- 1 g IV every 6 hrs)
minocycline/doxycycline (100 mg twice daily orally)
TMP/SMX + fluoroquinolone (moxifloxacin 400mg daily orally)
linezolid (600mg twice daily orally)
TMP/SMX (10-20 mg/kg/day TMP and 50-75 mg/kg/day SMX divided every 6- 12 hrs oral/IV)
TMP/SMX + 3rd generation cephalosporin (ceftriaxone 1-2 g daily oral/IV)
TMP/SMX + fluoroquinolone (moxifloxacin 400 mg daily oral/IV)
imepenem (500mg four times daily oral/IV) + amikacin (10-15mg/k/day twice daily oral/IV)
linezolid (600mg twice daily oral/IV)
sulfadiazine (6-12 g/day every 4-6hrs oral/IV)
imepenem (500 mg four times daily oral/IV) + amikacin (10-15 mg/k/day twice daily oral/IV)
TMP/SMX (10-20 mg/kg/day TMP and 50-75mg/kg/day SMX twice daily oral/IV) + imepenem (500mg four times daily oral/IV) + amikacin (10-15mg/kg/day twice daily oral/IV)
TMP/SMX + cefriaxone (1-2g daily oral/IV)+ amikacin (10-15mg/kg/day twice daily oral/IV)
linezolid (600mg twice daily oral/IV)
|Comments||give by mouth if tolerated||add a fluoroquinolone for mycetomas||start with 3-6 wks IV therapy then switch to oral as tolerated||start with 3-6 wks IV therapy then switch to oral as tolerated|
|Surgical Therapy||incision and drainage, surgical debridement or excision of infected tissue||incision and drainage, surgical debridement or excison of infected tissue||incision and drainage, surgical debridement or excision of infected tissue|
|Physical Modalities||no role||no role||no role|
|IV: intravenous, hrs:hours, wks: weeks|
Optimal Therapeutic Approach for this Disease
After nocardial infection is diagnosed, all patients with clinically significant disease should have cultures sent for speciation and susceptibility testing due to highly variable resistance patterns across species. Until susceptibilities are available, sulfa-based therapy is the treatment of choice. Trimethoprim-sulfamethoxazole (TMP/SMX) or sulfadiazine are the first-line options. Sulfadiazine should be used with any CNS disease because of its superior cerebrospinal fluid (CSF) penetration.
Immunocompetent patients with primary cutaneous or lymphocutaneous disease can be treated with oral TMP/SMX for 6-12 weeks with concurrent incision and drainage of any associated abscesses. Immunocompromised patients must be treated for a minimum of 3 months for cutaneous disease, but therapy will commonly be continued for up to 1 year. Multitherapy beginning with 3-6 weeks of intravenous (IV) therapy followed by 6-12 months of oral antibiotics is recommended for mycetomas or cutaneous disease with associated systemic symptoms.
For patients with contraindications to sulfa drugs (hypersensitivity, bone marrow suppression, glucose-6-phosphate dehyrogenase deficiency, liver failure, pregnancy), alternative therapy should be based on susceptibility profiles. In patients with multiple comorbidities or drug interactions, linezolid may be a good option. Linezolid has good CNS penetration and oral bioavailability, can be used as a monotherapy, does not require adjustment for renal or liver disease, has few drug interactions, and is the only antimicrobial that is currently active against all strains of nocardia. However due to reported in vitro drug antagonism with amikacin and imipenem, its efficacy in multidrug therapies is unclear.
Alternative IV therapy options include imipenem, third-generation cephalosporins (cefotaxime or ceftriaxone), ampicillin, moxifloxacin, and amikacin. The current preferred alternative regimen may be imipenem plus amikacin. Alternative oral therapies include minocycline or doxycycline, fluoroquinolones, and amoxicillin/clavulanate. These may be used initially or after an induction course of IV therapy.
Surgery is often a critical adjunctive treatment for nocardiosis. Due to variable penetration of antibiotics, abscesses should be incised and drained, and deep locations may require consultation for interventional radiology-guided drainage. Mycetomas often require repeated surgical debridements and need careful follow-up for wound care. Excisions can also help resolve refractory lymphocutaneous infections.
Depending on the extent of disease, specialty consultations can be vital in the management of nocardiosis. An infectious disease specialist can assist with the diagnostic work-up and optimization of therapy. Severe disseminated disease often requires admission to an intensive care unit (ICU) for close multispecialty care.
