Disseminated Nocardia farcinica: Literature Review and Fatal Outcome in an Immunocompetent Patient

Abstract

Background

Nocardia farcinica is a gram-positive, partially acid-fast, methenamine silver-positive aerobic actinomycete. Nocardia spp. are opportunistic pathogens, and N. farcinica is the least common species of clinical importance.

Methods

Review of the recent literature and description of a immunocompetent patient with no known risk factors who contracted fatal N. farcinica sepsis.

Results

Positive pre-mortem and post-mortem cultures from the lung and synovium correlated with acute bronchopneumonia and synovitis at autopsy. Colonies of filamentous bacteria, which were not apparent in conventional hematoxylin and eosin-stained sections, were observed with gram and methenamine silver stains, but acid-fast stains were negative. A literature review revealed that disseminated N. farcinica often is associated with an underlying malignant tumor or autoimmune disease (88% of patients). Chemotherapy or corticosteroid treatments are additional risk factors.

Conclusions

Trimethoprim–sulfamethoxazole typically is the first-line therapy for N. farcinica; treatment with amikacin and imipenem-cilastatin is used less often (7% of patients). Despite aggressive therapy, we observed that the death rate (39%) associated with N. farcinica in recent publications was eight percentage points higher than reported in a review from 2000.

Nocardiosis is a localized or disseminated infection caused by the soil-dwelling, weakly gram-positive aerobic actinomycete Nocardia [1]. The organism, characterized by filamentous branches measuring less than 1 micron thick, is not easily observed on conventional hematoxylin and eosin-stained sections, possibly because of its failure to form the “granules” characteristic of other actinomycetes. Nocardia is partially acid-fast by conventional Ziehl–Nielsen staining and is reactive with Gomori methenamine silver. The typical portal of entry for Nocardia is the respiratory tract with subsequent dissemination to distant organs [2]. Nocardia is considered an opportunistic pathogen [3,4] and is associated with compromised immune function (for example, solid organ or bone marrow transplant [5], long-term steroid use, connective tissue disease, or human immunodeficiency virus [HIV] infection), chronic obstructive pulmonary disease (COPD), alcoholism, cirrhosis, systemic vasculitis, ulcerative colitis, or renal failure) [6]. Nocardia asteroides typically is reported as the most frequent cause of nocardiosis in the United States [4–6]. Other clinically significant species are N. brasiliensis [7], N. farcinica, N. nova, N. pseudobrasiliens, and N. transvalensis. Nocardia brasiliensis is commonly associated with primary cutaneous infection following trauma in immunocompetent patients. N. farcinica is one of the least frequent clinically important species, with a reported prevalence of 5% in Switzerland and 6.7% in Crete [6, 8] and a modestly increased prevalence in Turkey [9]. It is found in a 2:1 ratio over other strains of Nocardia in Germany [10]. A recent report identified N. farcinica as a nosocomial pathogen that infected three patients in the same ward over a six-month period [11]. In the United States, 500–1,000 cases of nocardiosis are diagnosed each year [4], with N. farcinica constituting 19% of isolates [12]. The present report of fatal systemic nocardiosis concerns N. farcinica in an immunocompetent patient for whom the portal of entry was not established definitively. The diagnostic elements of, and recent literature on, this unusual infection are reviewed.

Case Report

A 78-year old male presented with a one-day history of right knee pain and swelling. The patient had received a steroid injection in the same knee one week before admission. Three years prior to admission, the patient had an unexplained illness consisting of one month of fever (100.3°F), a 19-pound weight loss, and an elevated white blood cell count (15,300/mm³). At that time, he also had an infected cyst in the posterior scalp, which was treated with cephalexin but was not cultured. The full extent of clinical evaluation at that time is unknown.

On admission, laboratory evaluation revealed hemoglobin 13.4 g/dL, hematocrit 40.1%, white blood cell count 23,300/mm³, and platelets 435,000/mm³. Pertinent chemistry findings were blood urea nitrogen 74 mg/dL, creatinine 2.6 mg/dL, and glucose 151 mg/dL. Cultures from six knee synovial fluid aspirations and peripheral blood grew N. farcinica susceptible to ciprofloxacin (minimum inhibitory concentration [MIC] 1 mcg/mL), linezolid (2 mcg/mL), amikacin (2 mcg/mL), and sulfamethoxazole (4 mcg/mL). A computed tomography (CT) scan revealed numerous subcentimeter non-calcific pulmonary nodules (Fig. 1). The patient was treated with intravenous trimethoprim–sulfamethoxazole (TMP-SMX). The patient's renal function improved with hydration. Eleven days after admission, the patient developed tachypnea and respiratory distress acutely and died.

