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A Case Series and Focused Review of Nocardiosis

Clinical and Microbiologic Aspects

Lederman, Edith R. LCDR, USNR, MC; Crum, Nancy F. LCDR, USNR, MC

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doi: 10.1097/01.md.0000141100.30871.39
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Abstract

INTRODUCTION

Nocardia species are ubiquitous soil-dwelling Gram-positive bacteria that are responsible for a wide spectrum of disease in patients with both normal and abnormal immune systems. The current incidence of nocardiosis is unknown; the most recent nationwide survey was performed over 3 decades ago6. Since then, new Nocardia spp. have been identified133,138; immunocompromised patients have become more prevalent secondary to advances in therapy for malignancy, autoimmune disease, and the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic; drug resistance patterns and mechanisms of Nocardia have been elucidated7,73,128,129,132; and treatment courses have become more complex35,79,103,114. We report 5 cases that demonstrate the classic features of nocardiosis, the clinical features of which are summarized in Table 1. We review the English-language literature, highlighting key aspects of the diagnosis, clinical manifestations, and treatment of this infection.

TABLE 1
TABLE 1:
Cases of Nocardial Disease, Present Report

CLINICAL CASE REPORTS

Case 1

A 79-year-old woman with oxygen-dependent chronic obstructive pulmonary disease (COPD) presented with increasing cough and dyspnea. The patient was diagnosed with bibasilar pneumonia and empirically treated with oral prednisone and levofloxacin. After 1 week with no improvement, she returned to clinic. Her pulse was 119 beats/minute with an oxygen saturation of 83% on 2 liters of oxygen. She appeared ill and her pulmonary examination was remarkable for the use of accessory muscles, bibasilar inspiratory crackles, and expiratory wheezing. A chest radiograph revealed bibasilar infiltrates and bilateral pleural effusions. She was admitted to the hospital and empirically treated with intravenous solumedrol as well as ceftriaxone and azithromycin for a COPD exacerbation and community-acquired pneumonia. A thoracentesis revealed exudative fluid with a pH of 7.0, white count of 4367/mm3 (90% neutrophils), and negative Gram stain and culture. The peripheral white blood count was 34,100/mm3. Blood cultures before antibiotics were negative; however, the sputum culture grew Nocardia asteroides sensitive to trimethoprim-sulfamethoxazole (TMP-SMX) (minimum inhibitory concentration [MIC] 0.3 μg/mL), minocycline (MIC 0.3 μg/mL), and ceftriaxone (MIC 0.16 μg/mL). The patient stabilized and was discharged on TMP-SMX 1 tablet twice daily. She continued to improve over the next several weeks, but an enlarging left-sided infiltrate prompted an increase in TMP-SMX to 2 tablets twice daily. Three weeks later the patient developed hepatitis, and the TMP-SMX was stopped in favor of minocycline 100 mg twice daily. Over the next 2 months, both the patient's symptoms and the pulmonary infiltrates resolved. During the fourth month of therapy for Nocardia she was diagnosed with stage IIa breast cancer after an abnormal routine mammogram and was treated with a modified radical mastectomy. Minocycline was administered for a total of 12 months with resolution of the Nocardia pneumonia. She did well off the antibiotics, and there is no evidence of recurrence of the breast carcinoma.

Case 2

A 54-year-old woman presented in October of 2001 with massive hemoptysis. Her history was remarkable for Nocardia asteroides pneumonia in February 1994, which had been treated with TMP-SMX for 3 months with clinical improvement. She had residual right middle lobe and left lingular consolidations with bronchiectasis, but was subsequently lost to follow-up. Upon presentation, she had hemoptysis resulting in a hematocrit drop from 39% to 30%, necessitating admission to the intensive care unit. A bronchoscopy revealed bleeding from the lingula without evidence of endobronchial lesions, and a chest computed tomography (CT) scan showed bilateral consolidations. Bilateral bronchial artery arteriograms showed beaded-appearing arteries to the lingula and right middle lobe; attempts at arterial embolization were unsuccessful. The patient underwent left upper lobe and lingular lobectomies with resolution of the hemoptysis. Bronchoscopy specimens and tissue cultures grew Nocardia asteroides. Sensitivities were not performed at this time, and the patient was empirically treated with TMP-SMX; she developed tongue swelling and the medication was switched to minocycline 200 mg twice daily. After 4 months of therapy, sputum cultures remained positive, and she had persistent dyspnea at rest. The patient denied fevers, sweats, or weight loss and had no signs or symptoms consistent with skin or central nervous system (CNS) involvement. She was HIV seronegative. Nocardia sensitivities were performed in January 2002 showing intermediate resistance to minocycline (5 μg/mL) and susceptible sensitivities for ceftriaxone (1 μg/mL), cefuroxime (2.5 μg/mL), and tobramycin (1 μg/mL). Given the intermediate resistance to minocycline and persistence of dyspnea and positive cultures, minocycline was discontinued, and she was treated with 6 weeks of intravenous ceftriaxone 2 g daily and inhaled tobramycin 300 mg twice daily. Sputum cultures became negative, dyspnea improved, and a CT scan showed a reduction in opacities (Figure 1). The patient subsequently completed a 6-month course of cefuroxime 500 mg twice daily and has done well for over 1 year.