Primary cutaneous and lymphocutaneous forms of the disease have an approximately 100% cure rate with appropriate therapy. Mycetomas respond well to appropriate debridement and combination long-term antimicrobials. However, without appropriate treatment, progressive disease can lead to permanent damage to underlying soft tissue, muscle, and bone. Ninety percent of pleuropulmonary infections resolve with appropriate therapy, but only 63% of disseminated disease can be cured. CNS disease has a particularly high morbidity; only 50% of brain abscesses resolve.
Once patients are stable and show clinical improvement, they may be transitioned to oral antibiotics and monitored on an outpatient basis. Primary cutaneous and lymphocutaneous nocardiosis can be fully managed in an outpatient setting. For cutaneous disease, clinical signs of improvement include regression of induration, erythema, and lymphadenopathy. Purulent drainage should cease. For deep abscesses, sequential imaging may be necessary to ensure resolution.
With all forms of the disease, clinical improvement can be expected within 3-6 weeks of starting appropriate therapy. If a patient continues to show progression, the clinician should suspect resistance to therapy and consider repeating susceptibility testing. Consider further imaging to evaluate recurring abscess formation or other unidentified organ involvement necessitating surgical intervention. Follow-up radiographic studies may be obtained to monitor response of organ involvement to therapy.
All patients on long-term antibiotic therapy need to be followed with labs to monitor for adverse effects. The most common long-term therapy for patients is oral TMP/SMX, which can cause bone marrow suppression, renal dysfunction, hyperkalemia, hepatic dysfunction, and urolithiasis. Thus, complete blood count with differential, basic metabolic panel with BUN and creatinine levels and liver function testing should be obtained every 3 months while on TMP/SMX. Adequate fluid intake should also be encouraged to avoid urolithiasis.
Nocardiosis has a tendency to recur. Exacerbations may occur even during therapy when therapeutic concentration is not optimal. Thus, all patients need to be counseled on the need for strict adherence to their long-term antibiotic schedule. In particular, patients must be warned that although the infection may no longer be symptomatic, in order to prevent recurrence, they must continue all medications for the full course.
Ideally, an infectious disease specialist should continue to follow the patient to determine the optimal dosage and length of therapy based on clinical improvement.
Unusual Clinical Scenarios to Consider in Patient Management
Patients affected by nocardiosis are commonly taking immunosuppressive drugs for other chronic conditions. These medications may be continued during treatment for nocardiosis if there are otherwise no adverse interactions. Methotrexate should not be administered with TMP/SMX due to increased risk of severe bone marrow suppression. Special consideration should be made when prescribing antibiotics, particularly macrolides, aminoglycosides and TMP-SMX, for patients taking cyclosporine or the mTOR inhibitors sirolimus and everoliums due to cytochrome P450 interactions. Potential effects include increased serum levels of immunosuppressives and nephrotoxicity.
Nocardia brain abscesses require special consideration. Due to the high risk of damage to surrounding tissue, brain abscesses should first be treated with high-dose IV therapy (sulfadiazine is first line). Surgical drainage may be considered if the abscess is particularly large, readily accessible, or continues to progress despite 2 weeks of appropriate IV antibiotics.
Patients with a confirmed nocardia infection without apparent immunosuppression or an antecedent exposure should undergo a comprehensive evaluation to rule out all forms of disease that could lead to altered immunity. Nocardia infection could be the first indication of a underlying condition compromising the patient’s immune defenses.
What is the Evidence?
Filice, GA. “Nocardiosis in persons with human immunodeficiency virus infection, transplant recipients, and large, geographically defined populations”. J Lab Clin Med.. vol. 145. 2005. pp. 156-62. (A systematic review that quantifies and compares the risk of nocardiosis in geographically defined populations versus populations with human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome (AIDS) and organ transplants. An interesting point is that the frequency of nocardiosis in transplant patients approaches the same range as HIV patients.)
Jodlowski, TZ, Melnychuk, I, Conry, J. “Linezolid for the treatment of Nocardia spp. infections”. Ann Pharmacother. vol. 41. 2007. pp. 1694-99. (A review of 11 published cases of linezolid use for nocardia infections indicating that with central nervous system and disseminated disease where other medications failed or caused adverse effects, linezolid was associated with cure or improvement in all cases. However, with a high cost and potentially serious long-term toxicities, its usage may be limited.)
Kilincer, C, Hamamcioglu, MK, Simsek, O. “Nocardial brain abscess: review of clinical management”. J Clin Neurosci. vol. 13. 2006. pp. 481-85. The diagnosis, clinical course, and management of nocardial brain abscess are discussed with a review of the literature. A presentation of two patients with nocardial brain abscesses highlight successful treatment options including imipenem and amikacin followed by minocycline, and ceftriaxone followed by oral trimethoprime-sulfamethoxazole.)