FIG. 1.

Chest CT scan demonstrates multiple subcentimeter nodules in both lungs.

Autopsy findings included bilateral serosanguinous pleural effusions (200–300 mL) and copious turbid, greenish fluid in the right knee. Histologically, there was acute suppurative and chronic synovitis (Fig. 2A). In both lungs, extensive organizing, nodular, intra-alveolar pneumonia (Fig. 2B, C) with abscesses and associated miliary granulomas (Fig. 2D) were observed. Cultures of both lungs and the synovial fluid were positive for N. farcinica. Gram-positive, methenamine silver-positive, beaded, branching, filamentous bacteria were identified in both locations. Although acid-fast stains were negative, N. farcinica was identified by polymerase chain reaction amplification and sequencing of the bacterial rRNA.

FIG. 2.

Histologic views. (A) Acute fibrinous and chronic synovitis. No organisms are visible by hematoxylin and eosin stain. Insets show fibrinous exudates. Lower right: Gram stain demonstrating gram-positive thin, branching, filamentous forms. Lower left: Gomori methenamine silver (GMS) stain, similarly demonstrating organism morphology. (B) Lung nodule. Low-magnification view of lung with centrally necrotic nodule of organizing pneumonia, lower left. (C) Higher-magnification view of the nodule showing central necrotic focus and peripheral lymphoid infiltrate. Lower right: Gram stain of center of nodule demonstrating numerous gram-positive thin, branching, filamentous organisms. Lower left: GMS stain showing similar organisms. (D) Microscopic, non-necrotic granulomas were associated with nodular abscess.

Discussion

A relatively infrequent cause of nocardiosis, N. farcinica is a clinically aggressive infection, particularly in immunocompromised patients. For unknown reasons, small numbers of immunocompetent patients also are affected. In the last review of N. farcinica sepsis by Torres et al. in 2000, a retrospective analysis of 53 patients identified eight cases (15%) in which no predisposing factors for infection were discernible [13]. Of the eight patients, one presented with a brain abscess [14] and two had lung or kidney involvement or both [15,16]. Similarly, Beaman et al. reported that 15% of patients infected with Nocardia had no identifiable underlying condition [4]. In most cases, the pathogenesis of Nocardia infection is presumed to be via an airborne route from soil inhabited by latent forms. Following colonization of the respiratory tract, T lymphocyte-mediated cellular immunity is activated after phagocytosis of the organism [15,16]. The infection may remain localized or disseminate promptly. If the infection is localized, latency and subsequent reactivation may occur, resembling the pathogenesis of tuberculosis.

Our search of the literature for cases of N. farcinica published since the last review [14] demonstrates the continued rare occurrence of N. farcinica infection in immunocompetent patients [17]. Of the 67 cases reported since 2000, 59 (88%) patients suffered from a predisposing illness or had risk factors associated with diminished immunocompetence (Table 1). Of the eight immunocompetent patients in this cohort, six presented with brain abscesses and two with disseminated disease. Previous reports indicate that Nocardia spp. were responsible for 2%–20% of cerebral abscesses in immunocompromised patients [18,19], with a mortality rate of 30%–80% [14,20].

Table 1.

Clinical Characteristics of 67 Patients with Nocardia farcinica Infections since Last Review by Torres et al. [13]