FIGURE 1
FIGURE 1:
Case 2: A. CT scan at presentation; B. CT scan at 7 months after therapy was initiated demonstrating improved bilateral, anterior infiltrates.

Case 3

A 66-year-old man with a history of Waldenström macroglobulinemia and myelodysplastic syndrome presented with a 2-week history of progressive dyspnea, fevers, night sweats, and fatigue after traveling to Australia. He recalls picking up a handful of soil in Australia "to smell the earth" 1 week before his symptoms occurred. The patient also noted a cough productive of scant amounts of pink-tinged sputum and right-sided pleuritic chest pain. The patient had been well before admission except for the occurrence of dermatomal herpes zoster 2 weeks previously. He had received transfusions via an indwelling central catheter since August 2000 and prednisone 20 mg daily for the hematologic disorders. His temperature was 37.2 °C, pulse 70, blood pressure 130/64, respiratory rate 14, with a pulse-ox of 93% on room air. Examination was remarkable for decreased breath sounds and dullness to percussion over the lower right lung field without rubs, wheezes, or crackles. The cardiovascular, neurologic, and skin examinations were unremarkable, as was his PORT-A-CATH site. His white blood count was 13,100/mm3, hemoglobin 9.3 mg/dL, platelets 43,000/mm3, creatinine 1.3 mg/dL; renal and liver function tests were normal. A chest radiograph showed a large right-sided pleural effusion with loculations. After platelet transfusion, the patient underwent an ultrasound-guided thoracentesis which revealed yellow fluid with a white count of 13 cells/μL with 68% neutrophils, protein 3.8 mg/dL (serum 5.8 mg/dL), lactate dehydrogenase 208 (serum 125 mg/dL), pH 8.0, and a negative Gram stain. Blood cultures were obtained, and the patient was treated with ceftriaxone and levofloxacin for presumed pneumonia and parapneumonic effusion. During the first day a fever of 39.4 °C prompted a chest CT scan which showed multiple loculated fluid collecting in the right middle and lower lobes. Due to persistent fevers, the prednisone dose was reduced to 10 mg daily, antibiotics switched to piperacillin/tazobactam and levofloxacin, and 2 chest tubes were inserted for drainage of the loculated effusions. On hospital day 3, blood cultures (Organon Teknika Bacte Alert 3d system) were positive for beading, branching Gram-positive rods later identified as Nocardia asteroides. Three of 6 blood cultures and the pleural fluid grew Nocardia asteroides. The patient's antibiotic regimen was changed to piperacillin/tazobactam and TMP-SMX. Antibiotic sensitivities were not obtained. A transthoracic echocardiogram was negative for vegetations; the blood cultures became sterile, and the patient had no CNS manifestations to suggest CNS involvement. The indwelling central catheter was also removed given the Nocardia bacteremia; a culture of the catheter tip was negative. The patient was discharged after 7 days of hospitalization on oral TMP-SMX. There was full resolution of radiographic findings after 6 weeks of therapy. The patient completed a 3-month course of TMP-SMX and remains well 10 months after the initial diagnosis.

Case 4

A 70-year-old man developed a right proximal lower extremity nodule with central pustules 1 week after kneeling in his garden. He became febrile, and his primary care provider treated him empirically with amoxicillin-clavulanate. Despite this intervention, the nodule became erythematous, and he was admitted for worsening cellulitis accompanied by tender right groin lymphadenopathy (Figure 2A). He was febrile to 101 °F on admission. Routine laboratory exams were within normal limits, and blood cultures were negative. Oxacillin therapy was initiated, and after mild improvement, he was discharged. A culture of the pustules grew Nocardia brasiliensis. The central nodule was biopsied, and the cultures again yielded Nocardia brasiliensis. The isolate was sensitive to TMP-SMX (MIC 0.3 μg/mL), minocycline (MIC 0.6 μg/mL), cefuroxime (MIC 10 μg/mL), and amoxicillin clavulanate (MIC 2.5 μg/mL). Therapy was changed to TMP-SMX and after 2 months of therapy, the nodule had nearly resolved (Figure 2B). A second biopsy at this time of an irregular, purpuric remnant of the nodule revealed mild perivascular and interstitial inflammation, and therapy was continued for an additional 4 months. Malignancy screening revealed numerous adenomatous colon polyps, for which he underwent a hemicolectomy. Surgical pathology was negative for colon adenocarcinoma. Magnetic resonance imaging (MRI) of the brain was performed, given a new complaint of headaches, but was negative. The patient remains well 12 months after the initial diagnosis.

FIGURE 2
FIGURE 2:
Case 4: A. Nodule at presentation; B. nodule after 2 months of therapy.

Note: This case was presented in part as an abstract at the 2002 Infectious Diseases Society of America Meeting (see footnote on title page.)