Lederman, ER, Crum, NF. “A case series and focused review of nocardiosis: clinical and microbiologic aspects”. Medicine (Baltimore).. vol. 83. 2004. pp. 300-13. (A case series of 5 patients with nocardiosis that highlights various unique presentations of the disease as a "great imitator." A review of the literature points out a recommendation for resistance testing due to emerging drug resistance, high rates of adverse reactions, and the potential for nephrotoxicity in transplant recipients on cyclosporine.)
Minero, MV, Marin, M, Cercenado, E, Rabadan, PM, Bouza, E, Munoz, P. “Nocardiosis at the turn of the century”. Medicine (Baltimore). vol. 88. 2009. pp. 250-61. (A study describing the microbiologic and clinical characteristics of nocardiosis presenting in a general hospital over 12 years. Additionally the diagnosis and management of nocardiosis are reviewed, highlighting the recent changes in clinical and microbiologic spectrums. New types of immunosuppressed patients that may be at risk are pointed out. HIV infection is reported as the most common underlying condition for invasive nocardiosis.)
Satterwhite, TK, Wallace, RJ. “Primary cutaneous nocardiosis”. JAMA. vol. 242. 1979. pp. 333-36. (Seven patients with cutaneous nocardiosis seen over 20 months are presented to review clinical characteristics of the isolated cutaneous form of the disease and its management. Emphasis points are the relatively benign nature of this form of the disease and a common failure to obtain cultures of superficial skin infections.)
Singh, SM, Rau, NV, Cohen, LB, Harris, H. “Cutaneous nocardiosis complicating management of Crohn's disease with infliximab and prednisone”. CMAJ. vol. 171. 2004. pp. 1063-4. (A report of a cutaneous nocardia infection in a patient who was taking infliximab for Crohn's disease, highlighting challenges in the diagnosis and management of this disease and the need for increased suspicion in patients on immunomodulators.)
Sorrell, TC, Mitchell, DH, Iredell, JR, Mandell, GL, Bennett, JE, Dolin, R. “Nocardia species”. Principles and practice of infectious diseases. vol. 2. 2005. (A comprehensive resource for diagnosing and treating challenging infectious diseases. Useful to work through differential diagnoses.)
Ambrosioni, J, Lew, D, Garbino, J. “Nocardiosis: updated clinical review and experience at a tertiary center”. Infection. vol. 38. 2010. pp. 89-97. (A concise up-to-date clinical review discussing 28 cases at a single institution. Highlights risk factors and new strategies for diagnosis and treatment.)
Ferrer, A, Llorenc, V, Codina, G, de Gracia-Roldan, J. “Nocardiosis and bronchiectasis. An uncommon association”. Enferm Infec Microbiol Clin. vol. 23. 2005. pp. 62-6. (Bronchiectasis is an important risk factor for colonization by Nocardia species, and for infection in patients without cystic fibrosis. Highlights the use of BCYE-alpha (m) medium in processing respiratory secretions to facilitate the isolation of Nocardia.)
Wilson, JW. “Nocardiosis: updates and clinical overview”. Mayo Clin Proc. vol. 87. 2012. pp. 403-7. (A review of nocardiosis that gives an updated overview of the disease and treatment options.)
Oliverio, Wels, Lucio, Vera-Cabrera, Mario Cesar, Salinas-Carmona. “Current treatment for nocardia infections, Expert Opinion on Pharmacotherapy”. vol. 14. 2013. pp. 2387-2398. (A comprehensive review of taxonomy, clinical features, diagnosis and species identification of nocardiosis, as well as an overview and update of available treatments.)
Lebeaux, E, Morelon, F, Suarez, F, Lanternier, A, Scemla, P, Frange, J-L, Mainardi, M, Lecuit, O, Lortholary. “Nocardia in transplant recipients”. Eur J Clin Microbiol Infect Dis. vol. 33. 2014. pp. 689-702. (A review of nocardiosis in transplant patients, including epidemiology by transplant type, treatment and special considerations for this population.)
Hardak, E, Yigla, M, Berger, G, Hannah Spreche, H, Oren, I. “Clinical Spectrum and Outcome of Nocardia Infection: Experience of 15-Year Period From a Single Tertiary Medical Center”. The American journal of the sciences. vol. 343. 2012. pp. 286-290. (A review clinical features and outcomes of 53 cases of nocardiosis in a tertiary medical center over a 15 year period. Patients with hematological malignancies and chronic lung disease were noted as having a higher incidence.)
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