Age/sex	Underlying condition	Systemic steroids?	Prophylaxis with TMP-SMX	Disease	Therapy	Outcome	Ref.
78/M	None	No	No	Lung, joint, blood	TMP-SMX (11 days)	Death	This study
85/M	NHL, DM, chronic bronchitis	Yesa	No	Lung, blood	IV CTX (1 g qid)+IND (20 days)	Death	14
67/M	Liver transplant	Yes	Yes	Lung	TMP-SMX (12 mos)	Survived	48
28/M	Sarcoidosis	Yes	No	CNS	TMP-SMX+MER (15 days); TMP-SMX (6 mos)	Survived	48
81/M	COPD	Yes	No	Lungb	AMK+AMX/CLAV (12 days)	Death: Related	48
65/F	CLL, hemolytic anemia	No	Yes	Disseminated	TMP-SMX+MER (1.5 mos); TMP-SMX+AMK (4 mos); TMP-SMX+AMX/CLAV (6 mos)	Survived	48
38/F	Transplantation of intestine (Gardner's syndrome)	Yes	No	Lung, liverc	TMP-SMX (800 mg/160 mg qd); CPX (200 mg q 12 h)+AMX/CLAV (2.2 g q 8 h)+CFZ+IMI	Death: Related	8
77/M	COPD, invasive Aspergillus	No	No	Lung	TMP-SMX (3 mos)	Survived	48
29/M	HIV	No	No	Cerebral	Surgery	Died	49
30/F	HIV, MAC	No	No	Cerebral, pulmonary	TMP-SMX; MIN (6 weeks)	Died	49
34/F	SLE, drug abuse	Yes	No	Brain abscess, subcutaneous leg abscess		Died	50
70/M	COPD, pneumoconiosis	Yes	No	Lung	TMP-SMX (10 mg/kg/d; 7 mos)	Death: Related	51
62/M	Kidney transplant	NR	NR	Soft tissue/blood	TMP-SMX+CPX	Survived	38
60/F	Kidney transplant	NR	NR	Soft tissue/blood	TMP-SMX	Survived	38
51/M	Kidney transplant	NR	NR	Soft tissue/lung/brain	TMP-SMX+CTR	Survived	38
50/F	Lymphoma	NR	NR	Blood	IMI	Survived	38
58/F	COPD	NR	NR	Lung	TMP-SMX+IMI+AMK	Survived	38
74/F	Glioma	Yes	No	Lung	MER (7 days); TMP-SMX (3 mos)	Survived	48
47/F	Lung transplant	Yesd	No	Lung	TMP-SMX+CTR+IMI	Death	20
46/M	Lung transplant	Yese	Yes	Lung	TMP-SMX+CTR	Death	20
54/M	Alcoholism	No	No	Spine, CNS, psoas	Surgery, DXN+GEN	Survived	52
2 mo/M	None	No	No	Disseminated lymphatic abscesses	CTX+CXN+MET; AMK (3 weeks); TMP-SMX (3 mos)	Survived	24
37/M	HIV	No	No	Lung	TMP-SMX (7 mos)	Survived	48
	Leg fracture/trauma	No	No	Brain abscesses	VAN+GEN+CTZ; TEI+CTZ, TMP-SMX; VAN+AMK; LIN+MIN	Survived	53
62/M	Evans syndrome	Yes	No	CNS	TMP-SMX+IMI (90 days)	Death: Not related	48
68/M	COPD, DM2	Yes	No	Septic arthritis of kneef	TMP-SMX (6 mos)	Survived	54
60/M	Insulin-dependent DM2, systemic vasculitis with ESRD	Yes	No	Brain abscess	MER (2 g/d)+AMP (2 g/d) (7 days)	Death	55
52/M	Non-small-cell lung cancer, radiation, chemotherapy	No	No	Bacteremia	IV CFZ 1 g tid; AMK 500 mg bid; MET (600 mg tid) (24 h)	Death	56
58/M	Immunosuppression	Yes	No	Brain abscesses	CFZ+MER; LIN+MER	Survived	57
75/M	Immunosuppression	Yes	No	Thyroid, psoas, spine, basal ganglia, lungs	TMP-SMX (320/1600 mg q 6 h; 2 days)	Death: Related	34
NR	Renal transplant, DM	Yes	No	Lung	CTR+AMK; IMI; TMP-SMX (6 mos)	Survived	11