Case 5

A 73-year-old man without a history of diabetes mellitus presented with blood-tinged drainage 25 days after undergoing a single-vessel coronary artery bypass and placement of a mechanical aortic valve. The patient reported fevers and anorexia, but denied any other systemic complaints. On examination, the patient had a temperature of 100.4 °F with erythema and serosanguinous drainage from the distal portion of the sternal wound (Figure 3). The patient had an unchanged systolic ejection murmur at the aortic position. The remainder of his examination was unremarkable. The white blood cell count was 8,000/mm3, hematocrit 28%, and international normalized ratio (INR) 5.5; all other laboratories were unremarkable including sputum cultures. A CT scan showed abscesses in the soft tissue above the sternum and in the anterior mediastinum, bony destruction of the manubrium consistent with osteomyelitis, and bilateral small pleural effusions; the lung parenchyma was unremarkable. The patient underwent extension debridement with evacuation of the abscesses. A transesophageal echocardiogram showed normal ventricular function, and the aortic valve was without vegetation or ring abscess. Deep wound tissue cultures and a sternal bone culture grew Nocardia farcinica sensitive to imipenem, amikacin, minocycline, and TMP-SMX, and resistant to the fluoroquinolones. Sputum and pleural fluid cultures were sterile; a brain CT scan was unremarkable. The patient was treated with imipenem, amikacin, and TMP-SMX. He subsequently developed hyperkalemia and eosinophilia, necessitating discontinuation of the TMP-SMX. A follow-up CT scan demonstrated the successful removal of the abscess areas with reduced soft tissue enhancement. A bilateral pectoralis flap was performed 2 weeks after debridement; the patient subsequently developed a sternal wound superinfection with methicillin-resistant Staphylococcus aureus that was treated with vancomycin. The patient eventually recovered after a 70-day hospitalization. The Nocardia farcinica infection was treated with 6 weeks of intravenous amikacin and imipenem, followed by 6 months of minocycline. At the 6-month follow-up, he had a well-healed sternal incision site. No other cases of postoperative infections with Nocardia have been noted at this facility.

FIGURE 3
FIGURE 3:
Case 5: Sternal wound at presentation; note dehiscence in lower portion (arrow).

METHODS

We performed a MEDLINE (National Library of Medicine, Bethesda, MD) search of the literature from 1966 to 2003 using the key words Nocardia and drug resistance, pulmonary infection, pneumonia, pleural effusion, sternal wound infection, cutaneous infection, skin, bacteremia, catheter or foreign body infection. We limited our review to the English literature with few exceptions77,92. We present a summary of the microbiologic and clinical aspects of nocardiosis.

MICROBIOLOGY

In 1888, Edmund Nocard first described this genus as a bovine pathogen77. Nocardia spp. are soil-dwelling, Gram-positive, branching, beaded bacilli, which are weakly acid-fast positive in young cultures (Figure 4). Nocardia are relatively slow-growing organisms that produce dry and rugous colonies that may be white, yellow, or orange in color and emit an earthy odor (Figure 5). These organisms will grow on standard blood agar but prefer enriched media such as Lowenstein Jensen or Sabouraud-dextrose agar. Routine cultures usually require 5-21 days to exhibit growth; many routine cultures are discarded before the fifth day, and as a result, the diagnosis may be missed. They are able to proliferate in the presence of lysozyme and produce urease and catalase. Streptomyces spp., which have a similar appearance on Gram stain and are also aerobic organisms, are not modified acid-fast positive and utilize complex carbohydrates (positive iodine test). Nocardia spp. are differentiated by hydrolysis of casein, xanthine, hypoxanthine, and tyrosine; more recently they may be separated by more sophisticated means such as high-pressure liquid chromatography (HPLC) and 16S and 32S-ribosomal gene analysis46,68,141. Techniques such as randomly amplified polymorphic DNA (RAPD) analysis31 may be useful for strain typing.

FIGURE 4
FIGURE 4:
Nocardia Gram stain demonstrating beaded, branching morphology.
FIGURE 5
FIGURE 5:
Typical chalky, white colonies of Nocardia.

Nocardia asteroides is the most common species associated with human disease2,30. It is a member of the Nocardia asteroides complex, which includes less-common species, such as Nocardia nova, Nocardia farcinica, and Nocardia transvalensis. Nocardia nova shares only 39% DNA homology with Nocardia asteroides sensu strictu despite having similar biochemical properties138 and is universally sensitive to erythromycin130. Nocardia farcinica is less commonly isolated but is associated with a higher risk of dissemination, drug resistance, and, therefore, a higher mortality rate120,132,135. There may be geographic variations in Nocardia spp. distribution; for instance, Nocardia farcinica has been reported more frequently in western European countries9,105, while cases of Nocardia brasiliensis are more often observed in the southern United States66. Over the last decade, a new species, Nocardia pseudobrasiliensis has been identified; this species can be differentiated from Nocardia brasiliensis by HPLC, RFLP, and drug sensitivity patterns (sensitive to ciprofloxacin in 95% of isolates) and is associated with a higher rate of dissemination12,133. Other more rare species of Nocardia include Nocardia otitidiscaviarum (formerly Nocardia caviae), which is associated with infection of traumatic wounds in normal hosts40 and is thought to be less pathogenic than other Nocardia species42.