NR	Bullous pemphigoid, DM	Yes	No	Pulmonary and cerebral	CTR+AMK; IMI; TMP-SMX, surgery (37 days)	Death	11
NR	None	No	No	Brain abscess	CTR+AMK; MER; TMP-SMX, surgery (6 mos)	Survived	11
NR	None	No	No	Brain abscess	CTR+AMK; TMP-SMX, surgery (6 mos)	Survived	11
NR	None	No	No	Brain abscess	CTR+AMK; MER; TMP-SMX, surgery (6 mos)	Survived	11
75/M	Interstitial pneumonia	Yes	No	Lung	CFP; TMP-SMX (12 mos)	Survived	7
28/M	Ulcerative colitis	Yes	No	Subcutaneous abscess in left popliteal space	Surgery, TMP-SMX	Survived	7
72/F	BOOP, cirrhosis	Yes	No	Lung	IMI+ITC; TMP-SMX	Death	7
68/M	ITP	Yes	No	Lung, brain abscesses, blood	AMP/SULB (1.5 g/day; TMP-SMX (160 mg/800 mg/day)	Survived	58
12/M	Renal transplant	Yes	Yes	Brain abscesses	TEI+CTR; LIN 600 mg bid, MER (20 days); AMX/CLAV (PO)	Survived	22
91/M	IPF	Yesg	No	Lung	IV TMP-SMX	Death	41
76/F	COPD, vasculitis	Yesa	Yes	Lung	LVX+CTX; MER	Survived	41
49/M	Renal transplant, alcoholism	Yes	No	Lung, brain	IMI (1 g tid)+TMP-SMX (320 mg/1600 mg qid); MOX	Survived	44
42/M	DM, alcoholism	No	No	Brain abscess	CTR+MET+TMP-SMX	Survived	36
26/F	SLE	Yesa	No	Subretinal abscess, lung abscess	Vitreous tap with injection of AMK; BAL; TMP-SMX IV (80 mg/400 mg/q 6 h); CPX PO (1 g qd)	Survived	42
57/M	None	No	No	Brain abscess	Surgery, TMP-SMX+IMI; MOX+IMI; MOX (1 yr)	Survived	59
62/F	SLE, COPD, DM	Yes	NR	Lung	Unknown	Death	60
35/M	HIV, COPD	No	NR	Lung, disseminated	SUF	Death	60
78/M	COPD	Yes	NR	Lung	SUF	Survived	60
73/F	Hodgkin's disease	No	NR	Disseminated	TMP-SMX	Death	60
46/M	HIV	No	NR	Lung, disseminated	TMP-SMX	Death	60
65/F	COPD	No	NR	Lung	TMP-SMX	Death	60
79/M	Rheumatoid arthritis	Yes	NR	Lung, disseminated	IMI; AMK	Death	60
85/M	Lymphoma, COPD	Yes	NR	Lung, disseminated	CTR	Death	60
68/M	Renal transplant, HCV	Yes	NR	Lung	SUF	Survived	60
NR	NHL	Noh	No	Lung, gluteal region, iliac fossa, kidney, cerebrum	TMP-SMX+IMI; AMK+TMP-SMX; TMP-SMX (630 days)	Survived	33
NR	Multiple myeloma	Noh	No	Lung	TMP-SMX 2×1920 mg IV (60 days)	Survived	33
NR	Polymyalgia rheumatica	Yes	No	Upper leg abscess	TMP-SMX 2×1920 mg IV (90 days)	Survived	33
49/M	ITP	Yes	No	Lung	TMP-SMX (3 mos)	Death	61
8/M	CF, ABPA	Yes	No	Lung	TMP-SMX 80/400 mg (62 days)	Survived	23
73/M	Multiple myeloma	Yes	No	Disseminated subcutaneous nodules	TMP-SMX 800 mg (6 mos)	Survived	37
65/F	HIV, COPD, vasculitis	Yes	No	Lungs	IV TMP-SMX+IMI (5 days)	Death	62
43/M	None	No	No	Brain abscess	CTR; TMP-SMX+MOX	Survived	63
64/M	Lung transplant	Noi	Yes	Lung	IMI+AMK; TMP-SMX IV	Survived	25
NR	Lung transplant	Yesd,g	Yes	Lung	TMP-SMX 160/800 mg PO bid)	Survived	31
53/M	None	No	No	Brain abscess, lung	TMP-SMX (7 days); IMI; LIN; TMP-SMX (1 yr)	Survived	19
71/M	Bladder cancer	Yes	No	Lung	IMI+AMK	Survived	10

^aPlus cyclophosphamide.

^bCo-infection with cytomegalovirus and Pneumocystis jirovecii.

^cCo-infection with Pseudomonas aeruginosa.

^dPlus tacrolimus.

^ePlus cyclosporine.

^fCo-infection of lungs with P. aeruginosa, and Escherichia coli.

^gPlus azathioprine.

^hPatients were treated with chemotherapy and immunotherapy for cancer.

ⁱMicrophenolate+tacrolimus immunosuppression.

ABPA=allergic bronchopulmonary aspergillosis; AMK=amikacin; AMP/SULB=ampicillin/sulbactam; AMX/CLAV=amoxicillin/clavulanic acid; BAL=bronchoalveolar lavage; BOOP=bronchiolitis obliterans organizing pneumonia; CF=cystic fibrosis; CFP=cefozopran; CFZ=ceftazidime; CLL=chronic lymphocytic leukemia; CPX=ciprofloxacin; COPD=chronic obstructive pulmonary disease; CTR=ceftriaxone; CTX=cefotaxime; CTZ=ceftazidine; CXN=cloxacillin; DXN=dicloxacillin; DM=diabetes mellitus; ESRD=end-stage renal disease; GEN=gentamicin; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IMI=imipenem-cilastatin; IND=indomethacin; IPF=idiopathic pulmonary fibrosis; ITC=itraconazole; ITP=idiopathic thrombocytopenic purpura; IV=intravenous; LIN=linezolid; LVX=levofloxacin; MAC=Mycobacterium avium complex; MER=meropenem; MET=metronidazole; MIN=minocycline; MOX=moxifloxacin; NHL=non-Hodgkin lymphoma; NR=not reported; PO=orally; SLE=systemic lupus erythematosus; SUF=sulfadiazine; TEI=teicoplanin; TMP-SMX=trimethoprim–sulfamethoxazone; VAN=vancomycin.

In agreement with previously published reports [13], the ratio of male:female infection was 3:1. Although typically responsible for infections in adults, N. farcinica also infected a 12-year-old adolescent following renal transplant [21], an 8-year-old boy with cystic fibrosis [22], and an otherwise-healthy 2-month-old boy [23]. Our review of the literature demonstrated that 10.4% of patients receiving TMP-SMX prophylaxis became infected. Nocardia infection also is reported in 60% of lung transplant recipients [19,24]. Furthermore, most of the patients (61.2%) infected with N. farcinica were receiving systemic steroids or chemotherapy. Corticosteroid treatment inhibits the cytokine response and phagocytic killing of microbes by macrophages [25].

Table 2 summarizes the co-morbidity factors most commonly associated with infection for the cases in Table 1. Hui et al. [26] reported that 63% of pulmonary nocardiosis patients had underlying respiratory disorders. In particular, COPD was identified as a risk factor in 23% of patients with pulmonary nocardiosis [27]. Nocardia infection is reported in as many as 3% of transplant recipients [7] with an associated mortality rate ranging from 0% to 75% in lung transplant recipients [19,28]. Alcoholism (3.0%), hematologic malignancy (4.5%), HIV infection (7.5%), idiopathic thrombocytopenic purpura (ITP) (3.0%), systemic lupus erythematosus (SLE)(4.5%), neoplastic disease (7.5%), diabetes mellitus (9.0%), and vasculitis (4.5%) were co-morbid conditions identified in at least two patients.

Table 2.

Co-Morbid Conditions in 67 Cases of Nocardia farcinica Infection^a

Predisposing factor	No. (%) of patients
Solid organ transplant recipient	12 (17.9)
Chronic obstructive pulmonary disease	9 (13.4)
Hematologic neoplasm	3 ( 4.5)
Human immunodeficiency virus infection	5 ( 7.5)
Idiopathic thrombocytopenic purpura	2 ( 3.0)
Systemic lupus erythematosus	3 ( 4.5)
Solid neoplasm	5 ( 7.5)
Alcoholism	2 ( 3.0)
Diabetes mellitus	6 ( 9.0)
Vasculitis	3 ( 4.5)
Immunosuppression (steroids or chemotherapy)	41 (61.2)
Miscellaneousb	17 (25.4)

^aSome patients presented with more than one factor.