EPIDEMIOLOGY

Although the exact incidence of any nonreportable infection is hard to estimate, approximately 1000 cases occur annually in the United States6. This incidence has risen over the last few decades as oncology, rheumatology, and transplant medicine have flourished as disciplines. It is estimated that at least 50% of patients with Nocardia asteroides infection have underlying immune compromise84, and as many as 4% of AIDS patients may die with evidence of nocardiosis on autopsy64. Immunocompetent hosts may succumb to nocardiosis (10%-50% of cases)27,33,84, but infection is more common among the immunocompromised; particular risk factors include transplantation (solid organ or bone marrow), AIDS (CD4 count usually less than 50 cells/mL and the patient is not on Pneumocystis carinii prophylaxis with TMP-SMX)56, glucocorticoid use, underlying malignancy, intravenous drug abuse (presumably from contaminated paraphernalia)124,125, and underlying pulmonary disease2. Nocardiosis is very rare in the pediatric population and is seen primarily in children with severe pulmonary disease or with significant immunocompromise72. Infection occurs more commonly in males21,56,111.

ASSOCIATION WITH IMMUNE DYSREGULATION (TABLE 2)

TABLE 2
TABLE 2:
Immunocompromised Hosts and Characteristics of Nocardial Disease, Previous Series

Malignancy

Malignancies, both solid organ and hematologic, have been associated with nocardial infections. Seventeen percent of cases voluntarily reported in an Infectious Diseases Society of America survey had an underlying malignancy6. This predisposition may arise from antineoplastic therapy or a yet-to-be elucidated genetic or acquired immune surveillance deficiency responsible for the development of the malignancy. In a series of 43 patients, more than 80% of the patients who developed nocardial infection had been given chemotherapy and/or corticosteroids within 30 days before the infection. Nocardia asteroides, an apparently less pathogenic species, causes the majority of cases8. Although nocardial infections in patients with colon adenocarcinoma and intestinal lymphoma108 have been reported8, we could find no case reports of nocardiosis associated with colon cancer precursors (that is, colon polyps). In the current report, Case 4 had numerous colon polyps discovered during his evaluation. A sulfonamide-containing regimen remains the therapy of choice in these individuals111, although minocycline108 has been used with success. Mortality in cancer patients with nocardiosis may be as high as 60% even with adequate therapy, and those who succumb do so most often in the first week of therapy119.

Transplantation

Transplant recipients are at risk for nocardiosis and comprise up to 13% of reported cases of nocardial infection in the United States6. In an autopsy series of renal transplant recipients, 10.6% of the infectious deaths were due to Nocardia (7.6% overall, including noninfectious causes)96. Nosocomial outbreaks in transplant patients have been described31. An additional risk factor for developing nocardial infection in transplant recipients may be concomitant pulmonary embolus122; nocardial growth has been documented in the embolized segments at autopsy16.

The risk of nocardial infections in transplant patients is most intense during the first year posttransplant, likely due to the higher doses of antirejection drugs necessary to maintain the graft during that time. It has become less likely overall with the advent of drug regimens that suppress the immune system with more precision than before18,44. The incidence of Nocardia in renal transplant recipients in 1 series (1255 patients from 1980 to 1992) was reported as 0.7%, which is significantly decreased from the precyclosporine era incidence of 2.6%3. In another series of 110 patients, the incidence of nocardial infections in heart transplant patients had decreased from 13% to 4% with the use of a cyclosporine-based regimen44. In a more recent (2003) study87 of heart transplant patients, the incidence was found to be 0.9%. It is also noteworthy that these infections are likely to occur much later after the transplant (>3 mo) than other bacterial infections44,87, although early cases have been reported98. Eighty to ninety percent of cases of nocardiosis will occur as primary pulmonary disease in these patients, and up to 40% of these cases will experience dissemination136.

TMP-SMX remains the drug of choice, and treatment is recommended for at least 6 months in the transplant population. Caution must be used as reversible nephrotoxicity has been noted when TMP-SMX and cyclosporine are used concomitantly103. In addition, TMP-SMX may lower the cyclosporine levels, leading to graft rejection and, in the case of renal transplant patients, further exaggerating nephrotoxicity103. Amoxicillin-clavulanate3 and minocycline79,103 may be alternative efficacious regimens that will not significantly interact with cyclosporine. Minocycline/amoxicillin and minocycline/ciprofloxacin were successfully used to treat TMP-SMX failures in heart transplant patients87. The use of prophylactic TMP-SMX may decrease the incidence of nocardiosis in this population90. Although many case reports mention decreasing the doses of or discontinuing immunosuppressive agents during the course of treatment for nocardiosis, this may not always be necessary76.

AIDS

Despite the association between the loss of cell-mediated immunity and nocardial infection, AIDS patients rarely develop symptomatic nocardial infection (incidence between 0.19% and 2.0%)45,54,64,91,124. This may be due in part to the use of TMP-SMX for Pneumocystis prophylaxis, although, that regimen does not always prevent nocardial infection54. Evidence of nocardial infection at autopsy appears to be more common, approaching 4% in 1 study64. Upper lobe disease is common, as is pulmonary co-infection with other pathogenic organisms, and these factors may delay therapy for Nocardia124. Intravenous drug abuse may be a risk factor in this population due to introduction of soil and its resident Nocardia into the bloodstream54,91,124. Relapse and progression of disease may be as high as 64% if treatment is discontinued prematurely124, and, as a result, some authors support life-long therapy48,124.

Miscellaneous

There are case reports of less well defined states of immune suppression, some of which may be influenced by concomitant medication, resulting in Nocardia infection. These include systemic lupus erythematosus97,121, sarcoidosis94, temporal arteritis97, chronic granulomatous disease73, Evans syndrome (autoimmune thrombocytopenia and hemolytic anemia)123, pregnancy52, and patients splenectomized for complications related to a hematologic malignancy132. Drug-induced states of immune suppression are increasing in frequency as therapy for malignancy and autoimmune disorders becomes more aggressive; therefore, the incidence of nocardial infection will likely increase.

Corticosteroids

One common thread that exists among the patient classes listed above is the frequent and confounding use of corticosteroids. In a series12 of 43 cases of Nocardia pseudobrasiliensis, corticosteroid use was the most common risk factor (74% of cases). In another series119 of 42 patients with various malignancies, 58% had received corticosteroids within 30 days of presenting with the diagnosis of nocardiosis-more than twice the number of patients whose risk factor was a chemotherapeutic agent alone (23%). Most often the corticosteroid use is in conjunction with other immunomodulating agents or chemotherapy, and it is often difficult to assess the independent risk from steroids in the transplant and malignancy populations. However, a case series93 of 147 patients with nocardiosis revealed that patients with underlying disease who were not on corticosteroids or other immunomodulating agents did as well as otherwise healthy hosts, underscoring the importance of agents such as corticosteroids in the pathogenesis of nocardial disease. Corticosteroid use alone may be the primary risk factor in nephrotic syndrome109. In 1 case10, a patient with thymoma previously receiving corticosteroids presented with an occult case of nocardiosis; administration of high-dose corticosteroids for presumed adrenal crisis hastened his demise. As newer immunomodulating agents have become available, decreasing the doses of corticosteroids necessary for transplant recipients and patients with autoimmunity, a subsequent decrease in the frequency of infections has been noted, especially nocardiosis18,44.

PULMONARY INVOLVEMENT

As Nocardia spp. are not considered normal oropharyngeal or bronchopulmonary residents, the isolation of Nocardia from a sputum specimen is nearly always a significant finding94. The lungs are the primary site of Nocardia infection in more than two-thirds of cases56,84,111. As in Cases 1 and 2, lung disease predisposed patients to pulmonary nocardiosis and has been reported in patients with silicosis73, pulmonary fibrosis33, and COPD (often with concomitant corticosteroids). There is 1 report of alveolar proteinosis associated with a Nocardia pulmonary abscess8.

The radiographic appearance of nocardial infection is protean. Parenchymal disease may range from a small nodule to bilateral infiltrates with cavitation. Nocardia tends to produce a necrotizing, poorly contained pneumonia resulting in erosion into bony structures98, resulting in a misdiagnosis of malignancy. Upper lobe disease is common, and these patients are often considered to have tuberculosis before the culture results are confirmed; since Nocardia is weakly acid-fast positive, smears of the sputum or pleural fluid may be misleading81. Cavitation may occur in up to one-third of patients56. A solitary oval or round mass may present in 24%-58% of patients13,58. Nodules may be intraparenchymal140 or pleural based13,98. Lymphadenopathy is not always a prominent radiographic feature and was reported in only 3/24 cases of 1 series13 and 0/5 in another140. Isolated pulmonary infection may be cured in over 90% of cases111, but other authors report less successful cure rates likely secondary to continued immunosuppression58. Ten percent of pulmonary infections disseminate to the skin51.

Concomitant pleural effusions occur in 10%-33% of cases56,58,119,124,136. In a review of 5 patients with CT findings, 4/5 had pleural effusions; this higher incidence may be a result of small sample size or higher sensitivity of CT scan for detecting pleural effusions. In another study of hospitalized AIDS patients with pleural effusions, 3% were attributed to nocardial infection49. Case reports rarely mention the characteristics of the pleural fluid in Nocardia patients; when reported, the vast majority of effusions are noted to be exudative or frankly purulent98,121,125 and nearly all yield positive cultures for Nocardia. Treatment of a significant pleural effusion should include drainage of the fluid via a chest tube8; however, small effusions (blunting of the costophrenic angle) often resolve with medical therapy alone49,98. A pigtail catheter was used in Case 3 to direct drainage of the loculated pleural fluid without risking the additional morbidity of thoracoscopy or chest tube placement. Bronchopleural fistulae may develop spontaneously74 or as a result of resecting the infected lung8.

The standard treatment of pulmonary nocardiosis would include a sulfa-containing regimen; however, cure has been reported with imipenem121, ampicillin97, and minocycline. The length of treatment is a subject of debate, but usual courses span 3 to 6 months.

BACTEREMIA

Nocardia species comprised 0.003% of all positive blood cultures from 1 hospital review56 and 0.07% of positive acid-fast bacillus and mycology cultures in another85. Nocardemia may be relatively common in patients with concomitant malignancy, likely due to the frequent use of central venous catheters119. Most case reports cite Nocardia asteroides as the species causing bacteremia, but less common species such as Nocardia caviae17,89, Nocardia nova72, and Nocardia farcinica56,89,120 have been isolated from blood cultures. We did not find any case reports of blood cultures positive for Nocardia brasiliensis. There is a male predilection for nocardemia, nearly 3:156.