^bOne case each of invasive aspergillosis, Mycobacterium avium complex, drug abuse, pneumoconiosis, Evans syndrome, bullous pemphigoid, interstitial pneumonia, ulcerative colitis, bronchiolitis obliterans organizing pneumonia, idiopathic pulmonary fibrosis, polymyalgia rheumatica, cystic fibrosis, allergic bronchopulmonary aspergillosis, cirrhosis, sarcoidosis, trauma, and chronic bronchitis.

Disseminated nocardiosis is associated with a mortality rate ranging from 7% to 85% in immunocompromised hosts [29]. Disseminated disease and bacteremia occurred in 37% of the cases reported since 2000 (Table 3). Assuming that patients with central nervous system lesions also had a lung infection that was unrecognized [13], 39 patients (58%) had disseminated disease. Soft tissue infection involving muscles or connective tissue, including subcutaneous abscesses, was present in 17.9% of the cases. Torres et al. [13] reported a mortality rate of 31% in cases diagnosed before 2000; the mortality rate in the cases reported since then was 39%.

Table 3.

Organ Involvement in 67 Patients with Nocardia farcinica Infection

Organ or site	No. (%) of patients
Lung	40 (59.7)
Brain	22 (32.8)
Soft tissue	12 (17.9)
Spine	2 ( 3.0)
Kidneys	1 ( 1.5)
Lymphatics	1 ( 1.5)
Disseminateda	25 (37.3)

^a“Disseminated” includes bacteremia or more than one organ involved.

The diagnosis rests on the demonstration of organisms in tissue, cultures, or both. Histologically, organisms are difficult to recognize by hematoxylin and eosin stains. Also, as demonstrated here, acid-fast staining is variable and unreliable [1, 13]. Gram and methenamine silver (GMS) stains usually are positive, although gram staining may be weak. Cultures of Nocardia can take more than five days to grow [30]. Biochemical tests may be used for identification of a subset of Nocardia spp., but 16S rRNA gene sequencing or restriction analysis of amplified DNA (16S rRNA or hsp65 genes) allows rapid identification [31, 32]. This is significant, as it is important to distinguish N. farcinica from N. asteroides—the former is more resistant to antimicrobial agents and has a higher risk of dissemination [33]. The treatment for N. farcinica is complicated by its resistance to most β-lactam anti-microbials, tobramycin, and tetracyclines [12, 34]. The treatment of choice is TMP-SMX [35]. However, side effects such as skin reactions may necessitate alternative therapy [6,24,36]. In addition, as many as 50% of isolates demonstrate TMP-SMX resistance, emphasizing the need for antibiotic susceptibility testing of clinical isolates [13,37,38].

N. farcinica is susceptible to TMP-SMX, minocycline, linezolid, moxifloxacin, and amikacin and demonstrates variable susceptible to imipenem-cilastatin and ciprofloxacin [20, 39–43]. It is recommended that immunocompetent patients be treated for at least six months [44]. If the central nervous system is involved, 12 months of therapy is recommended [44]. Therapy for N. farcinica has become more aggressive, with increasing administration of multiple antimicrobials. In this review, 74.6% of patients (n=50) received TMP-SMX as part of their treatment. Carbapenems (n=25; 37.3%), amikacin (n=16; 23.9%), and ceftriaxone (n=12; 17.9%) also were used commonly (see Table 1). A previous review found TMP-SMX was administered in 54% of patients infected with N. farcinica, whereas amikacin with imipenem-cilastatin and amoxicillin/clavulanic acid were used in only 7% [13]. Nevertheless, the death rate was 31% with TMP-SMX and 38.8% with carbapenems and amikacin [13].

The patient described here was unusual in that he was immunocompetent. Although the primary origin of his infection is not documented, it is tempting to speculate that the prior febrile episode and infected cyst of three years earlier was his initial encounter with the organism. Subsequent reactivation with dissemination may have been prompted by unknown factors and perhaps facilitated by the local steroid injection. The distribution of his infection was pulmonary and musculoskeletal (limited to the right knee) with no radiologic or post-mortem evidence of central nervous system involvement. Despite therapy, the patient died from Nocardia sepsis, attesting to the virulence N. farcinica.

Acknowledgments

JMB is a trainee of the National Institutes of Health Medical Scientist Training Program (Grant GM07281) at the University of Chicago.

Author Disclosure Statement

No conflicting financial interests exist.