Manifestations of nocardiosis associated with bacteremia include psoas abscess30, pneumonia with or without abscess or pleural effusion56,89, cutaneous or subcutaneous nodules56, brain abscess88, retinitis14, septic joint with myositis56, catheter tip infection57, hepatic abscesses22, adrenal abscess2, and multiple intraabdominal abscesses10. Pulmonary disease, not surprisingly, usually accounts for the origin of the nocardemia56. The positive blood culture may precede the isolation from the primary site in nearly half of the cases56, and the average incubation time is 5 days (but varies based on the system of media used).

Although disseminated nocardiosis is presumed to occur via hematogenous spread, capture of the organism in blood cultures is unusual. In tribute to its fastidious nature in blood cultures, a case was reported of endocarditis (autopsy proven) in which all blood cultures were negative32. Hypotheses to explain the rarity of documented bacteremia include co-infection with more resilient organisms, infrequent and intermittent bacteremia, and failure to retain blood cultures for sufficient time to allow for detectable growth of this fastidious genus56,99. Positive blood cultures may be obtained using routine systems99, but use of biphasic brain-heart infusion or Castañeda media increases the yield89,97. Other techniques to improve the yield of cultures include increasing the incubation times and early subculture to blood agar126. Despite its usual fastidiousness, high-grade nocardemia has been reported89 and may be associated with an indwelling catheter, advanced AIDS, or a heavy bacterial burden2.

Catheter-associated nocardemia is well documented. Although most authorities would recommend the removal of the intravascular device, 2 cases of cure with retention of the device have been reported60,65; in both of these cases, the patients were not immunocompromised, their catheters were used for blood transfusions, and they received 2-3 weeks of a carbapenem. However, failures have also been reported with retention of the catheter72. Removal of the catheter alone is often not curative57, and several months of antimicrobials should be administered. Therefore, to maximize the chance of cure for catheter-associated nocardemia, the catheter should be removed and antimicrobials administered.

Blood cultures positive for Nocardia spp. may represent contamination more often than originally recognized. In a review30 of positive blood cultures over 4 years in a teaching hospital, authors found 8 with Nocardia spp., only 1 of which was from a patient with definitive evidence of nocardial disease. Another review56 of 43 cases found 7 to be probable contaminants. Underreporting of this phenomenon may occur as cultures positive for Gram-positive rods are thought to be Corynebacterium spp. and are discarded without identification. Pseudoepidemics of Nocardia bacteremia have been reported as well85 and may have been caused by a faulty needle heater in the blood culture system.

Even more rare than nocardemia is Nocardia endocarditis. Nearly all cases thus far reported have been in conjunction with prosthetic valves23,28,29,32,56,127. One surviving patient received a valve replacement and treatment with 3 weeks of imipenem and amikacin followed by oral TMP-SMX29; more recently23(2003), a patient with a prosthetic valve infected with Nocardia asteroides survived with medical therapy only (imipenem/cilastatin and amikacin for 2 months followed by TMP-SMX for 4 months). To our knowledge, the only case of native valve endocarditis reported134 occurred in an intravenous drug user and required valve replacement.

Skin manifestations (multiple abscesses or subcutaneous nodules) occur in up to 28% of cases with bacteremia56. The skin may be the portal of entry for bacteremia in 11% of cases56.

STERNAL WOUND INFECTIONS

Surgical site infections with Nocardia are rare as most respectable surgical suites contain very little soil; sternal wound infections are exceptionally uncommon. The mean time to symptoms after surgery is approximately 1 month117,135, but the infection may present as late as 6 months after139. This long prepatent period may be due to contamination of the wound after discharge from the hospital, or to the slow-growing nature of the organism. Symptoms include erythema of the incision, clear to purulent drainage, wound dehiscence, and/or fever92. Diabetes mellitus appears to be the only significant risk factor135. Although settle plates from the operating suite were negative for the offending organism in 1 outbreak investigation, an anesthesiologist's hands were culture positive for the strain of Nocardia farcinica associated with 4/5 cases135. Another outbreak of 7 cases was reported from Germany due to Nocardia asteroides, but the source of the outbreak was never determined92. One case of Nocardia brasiliensis sternal osteomyelitis with an anterior mediastinal abscess likely occurred as a result of occupational exposure (carried wooden crates loaded with vegetables), as the patient had no history of chest surgery or trauma59.

Treatment regimens may include surgical debridement (often complete sternectomy)135. Previous successful regimens have included the following: imipenem/ciprofloxacin for 1 month followed by a year of ciprofloxacin117; 1-2 months of TMP-SMX or sulfisoxazole or sulfadiazine followed by 1 year of ciprofloxacin, minocycline, TMP-SMX, or sulfisoxazole135; and ofloxacin139 alone for 5 or 9 months. Extended use of an antimicrobial may be necessary for this subset of infections, and standard 6-month regimens have failed35. Although more than 50% of the patients with Nocardia sternal osteomyelitis survive, the average length of hospital stay was over 3 months, emphasizing the significant morbidity associated with this postsurgical complication.

PRIMARY CUTANEOUS NOCARDIOSIS

Primary cutaneous nocardiosis (PCN) occurs when the organism enters the host via the skin and/or skin appendages, and may comprise up to 5% of all cases of nocardiosis84. The incidence of PCN may be higher in Europe where Nocardia brasiliensis is more commonly isolated9. PCN may present in a number of ways. Acute manifestations include cellulitis107, ulcerative/bullous lesions102, linear/keloid-like lesions75, and nodular-pustular lesions, which may progress in a sporotrichoid fashion107,137. Chronic forms may present as hyperkeratotic plaques20,25 or tumor-like masses known as actinomycetomas that are endemic to many developing nations1,15. Lesions may occur suddenly141 and rapidly progress, reactivate after 2 years of dormancy52, or slowly expand over 10 years109. PCN has been mistaken for lesions of sporotrichosis107, atypical mycobacterial infection107, leishmaniasis, and systemic lupus erythematosus20.

Patients infected simultaneously may present with different cutaneous manifestations, as illustrated by a husband and wife infected by the same rose thorns1; it is likely that host factors influence the type of skin lesions that develop. Different cutaneous manifestations may exist within the same patient100. Very rarely, primary cutaneous lesions may lead to systemic illness51,80.

Most Nocardia species have been implicated in cutaneous disease, including Nocardia brasiliensis11,15,107 (most common), Nocardia asteroides25,47,52, Nocardia otitidis-caviarum21,36,69,100, and Nocardia nova106,109. Rarely, 2 species of Nocardia may be isolated from the same skin lesion113. Nocardia brasiliensis is thought to be a more aggressive species; it accounts for the majority of cases in immunocompetent individuals141.

Specific risk factors for PCN include soil or sand exposure47, gardening102,107, farming15,53, superficial injury from domestic shrubbery1,36,137, or trauma from motor vehicle accidents leading to abrasions (that is, "road rash")21,51,69. Lesions are most often noted on the lower extremity, except for the sporotrichoid form which is most often found on the upper extremity75. The mild T-cell suppression of pregnancy has been demonstrated to accelerate cases of PCN25. Occasional reports of other routes of infection (usually in some way related to soil exposure) include administration of contaminated injectable "immunotherapy" offered by an alternative medicine clinic115, intraarticular steroid injections5, insect bites70,80, and cat scratches4,11,101.

The diagnosis may be confirmed with culture of purulent drainage and/or punch biopsy. Even in biopsies yielding positive cultures, the histopathology specimen may not reveal organisms on special stains1,52,75. Histopathology may reveal any combination of the following: coccobacillary organisms102, fibrinopurulent exudates102, monocytic infiltrates, granuloma formation20, chronic nodular dermatitis52, microabscess formation75, and/or sulphur granules108 (conglomeration of organisms). Antibodies to Nocardia brasiliensis have been demonstrated in a patient with PCN46, but serology is not widely available or accepted as a primary diagnostic tool.

A sulfonamide-containing regimen is preferred, although other therapies have been successful, including amoxicillin-clavulanate78,141, imipenem followed by erythromycin46, dapsone and ampicillin-clavulanate70, and doxycycline71,107. Anecdotal cases of cure with potassium iodide55,95 and fluconazole20 have been reported, but insufficient data are available to support the use of these agents. Some authors advocate the use of intravenous TMP-SMX, imipenem-cilastin, and/or amikacin during the initial part of therapy, but no trials have been conducted to compare the efficacy of oral regimens to intravenous preparations. As in our case, effective therapy is often delayed as the patients receive empiric antistaphylococcal regimens15,36,80,101,112.

Two to 4 months of therapy usually suffices for PCN, but in the cases of underlying abnormal immunity, 6-12 months would be prudent. In some cases 2-4 weeks of therapy may be sufficient5,36,75,102, and rarely, these infections may spontaneously resolve104. Cases of cure with surgery alone have been reported4,104, and surgery, in addition to antimicrobial therapy, may be needed for large lesions107, especially actinomycetomas100, although pharmacologic cure of bulky lesions has been reported71. Debridement of purulent lesions may shorten the course of antibiotics necessary for cure to as little as 30 days in otherwise healthy hosts1; occasionally these infections may be cured with surgery alone118.

TREATMENT

Antimicrobial Resistance and Potential Clinical Impact

No standardized method for antimicrobial resistance testing has been universally accepted for Nocardia isolates, nor is there an established National Committee for Clinical Laboratory Standards (NCCLS) guideline for MIC breakpoints. Methods used include disk diffusion, agar dilution, E-test, and broth microdilution2. Difficulty in standardizing in vitro testing arises from variability in pH, inoculum size, and the selection of agar61. Agar dilution may be performed by inoculating a 0.5 McFarland concentration of organism cultured in brain-heart infusion broth with sterile glass beads26 onto Mueller-Hinton agar which contained twofold dilutions of various antibiotics38; these plates may be interpreted after 48 hours. Maintaining a low inoculum of organisms does appear to improve the correlation between in vitro sensitivities and experimental models of efficacy82. The disk diffusion method may allow for more flexibility where time of incubation and inoculum size is concerned131. Cases of successful therapy guided by in vitro sensitivities have been reported54. We found sensitivity testing particularly useful for Cases 1, given drug reactions, and for Case 2, given ineffective therapy.

Despite the use of in vitro sensitivity data to guide therapy, failures occur, often secondary to underlying poor immune status of the host123. Although TMP-SMX is touted as the most efficacious regimen for nocardiosis, rare cases of de novo resistance to, and corresponding clinical failure with, TMP-SMX have been reported22,63,114,131. This may occur because although in vitro sensitivity is observed, the ideal ratio of trimethoprim to sulfamethoxazole may not be maintained in the respective body fluids (>1:5 is desirable); adding additional trimethoprim may improve this ratio131. A case of doxycycline resistance developing during treatment has been reported2; the same situation may have occurred in case # 2, but since sensitivity data were not available on the initial cultures we cannot prove this.

Current Options

Sulfonamides have been used successfully in the treatment of nocardiosis since the 1940s18, and many, although not all, Nocardia isolates demonstrate in vitro sensitivity to sulfonamides. Resistance is most common among Nocardia farcinica isolates120. In cases of disseminated disease, treatment with a sulfonamide regimen appears to yield a better response rate (70% vs 31%)56. Synergy against Nocardia spp. has been demonstrated between TMP and SMX7,66,86, and given its ability to penetrate the blood-brain barrier effectively, it is an obvious first choice for the therapy of disseminated nocardiosis66.

Despite their obvious benefits, sulfa-containing regimens are commonly discontinued either for intolerance or frank drug hypersensitivity. In our series of 5 patients, only 2 patients were able to complete the full course with TMP-SMX. Other authors have reported various causes for discontinuation of TMP-SMX including leukopenia54,107 and rash71,88. Therefore, obtaining in vitro drug sensitivities at the time of organism isolation is advisable, as an adverse event may prompt using an alternative.

The search for additional agents continues. Efficacious agents include minocycline54,62, carbapenems33, amikacin38,41, ampicillin and amikacin followed by amoxicillin22, cefuroxime41, amoxicillin-clavulanate and amikacin50, and ceftriaxone24,34. Beta-lactamase production may limit the use of ampicillin129. Synergy may exist between imipenem and TMP-SMX, imipenem and cefotaxime, and amikacin and TMP-SMX39. One case series of immunocompromised patients who were treated with amikacin-containing regimens demonstrated an 88% cure rate, stressing the potential utility of this aminoglycoside in the treatment of nocardiosis37.

Newer antimicrobials have promising attributes. All Nocardia spp. demonstrate sensitivity to linezolid in vitro, and Moylett et al73 report 6 cases of successful treatment using linezolid. Unfortunately, 3 of the 6 suffered linezolid hematologic adverse reactions, as did another subject from a separate case report62. Given the relatively long course of treatment necessary to cure nocardiosis and the high incidence of marrow toxicity from linezolid after 4 weeks of therapy, linezolid is not likely to be a useful component in the treatment of nocardiosis.

Newer methods of administration of antibiotics (for example, nebulized) may allow for the long-term use of aminoglycosides for those with disease limited to pneumonia without the risk of systemic toxicity; aerosolized antimicrobials have been successful in treating patients with cystic fibrosis, influenza, Pneumocystis carinii and Wegener granulomatosis83,116. We used nebulized tobramycin as adjunctive therapy in Case 2 given the in vitro susceptibility of the organism and the relatively low toxicity of the drug when administered in this fashion. The therapy was not continued beyond the first 6 weeks because the patient developed hoarseness; this symptom resolved upon discontinuation of the therapy and is a known complication of nebulized aminoglycosides.

PROGNOSIS

Patients with acute disease (symptoms of less than 1 month's duration) may have a worse prognosis than those with a chronic course (mortality rate 66% vs 18%, respectively)56. Mortality rate overall for patients who are nocardemic is 44%-85%, depending on the underlying immune status of the host67,93. Treatment failure in cases of widespread dissemination may approach 20%111. Mortality rates in CNS disease may range from 40% to 87% despite adequate therapy43,111. Additional poor prognostic indicators include concomitant Cushing disease and corticosteroid administration93.

SUMMARY

Nocardiosis is a protean disease that predominately affects adult men who are immunocompromised or have underlying lung disease. Introduction through the respiratory tract is most common; however, primary cutaneous disease occurs in normal hosts with significant soil contact or as postoperative infections. Although Nocardia may disseminate from the primary site of infection, blood cultures are rarely positive. Nocardial infections are frequently mistaken for routine pyogenic processes, delaying appropriate therapy and increasing morbidity and mortality. Sulfa-containing regimens are often effective in treating nocardial infections; however, in vitro resistance testing is helpful in tailoring regimens and should be obtained on the initial isolates in case of future clinical failure or drug reaction. An absolute length of therapy for nocardiosis has not been established, but at least 2 months should suffice for limited cutaneous manifestations, while 6 months or longer is necessary with disseminated disease to prevent relapse; courses of therapy should be based on underlying host immunity and estimated bacterial burden. To optimize therapy, foreign bodies should be removed, and purulent and/or necrotic tissue should be debrided when possible.

ACKNOWLEDGMENTS

The authors thank Dr. Philip Higginbottom and Dr. Miguel A. Goicoechea for their kind contributions to this article, Ms. Heidi Fahl for translation of the article by Polay et al, Ms. Melissa Dull for her technical advice, Ms. Waine MacAllister for her excellent technical assistance in manuscript preparation, and Dr. Mark Wallace for his critical review of the manuscript.

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